WO2003000842A2

WO2003000842A2 - Novel proteins and nucleic acids encoding same

Info

Publication number: WO2003000842A2
Application number: PCT/US2002/017443
Authority: WO
Inventors: Michele L. Agee; David W. Anderson; Constance Berghs; Stacie J. Casman; Elina Catterton; Vincent A. Dipippo; Shlomit R. Edinger; Andrew Eisen; Karen Ellerman; Esha A. Gangolli; Valerie L. Gerlach; Linda Gorman; Xiaojia Guo; John L. Herrmann; Tord Hjalt; Weizhen Ji; Ramesh Kekuda; Nikolai V. Khramtsov; Li Li; Xiaohong Liu
Original assignee: Curagen Corporation
Priority date: 2001-06-04
Filing date: 2002-06-04
Publication date: 2003-01-03
Also published as: JP2005518185A; WO2003000842A3

Abstract

The present invention provides novel isolated polynucleotides and small molecule target polypeptides encoded by the polynucleotides. Antibodies that immunospecifically bind to a novel small molecule target polypeptide or any derivative, variant, mutant or fragment of that polypeptide, polynucleotide or antibody are disclosed, as are methods in which the small molecule target polypeptide, polynucleotide and antibody are utilized in the detection and treatment of a broad range of pathological states. More specifically, the present invention discloses methods of using recombinantly expressed and/or endogenously expressed proteins in various screening procedures for the purpose of identifying therapeutic antibodies and therapeutic small molecules associated with diseases.

Description

NOVEL PROTEINS AND NUCLEIC ACIDS ENCODING SAME

FIELD OF THE INVENTION

The present invention relates to novel polypeptides that are targets of small molecule drugs and that have properties related to stimulation of biochemical or physiological responses in a cell, a tissue, an organ or an organism. More particularly, the novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use encompass diagnostic and prognostic assay procedures as well as methods of treating diverse pathological conditions.

BACKGROUND

Eukaryotic cells are characterized by biochemical and physiological processes which under normal conditions are exquisitely balanced to achieve the preservation and propagation of the cells. When such cells are components of multicellular organisms such as vertebrates, or more particularly organisms such as mammals, the regulation of the biochemical and physiological processes involves intricate signaling pathways. Frequently, such signaling pathways are constituted of extracellular signaling proteins, cellular receptors that bind the signaling proteins and signal transducing components located within the cells.

Signaling proteins may be classified as endocrine effectors, paracrine effectors or autocrine effectors. Endocrine effectors are signaling molecules secreted by a given organ into the circulatory system, which are then transported to a distant target organ or tissue. The target cells include the receptors for the endocrine effector, and when the endocrine effector binds, a signaling cascade is induced. Paracrine effectors involve secreting cells and receptor cells in close proximity to each other, for example two different classes of cells in the same tissue or organ. One class of cells secretes the paracrine effector, which then reaches the second class of cells, for example by diffusion through the extracellular fluid. The second class of cells contains the receptors for the paracrine effector; binding of the effector results in induction of the signaling cascade that elicits the corresponding biochemical or physiological effect. Autocrine effectors are highly analogous to paracrine effectors, except that the same cell type that secretes the autocrine effector also contains the receptor. Thus the autocrine effector binds to receptors on the same cell, or on identical neighboring cells. The binding process then elicits the characteristic biochemical or physiological effect.

Signaling processes may elicit a variety of effects on cells and tissues including by wa)^r of nonlimiting example induction of cell or tissue proliferation, suppression of growth or proliferation, induction of differentiation or maturation of a cell or tissue, and suppression of differentiation or maturation of a cell or tissue.

Many pathological conditions involve dysregulation of expression of important effector proteins. In certain classes of pathologies the dysregulation is manifested as diminished or suppressed level of synthesis and secretion protein effectors. In a clinical setting a subject may be suspected of suffering from a condition brought on by diminished or suppressed levels of a protein effector of interest. Therefore there is a need to be able to assay for the level of the protein effector of interest in a biological sample from such a subject, and to compare the level with that characteristic of a nonpathological condition. There further is a need to provide the protein effector as a product of manufacture. Administration of the effector to a subject in need thereof is useful in treatment of the pathological condition, or the protein effector deficiency or suppression may be favorably acted upon by the administration of another small molecule drug product. Accordingly, there is a need for a method of treatment of a pathological condition brought on by a diminished or suppressed levels of the protein effector of interest.

Small molecule targets have been implicated in various disease states or pathologies. These targets may be proteins, and particularly enzymatic proteins, which are acted upon by small molecule drugs for the purpose of altering target function and achieving a desired result. Cellular, animal and clinical studies can be performed to elucidate the genetic contribution to the etiology and pathogenesis of conditions in which small molecule targets are implicated in a variety of physiologic, pharmacologic or native states. These studies utilize the core technologies at CuraGen Corporation to look at differential gene expression, protein-protein interactions, large-scale sequencing of expressed genes and the association of genetic variations such as, but not limited to, single nucleotide polymorphisms (SNPs) or splice variants in and between biological samples from experimental and control groups. The goal of such studies is to identify potential avenues for therapeutic intervention in order to prevent, treat the consequences or cure the conditions.

In order to treat diseases, pathologies and other abnormal states or conditions in which a mammalian organism has been diagnosed as being, or as being at risk for becoming, other than in a normal state or condition, it is important to identify new therapeutic agents. Such a procedure includes at least the steps of identifying a target component within an affected tissue or organ, and identifying a candidate therapeutic agent that modulates the functional attributes of the target. The target component may be any biological macromolecule implicated in the disease or pathology. Commonly the target is a polypeptide or protein with specific functional attributes. Other classes of macromolecule may be a nucleic acid, a polysaccharide, a lipid such as a complex lipid or a glycolipid; in addition a target may be a sub-cellular structure or extra-cellular structure that is comprised of more than one of these classes of macromolecule. Once such a target has been identified, it may be employed in a screening assay in order to identify favorable candidate therapeutic agents from among a large population of substances or compounds.

In many cases the objective of such screening assays is to identify small molecule candidates; this is commonly approached by the use of combinatorial methodologies to develop the population of substances to be tested. The implementation of high throughput screening methodologies is advantageous when working with large, combinatorial libraries of compounds.

SUMMARY OF THE INVENTION

The invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides. These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as "NOVX'" nucleic acid, which represents the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or polypeptide sequences, which represents the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129.

In one aspect, the invention provides an isolated polypeptide comprising a mature form of a NOVX amino acid. One example is a variant of a mature form of a NOVX amino acid sequence, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed. The amino acid can be, for example, a NOVX amino acid sequence or a variant of a NOVX amino acid sequence, wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed. The invention also includes fragments of any of these. In another aspect, the invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof.

Also included in the invention is a NOVX polypeptide that is a naturally occurring allelic variant of a NOVX sequence. In one embodiment, the allelic variant includes an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a NOVX nucleic acid sequence. In another embodiment, the NOVX polypeptide is a variant polypeptide described therein, wherein any amino acid specified in the chosen sequence is changed to provide a conservative substitution. In one embodiment, the invention discloses a method for determining the presence or amount of the NOVX polypeptide in a sample. The method involves the steps of: providing a sample; introducing the sample to an antibody that binds immunospecifically to the polypeptide; and determining the presence or amount of antibody bound to the NOVX polypeptide, thereby determining the presence or amount of the NOVX polypeptide in the sample. In another embodiment, the invention provides a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide in a mammalian subject. This method involves the steps of: measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and comparing the amount of the polypeptide in the sample of the first step to the amount of the polypeptide present in a control sample from a second mammalian subject known not to ha e, or not to be predisposed to, the disease, wherein an alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

In a further embodiment, the invention includes a method of identifying an agent that binds to a NOVX polypeptide. This method involves the steps of: introducing the polypeptide to the agent; and determining whether the agent binds to the polypeptide. In various embodiments, the agent is a cellular receptor or a downstream effector.

In another aspect, the invention provides a method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of a NOVX polypeptide. The method involves the steps of: providing a cell expressing the NOVX polypeptide and having a property or function ascribable to the polypeptide; contacting the cell with a composition comprising a candidate substance; and determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition devoid of the substance, the substance is identified as a potential therapeutic agent. In another aspect, the invention describes a method for screening for a modulator of activity or of latency or predisposition to a pathology associated with the NOVX polypeptide. This method involves the following steps: administering a test compound to a test animal at increased risk for a pathology associated with the NOVX polypeptide, wherein the test animal recombinantly expresses the NOVX polypeptide. This method involves the steps of measuring the activity of the NOVX polypeptide in the test animal after administering the compound of step; and comparing the activity of the protein in the test animal with the activity of the NOVX polypeptide in a control animal not administered the polypeptide, wherein a change in the activity of the NOVX polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency of, or predisposition to, a pathology associated with the NOVX polypeptide. In one embodiment, the test animal is a recombinant test animal that expresses a test protein transgene or expresses the transgene under the control of a promoter at an increased level relative to a wild-type test animal, and wherein the promoter is not the native gene promoter of the transgene. In another aspect, the invention includes a method for modulating the activity of the NOVX polypeptide, the method comprising introducing a cell sample expressing the NOVX polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide.

The invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof. In a preferred embodiment, the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant. In another embodiment, the nucleic acid encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant. In another embodiment, the nucleic acid molecule differs by a single nucleotide from a NOVX nucleic acid sequence. In one embodiment, the NOVX nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or a complement of the nucleotide sequence. In another aspect, the invention provides a vector or a cell expressing a NOVX nucleotide sequence.

In one embodiment, the invention discloses a method for modulating the activity of a NOVX polypeptide. The method includes the steps of: introducing a cell sample expressing the NOVX polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide. In another embodiment, the invention includes an isolated NOVX nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising a NOVX amino acid sequence or a variant of a mature form of the NOVX amino acid sequence, wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed. In another embodiment, the invention includes an amino acid sequence that is a variant of the NOVX amino acid sequence, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed.

In one embodiment, the invention discloses a NOVX nucleic acid fragment encoding at least a portion of a NOVX polypeptide or any variant of the polypeptide, wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed. In another embodiment, the invention includes the complement of any of the NOVX nucleic acid molecules or a naturally occurring allelic nucleic acid variant. In another embodiment, the invention discloses a NOVX nucleic acid molecule that encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant. In another embodiment, the invention discloses a NOVX nucleic acid, wherein the nucleic acid molecule differs by a single nucleotide from a NOVX nucleic acid sequence.

In another aspect, the invention includes a NOVX nucleic acid, wherein one or more nucleotides in the NOVX nucleotide sequence is changed to a different nucleotide provided that no more than 15% of the nucleotides are so changed. In one embodiment, the invention discloses a nucleic acid fragment of the NOVX nucleotide sequence and a nucleic acid fragment wherein one or more nucleotides in the NOVX nucleotide sequence is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed. In another embodiment, the invention includes a nucleic acid molecule wherein the nucleic acid molecule hybridizes under stringent conditions to a NOVX nucleotide sequence or a complement of the NOVX nucleotide sequence. In one embodiment, the invention includes a nucleic acid molecule, wherein the sequence is changed such that no more than 15% of the nucleotides in the coding sequence differ from the NOVX nucleotide sequence or a fragment thereof. In a further aspect, the invention includes a method for determining the presence or amount of the NOVX nucleic acid in a sample. The method involves the steps of: providing the sample; introducing the sample to a probe that binds to the nucleic acid molecule; and determining the presence or amount of the probe bound to the NOVX nucleic acid molecule, thereby determining the presence or amount of the NOVX nucleic acid molecule in the sample. In one embodiment, the presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.

In another aspect, the invention discloses a method for determining the presence of or predisposition to a disease associated with altered levels of the NOVX nucleic acid molecule of in a first mammalian subject. The method involves the steps of: measuring the amount of NOVX nucleic acid in a sample from the first mammalian subject; and comparing the amount of the nucleic acid in the sample of step (a) to the amount of NOVX nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel nucleotides and polypeptides encoded thereby. Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compounds. The sequences are collectively referred to herein as "NOVX nucleic acids" or "NOVX polynucleotides" and the corresponding encoded polypeptides are referred to as "NOVX polypeptides" or "NOVX proteins." Unless indicated otherwise, "NOVX" is meant to refer to any of the novel sequences disclosed herein. Table 1 provides a summary of the NOVX nucleic acids and their encoded polypeptides.

TABLE 1. Sequences and Corresponding SEQ ID Numbers

Table 1 indicates homology of NOVX nucleic acids to known protein families. Thus, the nucleic acids and polypeptides, antibodies and related compounds according to the invention corresponding to a NOVX as identified in column 1 of Table 1 will be useful in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table 1.

NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

Consistent with other known members of the family of proteins, identified in column 5 of Table 1, the NOVX polypeptides of the present invention show homology to, and contain domains that are characteristic of, other members of such protein families. Details of the sequence relatedness and domain analysis for each NOVX are presented in Example A.

The NOVX nucleic acids and polypeptides can also be used to screen for molecules, that inhibit or enhance NOVX activity or function: Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table 1.

The NOVX nucleic acids and polypeptides are also useful for detecting specific cell types. Details of the expression analysis for each NOVX are presented in Example C.

ι: Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection of a variety of diseases with differential expression in normal vs. diseased tissues, e.g. a variety of cancers. Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein.

The present invention is based on the identification of biological macromolecules differentially modulated in a pathologic state, disease, or an abnormal condition or state. Among the pathologies or diseases of present interest include metabolic diseases including those related to endocrinologic disorders, cancers, various tumors and neoplasias, inflammatory disorders, central nervous system disorders, and similar abnormal conditions or states. In very significant embodiments of the present invention, the biological macromolecules implicated in the pathologies and conditions are proteins and polypeptides, and in such cases the present invention is related as well to the nucleic acids that encode them. Methods that may be employed to identify relevant biological macromolecules include any procedures that detect differential expression of nucleic acids encoding proteins and polypeptides associated with the disorder, as well as procedures that detect the respective proteins and polypeptides themselves. Significant methods that have been employed by the present inventors, include GeneCalling"^3' technology and SeqCalling ¹ technology, disclosed respectively, in U. S. Patent No. 5,871,697, and in U. S. Ser. No. 09/417,386, filed Oct. 13, 1999, each of which is incorporated herein by reference in its entirety. GeneCalling^" is also described in Shimkets, et al., "Gene expression analysis by transcript profiling coupled to a gene database query" Nature Biotechnology 17:198-803 (1999).

The invention provides polypeptides and nucleotides encoded thereby that have been identified as having novel associations with a disease or pathology, or an abnormal state or condition, in a mammal. The present invention further identifies a set of proteins and polypeptides, including naturally occurring polypeptides, precursor forms or proproteins, or mature forms of the polypeptides or proteins, which are implicated as targets for therapeutic agents in the treatment of various diseases, pathologies, abnormal states and conditions. A target may be employed in any of a variety of screening methodologies in order to identify candidate therapeutic agents which interact with the target and in so doing exert a desired or favorable effect. The candidate therapeutic agent is identified by screening a large collection of substances or compounds in an important embodiment of the invention. Such a collection may comprise a combinatorial library of substances or compounds in which, in at least one subset of substances or compounds, the individual members are related to each other by simple structural variations based on a particular canonical or basic chemical structure. The variations may include, by way of nonlimiting example, changes in length or identity of a basic framework of bonded atoms; changes in number, composition and disposition of ringed structures, bridge structures, alicyclic rings, and aromatic rings; and changes in pendent or substituents atoms or groups that are bonded at particular positions to the basic framework of bonded atoms or to the ringed structures, the bridge structures, the alicyclic structures, or the aromatic structures.

A polypeptide or protein described herein, and that serves as a target in the screening procedure, includes the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide. precursor or proprotein includes, e.g., the full-length gene product, encoded by the corresponding gene. The naturally occurring polypeptide also includes the polypeptide, precursor or proprotein encoded by an open reading frame described herein. A "mature" form of a polypeptide or protein arises as a result of one or more naturally occurring processing steps as they may occur within the cell, including a host cell. The processing steps occur as the gene product arises, e.g., via cleavage of the amino-terminal methionine residue encoded by the initiation codon of an open reading frame, or the proteolytic cleavage of a signal peptide or leader sequence. Thus, a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N- terminal methionine, would have residues 2 through N remaining. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an amino-terminal signal sequence from residue 1 to residue M is cleaved, includes the residues from residue M+l to residue N remaining. A "mature" form of a polypeptide or protein may also arise from non-proteolytic post-translational modification. Such non-proteolytic processes include, e.g., glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or the combination of any of them.

As used herein, "identical" residues correspond to those residues in a comparison between two sequences where the equivalent nucleotide base or amino acid residue in an alignment of two sequences is the same residue. Residues are alternatively described as

"similar" or "positive" when the comparisons between two sequences in an alignment show that residues in an equivalent position in a comparison are either the same amino acid or a conserved amino acid as defined below. As used herein, a "chemical composition" relates to a composition including at least one compound that is either synthesized or extracted from a natural source. A chemical compound may be the product of a defined synthetic procedure. Such a synthesized compound is understood herein to have defined properties in terms of molecular formula, molecular structure relating the association of bonded atoms to each other, physical properties such as chromatographic or spectroscopic characterizations, and the like. A compound extracted from a natural source is advantageously analyzed by chemical and physical methods in order to provide a representation of its defined properties, including its molecular formula, molecular structure relating the association of bonded atoms to each other, physical properties such as chromatographic or spectroscopic characterizations, and the like.

As used herein, a "candidate therapeutic agent" is a chemical compound that includes at least one substance shown to bind to a target biopolymer. In important embodiments of the invention, the target biopolymer is a protein or polypeptide, a nucleic acid, a polysaccharide or proteoglycan, or a lipid such as a complex lipid. The method of identifying compounds that bind to the target effectively eliminates compounds with little or no binding affinity, thereby increasing the potential that the identified chemical compound may have beneficial therapeutic applications. In cases where the "candidate therapeutic agent" is a mixture of more than one chemical compound, subsequent screening procedures may be carried out to identify the particular substance in the mixture that is the binding compound, and that is to be identified as a candidate therapeutic agent.

As used herein, a "pharmaceutical agent" is provided by screening a candidate therapeutic agent using models for a disease state or pathology in order to identify a candidate exerting a desired or beneficial therapeutic effect with relation to the disease or pathology. Such a candidate that successfully provides such an effect is termed a pharmaceutical agent herein. Nonlimiting examples of model systems that may be used in such screens include particular cell lines, cultured cells, tissue preparations, whole tissues, organ preparations, intact organs, and nonhuman mammals. Screens employing at least one system, and preferably more than one system, may be employed in order to identify a pharmaceutical agent. Any pharmaceutical agent so identified may be pursued in further investigation using human subjects. NOVX Nucleic Acids and Polypeptides

NOVX clones

NOVX nucleic ?,:ids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy. Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are described for each of the NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders.

The NOVX nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon. In one specific embodiment, the invention includes an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) an amino acid sequence selected from the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n and 539, wherein n is an integer between 1 and 129 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15%) of the amino acid residues in the sequence are so changed; and (e) a fragment of any of (a) tlirough (d). In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n and SEQ ID NO: 539, wherein n is an integer between 1 and 129. wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) the amino acid sequence selected from the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129 or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules. In yet another specific embodiment, the invention includes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; (c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129; and (d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538. wherein n is an integer between 1 and 129 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.

One aspect of the invention pertains to isolated nucleic acid molecules that encode NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify NOVX- encoding nucleic acids (e.g., NOVX mRNAs) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double- stranded DNA.

An NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a "mature" form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product, encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product "mature" form arises, again by way of nonlimiting example, as a result of one or more naturally occuning processing steps as they may take place within the cell, or host cell, in which the gene product arises. Examples of such processing steps leading to a "mature" form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of an ORF, or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+l to residue N remaining. Further as used herein, a "mature" form of a polypeptide or protein may arise from a step of post-translational modification other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristoyl ati on or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them.

The term "probes", as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.

The term "isolated" nucleic acid molecule, as utilized herein, is one, which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5'- and 3 '-termini of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material or culture medium when produced by recombinant techniques, or of chemical precursors or other chemicals when chemically synthesized.

A nucleic acid molecule of the invention, e.g., a nucleic acid molecule having the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or a complement of this aforementioned nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2ND ED., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993.) A nucleic acid of the invention can be amplified using cDNA, mRNA or alternatively, genomic DNA, as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.

As used herein, the term "oligonucleotide" refers to a series of linked nucleotide residues, which oligonucleotide has a sufficient number of nucleotide bases to be used in a PCR reaction. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise portions of a nucleic acid sequence having about 10 nt. 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides from a sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes.

In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of an NOVX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129 is one that is sufficiently complementary to the nucleotide sequence from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129 that it can hydrogen bond with little or no mismatches to the nucleotide sequence from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, thereby forming a stable duplex.

As used herein, the term "complementary" refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term "binding" means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates.

Fragments provided herein are defined as sequences of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, respectively, and are at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice. Derivatives are nucleic acid sequences or amino acid sequences formed from the native compounds either directly or by modification or partial substitution. Analogs are nucleic acid sequences or amino acid sequences that have a structure similar to, but not identical to, the native compound but differs from it in respect to certain components or side chains. Analogs may be synthetic or from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type. Homologs are nucleic acid sequences or amino acid sequences of a particular gene that are derived from different species.

A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 5' direction of the disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment of the respective NOVX polypeptide, and requires that the conesponding full-length cDNA extend in the 3' direction of the disclosed sequence.

Derivatives and analogs may be full length or other than full length, if the derivative or analog contains a modified nucleic acid or amino acid, as described below. Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 10%, 80%, or 95% identity (with a prefened identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement of a sequence encoding the aforementioned proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993, and below.

A "homologous nucleic acid sequence" or "homologous amino acid sequence." or variations thereof, refer ιo sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences encode those sequences coding for isoforms of NOVX polypeptides. Isoforms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, homologous nucleotide sequences include nucleotide sequences encoding for an NOVX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations of the nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human NOVX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, as well as a polypeptide possessing NOVX biological activity. Various biological activities of the NOVX proteins are described below. An NOVX polypeptide is encoded by the open reading frame ("ORF") of an NOVX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG "start" codon and terminates with one of the three "stop" codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bona fide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more.

The nucleotide sequences determined from the cloning of the human NOVX genes allows for the generation of probes and primers designed for use in identifying and/or cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense ^'strand nucleotide sequence of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129; or an anti-sense strand nucleotide sequence of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129. Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe further comprises a label group attached thereto, e.g. the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis- express an NOVX protein, such as by measuring a level of an NOVX-encoding nucleic acid in a sample of cells from a subject e.g., detecting NOVX mRNA levels or determining whether a genomic NOVX gene has been mutated or deleted.

"A polypeptide having a biologically-active portion of an NOVX polypeptide" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a "biologically- active portion of NOVX" can be prepared by isolating a portion of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, that encodes a polypeptide having an NOVX biological activity (the biological activities of the NOVX proteins are described below), expressing the encoded portion of NOVX protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of NOVX.

NOVX Nucleic Acid and Polypeptide Variants

The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences shown in any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129 due to degeneracy of the genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences shown in any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence shown in any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO: 539, wherein n is an integer between 1 and 129. In addition to the human NOVX nucleotide sequences shown in any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129. it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of the NOVX polypeptides may exist within a population (e.g. , the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame (ORF) encoding an NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides. which are the result of natural allelic variation and that do not alter the functional activity of the NOVX polypeptides, are intended to be within the scope of the invention.

Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from any one of the group consisting of the human SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129 are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.

Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding region. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% homologous to each other typically remain hybridized to each other.

Homologs (i.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.

As used herein, the phrase "stringent hybridization conditions" refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5 °C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% of the probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30°C for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60°C for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide.

Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al. (eds.). CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%. 75%, 85%, 90%, 95%>, 98%>, or 99%. homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6X SSC, 50 mM Tris-HCI (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65°C, followed by one or more washes in 0.2X SSC, 0.01% BSA at 50°C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to the sequence in any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, corresponds to a naturally-occuning nucleic acid molecule. As used herein, a "naturally-occuning" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538. wherein n is an integer between 1 and 129, or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6X SSC, 5X Denhardt's solution, 0.5%) SDS and 100 mg/ml denatured salmon sperm DNA at 55°C, followed by one or more washes in IX SSC, 0.1% SDS at 37°C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY. In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40°C, followed by one or more washes in 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50°C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.

Conservative Mutations

In addition to naturally-occuning allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into any one of the group consisting of the nucleotide sequences SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, thereby leading to changes in the amino acid sequences of the encoded NOVX proteins, without altering the functional ability of said NOVX proteins. For example, nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues can be made in any one of the group consisting of the sequences SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequences of the NOVX proteins without altering their biological activity, whereas an "essential" amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins of the invention are predicted to be particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art. Another aspect of the invention pertains to nucleic acid molecules encoding NOVX proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129 yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 45% homologous to any one of the group consisting of the amino acid sequences SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129; more preferably at least about 70% homologous to any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129; still more preferably at least about 80% homologous to any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129; even more preferably at least about 90% homologous to any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and

129; and most preferably at least about 95% homologous to any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129.

An isolated nucleic acid molecule encoding an NOVX protein homologous to any one of the group consisting of the protein of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129 can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein. Mutations can be introduced into any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129 standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine. arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of an NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, the encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined.

The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved "strong" residues or fully conserved "weak" residues. The "strong^" group of conserved amino acid residues may be any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the "weak" group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, HFY, wherein the letters within each group represent the single letter amino acid code.

In one embodiment, a mutant NOVX protein can be assayed for (z) the ability to form protein :protein interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (//) complex formation between a mutant NOVX protein and an NOVX ligand; or (///) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins).

In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release).

Antisense Nucleic Acids

Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or fragments, analogs or derivatives thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a protein (e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of an NOVX protein of any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129, or antisense nucleic acids complementary to an NOVX nucleic acid sequence of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, are additionally provided.

In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence encoding an NOVX protein. The term "coding region" refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence encoding the NOVX protein. The term "noncoding region" refers to 5' and 3' sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions).

Given the coding strand sequences encoding the NOVX protein disclosed herein, antisense nucleic acids of the invention can be designed according to the rules of Watson and C ick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of NOVX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g.. phosphorothioate derivatives and acridine substituted nucleotides can be used). Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl- 2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1 -methylguanine, 1 -methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5 -methylaminomethyluracil, 5 -memoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil,

2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester. uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an NOVX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g. , by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are prefened. In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a

2'-o-methylribonucleotide (See, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See, e.g., Inoue, et al, 1987. FEBS Lett. 215: 327-330.

Ribozymes and PNA Moieties

Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.

In one embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Hasεlhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave NOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for an NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of an NOVX cDNA disclosed herein (i.e., any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an NOVX-encoding mRNA. See, e.g., U.S. Patent 4,987,071 to Cech, et al. and U.S. Patent

5,116,742 to Cech, et al. NOVX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261 :1411-1418.

Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the NOVX nucleic acid (e.g., the NOVX promoter and/or enhancers) to form triple helical structures that prevent transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al 1992. Ann. N. Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15. In various embodiments, the NOVX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al, 1996. Bioorg Med Chem 4: 5-23. As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al, 1996. supra; Perry-O'Keefe, et al, 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.

PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S_\ nucleases (See, Hyrup, et al, 1996. supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al, 1996, supra; Perry-O'Keefe. et al, 1996. supra). In another embodiment, PNAs of NOVX can be modified, e.g. , to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of NOVX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al, 1996. supra and Finn, et al, 1996. Nucl Acids Res 24: 3357-3363. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5' end of DNA. See, e.g., Mag, et al, 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment. See, e.g., Finn, et al, 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment. See, e.g., Petersen, et al, 1975. Bioorg. Med. Chew. Lett. 5: 1 119-11124. In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al, 1989. Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556; Lemaitre, et al, 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g. , PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al, 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988. Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like. NOVX Polypeptides

A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129. The invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residues shown in any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129, while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof.

In general, an NOVX variant that preserves NOVX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.

One aspect of the invention pertains to isolated NOVX proteins, and biologically- active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-NOVX antibodies. In one embodiment, native NOVX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment. NOVX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression,^' an NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.

An "isolated" or "purified" polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of NOVX proteins in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly-produced. In one embodiment, the language "substantially free of cellular material" includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a "contaminating protein"), more preferably less than about 20%o of non-NOVX proteins, still more preferably less than about 10% of non-NOVX proteins, and most preferably less than about 5% of non-NOVX proteins. When the NOVX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, e , culture medium represents less than about 20%, more preferably less than about 10%>, and most preferably less than about 5% of the volume of the NOVX protein preparation.

The language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20% chemical precursors or non-NOVX chemicals, still more preferably less than about 10% chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals. Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the NOVX proteins (e.g., the amino acid sequence shown in any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of an NOVX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity of the NOVX protein. A biologically-active portion of an NOVX protein can be a polypeptide which is, for example. 10, 25, 50, 100 or more amino acid residues in length. Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant technique^'s and evaluated for one or more of the functional activities of a native NOVX protein.

In an embodiment, the NOVX protein has an amino acid sequence shown in any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129. In other embodiments, the NOVX protein is substantially homologous to any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129, and retains the functional activity of the protein of any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence of any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129, and retains the functional activity of the NOVX proteins of any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129.

Determining Homology Between Two or More Sequences

To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at conesponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid "homology" is equivalent to amino acid or nucleic acid "identity").

The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GGG program package. See, Needleman and Wunsch, 1970. JMol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3. the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129.

The term "sequence identity" refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C. G. U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term "substantial identity" as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region. Chimeric and Fusion Proteins

The invention also provides NOVX chimeric or fusion proteins. As used herein, an NOVX "chimeric protein" or "fusion protein" comprises an NOVX polypeptide operatively- 1 inked to a non-NOVX polypeptide. An "NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to an NOVX protein of any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129, whereas a "non-NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the NOVX protein, e.g., a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within an NOVX fusion protein the NOVX polypeptide can conespond to all or a portion of an NOVX protein. In one embodiment, an NOVX fusion protein comprises at least one biologically-active portion of an NOVX protein. In another embodiment, an NOVX fusion protein comprises at least two biologically-active portions of an NOVX protein. In yet another embodiment, an NOVX fusion protein comprises at least three biologically-active portions of an NOVX protein. Within the fusion protein, the term "operatively-linked" is intended to indicate that the NOVX polypeptide and the non-NOVX polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or C-tenninus of the NOVX polypeptide. In one embodiment, the fusion protein is a GST-NOVX fusion protein in which the

NOVX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX polypeptides.

In another embodiment, the fusion protein is an NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of NOVX can be increased through use of a heterologous signal sequence.

In yet another embodiment, the fusion protein is an NOVX-immunoglobulin fusion protein in which the NOVX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between an NOVX ligand and an NOVX protein on the surface of a cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX-immunoglobulin fusion proteins can be used to affect the bioavailability of an NOVX cognate ligand. Inhibition of the NOVX ligand NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with an NOVX ligand.

An NOVX chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling- in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be canied out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplifiεd to generate a chimeric gene sequence (see, e.g., Ausubel, et al (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g. , a GST polypeptide). An NOVX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein.

NOVX Agonists and Antagonists

The invention also pertains to variants of the NOVX proteins that function as either

NOVX agonists (i.e., mimetics) or as NOVX antagonists. Variants of the NOVX protein can be generated by mutagenesis (e.g., discrete point mutation or truncation of the NOVX protein). An agonist of the NOVX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurring form of the NOVX protein. An antagonist of the NOVX protein can inhibit one or more of the activities of the naturally occurring form of the NOVX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins.

Variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) of the NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential NOVX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of NOVX sequences therein. There are a variety of methods which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential NOVX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al. 1984. Annu. Rev. Biochem. 53: 323; Itakura, et al, 1984. Science 198: 1056; Ike, et al, 1983. Nucl. Acids Res. 11 : 477.

Polypeptide Libraries

In addition, libraries of fragments of the NOVX protein coding sequences can be used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of an NOVX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of an NOVX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with Si nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the NOVX proteins. Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of NOVX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants. See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, et al, 1993. Protein Engineering 6:327-331. NOVX Antibodies

The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, F_a|,. F_ab- and F_(ab')2 fragments, and an F_ab expression library. In general, antibody molecules obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgGi, IgG , and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.

An isolated protein of the invention intended to serve as an antigen, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence shown in any one of the group consisting of SEQ ID NO: 2n and SEQ ID NO:539, wherein n is an integer between 1 and 129, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.

In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a region of NOVX that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mol Biol 157: 105-142. each incorporated herein by reference in their entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein. A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.

Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A

Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference). Some of these antibodies are discussed below.

Polyclonal Antibodies For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants which can be employed include MPL- TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).

The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No. 8 (April 17, 2000), pp. 25-28).

Monoclonal Antibodies

The term "monoclonal antibody" (MAb) or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it. Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature. 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro. The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-

103]. Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells. Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia.

Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63]. The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen. After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding,1986). Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI- 1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal. The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a prefened source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Patent No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non- immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.

Humanized Antibodies

The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')₂ or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non- human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321 :522-525 (1986); Riechmann et al., Nature, 332:323- 327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S.

Patent No. 5,225,539.) In some instances, Fv framework residues of the human « immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions conespond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)). Human Antibodies

Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies", or "fully human antibodies" herein. Human monoclonal antibodies can be prepared by the trioma teclmique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al, 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Ba Virus in vitro (see Cole, et al.. 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).

In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol.. 227:381 (1991); Marks et al., J. Mol. BioL, 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545.806; 5,569,825; 5,625,126; 5,633,425; 5,661 ,016, and in Marks et al. (Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859 (1994)); Morrison ( Nature 368, 812-13 (1994)); Fishwild et al.( Nature Biotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13_.65-93 (1995)). Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT publication WO94/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse^1M as disclosed in PCT publications WO 96/33735 and ^• WO 96/34096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.

An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Patent No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.

A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Patent No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain. In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.

F_ab Fragments and Single Chain Antibodies According to the invention, tecliniques can be adapted for the production of single-chain antibodies_ specific to an antigenic protein of the invention (see e.g., U.S. Patent No. 4,946,778), In addition, methods can be adapted for the construction of F_ab expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal F_ab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(_ab_')2 fragment produced by pepsin digestion of an antibody molecule; (ii) an F_ab fragment generated by reducing the disulfide bridges of an F^_b'μ fragment; (iii) an F_ab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) F fragments.

Bispecific Antibodies

Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.

Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture often different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).

Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CHI) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co- transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al, Methods in Enzymology, 121:210 (1986).

According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.

Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab') bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytic ally cleaved to generate F(ab')₂ fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thiomtrobenzoate (TNB) derivatives. One of the Fab^*-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab' -TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes. Additionally, Fab' fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab^")₂ molecule. Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5): 1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The "diabody" technology described by Hollinger et al, Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (V_H) connected to a light-chain variable domain (V_L) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the V_H and V domains of one fragment are forced to pair with the complementary V_L and V_H domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994). Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al, J. Immunol. 147:60 (1991). Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CDS, CD28. or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD 16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA. DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).

Heteroconjugate Antibodies

Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Patent No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO

92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl -4-mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No. 4,676,980. Effector Function Engineering

It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved intemalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1 191- 1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).

Immunoconjugates

The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).

Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin. Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include ^2,2Bi, ¹³¹I, ^{l3 I}In, ⁹⁰Y, and ¹⁸⁶Re.

Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis- diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro- 2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al.. Science. 238: 1098 (1987). Carbon- 14-labeled l-isothiocyanatobenzyl-3- methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026. In another embodiment, the antibody can be conjugated to a "receptor" (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) that is in turn conjugated to a cytotoxic agent. Immunoϊiposomes

The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al, Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA. 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG- de ivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al .,_J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst, 81(19): 1484 (1989).

Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention Antibodies directed against a protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of the protein (e.g., for use in measuring levels of the protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies against the proteins, or derivatives, fragments, analogs or homologs thereof, that contain the antigen binding domain, are utilized as pharmacologically-active compounds (see below).

An antibody specific for a protein of the invention can be used to isolate the protein by standard techniques, such as immunoaffinity chromatography or immunoprecipitation. Such an antibody can facilitate the purification of the natural protein antigen from cells and of recombinantly produced antigen expressed in host cells. Moreover, such an antibody can be used to detect the antigenic protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic protein. Antibodies directed against the protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein. fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ²T, ¹³¹L ³⁵S or ³H.

Antibody Therapeutics

Antibodies of the invention, including polyclonal, monoclonal, humanized and fully human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect may be one of two kinds, depending on the specific nature of the interaction between the given antibody molecule and the target antigen in question. In the first instance, administration of the antibody may abrogate or inhibit the binding of the target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, wherein the ligand serves as an effector molecule. Thus the receptor mediates a signal transduction pathway for which ligand is responsible. Alternatively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the disease or pathology, binds the antibody as a surrogate effector ligand, initiating a receptor-based signal transduction event by the receptor.

A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target, and in other cases, promotes a physiological response. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered. Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.

Pharmaceutical Compositions of Antibodies Antibodies specifically binding a protein of the invention, as well as other molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington : The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa. : 1995; Drug Absorption Enhancement : Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York.

If the antigenic protein is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA teclmology.

See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine. chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.

The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

Sustained-release preparations can be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ ethyl-L-glutamate. non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT ^1M (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3 -hydroxybutync acid. While polymers such as ethylene- vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.

ELISA Assay An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., F_ab or F_{(a )2}) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term "biological sample", therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in "ELISA: Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, NJ, 1995; "Immunoassay", E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and "Practice and Thory of Enzyme Immunoassays", P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. NOVX Recombinant Expression Vectors and Host Cells

Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding an NOVX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.

Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are refened to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably-linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g. , NOVX proteins, mutant forms of NOVX proteins, fusion proteins, etc.).

The recombinant expression vectors of the invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase. Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: (/) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Ine; Smith and Johnson, 1988. Gene 61: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.

Examples of suitable inducible non- fusion E. coli expression vectors include pTrc (Amrann et al, (1988) Gene 69:301-315) and pET l id (Studier et al, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89).

One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et /., 1992. Nucl Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.

In another embodiment, the NOVX expression vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSecl (Baldari, et al, 1987. EMBOJ. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al, 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif), and picZ (InVitrogen Corp, San Diego, Calif).

Alternatively, NOVX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al, 1983. Mol Cell. Biol 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology) 170: 31-39).

In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDMS (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al, 1987. EMBO J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989. In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al, 1987. Genes Dev. 1 : 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, et al, 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al, 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).

The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid. phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub, et al, "Antisense RNA as a molecular tool for genetic analysis," Reviews-Trends in Genetics, Vol. 1(1) 1986.

Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell" and "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.

Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.

For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection teclmique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).

A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method further comprises isolating NOVX protein from the medium or the host cell.

Transgenic NOVX Animals

The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

A transgenic animal of the invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human NOVX cDNA sequences of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue of the human NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the NOVX transgene to direct expression of NOVX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866; 4,870,009; and 4,873,191 ; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the NOVX transgene in its genome and/or expression of NOVX mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding NOVX protein can further be bred to other transgenic animals carrying other transgenes.

To create a homologous recombinant animal, a vector is prepared which contains at least a portion of an NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g., the cDNA of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129), but more preferably, is a non-human homologue of a human NOVX gene, For example, a mouse homologue of human NOVX gene of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129 can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous NOVX gene is functionally disrupted (i.e., no longer encodes a functional protein; also refened to as a "knock out" vector).

Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion of the NOVX gene is flanked at its 5'- and 3 '-termini by additional nucleic acid of the NOVX gene to allow for homologous recombination to occur between the exogenous NOVX gene carried by the vector and an endogenous NOVX gene in an embryonic stem cell. The additional flanking NOVX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5'- and 3 '-termini) are included in the vector. See, e.g., Thomas, et al, 1987. Cell 51 : 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced NOVX gene has homologously-recombined with the endogenous NOVX gene are selected. See, e.g., i, et al, 1992. Cell 69: 915.

The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously-recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01 140; WO 92/0968; and WO 93/04169.

In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage PI. For a description of the cre/loxP recombinase system, See, e.g., Lakso, et al, 1992. Proc. Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al, 1991. Science 251:1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al, 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter Go phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from which the cell (e.g., the somatic cell) is isolated.

Pharmaceutical Compositions

The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as "active compounds") of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous admimstration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ^' (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and anti fungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound (e.g., an NOVX protein or anti -NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible canier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable caniers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No. 5,328,470) or by stereotactic injection (.see, e.g., Chen, et al, 1994. Proc. Natl. Acad. Sci. USA 91 : 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

Screening and Detection Methods

The isolated nucleic acid molecules of the invention can be used to express NOVX protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect NOVX mRNA (e.g., in a biological sample) or a genetic lesion in an NOVX gene, and to modulate NOVX activity, as described further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g.; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies of the invention can be used to detect and isolate NOVX proteins and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion.

The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra.

Screening Assays

The invention provides a method (also refened to herein as a "screening assay") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX protein activity. The invention also includes compounds identified in the screening assays described herein. In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of an NOVX protein or polypeptide or biologically-active portion thereof. The test compounds of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997 '. Anticancer Drug Design 12: 145.

A "small molecule" as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention.

Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al, 1993. Proc. Natl. Acad. Sci. U.S.A. 90: 6909; Erb, et al, 1994. Proc. Natl. Acad. Sci. U.S.A. 91: 11422; Zuckermann, et al, 1994. J. Med. Chem. 37: 2678; Cho, et al, 1993. Science 261 : 1303; Carrell, et al, 1994. Angew. Chem. Int. Ed. Engl. 33: 2059; Carell, et al, 1994. Angew. Chem. Int. Ed. Engl. 33: 2061 ; and Gallop, et al, 1994. J. Med. Chem. 37: 1233. Libraries of compounds may be presented in solution (e.g., Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Patent No. 5,223,409). spores (Ladner, U.S. Patent 5,233,409), plasmids (Cull, et al, 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al, 1990. Proc. Nail Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol. 222: 301-310; Ladner, U.S. Patent No. 5,233,409.).

In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof on the cell surface is contacted with a test compound and the ability of the test compound to bind to an NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the NOVX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with ²T, ^3:>S, ' C, or Η, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with an NOVX protein, wherein determining the ability of the test compound to interact with an NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX protein or a biologically-active portion thereof as compared to the known compound.

In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX or a biologically-active portion thereof can be accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with an NOVX target molecule. As used herein, a "target molecule" is a molecule with which an NOVX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses an NOVX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. An NOVX target molecule can be a non-NOVX molecule or an NO X protein or polypeptide of the invention. In one embodiment, an NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound NOVX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX.

Determining the ability of the NOVX protein to bind to or interact with an NOVX target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of the NOVX protein to bind to or interact with an NOVX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by

74- detecting induction of a cellular second messenger of the target (i.e. intracellular Ca^~ , diacylglycerol, IP₃, etc.). detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising an NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e. , luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.

In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting an NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the NOVX protein or biologically- active portion thereof. Binding of the test compound to the NOVX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with an NOVX protein, wherein determining the ability of the test compound to interact with an NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound. In still another embodiment, an assay is a cell-free assay comprising contacting NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g. stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability of the NOVX protein to bind to an NOVX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of NOVX protein can be accomplished by determining the ability of the NOVX protein further modulate an NOVX target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as described, supra.

In yet another embodiment, the cell-free assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with an NOVX protein, wherein determining the ability of the test compound to interact with an NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the activity of an NOVX target molecule.

The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound form of NOVX protein. In the case of cell-free assays comprising the membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton^® X-100, Triton" X-l 14, Thesit",

IsotridecypoIy(ethylene glycol ether)_n, N-dodecyl— N,N-dimethyl-3 -ammonio- 1 -propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1 -propane sulfonate (CHAPS), or 3 -(3 -cholamidopropyl)dimethylamminiol-2 -hydro xy-1 -propane sulfonate (CHAPSO).

In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a test compound to NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST-NOVX fusion proteins or GST- target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity determined using standard techniques.

Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated NOVX protein or target molecules can be prepared from biotin-NHS

(N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit. Pierce Chemicals, Rockford, 111.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding of the NOVX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or NOVX protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the NOVX protein or target molecule.

In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of NOVX mRNA or protein in the cell is determined. The level of expression of NOVX mRNA or protein in the presence of the candidate compound is compared to the level of expression of NOVX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of NOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of NOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein.

In yet another aspect of the invention, the NOVX proteins can be used as "bait proteins" in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Patent No. 5,283,317; Zervos, et al, 1993. Cell 72: 223-232; Madura, et al, 1993. J. Biol. Chem. 268: 12046-12054; Bartel, et al, 1993. Biotechniques 14: 920-924; Iwabuchi, et al, 1993. Oncogene 8:

1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with NOVX ("NOVX-binding proteins" or "NOVX-bp") and modulate NOVX activity. Such NOVX-binding proteins are also likely to be involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements of the NOVX pathway. The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for NOVX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming an NOVX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with NOVX.

The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein.

Detection Assays

Portions or fragments of the cDNA sequences identified herein (and the conesponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: ( ) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (/^'/^") identify an individual from a minute biological sample (tissue typing); and (7/7) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below. Chromosome Mapping

Once the sequence (or a portion of the sequence) of a gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of the NOVX sequences selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or fragments or derivatives thereof, can be used to map the location of the NOVX genes, respectively, on a chromosome. The mapping of the NOVX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.

Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the NOVX sequences. Computer analysis of the NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the NOVX sequences will yield an amplified fragment.

Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al, 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions. PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the NOVX sequences to design oligonucleotide primers, sub- localization can be achieved with panels of fragments from specific chromosomes. Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1 ,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al, HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988).

Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al, 1987. Nature, 325: 783-787. Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the NOVX gene, can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms. Tissue Typing

The NOVX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA markers for RFLP ("restriction fragment length polymorphisms," described in U.S. Patent No. 5,272,057). Furthermore, the sequences of the invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5'- and 3 '-termini of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.

Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used to obtain such identification sequences from individuals and from tissue. The NOVX sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs).

Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If predicted coding sequences, such as those in any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129 are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

Predictive Medicine

The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining NOVX protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with abenant NOVX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in an NOVX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity.

Another aspect of the invention provides methods for determining NOVX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as "pharmacogenomics"). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent.) Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX in clinical trials.

These and other agents are described in further detail in the following sections. Diagnostic Assays

An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting NOVX protein or nucleic acid (e.g. , mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of any one of the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to NOVX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.

An agent for detecting NOVX protein is an antibody capable of binding to NOVX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')₂) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently- labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect NOVX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of NOVX protein include introducing into a subject a labeled anti-NOVX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A prefened biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.

In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the test sample.

The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect NOVX protein or nucleic acid.

Prognostic Assays

The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression or activity in which a test sample is obtained from a subject and NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.

Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic acid^'is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX expression or activity).

The methods of the invention can also be used to detect genetic lesions in an NOVX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding an NOVX-protein, or the misexpression of the NOVX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of: (/^') a deletion of one or more nucleotides from an NOVX gene; (/^'/^') an addition of one or more nucleotides to an NOVX gene; (iii) a substitution of one or more nucleotides of an NOVX gene, (iv) a chromosomal rearrangement of an NOVX gene; (v) an alteration in the level of a messenger RNA transcript of an NOVX gene, (vi) aberrant modification of an NOVX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non- wild-type splicing pattern of a messenger RNA transcript of an NOVX gene, (viii) a non- wild-type level of an NOVX protein, (ix) allelic loss of an NOVX gene, and (x) inappropriate post-translational modification of an NOVX protein. As described herein, there are a large number of assay tecliniques known in the art which can be used for detecting lesions in an NOVX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Patent Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al, 1988. Science 241 : 1077-1080; and Nakazawa, et al, 1994. Proc. Natl Acad. Sci. USA 91 : 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al, 1995. Nucl. Acids Res. 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to an NOVX gene under conditions such that hybridization and amplification of the NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.

Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al, 1990. Proc. Nail. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al, 1989. Proc. Natl. Acad. Sci. USA 86: 1 173-1177); Qβ Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. In an alternative embodiment, mutations in an NOVX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Patent No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

In other embodiments, genetic mutations in NOVX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density anays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al, 1996. Human Mutation 7: 244-255; Kozal, et al, 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NOVX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al, supra. Briefly, a first hybridization array of probes can be used to scan tlirough long stretches of DNA in a sample and control to identify base changes between the sequences by making linear anays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe anays complementary to all variants or mutations detected. Each mutation anay is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence of the sample NOVX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al, 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen, et al, 1996. Adv. Chromatography 36: 127-162; and Griffin, et al, 1993. Appl. Biochem. Biotechnol. 38: 147-159).

Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al, 1985. Science 230: 1242. In general, the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with Si nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, et al, 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, et al, 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection.

In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al, 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on an NOVX sequence, e.g. , a wild-type NOVX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Patent No. 5,459,039.

In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in NOVX genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et al, 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl 9: 73-79. Single-stranded DNA fragments of sample and control NOVX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al, 1991. Trends Genet. 7: 5.

In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g., Myers, et al, 1985. Nature 313: 495. When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753.

Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al, 1986. Nature 324: 163; Saiki, et al, 1989. Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.

Alternatively, allele specific amplification technology that depends on selective PCR • amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al, 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3'-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11 : 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparini, et al, 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3'-terminus of the 5' sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification. The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, w-'hich may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving an NOVX gene. Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which NOVX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

Pharmacogenomics

Agents, or modulators that have a stimulatory or inhibitory effect on NOVX activity (e.g., NOVX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders (The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer- associated cachexia, cancer, neurodegenerative disorders. Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.) In conjunction with such treatment, the pharmacogenomics (i.e. , the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g. , drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOλ⁷X genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.

Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol, 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the-body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymoφhisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome PREGNANCY ZONE PROTEIN PRECURSOR enzymes CYP2D6 and

CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drag response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification. Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with an NOVX modulator, such as a modulator identified by one of the exemplary screening assays described herein.

Monitoring of Effects During Clinical Trials

Monitoring the influence of agents (e.g.. drugs, compounds) on the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease NOVX gene expression, protein levels, or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting increased NOVX gene expression, protein levels, or upregulated NOVX activity. In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a "read out" or markers of the immune responsiveness of a particular cell. By way of example, and not of limitation, genes, including NOVX. that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates NOVX activity (e.g.. identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of NOVX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of NOVX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.

In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (/) obtaining a pre-administration sample from a subject prior to administration of the agent; (//^') detecting the level of expression of an NOVX protein, mRNA, or genomic DNA in the preadministration sample; (//^'/^') obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX protein, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of NOVX to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of NOVX to lower levels than detected, i.e., to decrease the effectiveness of the agent.

Methods of Treatment

The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant NOVX expression or activity. The disorders include cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright Hereditary Ostoeodystrophy, and other diseases, disorders and conditions of the like. These methods of treatment will be discussed more fully, below.

Disease and Disorders

Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: (/^') an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (//) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are "dysfunctional" (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to "knockout" endogenous function of an aforementioned peptide by homologous recombination (see. e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators ( i.e., inhibitors, agonists and antagonists, including additional peptide mimetic of the invention or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner.

Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability.

Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like).

Prophylactic Methods In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to the subject an agent that modulates NOVX expression or at least one NOVX activity. Subjects at risk for a disease that is caused or contributed to by aberrant NOVX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the NOVX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of NOVX aberrancy, for example, an NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections. Therapeutic Methods

Another aspect of the invention pertains to methods of modulating NOVX expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of NOVX protein activity associated with the cell. An agent that modulates NOVX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of an NOVX protein, a peptide, an NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more NOVX protein activity. Examples of such stimulatory agents include active NOVX protein and a nucleic acid molecule encoding NOVX that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of an NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another embodiment, the method involves administering an NOVX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX expression or activity.

Stimulation of NOVX activity is desirable in s/^'ti/ations in which NOVX is abnormally downregulated and/or in which increased NOVX activity is likely to have a beneficial effect. One example of such a situation is where a subject has a disorder characterized by abenant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia).

Determination of the Biological Effect of the Therapeutic

In various embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue.

In various specific embodiments. /^'// vitro assays may be performed with representative cells of the type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to administration to human subjects.

Prophylactic and Therapeutic Uses of the Compositions of the Invention The NOVX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders including, but not limited to: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer- associated cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.

As an example, a cDNA encoding the NOVX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions of the invention will have efficacy for treatment of patients suffering from: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias.

Both the novel nucleic acid encoding the NOVX protein, and the NOVX protem of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A further use could be as an anti-bacterial molecule (i.e., some peptides have been found to possess anti-bacterial properties). These materials are further useful in the generation of antibodies, which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods.

Sequence Analyses

The sequence of NOVX was derived by laboratory cloning of cDNA fragments, by in silico prediction of the sequence. cDNA fragments covering either the full length of the DNA sequence, or part of the sequence, or both, were cloned. In silico prediction was based on sequences available in CuraGen's proprietary sequence databases or in the public human sequence databases, and provided either the full length DNA sequence, or some portion thereof. The laboratory cloning was performed using one or more of the methods summarized below:

SeqCalling™Technology: cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then sequenced using CuraGen Corporation's SeqCalling technology which is disclosed in full in U. S. Ser. Nos. 09/417,386 filed Oct. 13, 1999, and 09/614,505 filed July 11, 2000. Sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatics programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity λvith another component was at least 95%> over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations. Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be refened to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration of the amino acid encoded by the gene at the position of the SNP. Intragenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result of the redundancy of the genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation of the expression pattern. Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message.

Presented information includes that associated with genomic clones, public genes and ESTs sharing sequence identity with the disclosed sequence and CuraGen Corporation's Electronic Northern bioinformatic tool.

EXAMPLES

Example A: Polynucleotide and Polypeptide Sequences, and Homology Data Example 1.

The NO VI clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 1 A.

Table IA. NOV1 Sequence Analysis

SEQ ID NO: 1 1423 bp

NOVla, AGCTTGGCCAAGAGAATAATAAAAACAGTTTAAGGAAATATTTCTTGGAAGCTGCTGA

CGI 00446-01 DNA AAAGGTATCTTTACAACTCCTGTTCTCTAGAGAAGCTTGCAGGCATGGGGGTAGGAAG

CACGGCTGATGCTCCGAAGGAGGGAAGACTGACCCGGTTTCTGGACTTCACCCAGCTG

Sequence ATGGACATGGCATCTGAATCCGTAGGAGGAAAAGTAATTTTATTTGCAACAGATGACT TTTTTGCTCCTGCAGAAAACCTCATAAAGAGTGACAGCCCGTGCTTCAAAGAGCATGA ATATACGGAGTTTGGGAAATGGATGGATGGCTGGGAGACCAGGAGGAAAAGGATTCCA GGTCACGACTGGTGTGTCCTCAGGCTGGGGATCCAAGGAGTCATCCGGGGCTTCGACG iTGGACGTTTCTTACTTCACGGGAGATTACGCTCCTCGAGTGTCCATTCAAGCAGCAAA ICTTGGAAGAAGATAAACTACCAGAAATCCCAGAAAGAGGAACCAGGACAGGAGCTGCA JGCCACTCCTGAGGAGTTTGAAGCCATTGCTGAGCTAAAATCCGACGACTGGAGTTACT TGGTTCCCATGACTGAGCTTAAGCCAGGAAACCCTGCTTCCGGCCACAACTATTTTCT TGTCAATTCCCAGCAGAGATGGACTCATATCAGACTCAACATTTTCCCAGATGGTGGA ATTGCACGACTTAGAGTATTCGGTACTGGACAAAAAGACTGGACTGCAACTGACCCCA AAGAACCTGCAGACCTAGTGGCCATCGCTTTTGGGGGTGTCTGTGTAGGATTTAGTAA TGCTAAGTTTGGGCACCCAAACAATATAATAGGTGTAGGAGTTAAGTCTATGGCGGAT GGTTGGGAAACTGCAAGAAGGCTGGACCGGCCACCAATATTAGAAGAGAATGGCATTC TCTTGGTTCCGGGTTGTGAATGGGCAGTTTTCCGATTGGCACATCCTGGAGTAATAAC TCGAATTGAAATTGACACAAAATATTTTGAAGGTAAATGCCCTGACAGCTGTAAAGTG GATGGGTGCATCCTGACAACTCAGGAAGAAGAAGCCGTGATCAGGCAAAAGTGGATTC TCCCGGCCCACAAGTGGAAACCACTGCTTCCAGTGACCAAGTTGTCTCCCAACCAAAG TCATCTGTTCGATAGCCTGACCCTAGAGCTCCAAGATGTCATCACTCACGCCAGGCTC ACCATCGTCCCCGACGGGGGAGTGAGCCGCCTTCGGCTCCGGGGCTTCCCCAGCTCCA TCTGCCTCCTGAGGCCCCGGGAGAAGCCCATGTTGAAGTTCTCGGTGAGCTTCAAAGC AAACCCTTAACACACACAAAGCCCCGGTGTCGGACACACAGCAGTAATTTCCCAGTCA fAGTCTTCTTTTCAAATGTTTTGAACACCTG

ORF Start: ATG at 103 iORF Stop: TAA at 1342

SEQ ID NO: 2 1413 aa MW at 46038.1kD

NOVla, MGVGSTADAPKEGR TRFLDFTQ DMASESVGGKVILFATDDFFAPAENLIKSDSPC CGI 00446-01 FKEHEYTEFGKWMDGWETRRKRIPGHDWCVLRLGIQGVIRGFDVDVSYFTGDYAPRVSJ IQAANLΞEDKLPEIPERGTRTGAAATPEEFΞAIAELKSDDWSYLVPMTE KPGNPASGI Protein Sequence HNYFLVNSQQR THIRLNIFPDGGIARLRVFGTGQKD TATDPKEPADLVAIAFGGVCI VGFSNAKFGHPNNIIGVGVKSMADG ETARRLDRPPI EΞNGILLVPGCEWAVFRLAHI PGVITRIEIDTKYFEGKCPDSCKVΌGCILTTQEEEAVIRQK ILPAHKKP LPVTKL! SPNQSHLFDS T E QDVITHAR TIVPDGGVSRLRRGFPSSICL RPREKPMLKFSJ VSFKA P I

Further analysis of the NOVla protein yielded the following properties shown in Table

IB.

Table IB. Protein Sequence Properties NOVla

PSort 0.6988 probability located in microbody (peroxisome); 0.3000 probability ! analysis: located in nucleus; 0.1584 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOVla protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1 C.

[WO200175067-A2, l l-OCT-2001]

ABG16807 | Novel human diagnostic protein #16798 I 53..124 72/72 (100%) 8e-39 ! - Homo sapiens, 195 aa. ! 57..128 72/72 (100%)

[WO200175067-A2, l l-OCT-2001]

AAB76764 Corynebacterium glutamicum MCT 268..295 11/28 (39%) 5.5 protein SEQ ID NO:510 - 481..508 19/28 (67%) Corynebacterium glutamicum, 551 aa. [WO200100805-A2, 04-JAN-2001]

AAG90677 C glutamicum protein fragment SEQ ID 26S..295 11/28 (39%) 5.5 NO: 4431 - Corynebacterium 481..508 19/28 (67%) glutamicum, 551 aa. [EP1108790-A2, 20-JUN-2001]

AAY72303 • Pseudomonas putida P450cam 107..183 23/81 (28%) 9.4 j monooxygenase mutant 150..227 35/81 (42%) (Y96F/F87W/T185A) - Pseudomonas 1 putida, 414 aa. [WO200078973-A1, 28- j DEC-2000]

In a BLAST search of public sequence databases, the NOVla protein was found to have homology to the proteins shown in the BLASTP data in Table ID.

PFam analysis indicates that the NOVla protein contains the domains shown in the Table IE.

Table IE. Domain Analysis of NOVla

Pfam Domain NOVla Match Region Expect Value j Similarities j

I for the Matched Region I

No Significant Matches Found

Example 2.

The NOV2 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 2A.

Table 2A. NOV2 Sequence Analysis

SEQ ID NO: 12239 bp

NOV2a, TCGCCGAGCCCGTCCGCCGCCGCCATGGCCACCACGGTGACCTGCACCCGCTTCACCG

CG101025-01 DNA ACGAGTACCAGCTCTACGAGGATATTGGCAAGGGGGCTTTCTCTGTGGTCCGACGCTG TGTCAAGCTCTGCACCGGCCATGAGTATGCAGCCAAGATCATCAACACCAAGAAGCTG Sequence TCAGCCAGAGATCACCAGAAGCTGGAGAGAGAGGCTCGGATCTGCCGCCTTCTGAAGC ATTCCAACATCGTGCGTCTCCACGACAGCATCTCCGAGGAGGGCTTCCACTACCTGGT CTTCGATCTGGTCACTGGTGGGGAGCTCTTTGAAGACATTGTGGCGAGAGAGTACTAC AGCGAGGCTGATGCCAGTCACTGTATCCAGCAGATCCTGGAGGCCGTTCTCCATTGTC ACCAAATGGGGGTCGTCCACAGAGACCTCAAGCCGGAGAACCTGCTTCTGGCCAGCAA GTGCAAAGGGGCTGCAGTGAAGCTGGCAGACTTCGGCCTAGCTATCGAGGTGCAGGGG GACCAGCAGGCATGGTTTGGTTTCGCTGGCACACCAGGCTACCTGTCCCCTGAGGTCC TTCGCAAAGAGGCGTATGGCAAGCCTGTGGACATCTGGGCATGTGGGGTGATCCTGTA CATCCTGCTCGTGGGCTACCCACCCTTCTGGGACGAGGACCAGCACAAGCTGTACCAG CAGATCAAGGCTGGTGCCTATGACTTCCCGTCCCCTGAGTGGGACACCGTCACTCCTG AAGCCAAAAACCTCATCAACCAGATGCTGACCATCAACCCTGCCAAGCGCATCACAGC CCATGAGGCCCTGAAGCACCCGTGGGTCTGCCAACGCTCCACGGTAGCATCCATGATG CACAGACAGGAGACTGTGGAGTGTCTGAAAAAGTTCAATGCCAGGAGAAAGCTCAAGG GAGCCATCCTCACCACCATGCTGGCCACACGGAATTTCTCAGCCAAGAGTTTACTCAA CAAGAAAGCAGATGGAGTCAAGCCCCAGACGAATAGCACCAAAAACAGTGCAGCCGCC ACCAGCCCCAAAGGGACGCTTCCTCCTGCCGCCCTGGAGCCTCAAACCACCGTCATCC ATAACCCAGTGGACGGGATTAAGGAGTCTTCTGACAGTGCCAATACCACCATAGAGGA TGAAGACGCTAAAGCCCCCAGGGTCCCCGACATCCTGAGCTCAGTGAGGAGGGGCTCG GGAGCCCCAGAAGCCGAGGGGCCCCTGCCCTGCCCATCTCCGGCTCCCTTTAGCCCCC TGCCAGCCCCATCCCCCAGGATCTCTGACATCCTGAACTCTGTGAGAAGGGGTTCAGG AACCCCAGAAGCCGAGGGCCCCCTCTCAGCGGGGCCCCCGCCCTGCCTGTCTCCGGCT CTCCTAGGCCCCCTGTCCTCCCCGTCCCCCAGGATCTCTGACATCCTGAACTCTGTGA GGAGGGGCTCAGGGACCCCAGAAGCCGAGGGCCCCTCGCCAGTGGGGCCCCCGCCCTG CCCATCTCCGACTATCCCTGGCCCCCTGCCCACCCCATGGATGGATGACATCCCAGGG CTGCTGCCACCCCCACCTGTGGGGAGACACCAGACTGGGGGTGGTGTGGAGATACTCT TAGAGAAGAGGCTGCTGGGCCACGGGCTCGGCATGGCAGGGCAGTGGCTAGCCCGGAA GCAGGAGATCATTAAGACCACGGAGCAGCTCATCGAGGCCGTCAACAACGGTGACTTT GAGGCCTACGCGAAAATCTGTGACCCAGGGCTGACCTCGTTTGAGCCTGAAGCACTGG GCAACCTGGTTGAAGGGATGGACTTCCACAGATTCTACTTCGAGAACCTGCTGGCCAA GAACAGCAAGCCGATCCACACGACCATCCTGAACCCACACGTGCACGTCATTGGAGAG GATGCCGCCTGCATCGCTTACATCCGGCTCACGCAGTACATTGACGGGCAGGGCCGGC CCCGCACCAGCCAGTCTGAGGAGACCCGCGTGTGGCACCGCCGCGACGGCAAGTGGCA GAATGTGCACTTCCACTGCTCGGGCGCGCCTGTGGCCCCGCTGCAGTGAAGAGCTGCG

CCCTGGTTTCGCCGGACAGAGTTGGTGTTTGGAGCCCGACTGCCCTCGGGCACACGGC CTGCCTGTCGCATGTTTGTGTCTGCCTCGTTCCCTCCCCTGGTGCCTGTGTCTGCAGA

AAAACAAGACCAGATGTGATTTGTTAAAAAAAAAA

ORF Start: ATG at 25 ORF Stop: TGA at 2077

SEQ ID NO: 4 684 aa MW at 74807.5kD

|NOV2a, MATTVTCTRFTDEYQLYEDIGKGAFSWRRCVKLCTGHEYAAKIINTKKLSARDHQKL EREARICRL.LKHSNIVRLHDSISEEGFHYLVFDLVTGGELFEDIVAREYYSEADASHC

SAAATSPKGTLPPAALEPQTTVIHNPλ/DGIKESSDSANTTIEDEDAKAPRVPDI SSV

RRGSGAPEAEGPLPCPSPAPFSP PAPSPRISDI NSVRRGSGTPEAEGPLSAGPPPC SPA LGP SSPSPRISDILNSVRRGSGTPEAEGPSPVGPPPCPSPTIPGP PTP MD !

DIPGLLPPPPVGRHQTGGGVEI LEKRL GHG GMAGQ LARKQEIIKTTEQLIEAλπST

NGDFEAYAKICDPG TSFEPEA GN VEG DFHRFYFEN LAIC SKPIHTTILNPHVH

VIGEDAACIAYIR TQYIDGQGRPRTSQSEETRWHRRDGK QNVHFHCSGAPVAPLQ

SEQ ID NO: 7 11689bp

|NOV2c, CATGGCCACCACGGTGACCTGCACCCGCTTCACCGACGAGTACCAGCTCTACGAGGAT

1CG101025-06DNA ATTGGCAAGGGGGCTTTCTCTGTGGTCCGACGCTGTGTCAAGCTCTGCACCGGCCATG AGTATGCAGCCAAGATCATCAACACCAAGAAGCTGTCAGCCAGAGATCACCAGAAGCT jSequence GGAGAGAGAGGCTCGGATCTGCCGCCTTCTGAAGCATTCCAACATCGTGCGTCTCCAC GACAGCATCTCCGAGGAGGGCTTCCACTACCTGGTCTTCGATCTGGTCACTGGTGGGG AGCTCTTTGAAGACATTGTGGCGAGAGAGTACTACAGCGAGGCTGATGCCAGGGCCAC TCGCACTAACCCACCTGCTGTTTGCCACAGTCACTGTATCCAGCAGATCCTGGAGGCC GTTCTCCATTGTCACCAAATGGGGGTCGTCCACAGAGACCTCAAGCCGGAGAACCTGC TTCTGGCCAGCAAGTGCAAAGGGGCTGCAGTGAAGCTGGCAGACTTCGGCCTAGCTAT CGAGGTGCAGGGGGACCAGCAGGCATGGTTTGGTTTCGCTGGCACACCAGGCTACCTG TCCCCTGAGGTCCTTCGCAAAGAGGCGTACGGCAAGCCCGTGGACATCTGGGCATGTG GGGTGATCCTGTACATCCTGCTCGTGGGCTACCCACCCTTCTGGGACGAGGACCAGCA CAAGCTGTACCAGCAGATCAAGGCTGGTGCCTATGACTTCCCGTCCCCTGAGTGGGAC ACCGTCACTCCTGAAGCCAAAAACCTCATCAΆCCAGATGCTGACCATCAΆCCCTGCCA AGCGCATCACAGCCCATGAGGCCCTGAAGCACCCGTGGGTCTGCCAACGCTCCACGGT AGCATCCATGATGCACAGACAGGAGACTGTGGAGTGTCTGAAAAΆGTTCAATGCCAGG AGAAAGCTCAAGGGAGCCATCCTCACCACCATGCTGGCCACACGGAATTTCTCAGCAG CCAAGAGTTTACTCAACAAGAAAGCAGATGGAGTCAAGCCCCATACGAATAGCACCAA AAACAGTGCAGCCGCCACCAGCCCCAAAGGGACGCTTCCTCCTGCCGCCCTGGAGTCT TCTGACAGTGCCAATACCACCATAGAGGATGAAGACGCTAAAGCCCGGAAGCAGGAGA TCATTAAGACCACGGAGCAGCTCATCGAGGCCGTCAACAACGGTGACTTTGAGGCCTA CGCGAAAATCTGTGACCCAGGGCTGACCTCGTTTGAGCCTGAAGCACTGGGCAACCTG GTTGAAGGGATGGACTTCCACAGATTCTACTTCGAGAACCTGCTGGCCAAGAACAGCA AGCCGATCCACACGACCATCCTGAACCCACACGTGCACGTCATTGGAGAGGATGCCGC CTGCATCGCTTACATCCGGCTCACGCAGTACATTGACGGGCAGGGCCGGCCCCGCACC AGCCAGTCTGAGGAGACCCGCGTGTGGCACCGCCGCGACGGCAAGTGGCAGAACGTGC ACTTCCACTGCTCGGGCGCGCCTGTGGCCCCGCTGCAGTGAAGAGCTGCGCCCTGGTT

TCGCCGGACAGAGTTGGTGTTTGGAGCCCGACTGCCCTCGGGCACACGGCCTGCCTGT

CGCATGTTTGTGTCTGCCTCGTTCCCTCCCCTGGTGCCTGTGTCTGCAGAAAAACAAG

CCCGACT

ORF Start: ATG at 2 ORF Stop: TGA at 1547

SEQ ID NO: 8 {515 aa jMW at 57692.2kD

;NOV2c, MATTVTCTRFTDEYQLYEDIGKGAFSWRRCVKLCTGHEYAAKIINTKKLSARDHQKL JCG101025-06 EREARICR LKHSNIVR HDSISEEGFHYLVFDLVTGGELFEDIVAREYYSEADARAT RTNPPAVCHSHCIQQILEAVLHCHQMGWHRD KPENL LASKCKGAAVK ABFG AI jProtein Sequence EVQGDQQA FGFAGTPGY SPEVLRKEAYGKPVDIWACGVI YI VGYPPFWDEDQH K YQQIKAGAYDFPSPE DTVTPEAKN INQM TINPAKRITAHEALKHP VCQRSTV AS HRQETVECLKKFNARRKLKGAILTTM ATRNFSAAKS LNKKADGVKPHTNSTK NSAAATSPKGT PPAA ESSDSANTTIEDEDAKARKQEIIKTTEQLIEAVISΓ GDFEAY AKICDPG TSFEPEA GNLVEGMDFHRFYFENLLAK SKPIHTTILNPHΛ VIGEDAA CIAYIR TQYIDGQGRPRTSQSEETRΛ HRRDGKWQNVΗFHCSGAPVAPLQ

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 2B.

Table 2B. Comparison ofNOV2a against NOV2b and NOV2c.

NOV2a Residues/ Identities/ Protein Sequence Match Residues Similarities for the Matched Region

Further analysis of the NOV2a protein yielded the following properties shown in Table

2C.

Table 2C. Protein Sequence Properties NOV2a

; PSort ^; 0.7900 probability located in plasma membrane; 0.3000 probability located in

: analysis: Golgi body; 0.2000 probability located in endoplasmic reticulum (membrane); I ] 0.1000 probability located in mitochondrial inner membrane

SignalP j No Known Signal Sequence Indicated analysis:

A search of the NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2D.

Table 2D. Geneseq Results for NOV2a

NOV2a Identities/

Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region

AAY68791 Amino acid sequence of a human 1..684 638/684 (93%) 0.0 phosphorylation effector PHSP-23 - 1..641 640/684 (93%) Homo sapiens, 641 aa. [WO200006728-A2, 10-FEB-2000]

AAY68786 Amino acid sequence of a human 1..417 I 376/423 (88%) 0.0 phosphorylation effector PHSP-18 - 1..407 582/423 (89%) Homo sapiens, 503 aa. [WO200006728-A2, 10-FEB-2000]

AAM25814 Human protein sequence SEQ ID 1..383 330/385 (85%) 0.0 NO: 1329 - Homo sapiens, 525 aa. 8..391 352/385 (90%) [WO200153455-A2, 26-JUL-2001]

AAM79441 Human protein SEQ ID NO 3087 1..383 330/385 (85%) 0.0 Homo sapiens, 525 aa. 8..391 352/385 (90%) [WO200157190-A2, 09-AUG-2001]

AAM78457 Human protein SEQ ID NO 1119 - 1..383 329/385 (85%) 0.0 Homo sapiens, 518 aa. 1..384 351/385 (90%) [WO200157190-A2, 09-AUG-2001]

In a BLAST search of public sequence databases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2E.

PFam analysis indicates that the NOV2a protein contains the domains shown in the Table 2F.

Example 3.

The NOV3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 3A. Table 3A. NOV3 Sequence Analysis

!SEQ ID NO: 9 j l455 bp

,NOV3a, JGCCGCCTGCGCCTCTGGGACCATGTTGCGCTGGCTGCGGGACTTCGTGCTGCCCACCG

JCG101 149-01 DNA ^'CGGCCTGCCAGGACGCGGAGCAGCCGACGCGCTACGAGACCCTCTTCCAGGCACTGGA CCGCAATGGGGACGGAGTGGTGGΆCATCGGCGAGCTGCAGGAGGGGCTCAGGAACCTG

[Sequence GGCATCCCTCTGGGCCAGGACGCCGAGGAGAAAATTTTTACTACTGGAGATGTCAACA AAGATGGGAAGCTGGATTTTGAAGAATTTATGAAGTACCTTAAAGACCATGAGAAGAA AATGAAATTGGCATTTAAGAGTTTAGACAAAAATAATGATGGAAAAATTGAGGCTTCA GAAATTGTCCAGTCTCTCCAGACACTGGGTCTGACTATTTCTGAACAACAAGCAGAGT TGATTCTTCAAAGCATTGATGTTGATGGGACAATGACAGTGGACTGGAATGAATGGAG AGACTACTTCTTATTTAATCCTGTTACAGACATTGAGGAAATTATCCGTTTCTGGΆAΆ CATTCTACAGGAATTGACATAGGGGATAGCTTAACTATTCCAGATGAATTCACGGAAG ACGAAAAAAAATCCGGACAATGGTGGAGGCAGCTTTTGGCAGGAGGCATTGCTGGTGC TGTCTCTCGAACAAGCACTGCCCCTTTGGACCGTCTGAAAATCATGATGCAGGTTCAC GGTTCAAAATCAGACAAAATGAACATATTTGGTGGCTTTCGACAGATGGTAAAAGAAG GAGGTATCCGCTCGCTTTGGAGGGGAAATGGTACAAACGTCATCAAAATTGCTCCTGA GACAGCTGTTAAATTCTGGGCATATGAACAGTACAAGAAGTTACTTACTGAAGAAGGA CAAAAAATAGGAACATTTGAGAGATTTATTTCTGGTTCCATGGCTGGAGCAACTGCAC AGACTTTTATATATCCAATGGAGGTTATGAAAACCAGGCTGGCTGTAGGCAAAACTGG GCAGTACTCTGGAATATATGATTGTGCCAAGAAGATTTTGAAACATGAAGGCTTGGGA GCTTTTTACAAAGGCTATGTTCCCAATTTATTAGGTATCATACCTTATGCAGGCATAG ATCTTGCTGTGTATGAGCTCTTGAAGTCCTATTGGCTGGATAATTTTGCAAAAGATTC TGTAAACCCTGGAGTCATGGTGTTGCTGGGATGCGGTGCCTTATCCAGCACCTGTGGT CAGCTGGCCAGCTACCCATTGGCTTTGGTGAGAACTCGCATGCAGGCTCAAGCCCTGT TAGAAGGTTCCCCACAGCTGAATATGGTTGGCCTCTTTCGACGAATTATTTCCAAAGA AGGAATACCAGGACTTTACAGAGGCATCACCCCAAACTTCATGAAGGTGCTCCCTGCT GTAGGCATCAGTTATGTGGTTTATGAAAATATGAAGCAAACTTTAGGAGTAACCCAGA

AATGA

ORF Start: ATG at 22 I ORF Stop: TGA at 1453

ISEQ ID NO: 10 1477 aa MW at 53335.9kD

NOV3a, ML WLRDFVLPTAACQDAΞQPTRYETLFQALDRNGDGWDIGELQEGLRNLGIPLGQD CG101 149-01 AEEKIFTTGDV KDGK DFEEFMKYLKDHEK^IK AFKSLDKNNDGKIEASEIVQΞLQ TLG TISEQQAE ILQSIDVDGTMTVD NE RDYFLFNPVTDIEEIIRFWKHSTGIDI ■Protein Sequence GDSLTIPDEFTΞDEKKSGQWWRQLLAGGΪAGAVSRTSTAPLTiRLKIMMQVHGSKSDKM NIFGGFRQMVKEGGIRSL RGNGTNVIKIAPETAVKF AYEQYKKL TEEGQKIGTFE RFISGS^AGATAQTFIYPMEV TR AVGK GQYSGIYDCAKKI KHEG GAFY GYV PN LGIIPYAGID AVYE LKS LDNFAKDSVNPGVMVLLGCGALSS CGQLASYPL JALVRTRMQAQALLEGSPQL MVGLFRRIISKEGIPGLYRGITPNFMKVLPAVGISYW YENMKQTLGVTQK

Further analysis of the NOV3a protein yielded the following properties shown in Table .

Table 3B. Protein Sequence Properties NOV3a

| PSort 0.4431 probability located in microbody (peroxisome); 0.4257 probability ^' analysis: located in mitochondrial matrix space; 0.1757 probability located in lysosome (lumen); 0.1027 probability located in mitochondrial inner membrane

I SignalP Cleavage site between residues 16 and 17 j analysis:

A search of the NOV3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3C.

In a BLAST search of public sequence databases, the NOV3a protein was found to have homology to the proteins shown in the BLASTP data in Table 3D.

Table 3D. Public BLASTP Results for NOV3a

Q96NQ4 : CDNA FLJ30339 FIS. CLONE 95..477 251/383 (65%) e-l 55

. BRACE2007401 , MODERATELY 2..384 319/383 (82%) SIMILAR TO ORYCTOLAGUS CUNICULUS PEROXISOMAL CA- DEPENDENT SOLUTE CARRIER MRNA - Homo sapiens (Human), 384 aa.

PFam analysis indicates that the NOV3a protein contains the domains shown in the Table 3E.

Example 4.

The NOV4 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 4A.

jACCAAAGTGGGCATGCATTGCTCTGGCCCCCTTGGTGGCCTTCTGCAGCTGGCTGCGG!

AGGTGAACGTGACATCGCGGGTGGCGCTGGCCGTGAGCTCAAGGGGCΆCACCCATCCT!

TATCCTCAAGCGCTGCAGCACGCTCCTGGGCCACATCAGCCTGTTCTCAGGGCTGCTG

CCCACACCACTCTTTGGGGTCGTGGAACAGATGCTCTTCAAGGTGCTTCCGGGACTGC

TGTGCCCCGTGGTGGACAGTGTGCTGGGTGTGGTGAATGAGCTCCTGGGGGCTGTGCT

GGGCCTGGTGTCCCTTGGGGCTCTTGGGTCCGTGGAATTCTCTCTGGCCACATTGCCT

CTCATCTCCAACCAGTACATAGAACTGGACATCAACCCTATCGTGAAGAGTGTAGCTG

GTGATATCATTGACTTCCCCAAGTCCCGTGCCCCAGCCAAGGTGCCCCCCAAGAAGGA

CCACACATCCCAGGTGATGGTGCCACTGTACCTCTTCAACACCACGTTTGGACTCCTG

CAGACCAACGGCGCCCTCGACATGGACATCACCCCTGAGCTGGTTCCCAGCGATGTCC

CACTGACAACTACAGACCTGGCAGCTTTGCTCCCTGAGGCCCTGGGGAAGCTGCCCCT

GCACCAGCAACTCCTACTGTTCCTGCGGGTGAGGGAAGCTCCCACGGTCACACTCCAC

AACAAGAAGGCCTTGGTCTCCCTCCCAGCCAACATCCATGTGCTGTTCTATGTCCCTA

AGGGGACCCCTGAATCCCTCTTTGAGCTGAACTCCGTCATGACTGTGCGTGCCCAGCT

GGCTCCCTCGGCTACCAAGCTGCACATCTCCCTGTCCCTGGAACGGCTCAGTGTCAAG

GTGGCCTCCTCCTTTACCCATGCCTTTGACGGATCGCGTTTAGAAGAATGGCTCAGCC

ATGTGGTCGGGGCAGTGTATGCACCAAAGCTTAACGTGGCCCTGGATGTTGGAATTCC

CCTGCCTAAGGTTCTTAATATCAATTTTTCCAATTCAGTTCTGGAGATCGTAGAGGTG

AGCCTTCTCTGCAGATACGGCCCAGGTGGGCCTTAAGCT iORF Start: ATG at 1 IORF Stop: TAA at 1426 i SEQ ID NO: 12 475 aa MW at 50231.7kD

;NOV4a, MLAL S LL WG ATPCQΞLLETVGTLARID DELGKAIQNS VGEPILQ V GSVTA JCG101169-01 VNRGL GSGGLLGGGGL GHGGVFGWΞELSGLKIEE TLPKV K PGFGVQ S H TKVGMHCSGPLGG Q AAEλ/NVTSRVALAVSSRGTPILILKRCST GHISLFSG L [Protein Sequence PTPLFGWEQMLFKVLPGLLCPWDSVLGλΛ NEL GAV GrjVS GA GSVEFSliATLP ISNQYIELDINPIVKSVAGDI IDFPKSRAPA VPP KDHTSQλ/MVPLYLFNTTFGL QTNGA DMDITPELVPSDVPLTTTDLAALLPEALGK P HQQ LLFLRVREAPTVTLH WKKALVS LPA IHVLFYVPKGTPE S FELNS M VRAQ AP S ATKLH I S S ERLS VK VASSFTHAFDGSRLEE LSHλTVGAVYAPKLNVA DVGIP PKV NINFSNSVLEIVEV SLLCRYGPGGP

Further analysis of the NOV4a protein yielded the following properties shown in Table

4B.

Table 4B. Protein Sequence Properties NOV4a

PSort 0.6400 probability located in plasma membrane; 0.4600 probability located in analysis: Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 17 and 18 analysis:

A search of the NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4C.

Table 4C. Geneseq Results for NOV4a

NOV4a Identities/

Geneseq Protein/Organism/Length [Patent Residues/ Similarities for Expect Identifier #, Date] Match the Matched Value Residues Region

In a BLAST search of public sequence databases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4D.

PFam analysis indicates that the NOV4a protein contains the domains shown in the Table 4E. Table 4E. Domain Analysis of NOV4a i

! ! Identities/ Pfam Domain ■ NOV4a Match Region j Similarities Expect Value j | for the Matched Region j LBP_BPI_CETP_C 281..461 46/191 (24%) 3.4e-ll i 120/191 (63%)

Example 5.

The NOV5 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 5A.

Table 5A. NOV5 Sequence Analysis

SEQ ID NO: 13 1763 bp iNOVSa, GGTTCCATGATGGGTCAACTTGATGGGAAAGTCATCATCCTGACAGCCGCTGCTCAGG

^'.CG101221-01 DNA GGATTGGCCAAGCAGCTGCCTTAGCTTTTGTAAGAGAAGGTGCCAAAGTCATAGCCAC AGACATTAATGTGTCCAAACTTCAGGAACTGGAAAAGTACCTGGGTATTCAAACTCGT Sequence GTCCTTGATGTCACAAAGAAGAAACAAATTGATCAGTTCGCCAATGAAGTTGAGAGAC TTGATGTTCTCTTTAATGTTGCTGGTTTTGTCCATCATGGAACTGTCCTGGATTGTGA GGAGAAAGACTGGGACTTCTCGATGAATCTCAATGTGCGCAGCACGTACCTGATGATC AAGGCATTCCTTCCTAAAATGCTTGCTCAAAAATCTGGCAATATTATCACCATGTTTT CTGTGGTTTCCAGCATCAAAGGAGTTGTGAACAGATGTGTGTACAGCACAACCAAGGC AGCCGTGATTGGCCTCACAAAATCTGTGGCTGCAGATTTCATCCAGCAGGGCATCAGG TGCAACTGTGTGTGCCCAGGAACGGTTGATACGCCATCTCTACAAGAAAGAATACAAG CCAGAGGAAATCCTGAAGAGGCACGGAATGATTTCCTGAAGAGACAAAAGATGGGACG ATTTGCAACTGCAGAAGAAATAGCCATGCTCTGCGTGTATGTGGCTTCTGATGAATCT GCTTATGTAACTGGTAACCCTGTCATCATTGATGGAGGATGGAGCTTGTGATTTTAGG ATCTCCATG

ORF Start: ATG at 7 jORF Stop: TGA at 745

SEQ ID NO: 14 246 aa MW at 26915.9kD

'NOV5a, MMGQLDGKVIILTAAAQGIGQAAALAFVREGAKVIATDINVSKLQELEKYLGIQTRVL CG101221-01 DVTKKKQIDQFANEVΞRLDVLFNVAGFVHHGTVLDCEEKDWDFSMNLNVRSTYLMIKA F PKMLAQKSGNIITMFSWSSIKGWNRCVYSTTKAAVIGLTKSVAADPIQQGIRCN Rrotein Sequence CVCPGTVDTPSLQERIQARGNPEEARNDFLKRQKMGRFATAEEIAMLCVYVASDESAY VTGNPVIIDGG SL

Further analysis of the NOV5a protein yielded the following properties shown in Table

5B.

Table 5B. Protein Sequence Properties NOV5a

; PSOrt 0.5500 probability located in endoplasmic reticulum (membrane); 0.2690 j analysis: probability located in lysosome (lumen); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP No Known Signal Sequence Indicated analysis: A search of the NOVSa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 5C.

In a BLAST search of public sequence databases, the NOV5a protein was found to have homology to the proteins shown in the BLASTP data in Table 5D.

AAK88976 AGR__L_807P - Agrobacterium 1..245 134/245 (54%) le-73 tumefaciens (strain C58 / ATCC 22..263 177/245 (71%) 33970), 264 aa.

AAL45260 OXIDOREDUCTASE - i 1..245 134/245 (54%) le-72

Agrobacterium tumefaciens str. i 1..242 177/245 (71%) C58 (U. Washington), 243 aa.

PFam analysis indicates that the NOV5a protein contains the domains shown in the Table 5E.

Example 6.

The NOV6 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 6A.

Protein Sequence EYDVGλΛ7^,ASFGR NEALILKFPSGILNVHPSCLPRWRGPAPVIHTVliHGDTVTGVTI MQIRPKRFDVGPILKQETVPVPPKSTAKELEAV SRLGANM ISVLKNLPESLSNGRQ QPMEGATYAPKISAGTSCIK EEQTSEQIFRLYRAIGNIVPLQTLWMANTIKL DLVE VNSSVIJ DPK TGQALIPGSVIYHKQSQIIiLVYCKDGWIGVRSVMLKKSl.TATDFYNG Y HP 7YQKNSQAQPSQCRFQTLRLPT KKQKKK LLCNNA SS

Further analysis of the NOVόa protein yielded the following properties shown in Table

6B.

Table 6B. Protem Sequence Properties NOVόa

PSort 0.8800 probability located in nucleus; 0.4657 probability located in analysis: mitochondrial matrix space; 0.3000 probability located in microbody (peroxisome); 0.2049 probability located in lysosome (lumen)

SignalP Cleavage site between residues 17 and 18 analysis:

A search of the NOVόa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6C.

In a BLAST search of public sequence databases, the NOVόa protein was found to have homology to the proteins shown in the BLASTP data in Table 6D.

Table 6D. Public BLASTP Results for NOVόa

NOVόa Identities/

Protein

Residues/ j Similarities for j Expect

Accession Protein/Organism/Length

Match j the Matched ; Value

Number Residues Portion

077480 Methi onyl -tRNA formyltransferase, 21..383 323/367 (88%) 0.0 mitochondrial precursor (EC 2.1.2.9) 3..309 348/367 (94%) (MtFMT) - Bos taurus (Bovine), 372 aa (fragment).

Q8VE89 j RIKEN CDNA 2310020P08 GENE - 3..391 318/389 (81%) 0.0 j Mus musculus (Mouse), 386 aa. 2..386 348/389 (88%)

Q9D799 j Methionyl-tRNA formyltransferase, 3..391 316/389 (81%) 0.0 j mitochondrial precursor (EC 2.1.2.9) 2..386 346/389 (88%) (MtFMT) - Mus musculus (Mouse), 386 aa.

Q96DP5 I CDNA FLJ31 126 FIS, CLONE 86.384 293/299 (97%) e-171

IMR322000838, HIGHLY SIMILAR 1..299 296/299 (98%) TO METHIONYL-TRNA FORMYLTRANSFERASE, MITOCHONDRIAL PRECURSOR (EC 2.1.2.9) - Homo sapiens (Human), 304 aa.

Q9V9Z0 CG1750 PROTEIN (LD21457P) - 142..350 73/212 (34%) 6e-29 Drosophila melanogaster (Fruit fly), 220 1..204 123/212 (57%) aa.

PFam analysis indicates that the NOVόa protein contains the domains shown in the Table 6E.

Example 7.

The NOV7 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 7A.

Table 7A. NOV7 Sequence Analysis

753 bp

NOV7a, J CCGCCGCCGCCGCCGGCCCCGCCTCCGGGCACCATGCTGCCCTCGCAGGAGGCCTCCA

CG101386-01 DNA AGCTCTACCACGAGCACTACATGCGGAACTCGCGGGCCATCGGCGTGCTGTGGGCCAT CTTCACCATCTGCTTCGCCATCATCAACGTGGTGGTCTTCATCCAGCCCTACTGGGTG Sequence GGCGACAGCGTGAGCACCCCCAAGCCTGGCTACTTCGGCCTCTTCCACTACTGCGTGG GCAGCGGGCTGGCGGGCCGCGAGCTCACCTGCCGGGGCTCCTTCACCGACTTCAGCAC CATCCCGTCCAGCGCCTTCAAGGCGGCCGCCTTCTTCGTGCTGCTCTCCATGGTGCTG ATCCTCGGCTGCATCACCTGCTTTTCGCTTTTCTTCTTCTGCAACACGGCTACGGTCT JACAAGATCTGCGCCTGGATGCAGCTCTTGTCAGCTCTGTGCCTCGTCCTGGGCTGCAT GATCTTTCCTGATGGCTGGGATGCCGAGACCATCCGGGACATGTGTGGGGCCAAGACG GGGAAGTACTCCCTGGGGGACTGTTCAGTGCGCTGGGCATACATCCTGGCCATCATCG GCATCCTCAACGCCCTCATCCTCTCCTTCCTCGCCTTCGTGCTGGGCAACCGGCAAAC AGACCTGCTGCAGGAGGAGCTCAAGCCGGAGAACAAAGGCGAGTGTGCTGTGGGCTGG JGGGGCAGCGGCGGGAGCCAGGCCTGGTCCTGGGAGGCAGGATAATTTCAAATAAAAG

ORF Start: ATG at 34 jORF Stop: TAA at 748 iSEQ ID NO: 18 ;238 aa MW at 26129.3kD _jNOV7a, MLPSQEASKLYHEHYMRNSRAIGV WAIFTICFAIINλΛΛFIQPY VGDSVSTPKPGY •CG101386-01 FGLFHYCVGSGLAGRELTCRGSFTDFSTIPSSAFKAAAFFVLLSMV ILGCITCFS F FFCNTATVYKICAWMQL SALC V GCMIFPDGWDAETIRD CGAKTGKYSLGDCSVR I Protein Sequence AYILAIIGILNALILSFLAFVLGNRQTDLLQEE PΞNKGECAVGWGAAAGARPGPG RQDNF

Further analysis of the NOV7a protein yielded the following properties shown in Table

7B.

Table 7B. Protein Sequence Properties NOV7a j PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in ' analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

! SignalP Cleavage site between residues 43 and 44 analysis:

A search of the NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7C.

Table 7C. Geneseq Results for NOV7a

NOV7a Identities/

Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region ABG02600 ' Novel human diagnostic protein #2591 1..140 136/142 (95%) j 2e-76 j - Homo sapiens, 291 aa. 113..254 138/142 (96%) | ! [WO200175067-A2, l l-OCT-2001]

In a BLAST search of public sequence databases, the NOV7a protein was found to have homology to the proteins shown in the BLASTP data in Table 7D.

Table 7D. Public BLASTP Results for NOV7a

PFam analysis indicates that the NOV7a protein contains the domains shown in the Table 7E.

Table 7E. Domain Analysis of NOV7a Identities/

Pfam Domain j NOV7a Match Region Similarities ; Expect Value | for the Matched Region

PMP22 Claudin 22..194 42/202 (21%) o.s: 1 13/202 (56%)

Example 8.

The NOV8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 8A.

Table 8A. NOV8 Sequence Analysis

I SEQ ID NO: 19 3189 bp

NOV8a, iCTGCACCGGGACCAGCGCCTCCCCGCTTCGCGCTGCCCTCGGCCTCGCCCCGGGCCCG

]CG101396-01 DNA GGTGGATGAGCCGCGCGCCCGGGGGACATGGAAGCGCTGACGCTGTGGCTTCTCCCCT

GGATATGCCAGTGCGTGTCGGTGCGGGCCGACTCCATCATCCACATCGGTGCCATCTT ; Sequence CGAGGAGAACGCGGCCAAGGACGACAGGGTGTTCCAGTTGGCGGTATCCGACCTGAGC CTCAACGATGACATCCTGCAGAGCGAGAAGATCACCTACTCCATCAAGGTCATCGAGG CCAACAACCCATTCCAGGCTGTGCAGGAAGCCTGTGACCTCATGACCCAGGGGATTTT GGCCTTGGTCACGTCCACTGGCTGTGCATCTGCCAATGCCCTGCAGTCCCTCACGGAT GCCATGCACATCCCACACCTCTTTGTCCAGCGCAACCCGGGAGGGTCGCCACGCACCG JCATGCCACCTGAACCCCAGCCCCGATGGTGAGGCCTACACACTGGCTTCGAGACCACC CGTCCGCCTCAATGATGTCATGCTCAGGCTGGTGACGGAGCTGCGCTGGCAGAAGTTC GTCATGTTCTACGACAGCGAGTATGATATCCGTGGGCTTCAAAGCTTTCTGGACCAGG CCTCGCGGCTGGGCCTTGACGTCTCTTTACAAAAGGTGGACAAGAACATTAGCCACGT ATTCACCAGCCTCTTCACCACGATGAAGACAGAGGAGCTGAATCGCTACCGGGACACG CTTCGCCGCGCCATCCTGCTGCTCAGCCCACAGGGAGCCCACTCCTTCATCAACGAGG LCCGTGGAGACCAACCTGGCTTCCAAGGACAGCCACTGGGTCTTTGTGAATGAGGAAAT JCAGTGACCCGGAGATCCTGGATCTGGTCCATAGTGCCCTTGGAAGGATGACCGTGGTC |CGGCAAATCTTTCCGTCTGCAAAGGACAATCAGAAATGCACGAGGAACAACCACCGCA J CTCCTCCCTGCTCTGCGACCCCCAGGAAGGCTACCTCCAGATGCTGCAGATCTCCAA ICCTCTATCTGTATGACAGTGTTCTGATGCTGGCCAACGCCTTTCACAGGAAGCTGGAG |GACCGGAAGTGGCATAGCATGGCGAGCCTCAACTGCATACGGAAATCCACTAAGCCAT JGGAATGGTGGGAGGTCCATGCTGGATACCATCAAAAAGGGCCACATCACTGGCCTCAC TGGGGTGATGGAGTTTCGGGAGGACAGTTCGAATCCCTATGTCCAGTTTGAΆATCCTT GGCACTACCTATAGTGAGACTTTTGGCAAAGACATGCGCAAGTTGGCGACATGGGACT CAGAGAAGGGCTTGAATGGCAGCTTGCAAGAGAGGCCCATGGGCAGCCGCCTCCAAGG ATTGACTCTTAAAGTGGTGACTGTCTTGGAAGAGCCTTTCGTGATGGTGGCTGAGAAC ATCCTAGGACAGCCCAAGCGCTACAAAGGGTTCTCCATAGATGTCCTGGATGCACTGG CCAAGGCTCTGGGCTTTAAATATGAGATTTACCAAGCCCCTGATGGCAGGTACGGTCA CCAGCTCCATAACACCTCCTGGAACGGGATGATCGGGGAGCTCATCAGCAAGAGAGCA GACTTGGCCATCTCTGCCATCACCATCACCCCAGAGAGGGAGAGCGTTGTGGACTTCA GCAAGCGGTACATGGACTATTCAGTGGGGATTCTAATTAAGAAGCCCGAGGAGAAAAT CAGCATCTTCTCCCTCTTTGCTCCATTTGATTTCGCTGTGTGGGCCTGCATTGCAGCA GCCATCCCTGTGGTTGGTGTGCTGATATTTGTGTTGAACAGGATACAGGCTGTGAGGG CTCAGAGTGCTGCCCAGCCCAGGCCGTCAGCTTCTGCCACTCTGCACAGCGCCATCTG GATTGTCTATGGAGCCTTCGTACAGCAAGGTGGCGAATCTTCCGTGAACTCCATGGCC ATGCGCATCGTGATGGGCAGCTGGTGGCTCTTCACGCTCATTGTGTGCTCCTCCTACA CAGCCAACCTTGCTGCCTTCCTCACAGTGTCCAGGATGGACAACCCCATAAGGACTTT CCAGGACCTGTCCAAACAAGTGGAAATGTCTTATGGCACTGTCCGGGATTCTGCTGTA TATGAGTACTTCCGAGCCAAGGGCACCAACCCCCTGGAGCAGGACAGCACGTTTGCTG AACTCTGGCGGACCATCAGC_AAGAACGGAGGGGCTGACAACTGCGTGTCCAGTCCTTC AGAAGGCATCAGGAAGGCA_AAGAAGGGGAACTACGCCTTCCTGTGGGATGTGGCCGTG GTGGAATACGCAGCCCTGA_CGGATGACGACTGCTCGGTGACTGTCATCGGCAACAGCA TCAGCAGCAAGGG_TT_ACGG_GATTGCCCTGCAGCATGGCAGCCCCTACAGGGACCTCTT CTCCCAGAGGATCCTGGAGCTGCAGGACACAGGGGACCTGGATGTGCTGAAGCAGAAG TGGTGGCCGCACATGGGCCGCTGTGACCTCACCAGCCATGCCAGCGCCCAGGCCGACG jGCAAATCCCTCAAGCTGCACAGCTTCGCCGGGGTCTTCTGCATCCTGGCCATTGGCCT! jGCTCCTGGCCTGCCTGGTGGCTGCCCTGGAGTTGTGGTGGAACAGCAACCGGTGCCAC CAGGAGACCCCCAAGGAGGACAAAGAAGTGAACTTGGAGCAGGTCCACCGGCGCATGA ACAGCCTCATGGATGAAGACATTGCTCACAAGCAGATTTCCCCAGCGTCGATTGAGCT CTCGGCCCTGGAGATGGGGGGCCTGGCTCCCACCCAGACCTTGGAGCCGACACGGGAG TACCAGAACACCCAGCTCTCGGTCAGCACCTTTCTGCCAGAGCAGAGCAGCCATGGCA CCAGCCGGACACTCTCATCAGGGCCCAGCAGCAACCTGCCGCTGCCGCTGAGCAGCTC GGCGACCATGCCCTCCATGCAGTGCAAACACAGGTCACCCAACGGGGGGCTGTTCCGG CAGAGCCCGGTGAAGACCCCCATCCCCATGTCCTTCCAGCCCGTGCCTGGAGGCGTCC TTCCAGAGGCTCTGGACACCTCCCACGGGACCTCCATCTGACTGCGCCGCCTGCCCTC

CTGCCCACCCTCCCACCCACCCGACCAGCAGAGCTTTTTAATACAAGAAAACAACAA

I ORF Start: ATG at 86 I ORF Stop: TGA at 3113

SEQ ID NO: 20 1009 aa MW at l l2129.7kD

NOVSa, MEALTL LLP ICQCVSVRADSIIHIGAIFEENAAKDDRVFQ AVSD SLNDDILQSE! ;CG101396-01 KITYSIKVIEAN PFQAVQEACDLMTQGI ALVTSTGCASAALQSLTDAMHIPHLFV^'

QRNPGGSPRTACHLNPSPDGEAYTLASRPPVR NDVM RLVTELRWQKFVMFYDSEYD ■ Protein Sequence IRGLQSFLDQASRLGLDVSLQKVDK ISHVFTSLFTTMKTEELNRYRDTLRRA1 L S

PQGAHSFINEAVETNLASKDSH VFVNEEISDPEILDLVΗSA GRMTWRQIFPSAKD

NQKCTRNNHRISSL CDPQEGY LQISN Y YDSV ML.ANAFHRKLEDRKWHSMAS

LNCIRKSTKP NGGRSM DTIKKGHITGLTGλ/MEFREDSSNPYVQFEI GTTYSETFG

KDMRKLAT DSEKGLNGSLQERPMGSR QGLTLKWTV EEPFVMVAENILGQPKRYK

GFSIDV DALAKALGFKYEIYQAPDGRYGHQLHNTSWNGMIGELISKRADLAISAITI

TPERΞSWDFSKRYMDYSVGILIKKPEEKISIFSLFAPFDFAVWACIAAAIPWGV I

FVLNRIQAVRAQSAAQPRPSASATLHSAIWIVYGAFVQQGGESSWSMA RIVMGSWW

LFT IVCSSYTANLAAF TVSRMDNPIRTFQD SKQVE SYGTVRDSAVYEYFRAKGT

NPLEQDSTFAEL RTISKNGGADNCVSSPSEGIRKAKKGNYAFIi DVAWEYAALTDD

DCSVTVIGNSISSKGYGIALQHGSPYRDLFSQRILELQDTGDLDV KQK PHMGRCD TSHASAQADGKS K HSFAGVFCILAIGLL ACLVAALEL NSNRCHQETPKEDKE

VNLEQVHRRMNS MDEDIAHKQISPASIE SALEMGG APTQTLEPTREYQNTQLSVS

TFLPEQSSHGTSRT SSGPSSN PLP SSSATMPSMQCKHRSPNGG FRQSPVKTPIPJ

MSFQPVPGGVLPEALDTSHGTSI !

Further analysis of the NOV8a protein yielded the following properties shown in Table

8B.

Table 8B. Protein Sequence Properties NOVSa

PSort 0.8720 probability located in mitochondrial inner membrane; 0.6000 probability analysis: located in plasma membrane; 0.4000 probability located in Golgi body; 0.3602 probability located in mitochondrial matrix space

SignalP Cleavage site between residues 21 and 22 analysis:

A search of the NOV8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 8C.

Table 8C. Geneseq Results for NOV8a

Geneseq NOV8a Identities/

Protein/Organism/Length [Patent Expect Identifier Residues/ Similarities for #, Date] Value

i i:

In a BLAST search of public sequence databases, the NOVSa protein was found to have homology to the proteins shown in the BLASTP data in Table 8D.

Q9ULK0 i KIAA 1220 PROTEIN - Homo 219..1009 ! 791/791 (100%) ^" 0.0 sapiens (Human), 791 aa 1..791 I 791/791 (100%) I ^j j (fragment). j ^!

PFam analysis indicates that the NOVSa protein contains the domains shown in the Table 8E.

Table 8E. Domain Analysis of NOV8a

Identities/

> Pfam Domain NOVSa Match Region Similarities ! Expect Value for the Matched Region

SBP bac 3 440..658 54/275 (20%) 0.0021 147/275 (53%)

¹ lig_chan 562..852 124/328 (38%) 1.9e-125 250/328 (76%)

Example 9.

The NOV9 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 9A.

Table 9A. NOV9 Sequence Analysis jSEQ ID NO: 21 15220 bp

^!NOV9a j TCGCCTCCCTCTCCGCCCGCTGCCTCCGGAGCTGGGGGGGAAACGCGAAGCCCCACTG j

"CG10154'^,-01 DNA ^{s c}Jι^{ATGGAGCCCGCCGCCGCGGCCACGGTA}^^

^{: J"} , CCGAGCTTCGGCTCCGGCGGCCGCCGCCGGGGGCGGCCGGAGTCCGGAGCCCGCGCTG i

Sequence JACCCCGGCGGCCCCGAGCGGCGGGAACGGCAGCGGCAGCGGGGCGCGGGAAGAGGCCC I _;CAGGCGAGGCGCCGCCGGGGCCGCTGCCGGGCAGAGCGGGGGGTGCCGGGCGCAGGAG

I ;GCGGCGCGGGGCGCCCCAGCCCATTGCCGGCGGGGCTGCCCCCGTACCCGGGGCCGGC

^'GGCGGCGCCAACTCCCTCCTGCTGAGGAGAGGGCGGCTGAAGAGGAATCTGTCCGCGG CCGCCGCGGCCGCCTCCTCGTCGTCGTCGTCCTCGGCCGCTGCTGCCTCGCACTCCCC CGGCGCTGCCGGCCTCCCCGCCTCCTGCTCGGCCTCGGCGTCGCTGTGCACCCGGAGC CTGGACAGGAAGACGCTGCTTCTGAAGCACCGGCAGACGCTGCAGCTGCAGCCGTCGG ACCGGGACTGGGTGAGGCACCAGCTCCAGCGCGGCTGCGTGCACGTCTTCGACCGCCA CATGGCCTCGACCTACCTGCGCCCGGTGCTCTGCACACTGGACACCACGGCCGGCGAG GTGGCCGCCCGCCTGCTGCAGCTGGGCCACAAAGGCGGCGGCGTGGTGAAGGTGCTGG GCCAGGGGCCCGGAGCCGCCGCCGCCCGGGAGCCCGCTGAACCGCCCCCCGAGGCCGG CCCCCGGCTGGCGCCCCCGGAGCCGCGGGACTCGGAGGTACCGCCCGCGAGGAGCGCG CCGGGTGCCTTCGGGGGGCCTCCGCGCGCGCCCCCCGCCGACCTACCCCTGCCCGTCG GCGGCCCGGGCGGGTGGTCGCGCCGCGCCAGCCCAGCGCCCTCGGACTCCAGCCCCGG CGAGCCGTTCGTTGGGGGCCCTGTCTCTTCGCCCCGCGCCCCACGGCCTGTGGTCTCC GACACCGAGAGCTTCAGTCTGAGTCCCAGCGCCGAGAGCGTGTCTGACCGGTTGGACC CCTACAGCAGCGGCGGCGGCTCCTCGTCGTCGTCGGAAGAGCTCGAGGCCGACGCAGC CTCGGCCCCGACGGGGGTCCCGGGCCAGCCCCGCCGTCCCGGCCACCCCGCGCAGCCC CTCCCGCTTCCCCAGACGGC_TTCCTCGCCTCAGCCGCAGCAGAAAGCCCCGAGGGCCA: TTGACAGCCCGGGCGGGGCCGTCCGCGAGGGGTCGTGCGAGGAGAAGGCAGCGGCAGC CGTGGCCCCGGGAGGCCTCCAGTCTACCCCCGGGAGGAGCGGGGTGACCGCGGAGAAG GCGCCTCCGCCGCCCCCGCCGCCCACCCTGTACGTGCAGCTCCΆCGGAGAGΆCCACCC GGCGCTTGG_AGGCGGAGG_AG_AAGCCATTGCAGATCCAAAATGACTACCTCTTCCAACT

GGGATTTGGGGAGCTGTGGAGGGTGCAGGAGGAAGGCATGGACTCGGAGATTGGCTGC CTCATCCGCTTCTATGCAGGAAAACCTCACAGCACGGGTAGCTCTGAACGGATTCAGC TCTCAGGAATGTATAATGTCCGTAAAGGCAAGATGCAGTTGCCAGTGAACCGATGGAC AAGACGCCAAGTCATCCTATGTGGGACCTGCCTGATAGTATCATCTGTGAAAGACAGC TTGACCGGAAAGATGCATGTTCTGCCACTAATTGGTGGAAAAGTAGAAGAAGTGAAAA AGCACCAACACTGTTTAGCATTTAGCTCCTCTGGACCCCAAAGCCAGACTTACTACAT TTGCTTTGATACTTTCACAGAATACTTAAGGTGGCTGCGACAAGTCTCCAAGGTTGCA TCCCAGCGCATTAGCTCAGTGGACCTCTCGTGTTGTAGCCTGGAACATCTGCCTGCCA ACCTCTTCTACAGCCAAGACCTCACTCATCTCAATTTAAAACAAAACTTCCTAAGGCA GAACCCTAGCCTTCCAGCTGCCAGGGGGCTTAATGAACTGCAAAGGTTCACCAAGTTG AAGAGTCTTAACCTTTCCAATAATCATTTAGGGGACTTCCCTCTGGCAGTCTGCAGTA TTCCAACCCTGGCAGAGCTGAACGTGTCCTGCAATGCCCTGCGATCAGTCCCGGCAGC CGTTGGAGTGATGCACAACTTACAGACATTTTTGTTGGATGGAAACTTTCTCCAATCC CTTCCTGCTGAGTTGGAGAACATGAAGCAGCTTAGTTATCTGGGTCTTTCTTTCAATG AATTTACTGACATTCCCGAAGTATTGGAGAAATTGACTGCTGTGGATAAACTTTGTAT GTCTGGAAACTGTGTGGAGACCCTTAGGCTACAGGCTTTAAGAAAAATGCCTCACATT AAACATGTGGATCTAAGGTTGAACGTAATTAGGAAGCTGATAGCAGATGAAGTGGACT TTCTACAGCATGTTACTCAGCTTGACCTACGAGACAATAAGCTTGGTGATCTAGATGC TATGATTTTCAACAACATTGAAGTTTTACACTGTGAAAGGAATCAACTGGTCACATTA GACATCTGTGGCTATTTCCTAAAAGCGCTCTATGCCTCTTCTAATGAACTTGTTCAAC TTGATGTTTACCCAGTTCCAAATTATCTGTCCTACATGGATGTTTCAAGGAACCGCTT AGAAAATGTGCCTGAGTGGGTATGTGAAAGCCGAAAGCTAGAAGTTTTGGATATTGGC CATAATCAAATATGTGAACTTCCTGCCCGCTTATTTTGTAATAGCAGTCTCCGGAAAC TACTGGCAGGACACAACCAGTTGGCAAGGCTGCCTGAAAGGCTAGAAAGAACCTCGGT GGAGGTCTTGGATGTGCAACACAACCAGCTCCTTGAGCTCCCACCTAACCTTCTGATG AAGGCTGACAGCCTGAGATTCCTGAACGCCTCTGCGAACAAACTGGAAAGCCTTCCTC CAGCCACGCTTTCCGAAGAGACAAACAGTATCTTACAAGAGTTGTATTTGACAAATAA CAGCCTCACAGACAAATGTGTGCCCTTGTTAACGGGACACCCCCATTTGAAGATCCTT CACATGGCCTATAACCGACTTCAGAGTTTTCCAGCAAGTAAAATGGCGAAACTGGAGG AACTTGAAGAAATTGATCTCAGTGGGAATAAGCTGAAAGCCATCCCAACAACGATCAT GAATTGCAGGCGCATGCACACCGTGATTGCTCACTCCAACTGCATCGAGGTCTTTCCC GAAGTTATGCAGCTCCCAGAGATCAAGTGTGTGGACCTGAGCTGTAATGAGCTAAGTG AAGTCACATTACCAGAAAACCTGCCTCCCAAACTGCAGGAGCTAGACCTGACTGGAAA CCCGCGCCTTGTCCTTGATCACAAAACCCTGGAACTACTGAATAATATCCGCTGTTTC AAGATTGATCAGCCTTCTACAGGAGACGCTTCCGGAGCCCCAGCTGTATGGAGTCATG GTTACACTGAAGCTTCGGGGGTAAAAAACAAGTTGTGTGTCGCAGCCCTGTCGGTGAA TAACTTCTGTGACAACCGCGAAGCCCTGTATGGTGTGTTTGACGGAGACCGGAATGTG GAGGTGCCCTACCTTCTCCAGTGCACTATGAGTGACATTTTGGCTGAAGAGCTGCAAA AAACAAAAAACGAAGAAGAATACATGGTCAATACATTCATTGTCATGCAAAGGAAACT TGGAACTGCTGGGCAGAAGCTTGGTGGTGCCGCTGTCCTTTGTCATATCAAGCATGAC CCTGTGGATCCAGGAGGATCCTTCACCTTGACCTCTGCTAATGTGGGCAAGTGCCAAA CAGTTCTCTGTCGAAATGGAAAGCCGCTGCCTCTGTCCAGATCTTACATCATGAGCTG TGAAGAAGAGCTGAAGAGGATTAAACAGCACAAGGCCATTATCACTGAGGATGGCAAG GTGAACGGAGTGACTGAGTCCACGCGCATCCTGGGCTACACCTTCCTCCATCCCAGTG TGGTGCCTCGCCCCCACGTGCAGTCCGTGCTCCTGACTCCCCAGGATGAGTTCTTCAT CCTAGGCAGTAAGGGGTTGTGGGACAGCCTGTCCGTCGAGGAGGCCGTGGAAGCCGTG CGCAACGTGCCCGATGCCCTGGCTGCTGCCAAGAAGCTGTGTACCCTGGCCCAGAGCT ACGGCTGCCACGACAGCATCAGCGCTGTGGTGGTGCAGCTCAGTGTCACTGAGGACAG CTTCTGCTGCTGCGAGCTCAGCGCCGGTGGGGCTGTGCCACCACCCAGTCCTGGCATC TTTCCTCCCTCAGTGAACATGGTGATCAAGGATCGGCCCTCAGATGGGCTGGGCGTGC CGTCCTCCAGCAGCGGCATGGCTTCCGAGATTAGCAGTGAGCTCTCCACTTCTGAGAT GAGCAGCGAGGTGGGGTCAACAGCCTCCGATGAGCCCCCGCCCGGAGCCCTAAGCGAG AACAGCCCTGCCTACCCCAGTGAGCAGCGCTGCATGCTCCACCCCATCTGTCTGTCCA ACTCCTTCCAGCGCCAGCTATCCAGCGCCACGTTCTCTAGCGCCTTCTCCGACAACGG CCTTGACAGTGACGATGAGGAGCCCATCGAGGGCGTCTTCACCAACGGCAGCCGGGTG GAGGTGGAGGTGGACATCCACTGCAGCCGGGCCAAGGAGAAGGAGAAACAGCAGCACC TGCTTCAGGTGCCAGCAGAGGCCAGTGATGAGGGCATTGTCATCAGCGCCAACGAGGA TGAGCCAGGTCTGCCCAGGAAGGCAGACTTCTCTGCCGTTGGGACCATTGGGCGCCGG AGGGCCAATGGCTCTGTTGCGCCCCAGGAAAGGAGCCACAATGTGATAGAGGTGGCTA CAGACGCACCTCTTCGAAAGCCTGGAGGCTATTTTGCTGCCCCGGCTCAGCCGGATCC TGATGATCAGTTTATCATACCCCCGGAGCTGGAAGAGGAGGTCAAAGAAATCATGAAG CATCACCAGGAGCAACAGCAGCAGCAGCAGCCGCCACCACCCCCTCAGCTCCAGCCGC lAGCTGCCGCGGCACTACCAGCTGGACCAGCTGCCAGATTATTACGACACGCCACTATG! - CCCAGCCGAGCTGTTTAACAAATAAACTAACCACAAAAGACTGAGTTGCAAGAGTCT

IORF Start: ATG at 61 ORF Stop: TGA at 5161

^■SEQ ID NO: 22 1700 aa MWatl83419.6kD jNOV9a, MEPAAAATVQRLPELGREDRASAPAAAAGGGRSPEPALTPAAPSGGNGSGSGAREEAP CG101543-01 GEAPPGPLPGRAGGAGRRRRRGAPQPIAGGAAPVPGAGGGANSLLLRRGRLKRNLSAA AAAASSSSSSSAAAASHSPGAAGLPASCSASASLCTRS DRKTLLLKHRQTLQ QPSD ! Protein Sequence RDWVRHQLQRGCVHVFDRHMASTYLRPVLCT DTTAGEVAARLLQLGHKGGGWKVLG QGPGAAAAREPAEPPPEAGPRLAPPEPRDSEVPPARSAPGAFGGPPRAPPADLP PVG GPGG SRRASPAPSDSSPGEPFVGGPVSSPRAPRPWSDTESFSLSPSAESVSDRLDP YSSGGGSSSSSEE EADAASAPTGVPGQPRRPGHPAQPLPLPQTASSPQPQQKAPRAI DSPGGAVREGSCEEKAAAAVAPGG QSTPGRSGVTAEKAPPPPPPPTLYVQLHGETTR RLEAEEKPLQIQ DY FQLGFGEL RVQEEG DSEIGCLIRFYAGKPHSTGSSERIQ SGMYNVRKGKMQ PVNRWTRRQVILCGTC IVSSVKDSLTGKMHV PLIGGKVEEVKK HQHCLAFSSSGPQSQTYYICFDTFTEYLRW RQVSKVASQRISSVDLSCCSLEHLPAN FYSQDLTHLNLKQNF RQNPSLPAARGLNELQRFTKLKS N S NHLGDFP AVCSI PTLAΞ NVSCNALRSVPAAVGλ/MHN QTFLLDGNFLQSLPAE ENMKQLSY G SFNE FTDIPEVLEKLTAVDKLCMSGNCVETLRLQA RKMPHIKHVD R NVIRKLIADEλDF QHVTQ DLRDNKLGD DAMIF IEVLHCERNQLVTLDICGYFLKALYASSNELVQL DVYPVPNY SY DVSRNRLENVPE VCESRKLEVLDIGHNQICELPARLFCNSS RKL LAGHNQ AR PERLERTSVEVLDVQHNQLLΞLPPNL MKADSLRFLNASANKLESLPP ATLSEETNSILQE YLTNNSLTDKCVP LTGHPHLKI HMAYNRLQSFPASKMAKLEE LEEID SGNKLKAIPTTIMNCRRMHTVIAHSNCIEVFPEVMQ PEIKCVD SCNELSΞ VTLPEN PPKLQELDLTGNPRLVLDHKT ELLNNIRCFKIDQPSTGDASGAPAVWSHG YTEASGVKNK CVAALSVNNFCDNREALYGVFDGDRNVEVPYLLQCTMSDILAEELQK TK EEEYMVNTFIλ QRKLGTAGQ LGGAAVLCHIKHDPλDPGGSFTLTSANVGKCQT VLCRNG PLPLSRSYI SCEEΞ KRIKQHKAIITEDGKλNGVTESTRILGYTFLHPSV VPRPHVQSVL TPQDEFFILGSKGL DSLSVEEAVEAVRNVPDALAAAKKLCTLAQSY GCHDSISAλΛAQLΞVTEDSFCCCELSAGGAVPPPSPGIFPPSVNMVIKDRPSDGLGVP SSSSGMASEISSELSTSEMSSEVGSTASDEPPPGALSENSPAYPSEQRCMLHPICLSN SFQRQLSSATFSSAFSDNGLDSDDEEPIEGVFTNGSRVEVEVDIHCSRAKEKEKQQHL QVPAEASDΞGIVISANEDEPG PRKADFSAVGTIGRRRA GSVAPQERSH VIEVAT DAPLRKPGGYFAAPAQPDPDDQFIIPPELEEEVKEI KHHQEQQQQQQPPPPPQLQPQ LPRHYQLDQLPDYYDTP

Further analysis of the NOV9a protein yielded the following properties shown in Table

9B.

A search of the NOV9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 9C.

Table 9C. Geneseq Results for NOV9a

Geneseq Protein/Organism/Length [Patent 1 NOV9a Identities/ Expect Identifier #, Date] j ^• Value

In a BLAST search of public sequence databases, the NOV9a protein was found to have homology to the proteins shown in the BLASTP data in Table 9D.

PFam analysis indicates that the N0V9a protein contains the domains shown in the Table 9E.

Example 10.

The NOV 10 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 10A.

NOV 10a, MAAYKLV IQHGESM NPENRFSS YNTDLSPAGHKEAKCGRQVLCEKPAEFDICFTS CG101574-01 VQKRVIQT TV DAIDQT LPWRDWC NEQHSGGLIGLNKAETAA HGΞAQVKI R HSYDVPPP MEPDHPFYNISKDRRFANLTEDQLPSCESLKDTIAKALPFWNΞEIVPQI Rrotein Sequence KEGKQVLIAAHGNSPPGIVKHLEGLSEEAIME NLPTGIPWYELD LKPIQFLGDE ETMRKAMEAVAAQGKAKK

Further analysis of the NOV1 Oa protein yielded the following properties shown in Table 10B.

Table 10B. Protein Sequence Properties NOVlOa

! PSort 0.6500 probability located in cytoplasm; 0.1000 probability located in ; analysis: mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOVlOa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table IOC.

In a BLAST search of public sequence databases, the NOVlOa protein was found to have homology to the proteins shown in the BLASTP data in Table 10D.

Table 10D. Public BLASTP Results for NOVlOa

PFam analysis indicates that the NOVlOa protein contains the domains shown in the Table 10E.

Example 11.

The NOVl 1 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 11 A.

CG101596-01 DNA TCTGGCCGCGGCGCTGCTGTTGCTGCTGCTGCGCCACGGCGGCCGGACGGTGGAGAAC ; Sequence ATGAGCATTATCGGCTGGTTCGTGCGAAGCTTCAAGTACTTTTACGGGCTCCGCTTCG AGGTGCGGGACCCGCGCAGGCTGCAGGAGGCCCGTCCCTGTGTCATCGTCTCCAACCA CCAGAGCATCCTGGACATGATGGGCCTCATGGAGGTCCTTCCGGAGCGCTGCGTGCAG ATCGCCAAGCGGGAGCTGCTCTTCCTGGGGCCCGTGGGCCTCATCATGTACCTCGGGG GCGTCTTCTTCATCAACCGGCAGCGCTCTAGCACTGCCATGACAGTGATGGCCGACCT GGGCGAGCGCATGGTCAGGGAGAACCTCAAAGTGTGGATCTATCCCGAGGGTACTCGC AACGACAATGGGGACCTGCTGCCTTTTAAGAAGGGCGCCTTCTACCTGGCAGTCCAGG CACAGGTGCCCATCGTCCCCGTGGTGTACTCTTCCTTCTCCTCCTTCTACAACACCAA GAAGAAGTTCTTCACTTCAGGAACAGTCACAGTGCAGGTGCTGGAAGCCATCCCCACC AGCGGCCTCACTGCGGCGGACGTCCCTGCGCTCGTGGACACCTGCCACCGGGCCATGA GGACCACCTTCCTCCACATCTCCAAGACCCCCCAGGAGAACGGGGCCACTGCGGGGTC TGGCGTGCAGCCGGCCCAGTAGCCCAGACCACGGCAGGGCATGACCTGGGGAGGGCAG

GTGGAAGCCGATGGCTGGAGGATGGGCAGAGGGGACTCCTCCCGGCTTCCAAATACCA

CTCTGTCCGGCTCCCCCAGCTCTCACTCAGCCCGGGAAGCAGGAAGCCCCTTCTGTCA

CTGGTCTCAGACACAGGCCCCTGGTGTCCCCTGCAGGGGGCTCAGCTGGACCCTCCCC

GGGCTCGAGGGCAGGGACTCGCGCCCACGGCACCTCTGGGAGCTGGGATGATAAAGAT

GAGGCTTGCGGCTGTGGCCCGCTGGTGGGCTGAGCCACAAGGCCCCCGATGGCCCAGG

AGCAGATGGGAGGACCCCGAGGCCAGACGCACACTGTCCGAGCCCTCTGCTCAGCCGC

CTGGGACCCACCAGGGTGCAGCTGGGCTCCAGGGTCCAGCCCACAAGCTGCATCAGGG

TCTCTGGGAGAGGAGGGGCCTCCAGGGCCAGGAGTCCCAGACTCACGCACCCTGGGCC

ACAGGGAGCCGGGAATCGGGGCCTGCTGCTCCTGCTGGCCTGGAAGACTCTGTGGGGT

CAGCACTGTACTCCGTTGCTGTTTTTTTATAAACACACTCTTGGAAGTGGAAAAAAAA

AAA

ORF Start: ATG at 42 ORF Stop: TAG at 774

;SEQ ID NO: 26 244 aa 'MW at 27294.7kD iNOVl la, MELWPCLAAALL LLRHGGRTVENMS11GWFVRSFKYFYGLRFEVRDPRRLQEARPC JCG101596-01 VIVSNHQSILD MGLMEVLPERCVQIAKRE FLGPVGLIMY GGVFFINRQRSSTA Tλ ADLGERMVRENLKV IYPEGTRNDNGDLLPFKKGAFYLAVQAQVPIVPWYSSFS I Protein Sequence SFYNTKKKFFTSGTVTVQVLEAIPTSGLTAADVPALVDTCHRAMRTTF HISKTPQEN GATAGSGVQPAQ

Further analysis of the NOVl la protein yielded the following properties shown in Table I IB.

Table IIB. Protein Sequence Properties NOVlla

PSort 0.7300 probability located in plasma membrane; 0.6400 probability located in analysis: endoplasmic reticulum (membrane); 0.2093 probability located in microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 23 and 24 analysis:

A search of the NOVl la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1 IC.

Table 11C. Geneseq Results for NOVlla

NOVlla Identities/

Geneseq j Protein/Organism/Length [Patent Residues/ Similarities for Expect Identifier 1 #, Date] Match the Matched Value Residues Region AAW86302 ' Human lysophosphatidic acid 1..244 j 244/278 (87%) e-134

! acyltransferase-1 - Homo sapiens, 278 1..278 j 244/278 (87%) j aa. [WO9854302-A2, 03-DEC-1998]

AAW29875 ' Lysophosphatidic acid acyltransferase 1..244 243/278 (87%) e-134 enzyme LPAAT II - Homo sapiens, 1..278 244/278 (87%) 278 aa. [RD400054-A, 10-AUG- 1997]

AAE 15289 Human LPAAT beta protein - Homo 1..244 243/278 (87%) - U JJ sapiens, 278 aa. [US6300487-B1, 09- 1..278 243/278 (87%) OCT-2001]

AAB30623 Amino acid sequence of 1..244 243/278 (87%) lysophosphatidic acid acyltransferase- 1..278 243/278 (87%) j beta - Homo sapiens, 278 aa. [US6136964-A, 24-OCT-2000]

AAY91082 Human lysophosphatidic acid 1..244 243/278 (87%) J e-l 33 acyltransferase beta - Homo sapiens, 1..278 243/278 (87%) I 278 aa. [US6060263-A, 09-MAY- 2000]

In a BLAST search of public sequence databases, the NOVl 1 a protein was found to have homology to the proteins shown in the BLASTP data in Table 11D.

PFam analysis indicates that the NOVl la protein contains the domains shown in the Table HE.

Table HE. Domain Analysis of NOVlla

Identities/

Pfam Domain NOVlla Match Region I Similarities j Expect Value for the Matched Region

Acyltransferase 49..225 68/198 (34%) 5.7e-57 151/198 (76%)

Example 12.

The NOV 12 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 12 A.

.Protein Sequence jSSPTCISQVSRPTSKTQRTH HYK IPMEDSHMADTNSHFQEAMDFIGCVRGKGGKVL IVHCΞAGISHSPTSCKSSPMKTRQLC KETFNYIKQRRSMI SNFGFMDQLLQKESEIP ; I STPTPS PLAKRGSRLFTEGHLQILSPGLQDAYCTFPSPVLA VPTHRTV

Further analysis of the NOV 12a protein yielded the following properties shown in Table 12B.

Table 12B. Protein Sequence Properties NOV12a

^; PSort 0.5500 probability located in endoplasmic reticulum (membrane); 0.1900 « analysis: probability located in lysosome (lumen); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOVl 2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 12C.

In a BLAST search of public sequence databases, the NOV 12a protein was found to have homology to the proteins shown in the BLASTP data in Table 12D. Table 12D. Public BLASTP Results for NOV12a

PFam analysis indicates that the NOV 12a protein contains the domains shown in the Table 12E.

Table 12E. Domain Analysis of NOV12a

Identities/

; Pfam Domain NOV12a Match Region Similarities Expect Value for the Matched Region I

DSPc 154..288 55/172 (32%) 1.3e-19 96/172 (56%)

Example 13.

The NOVl 3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 13 A.

■Sequence ^•GGGGGCTTTGGTGAGATCTACGAGGCCATGGACCTGCTGACCAGGGAGAATGTGGCCC

ITCAAGGTGGAGTCAGCCCAGCAGCCCAAGCAGGTCCTCAAGATGGAGGTGGCCGTGCTI

JCAAGAAGTTGCAAGGGAGAGGGAAGGACCATGTGTGCAGGTTCATTGGCTGTGGCAGGJ

[AACGAGAAGTTTAACTATGTAGTGATGCAGCTCCAGGGCCGGAACCTGGCCGACCTGC!

IGCCGTAGCCAGCCGCGAGGCACCTTCACGCTGAGCACCACATTGCGGCTGGGCAAGCA

GATCTTGGAGTCCATCGAGGCCATCCACTCTGTGGGCTTCCTGCACCGTGACATCAAG

CCTTCAAACTTTGCCATGGGCAGGCTGCCCTCCACCTACAGGAAGTGCTATATGCTGG

ACTTCGGGCTGGCCCGGCAGTACACCAACACCACGGGGGATGTGCGGCCCCCTCGGAA

TGTGGCCGGGTTTCGAGGAACGGTTCGCTATGCCTCAGTCAATGCCCACAAGAACCGG

GAGATGGGCCGCCACGACGACCTGTGGTCCCTCTTCTACATGCTGGTGGAGTTTGCAG

TGGGCCAGCTGCCCTGGAGGAAGATCAAGGACAAGGAACAGGTAGGGATGATCAAGGA

GAAGTATGAGCACCGGATGCTGCTGAAGCACATGCCGTCAGAGTTCCACCTCTTCCTG

GACCACATTGCCAGCCTCGACTACTTCACCAAGCCCGACTACCAGTTGATCATGTCAG

TGTTTGAGAACAGCATGAAGGAGAGGGGCATTGCCGAGGATGAGGCCTTTGACTGGGA

GAAGGCAGGCACCGATGCCCTCCTGTCCACGAGCACCTCTACCCCGCCCCAGCAGAAC

ACCCGGCAGACGGCAGCCATGTTTGGGGTGGTCAATGTGACGCCAGTGCCTGGGGACC

TGCTCCGGGAGAACACCGAGGATGTGCTACAGGGAGAGCACCTGAGTGACCAGGAGAA

TGCACCCCCAATTCTGCCCGGGAGGCCCTCTGAGGGGCTGGGCCCCAGTCCCCACCTT

GTCCCCCACCCCGGGGGTCCTGAGGCTGAAGTCTGGGAGGAGACAGATGTCAACCGGA

ACAAACTCCGGATCAACATCGGCAAAGTAACTGCCGCCAGGGCGAAGGGCAGCCCCTG

TGTGGAGGAGGAACAGAGCCGAGGCATGGGGGTCCCCAGCTCCCCAGTGCGTGCCCCC

CCAGACTCCCCCACAACCCCAGTCCGTTCTCTGCGCTACCGGAGGGTGAACAGCCCTG

AGTCAGAAAGGCTGTCCACGGCGGACGGGCGAGTGGAGCTACCTGAGAGGAGGTCACG

GATGGATCTGCCTGGCTCGCCCTCGCGCCAGGCCTGCTCCTCTCAGCCAGCCCAGATG

CTGTCAGTGGACACAGGCCACGCTGACCGACAGGCCAGTGGCCGCATGGACGTGTCAG

CCTCTGTGGAGCAGGAGGCCCTGAGCAACGCCTTCCGCTCGGTGCCGCTGGCTGAGGA

GGAGGATTTCGACAGCAAAGAGTGGGTCATCATCGACAAGGAGACGGAGCTCAAGGAC

TTCCCTCCAGGGGCTGAGCCCAGCACATCGGGCACCACGGATGAGGAGCCCGAGGAGC

TGCGGCCACTGCCCGAGGAGGGCGAAGAGCGGCGGCGGCTGGGGGCAGAGCCCACCGT

CCGGCCCCGGGGACGCAGCATGCAGGCGCTGGCGGAGGAGGACCTGCAGCATTTGCCG

CCCCAGCCCCTGCCACCCCAGCTGAGCCAGGGCGATGGCCGTTCCGAGACGTCACAGC

CCCCCACGCCTGGCAGCCCTTCCCACTCACCCCTGCACTCGGGACCCCGCCCTCGACG

GAGAGAGTCGGACCCCACAGGCCCACAGAGACAGGTGTTCTCCGTGGCGCCCCCATTT

GAGGTGAATGGCCTCCCACGAGCTGTGCCTCTGAGTCTGCCCTACCAGGACTTCAAAA

GAGACCTCTCCGATTACCGAGAACGGGCGCGGTTGCTCAACAGGGTCCGGAGGGTGGG

CTTCTCGCACATGCTGCTCACCACCCCCCAGGTCCCACTGGCTCCTGTTCAGCCTCAG

GCTAATGGGAAGGAGGAAGAGGAGGAGGAGGAGGAAGATGAGGAAGAGGAAGAAGAGG

ATGAGGAAGAAGAAGAGGAGGAAGAGGAAGAGGAGGAGGAAGAAGAGGAGGAGGAGGA

AGAGGAGGAGGAGGCTGCAGCGGCAGTTGCCTTGGGGGAGGTGCTGGGGCCTCGTAGT

GGCTCCAGCAGTGAGGGGAGTGAGAGGAGCACTGACCGGAGCCAGGAGGGTGCCCCGT

CCACGCTGCTGGCAGACGATCAGAAGGAGTCCAGGGGCCGGGCCTCCATGGCCGATGG

GGACCTGGAGCCTGAGGAGGGCTCCAAAACGCTGGTGCTTGTCTCTCCTGGCGACATG

AAGAAGTCGCCCGTCACTGCCGAACTGGCCCCCGACCCCGACCTGGGCACCCTGGCTG

CCCTCACTCCTCAGCATGAGCGGCCCCAGCCCACGGGCAGCCAGCTGGACGTATCTGA

GCCAGGCACCCTGTCCTCTGTCCTCAAGTCTGAGCCCAAGCCCCCGGGGCCTGGGGCA

GGGCTGGGGGCCGGGACAGTGACCACAGGGGTCGGGGGCGTGGCAGTCACCTCCTCAC

CCTTCACCAAAGTTGAGAGGACCTTTGTGCACATTGCGGAGAAAACCCACCTCAACGT

CATGTCTTCCGGTGGACAAGCCTTGCGGTCTGAGGAGTTCAGCGCTGGGGGCGAGCTG

GGTCTGGAGCTGGCCTCTGATGGGGGCGCTGTGGAGGAGGGGGCCCGAGCGCCCCTGG

AGAACGGCCTCGCCCTGTCAGGGCTGAATGGGGCTGAGATAGAGGGCTCTGCCCTGTC

TGGGGCCCCCCGGGAAACCCCCTCAGAGATGGCCACAAACTCACTGCCCAATGGCCCG

GCCCTTGCAGACGGGCCAGCCCCGGTGTCCCCGCTGGAGCCAAGCCCTGAGAAAGTGG

CCACCATCTCCCCCAGACGCCATGCTATGCCAGGCTCTCGCCCCAGGAGCCGTATCCC

TGTCCTGCTCTCTGAGGAGGACACGGGCTCGGAGCCCTCAGGCTCACTGTCGGCCAAA

GAGCGGTGGAGCAAGCGGGCTCGGCCGCAGCAGGACCTGGCGCGGCTGGTGATGGAGA

AGAGGCAGGGCCGCCTGCTGTTGCGGCTGGCCTCAGGGGCCTCGTCCTCCTCCAGTGA

GGAGCAGCGCCGTGCCTCTGAGACCCTCTCAGGCACGGGCTCTGAGGAGGACACGCCC

GCCTCTGAGCCGGCAGCGGCCTTGCCCAGGAAGAGCGGGAGGGCAGCCGCCACCAGGA

GCCGGATTCCCCGCCCCATTGGCCTCCGCATGCCCATGCCTGTTGCAGCCCAGCAGCC

CGCCAGCAGATCCCATGGCGCGGCCCCAGCATTGGACACAGCCATCACCAGCAGGCTC

CAGCTGCAGACGCCCCCAGGGTCGGCCACTGCTGCTGACCTCCGCCCCAAACAACCTC CTGGCCGCGGCCTGGGCCCAGGGCGAGCCCAAGCCGGAGCCAGGCCCCCAGCGCCGCG

CAGCCCGCGCCTCCCCGCGTCCACATCCGCCGCGCGCAATGCCAGCGCGTCCCCCCGG jAGCCAGTCCCTGTCCCGCAGAGAGAGCCCCTCCCCCTCGCACCAGGCCCGGCCCGGGG JTCCCCCCGCCCCGGGGCGTCCCGCCGGCCCGGGCCCAGCCTGATGGCACCCCCTCCCC ^'CGGGGGCTCCAAGAAAGGACCCAGAGGGAAACTCCAGGCTCAGCGCGCAACAACCAAA

GGCCGGGCAGGAGGCGCGGAGGGCCGGGCTGGGGCCAGATAATGACGCCCGCTGCTCT

CCGCGGTCCCCCACCCTCACCCCGGCCCCCCACCCGCAGCCGG

ORF Start: ATG at 49 ORF Stop: TAA at 4042

SEQ ID NO: 30 MW at 143704.5kD

|NOV13a, MQCLAAA KDETNMSGGGEQADILPANYVVKDRWKVLKKIGGGGFGEIYEA DLLTRE CG101758-01 NVA KVESAQQPKQV KMEVAVLKKLQGRGKDHVCRFIGCGRNEKFNYVVMQLQGRNL ADLRRSQPRGTFTLSTT RLGKQILESIEAIHSVGFIαHRDIKPSNFAMGRLPSTYRKC Protein Sequence YMLDFGLARQYTNTTGDVRPPRNVAGFRGTVRYASλ/NAHKNRE GRHDD SLFYMLV EFAVGQLP RKIKDKEQVGMIKEKYEHRMLLKHMPSEFH F DHIASLDYFTKPDYQL IMSVFENSM ERGIAEDEAFD EKAGTDALLSTSTSTPPQQNTRQTAAMFGλAΛ TPV PGD LRENTEDVLQGEH SDQENAPPILPGRPSEGLGPSPHLVPHPGGPEAEVWEETD VNRNK RINIGKVTAARAKGSPCVEEEQSRG GVPSSPVRAPPDSPTTPVRSLRYRRV NSPΞSERLSTADGRVELPERRSRMDLPGSPSRQACSSQPAQMLSVDTGHADRQASGRM DVSASVEQEALSNAFRSVPLAEEEDFDSKE VIIDKETE KDFPPGAΞPSTSGTTDEE PEΞLRPLPEEGΞERRRLGAEPTVRPRGRSMQA AEED QHLPPQP PPQLSQGDGRSΞ TSQPPTPGSPSHSPLHSGPRPRRRESDPTGPQRQVFSVAPPFEVNGLPRAVPLSLPYQ DF RDLSDYRERARLLNRVRRVGFSH TTPQVP APVQPQANGKEEEEEEΞEDEEΞ EEEDEEEEEEEEEEEEEEEΞEEEEEΞEAAAAVALGEVLGPRSGSSSEGSERSTDRSQE GAPST LADD KΞSRGRASMADGD EPEΞGSKT V VSPGDMKKSPVTAEIJAPDPDLG

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 13B.

Further analysis of the NOV13a protein yielded the following properties shown in

Table 13C.

Table 13C. Protein Sequence Properties NOV13a

PSort 0.6000 probability located in nucleus; 0.3000 probability located in microbody analysis: (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOVl 3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 13D.

In a BLAST search of public sequence databases, the NOV 13a protein was found to have homology to the proteins shown in the BLASTP data in Table 13E.

PFam analysis indicates that the NOV 13a protein contains the domains shown in the Table 13F.

Table 13F. Domain Analysis of NOV13a

Identities/

Pfam Domain j NOV13a Match Region Similarities j Expect Value for the Matched Region

, pkinase 34..270 63/273 (23%) 6.1e-32 170/273 (62%)

Example 14.

The NOV 14 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 14A.

I Table 14A. NOV14 Sequence Analysis

TCCGCCACATCTGGAACCTGAAGTTGATGCGTTGGACCCCTGCAGCTGCAGACATCTG CTTCACCAAGGAGCTACACTCCCACTTCTTCAGCTTGGGCAAGTGTGTGCCTGTGTGC CGAGGAGATGGCGTCTACCAGAAGGGGATGGACTTCATTTTGGAGAAGCTCAACCATG GGGACTGGGTGCATATCTTCCCAGAAGGAATCGGGCGCCTGATTGCTGAGTGTCATCT CAACCCCATCATCCTGCCCCTGTGGCATGTCGGAATGAATGACGTCCTTCCTAACAGT CCGCCCTACTTCCCCCGCTTTGGACAGAAAATCACTGTGCTGATCGGGAAGCCCTTCA GTGCCCTGCCTGTACTCGAGCGGCTCCGGGCGGAGAACAAGTCGGCTGTGGAGATGCG GAAAGCCCTGACGGACTTCATTCAAGAGGAATTCCAGCATCTGAAGACTCAGGCAGAG CAGCTCCACAACCACCTCCAGCCTGGGAGATAGGCCTTGCTTGCTGCCTTCTGGATTC

TTGGCCCGCACAGAGCTGGGGCTGAGGGATGGACTGATGCTTTTAGCTCAAACGTGGC

TTTTAGACAGATTTGTTCATAGACCCTCTCAAGTGCCCTCTCCGAGCTGGTAGGCATT

CCAGCTCCTCCGTGCTTCCTCAGTTACACAAAGGACCTCAGCTGCTTCTCCCACTTGG

CCAAGCAGGGAGGAAGAAGCTTAGGCAGGGCTCTCTTTCCTTCTTGCCTTCAGATGTT

CTCTCCCAGGGGCTGGCTTCAGGAGGGAGCATAGAAGGCAGGTGAGCAACCAGTTGGC

TAGGGGAGCAGGAGGGAGCGCGT

ORF Start: ATG at 103 ORF Stop: TAG at 901

SEQ ID NO: 38 266 aa JMW at 30263.0kD

NOV14b, MP HVK PFPAVPPLT T ASSWMGLVGTYSCF TSEWAQAEAGPPGYPCPAGEY N CG101786-04 H TVHNREλr YE IEKRGPATP ITVSlfflQSCMDDPH GILKlRHI lvr KI-MR TPA AADICFTKS HSHFFSLGKCVPVCRGDGVYQKGMDFI EK HGD VHIFPEGIGRLI Protein Sequence AECHLNPIILPLWHVGMNDV PNSPPYFPRFGQKITVLIGKPFSALPV ERLRAE KS AVΞ R ALTDFIQEEFQHLKTQAEQLH H QPGR

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 14B.

Further analysis of the NOV 14a protein yielded the following properties shown in Table 14C.

Table 14C. Protein Sequence Properties NOV14a

PSort 0.5500 probability located in endoplasmic reticulum (membrane); 0.3333 analysis: probability located in lysosome (lumen); 0.3200 probability located in microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 41 and 42 analysis:

A search of the NOV 14a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 14D.

Table 14D. Geneseq Results for NOV14a

In a BLAST search of public sequence databases, the NOV 14a protein was found to have homology to the proteins shown in the BLASTP data in Table 14E.

j (Fruit fly), 378 aa. 118..374 j 150/305 (49%)

Q9V6G5 j TAFAZZIN PROTEIN - Drosophila 1..289 j 110/305 (36%) 4e-47 j melanogaster (Fruit fly), 376 aa. 116..372 j 150/305 (49%)

PFam analysis indicates that the NOV 14a protein contains the domains shown in the Table 14F.

Example 15.

The NOV 15 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 15A.

Table 15A. NOV15 Sequence Analysis iSEQ ID NO: 39 1842 bp

NOV 15a, GCGGCCGCGCTGCCTGGCAGCCCGGGAAGCCGCGGCACAGCTGCTCGGCGCCTGCAGC

CGLOL S^Ό-01 DNA |^{TCCGGCTCGGGGGCTGG}^^CCG^^{GCGGGGGCGGCGGG}^^

- ^*" CGGGGAGAGGCGGAGGGGGTCCCTGGCCTGGGCGGAGAGGCTGAGCTGAGTGCGCGTG i equence AGAAAGAGGGCTGCACCGCTGCTCGGCGCGGACTCTGCCAGCCCCAGCTTCAGCCCCG IGCTCAGGTCGCCGCAGCCCGGGAGCCTCCCCGCTTGCGCCCCAAGGCACGCGCGGCAC

[AGCCATGAACACCAACGATGCCAAGGAGTATCTGGCCCGGAGGGAAATCCCTCAGTTA

TATTTGAGAGCCTTTTGAATGGACTGATGTGTTCTAAGCCCGAAGATCCAGTAGAATA

CTTGGAAAGTTGTTTACAAAAAGTAAAGGAACTGGGTGGCTGTGACAAGGTGAAATGG GATACATTTGTAAGCCAGGAAAAGAAGACCTTACCTCCACTAAATGGAGGACAGTCAC GGAGATCCTTTCTAAGAAATGTAATGCCTGAAAACTCAAACTTTCCATATCGGCGGTA TGACCGGCTCCCTCCAATCCATCAATTCTCCATAGAAAGTGACACGGATCTCTCTGAG ACTGCGGAGTTGATTGAGGAGTATGAGGTTTTTGATCCTACCAGACCTCGACCAAAAA TCATTCTTGTTATAGGTGGTCCAGGAAGTGGAAAGGGTACTCAGAGTTTGAAAATTGC AGAACGATATGGATTCCAATACATTTCTGTGGGAGAATTATTAAGAAAGAAGATCCAC AGTACCAGCAGCAATAGGAAATGGAGTCTTATTGCCAAGATAATTACAACTGGAGAAT TGGCCCCACAGGAAACAACAATTACAGAGATAAAACAAAAATTGATGCAAATACCTGA TGAAGAGGGCATTGTTATTGATGGATTTCCAAGAGATGTTGCCCAGGCTCTATCTTTT GAGGACCAGATCTGTACCCCCGATTTGGTGGTATTCCTGGCTTGTGCTAATCAGAGAC TCAAAGAAAGATTACTGAAGCGTGCAGAACAGCAGGGCCGACCAGACGACAATGTAAA AGCTACCCAAAGGAGACTAATGAACTTCAAGCAGAATGCTGCTCCATTGGTTAAATAC TTCCAGGAAAAGGGGCTCATCATGACATTTGATGCCGACCGCGATGAGGATGAGGTGT TCTATGACATCAGCATGGCAGTTGACAACAAGTTATTTCCAAACAAAGAGGCTGCAGC AGGTTCAAGTGACCTTGATCCTTCGATGATATTGGACACTGGAGAGATCATTGATACA GGATCTGATTATGAAGATCAGGGTGATGACCAGTTAAATGTATTTGGAGAGGACACTA TGGGAGGTTTCATGGAAGATTTGAGAAAGTGTAAAATTATTTTCATAATTGGTGGTCC TGGCTCTGGCAAAGGCACACAGTGTGAAAAGCTGGTGGAAAAATATGGATTTACACAT CTCTCAACTGGCGAGCTCCTGCGTGAGGAACTGGCATCAGAATCTGAAAGAAGCAAAT TGATCAGAGACATTATGGAACGTGGAGACCTGGTGCCCTCAGGCATCGTTTGGAGCTC CTGAAGGAGGCATGGTGGCAGCTCGGGGACACCAGGGGCTTCTGATGACGGTTATCTC GGGAGGGGAAGCAGGGGAAGAGTCGGACGGCAGATGGAGACCAACAGTGGGACTGGAT GGACTGCCCGAAACACCAGACAACGCTTCCAAAGGACGGAGATTGCTGGGAGAACACA ;AAAACAGGAACGCAAGCAAACGAAGGAACCAGGGAGCCCAGAAA jORF Start: ATG at 375 iORF Stop: TGA at 1626

SEQ ID NO: 40 !417 aa MW at 46958.7kD

NOVl 5a, MCSKPEDPVEY ESC QKVKELGGCDKV DTFVSQEKKT PPLNGGQSRRSFLRNVM jCG101826-01 PENSNFPYRRYDRLPPIHQFSIESDTDLSETAE IEEYEVFDPTRPRPKIILVIGGPG SGKGTQSLKIAERYGFQYISVGEL RKKIHSTSSNRK SLIAKIITTGELAPQETTIT

.Protein Sequence ΞIKQK MQIPDEEGIVIDGFPRDVAQALSFEDQICTPDLWFLACANQRLKERL KRA EQQGRPDDNVKATQRRL FKQNAAP VKYFQEKG IMTFDADRDEDEVFYDIS AVD NKLFPNKEAAAGSSDLDPSMILDTGEIIDTGSDYEDQGDDQ VFGEDT GGFMEDLR CKIIFIIGGPGSGKGTQCEKLVEKYGFTHLSTGEL REELASESERSK IRDIMERG D VPSGIVWSS

SEQ ID NO: 41 3309 bp

.NOV 15b, GCGGCCGCGCTGCCTGGCAGCCCGGGAAGCCGCGGCACAGCTGCTCGGCGCCTGCAGC 1CG101826-02 DNA TCCGGCTCGGGGGCTGGAACCGAAGCGGGGGCGGCGGGAGCGCGGAGACCACAGCCCC

ICGGGGAGAGGCGGAGGGGGTCCCTGGCCTGGGCGGAGAGGCTGAGCTGAGTGCGCGTG

Sequence •AGAAAGAGGGCTGCACCGCTGCTCGGCGCGGACTCTGCCAGCCCCAGCTTCAGCCCCG

GCTCAGGTCGCCGCAGCCCGGGAGCCTCCCCGCTTGCGCCCCAAGGCACGCGCGGCAC

AGCCATGAACACCAACGATGCCAAGGAGTATCTGGCCCGGAGGGAAATCCCTCAGCTT

TTTGAGAGCCTTTTGAATGGACTGATGTGTTCTAAGCCCGAAGATCCAGTAGAATACT TGGAAAGTTGTTTACAAAAAGTAAAGGAACTGGGTGGCTGTGACAAGGTGAAATGGGA TACATTTGTAAGCCAGGAAAAGAAGACCTTACCTCCACTAAATGGAGGACAGTCACGG AGATCCTTTCTAAGAAATGTAATGCCTGAAAACTCAAACTTTCCATATCGGCGGTATG ACCGGCTCCCTCCAATCCATCAATTCTCCATAGAAAGTGACACGGATCTCTCTGAGAC TGCAGAGTTGATTGAGGAGTATGAGGTTTTTGATCCTACCAGACCTCGACCAAAAATC ATTCTTGTTATAGGTGGTCCAGGAAGTGGAAAGGGTACTCAGAGTTTGAAAATTGCAG AACGATATGGATTCCAATACATTTCTGTGGGAGAATTATTAAGAAAGAAGATCCACAG TACCAGCAGCAATAGGAAATGGAGTCTTATTGCCAAGATAATTACAACTGGAGAATTG GCCCCACAGGAAACAACAATTACAGAGATAAAACAAAAATTGATGCAAATACCTGATG AAGAGGGCATTGTTATTGATGGATTTCCAAGAGATGTTGCCCAGGCTCTATCTTTTGA GGACCAAATCTGTACCCCCGATTTTGTGGTATTCCTGGCTTGTGCTAATCAGAGACTC AAAGAAAGATTACTGAAGCGTGCAGAACAGCAGGGCCGACCAGACGACAATGTAAAAG CTACCCAAAGGAGACTAATGAACTTCAAGCAGAATGCTGCTCCATTGGTTAAATACTT CCAGGAAAAGGGGCTCATCATGACATTTGATGCCGACCGCGATGAGGATGAGGTGTTC TATGACATCAGCATGGCAGTTGACAACAAGTTATTTCCAAACAAAGAGGCTGCAGCAG GTTCAAGTGACCTTGATCCTTCGATGATATTGGACACTGGAGAGATCATTGATACAGG ATCTGATTATGAAGATCAGGGTGATGACCAGTTAAATGTATTTGGAGAGGACACTATG GGAGGTTTCATGGAAGATTTGAGAAAGTGTAAAATTATTTTCATAATTGGTGGTCCTG GCTCTGGCAAAGGCACACAGTGTGAAAAGCTGGTGGAAAAATATGGATTTACACATCT CTCAACTGGCGAGCTCCTGCGTGAGGAACTGGCATCAGAATCTGAAAGAAGCAAATTG ATCAGAGACATTATGGAACGTGGAGACCTGGTGCCCTCAGGCATCGTTTTGGAGCTCC TGAAGGAGGCCATGGTGGCCAGCCTCGGGGACACCAGGGGCTTCCTGATTGACGGCTA TCCTCGGGAGGTGAAGCAAGGGGAAGAGTTCGGACGCAGGATTGGAGACCCACAGTTG GTGATCTGTATGGACTGCTCGGCAGACACCATGACCAACCGCCTTCTCCAAAGGAGCC GGAGCAGCCTGCCTGTGGACGACACCACCAAGACCATCGCCAAGCGCCTAGAAGCCTA CTACCGAGCGTCCATCCCCGTGATCGCCTACTACGAGACAAAAACACAGCTACACAAG ATAAATGCAGAGGGAACACCAGAGGACGTTTTTCTTCAACTCTGCACAGCTATTGACT CTATTATTTTCTGAAGGCAAAAATGCATGTTTGTTAGAATGGAAACAGAAAAACATTA

AAAAGTTCATTCCTTAACACAATGTTTCAAGTTAAACCTTTTGTGTCACCGCCCCCCA

CCAACCACCACCTCCTAAATCCTGACAGCACTGTTTGCTTCCCAGCTAGACCTGTGTG

AGAGGTGTCTGGAAATCATGCATGGTGTATTTGGGACTATATCAACCTATTCTCCACA

CTTCAGACAACTGTCTGCACTCACGGCACGCACACTTTGTATCATGCAGGCCACACTC

AGAGCTAGTCAGTACATGAACAGTGGTGCGGTGCCAGTCTGTGTCCGTTGTGATCACA

GGCCTTGCTAGACCCTGATCATCTGGTTCTCCTCTCATTAAGCATCCCTAACCCCCAG

TCACACCTTCCTCTTACATACTGTTCCCCAATGGAGGCCCCTGGCATAGGGGACAGCC

CTGGGCATCTTCCTTTGGTGTCTGGCTGTTTTGTCAACTCTCATCCACTGGTGGCTCA

GAGCCATAAGGTGGGTTGATTACACAATGCCTTGTACATGATATAGAGGCATCAAGCA AGTAAAATTTGACAGAAATTTTAAAATATGAAGATGTATAGCTTTCCCAAGATGATGG TAAAACCCAGGTTAGTCATCAGTAACCTTCTCTATTATTATTATTTTTTAGAAACTTG jGAATACTGTCATTATGGCTAAGAGAACAAATCTGATAAATTGTGTAACCTAGTCTCTT1 1CτCTACATGGTGATGCATTTCAGCAATTATAAATTAATATAAATGACCAAAAGTAACTj ϊ AAAAGCATGAGATATTTGCTATTTCATTCATTGGGCACATATCAAATTATAATTTTG1

ATTTTAAATGGTCACCCATGTATTTGTTGCCAAGCAAGTAAAAAAATACeCTAACAAA

CCTGATGTGGGTGGGAGGGGCATGTCAGTAAGTGGTGTGTTCAATGTGTTTGTTTCAT

ATGGGCCCTTTCCAGGAGTTTGCAAACCTTGTCATACCCATATGCAAAACTGTGTTTC

CTTGCATTAAACCAGTGAAGTTTGGGTTCTCTTTTGTGCTATCAATCAGTTGTAAAAT

CAGAGCTTCTTATATATTCTACTGGAATAACTGCATCTTCCACTCAGTCACTACAAAA

AAGCATAGTTTCAGTTTGCATGAATTTTTTTTTTTTTCTTCAATGGTTGTGCAGATAA

GGATCCATTTCTGGGATAGAATTGTATTTTTTAAGTCATTTTTTTTTCTTGAAATGGA

TATGTACAAATAAAATTAAATGGAAGACAGGAAAAAAAAAAAAAAAAAAAAAAAAAAA

AAA

ORF Start: ATG at 295 ORF Stop: TGA at 1984

SEQ ID NO: 42 563 aa MW at 63479.4kD

|NOV15b, NTNDAKEYLARREIPQLFESL NGLMCSKPEDPVEYLESCLQKVKE GGCDKVKWDT iCGl 01826-02 FVSQEKKT PPLNGGQSRRSFLRlvTVMPENSNFPYRRYDRLPPIHQFSIESDTD SETA ELIEEYEVFDPTRPRPKIILVIGGPGSGKGTQSLKIAERYGFQYISVGΞLLRKKIHST i Protein Sequence SSNRK S IAKIITTGELAPQETTITEIKQKLMQIPDEEGIVIDGFPRDVAQALSFED QICTPDFWFLACANQRLKERLLKRAEQQGRPDDNVKATQRRLMNFKQNAAPLVKYFQ EKGLIMTFDADRDEDEVFYDISMAVDNKLFPNKEAAAGSSDLDPSMILDTGEIIDTGS DYEDQGDDQLNVFGEDTMGGFMED RKCKIIFIIGGPGSG GTQCEK VEKYGFTH S TGELLREE ASESΞRS LIRDIMERGDLVPSGIVLE LKEAMVAS GDTRGFLIDGYP REVKQGEEFGRRIGDPQ VICMDCSADTMTNRLLQRSRSS PVDDTTKTIAKRLEAYY RASIPVIAYYETKTQLHKINAΞGTPΞDVFLQLCTAIDSIIF

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 15B.

Table 15B. Comparison of NOVlSa against NOVlSb.

NOVlSa Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV15b 1..414 399/414 (96%) 27..440 399/414 (96%)

Further analysis of the NOV 15a protein yielded the following properties shown in Table 15C.

Table ISC. Protein Sequence Properties NOV15a

PSort 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody analysis: (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOVl 5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 15D.

Table 15D. Geneseq Results for NOV15a ! NOVl 5a Identities/

Geneseq Protein/Organism/Length [Patent i Residues/ Similarities for Expect Identifier #, Date] Match the Matched Value Residues Region

AAU 17301 Novel signal transduction pathway 152..414 263/263 (100%) e-l 49 protein, Seq ID 866 - Homo sapiens, 1..263 263/263 (100%) 386 aa. [WO200154733-A1, 02- AUG-2001]

AAE 11776 Human kinase (PKIN)- 10 protein - 181..414 234/234 (100%) Homo sapiens, 357 aa. 1..234 234/234 (100%) [WO200181555-A2, 01-NOV-2001]

AAU30543 Novel human secreted protein #1034 253..414 160/162 (98%) 3e-88 - Homo sapiens, 297 aa. 3..164 161/162 (98%) [WO200179449-A2, 25-OCT-2001]

AAU 17300 Novel signal transduction pathway 295..414 120/120 (100%) 5e-64 protein, Seq ID 865 - Homo sapiens, 4..123 120/120 (100%) 245 aa. [WO200154733-A1, 02- AUG-2001]

AAU17612 Novel signal transduction pathway 296..414 118/119 (99%) 2e-62 protein, Seq ID 1177 - Homo 1..119 118/1 19 (99%) sapiens, 242 aa. [WO200154733-A1, 02-AUG-2001]

In a BLAST search of public sequence databases, the NOVl Sa protein was found to have homology to the proteins shown in the BLASTP data in Table 15E.

j - Rattus norvegicus (Rat), 194 aa. 7..192 '.7/188 (62%)

P00571 ! Adenylate kinase isoenzyme 1 (EC 105..290 65/187 (34%) le-31 ! 2.7.4.3) (ATP-AMP 7..191 120/187 (63%) ^' transphosphorylase) (AK1)

(Myokinase) - Sus scrofa (Pig), 194 aa.

PFam analysis indicates that the NOVl 5a protein contains the domains shown in the Table 15F.

Example 16.

The NOV 16 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 16A.

Table 16A. NOV16 Sequence Analysis

|SEQ ID NO: 43 3735 bp

NOV 16a, CCACCATGAGCACCGCCGCCTTCCACATCTCCAGCCTCCTGGAGAAGATGACGTCCAG

:CG102061-01 DNA CGACAAGGACTTCAGGTTCATGGCCACCAGCGACCTGATGTCGGAGTTGCAGAAGGAC TCCATCCAGCTGGACGAGGACAGCGAGCGCAAGGTGGTGAAGATGCTGCTCCGGCTCC 'Sequence TGGAGGACAAGAACGGTGAGGTGCAGAACCTGGCTGTCAAGAGCCTGGGTCCTCTGGT GGTCAAAGTGAAGGAGTACCAGGTGGAGACCATTGTGGACACCCTGTGCACCAACATG CGGTCAGACAAGGAGCAGCTGCGAGACATTGCCGGCATTGGCCTCAAGACCGTCCTCT CGGAGCTCCCTCCTGCAGCCACAGGTACCGGGCTGGCCACCAACGTGTGCCGGAAGAT CACAGGCCAGCTCACCAGTGCCATTGCCCAGCAGGAGGATGTGGCTGTGCAGCTGGAA GCCCTGGACATCCTCTCTGACATGCTGAGCAGGTGTGGGGTCCCGCTGGGCGCCTTCC ACGCCAGCCTCCTGCACTGTCTGCTGCCACAGCTGAGCAGCCCGCGCCTGGCGGTGCG CAAGCGGGCGGTCGGAGCGCTTGGCCACCTGGCGGCCGCCTGCAGCACCGACCTCTTC GTCGAGCTCGCTGACCACCTACTGGACCGGCTGCCCGGCCCGCGGGTGCCCACCAGCC CGACTGCCATCCGCACCCTGATCCAATGTTTGGGCAGCGTCGGCCGCCAGGCCGGCCA CCGCCTCGGTAAGCACCTGGACCGCCTGGTGCCCCTGGTGGAGGATTTCTGCAACCTG GATGATGATGAGCTCCGGGAGTCCTGCCTCCAGGCTTTTGAGGCCTTCTTGAGGAGGT GCCCCAAGGAAATGGGTCCTCACGTGCCCAACGTGACCAGCCTCTGCCTCCAATACAT AAAACACGACCCCAACTACAACTACGACAGTGATGAGGATGAGGAGCAGATGGAGACA GAGGATAGTGAATTCAGTGAGCAAGGTAGTGAAGACGAGTACAGCGATGACGATGACA TGAGCTGGAAGGTGCGCCGGGCAGCTGCCAAGTGCATCGCAGCCTTGATCAGCTCGCG GCCTGACCTGCTGCCCGATTTCCACTGCACCCTGGCACCTGTGCTCATCCGCCGCTTC AAAGAACGCGAGGAGAACGTCAAGGCTGACGTCTTCACTGCTTACATCGTGCTGCTGC GGCAAACACAGCCCCCGAAGGGATGGCTGGAGGCCATGGAGGAACCCACCCAGACCGG!

CAGCAACCTCCATATGCTACGTGGACAGGTGCCCCTTGTGGTCAAGGCCCTGCAGCGGI

CAGCTTAAAGATCGGAGCGTCAGAGCCCGCCAGGGATGCTTCAGCCTCCTCACCGAGC

TGGCGGGTGTCCTCCCAGGCAGCCTGGCCGAGCATATGCCTGTGCTGGTATCAGGTAT

CATCTTCTCGCTGGCCGACCGCTCCAGCTCCTCCACCATCCGGATGGATGCCCTGGCC

T'CTTGCAGGGGCTGCTGGGCACCGAACCAGCTGAGGCCTTCCACCCACACTTGCCTA

TCCTCCTGCCACCTGTGATGGCCTGTGTGGCTGACTCTTTCTACAAGATTGCAGCCGA

GGCCCTGGTGGTGCTGCAGGAGCTGGTGCGGGCCCTGTGGCCGCTGCACAGGCCTCGG

ATGCTGGATCCTGAGCCATATGTTGGAGAGATGTCTGCTGTCACCCTGGCGCGACTTC

GTGCCACTGACCTGGACCAGGAGGTGAAGGAGCGGGCCATTTCCTGCATGGGCCACCT

TGTAGGCCACCTGGGTGACCGGCTTGGGGATGACCTGGAGCCCACGTTACTGCTCCTC

CTGGACCGCCTGCGGAATGAGATCACCCGGCTGCCCGCCATCAAGGCGCTTACGCTGG

TGGCCGTATCCCCACTACAGCTTGACCTACAGCCCATCCTGGCCGAGGCACTGCACAT

TCTGGCCTCATTCCTGCGGAAGAACCAGCGGGCTTTGCGACTGGCCACACTGGCAGCC

CTGGACGCCCTGGCCCAGAGCCAGGGCCTCAGCCTCCCACCGTCTGCCGTGCAGGCCG

TGCTGGCTGAGCTGCCTGCCCTGGTCAACGAGAGCGACATGCATGTGGCCCAGCTGGCJ

TGTGGACTTCCTTGCCACAGTGACCCAGGCCCAGCCAGCCTCTTTGGTGGAGGTCAGTI

GGCCCTGTGCTCTCAGAGCTGCTGCGGCTGCTGCGTTCGCCCCTGTTGCCAGCCGGGGJ

TTCTGGCAGCTGCTGAAGGCTTCCTGCAGGCCCTGGTAGGGACCCGTCCCCCGTGTGT;

GGACTATGCCAAACTCATCAGCCTGCTCACTGCGCCTGTTTATGAGCAGGCTGTGGA J

GGTGGGCCTGGCCTGCACAAGCAGGTGTTCCACTCATTGGCCCGGTGTGTGGCAGCCCJ

TCTCAGCTGCCTGTCCCCAAGAGGCGGCAAGCACAGCCAGTCGCCTGGTCTGCGATGCJ

CAGGTCGCCCCACTCCAGCACGGGGGTCAAGGTCCTGGCATTCTTGTCGCTGGCTGAGJ

GTGGGTCAGGTGGCTGGGCCAGGCCACCAGCGGGAGCTGAAGGCGGTGCTCCTGGAAGI

CTTTGGGGTCACCCAGTGAGGATGTGAGGGCTGCAGCCTCGTATGCACTGGGCCGTGT|

GGGTGCTGGCAGCCTGCCCGACTTCCTGCCCTTCCTGCTGGAGCAGATCGAGGCTGAG

CCCCGACGACAGTACCTGCTGCTGCACTCACTCAGGGAGGCCCTGGGGGCCGCCCAGC

CTGACAGCCTGAAGCCCTACGCCGAGGACATCTGGGCCTTGCTGTTCCAGCGCTGCGA

GGGTGCTGAGGAGGGCACCCGGGGGGTGGTGGCCGAGTGCATTGGGAAGCTGGTCCTT

GTGAACCCTTCGTTCCTTCTGCCCCGCTTGCGGAAGCAGCTTGCTGCAGGTAGGCACA

CAGGTGTGGGCAAGGCAGCCCACCTCGGAGGTGGGCAGTTTGCCACTGAGCATCCACA

TCCCATTGACCCCCTCCTGAAGAGCTTCATCGGAGAGTTCATGGAGAGCCTGCAGGAC

CCAGACCTGAACGTGCGCCGTGCGACTCTGGCTTTCTTCAACTCAGCTGTGCACAACA

AGCCCTCGCTAGTCCGGGACCTGCTGGATGACATCCTGCCCCTCCTCTACCAGGAGAC

AAAGATCCGGCGGGACCTCATCCGAGAGGTGGAGATGGGGCCCTTTAAACATACAGTG

GACGATGGGCTGGACGTGCGGAAGGCGGCCTTTGAATGCATGTATTCACTGCTTGAGA

GCTGCCTGGGCCAGCTGGATATCTGTGAGTTCCTGAACCATGTGGAGGACGGGCTGAA

GGACCACTACGACATCCGGATGCTGACCTTCATCATGGTTGCCCGGCTGGCCACCCTG

TGTCCTGCACCTGTCCTGCAGAGGGTGGACCGACTCATTGAGCCACTAAGGGCCACCT

GCACTGCCAAGGTAAAAGCTGGTTCTGTGAAGCAGGAGTTTGAAAAGCAAGATGAACT

GAAGCGCTCTGCAATGAGGGCAGTGGCTGCCCTGCTGACCATCCCCGAGGTGGGGAAA

AGCCCCATCATGGCCGACTTCTCTTCCCAAATCAGATCCAACCCTGAACTTGCTGCCC

TCTTTGAAAGCATCCAGAAGGATTCCGCTTCAGCCCCCAGCACAGACTCAATGGAGCT

CAGCTAGTCCCCTCAGCACCAAG

ORF Start: ATG at 6 | ORF Stop: TAG at 3717

SEQ ID NO: 44 | 1237 aa MW at l35117.0kD

NOV 16a, ^' MSTAAFHISSLLEKMTSSDKDFRFMATSDLMSE QKDSIQLDEDSERKV'KMLLR LE CG102061-01 DKNGEVQN AVKSLGP λΛKVKEYQVETIVDTLCTNMRSDKEQLRDIAGIGLKTVLSE LPPAATGTGLATNVCRKITGQLTSAIAQQEDVAVQLEALDILSD LSRCGVPLGAFHA Protein Sequence SLLHCLLPQ SSPRLAVRKRAVGALGHLAAACSTDLFVELADH DR PGPRVPTSPT AIRT IQC GSVGRQAGHRLGKHLDRLVPLVΞDFCN DDDE RESCLQAFEAFLRRCP KEMGPHVPNVTSLCLQYIKHDPNYNYDSDΞDEEQMETEDSEFSEQGSEDEYSDDDD S WKVRRAAAKCIAALISSRPD LPDFHCT APVLIRRFKEREENVKADVFTAYIV LRQ TQPPKGW EAMEEPTQTGSNLHMLRGQVPLWKALQRQLKDRSVRARQGCFSLLTELA GVLPGSLAEHMPVLVSGIIFSLADRSSSSTIRMDALAFLQG GTEPAEAFHPHLPIL LPPVMACVADSFYKIAAEALWLQΞLVRAL P HRPRMLDPEPYVGEMSAVTLAR RA TDLDQEVKERAISCMGHLVGH GDRLGDDLEPTLLL LDRLRNEI RLPAlKALTLVA VSP QLD QPILAEALHILASFLRKNQRALRLATLAALDALAQSQGLSLPPSAVQAVL AELPALV ESDMHVAQLAVDFLATVTQAQPAS VEVSGPV SELLR LRSPLLPAGVL JAAAEGF QALVGTRPPCVDYAKLISL TAPVYEQAVDGGPGLHKQVFHSLARCVAALS J

AACPQEAASTASR VCDARSPHSSTGVKVLAFLSLAEVGQVAGPGHQREL AVLLEALI

GSPSEDVRAAASYALGRVGAGSLPDFLPF LEQIEAEPRRQYLL HSLREAGAAQPD

SLKPYAEDI ALLFQRCΞGAΞEGTRGWAECIGKVVNPSFLLPRLRKQLAAGRHTG

VGKAAH GGGQFATΞHPHPIDPLLKSFIGEFMESLQDPDLNVRRATLAFFNSAVΉNKP

SLVRD LDDILPLLYQETKIRRDLIREVEMGPFKHTVDDG DVRKAAFECMYS ESC GQLDICEF NHVEDG DHYDIRM TFIMVARLATLCPAPVLQRVDRLIEPLRATCT

AKVKAGSVKQEFEKQDELKRSAMRAVAAL TIPEVGKSPIMADFSSQIRSNPELAALF

ESIQKDSASAPSTDSMELS

SEQ ID NO: 45 3381 bp

;NOV16b, CCACCATGAGCACCGCCGCCTTCCACATCTCCAGCCTCCTGGAGAAGATGACGTCCAG

;CG102061-02 DNA CGACAAGGACTTCAGGTTCATGGCCACCAGCGACCTGATGTCGGAGTTGCAGAAGGAC

'Sequence TCCATCCAGCTGGACGAGGACAGCGAGCGCAAGGTGGTGAAGATGCTGCTCCGGCTCC

TGGAGGACAAGAACGGTGAGGTGCAGAACCTGGCTGTCAAGTGGCTGGGTGTCCCGCT

GGGCGCCTTCCACGCCAGCCTCCTGCACTGTCTGCTGCCACAGCTGAGCAGCCCGCGC

CTGGCGGTGCGCAAGCGGGCGGTCGGAGCGCTTGGCCACCTGGCGACCGCCTGCAGCA

CCGACCTCTTCGTCGAGCTCGCTGACCACCTACTGGACCGGCTGCCCGGCCCGCGGGT

GCCCACCAGCCCGACTGCCATCCGCACCCTGATCCAATGTTTGGGCAGCGTCGGCCGC

CAGGCCGGCCACCGCCTCGGGGCTCACCTGGACCGCCTGGTGCCCCTGGTGGAGGATT

TCTGCAACCTGGATGATGATGAGCTCCGGGAGTCCTGCCTCCAGGCTTTTGAGGCCTT

CTTGAGGAAGTGCCCCAAGGAAATGGGTCCTCACGTGCCCAACGTGACCAGCCTCTGC

CTCCAATACATAAAACACGACCCCAACTACAACTACGACAGTGATGAGGATGAGGAGC

JAGATGGAGACAGAGGATAGTGAATTCAGTGAGCAAGAGAGTGAAGACGAGTACAGCGA

TGACGATGACATGAGCTGGAAGGTGCGCCGGGCAGCTGCCAAGTGCATCGCAGCCTTG

ATCAGCTCGCGGCCTGACCTGCTGCCCGATTTCCACTGCACCCTGGCACCTGTGCTCA

TCCGCCGCTTCAAAGAACGCGAGGAGAACGTCAAGGCTGACGTCTTCACTGCTTACAT

_JCGTGCTGCTGCGGCAAACACGGCCCCCGAAGGGATGGCTGGAGGCCATGGAGGAACCC

JACCCAGACCGGCAGCAACCTCCATATGCTACGTGGACAGGTGCCCCTTGTGGTCAAGG

JCCCTGCAGCGGCAGCTTAAAGATCGGAGCGTCAGAGCCCGCCAGGGATGCTTCAGCCT

JCCTCACCGAGCTGGCGGGTGTCCTCCCAGGCAGCCTGGCCGAGCATATGCCTGTGCTG

JGTATCAGGCATCATCTTCTCGCTGGCCGACCGCTCCAGCTCCTCCACCATCCGGATGG

_JATGCCCTGGCCTTCTTGCAGGGGCTGCTGGGCACCGAACCAGCTGAGGCCTTCCACCC

JACACTTGCCTATCCTCCTGCCACCTGTGATGGCCTGTGTGGCTGACTCTTTCTACAAG

JATTGCAGCCGAGGCCCTGGTGGTGCTGCAGGAGCTGGTGCGGGCCCTGTGGCCGCTGC

JACAGGCCTCGGATGCTGGATCCTGAGCCATATGTTGGAGAGATGTCTGCTGTCACCCT

JGGCGCGACTTCGTGCCACTGACCTGGACCAGGAGGTGAAGGAGCGGGCCATTTCCTGC

IATGGGCCACCTTGTAGGCCACCTGGGTGACCGGCTTGGGGATGACCTGGAGCCCACGT

TACTGCTCCTCCTGGΆCCGCCTGCGGAATGAGATCACCCGGCTGCCCGCCATCAAGGC

GCTTACGCTGGTGGCCGTATCCCCACTACAGCTTGACCTACAGCCCATCCTGGCCGAG

GCACTGCACATTCTGGCCTCATTCCTGCGGAAGAACCAGCGGGCTTTGCGACTGGCCA

CACTGGCAGCCCTGGACGCCCTGGCCCAGAGCCAGGGCCTCAGCCTCCCACCGTCTGC

CGTGCAGGCCGTGCTGGCTGAGCTGCCTGCCCTGGTCAACGAGAGCGACATGCATGTG

GCCCAGCTGGCTGTGGACTTCCTTGCCACAGTGACCCAGGCCCAGCCAGCCTCTTTGG

TGGAGGTCAGTGGCCCTGTGCTCTCAGAGCTGCTGCGGCTGCTGCGTTCGCCCCTGTT

GCCAGCCGGAGTTCTGGCAGCTGCTGAAGGCTTCCTGCAGGCCCTGGTAGGGACCCGT

CCCCCGTGTGTGGACTATGCCAAACTCATCAGCCTGCTCACTGCGCCTGTTTATGAGC

AGGCTGTGGATGGTGGGCCTGGCCTGCACAAGCAGGTGTTCCACTCATTGGCCCGGTG

TGTGGCAGCCCTCTCAGCTGCCTGTCCCCAAGAGGCGGCAAGCACAGCCAGTCGCCTG

GTCTGCGATGCCAGGTCGCCCCACTCCAGCACGGGGGTCAAGGTCCTGGCATTCTTGT

CGCTGGCTGAGGTGGGTCAGGTGGCTGGGCCAGGCCCCCAGCGGGAGCTGAAGGCGGT

GCTCCTGGAAGCTTTGGGGTCACCCAGTGAGGATGTGAGGGCTGCAGCCTCGTATGCA

CTGGGCCGTGTGGGTGCTGGCAGCCTGCCCGACTTCCTGCCCTTCCTGCTGGAGCAGA

TCGAGGCTGAGCCCCGACGACAGTACCTGCTGCTGCACTCACTCAGGGAGGCCCTGGG

GGCCGCCCAGCCTGACAGCCTGAAGCCCTACGCCGAGGACATCTGGGCCTTGCTGTTC

CAGCGCTGCGAGGGTGCTGAGGAGGGCACCCGGGGGGTGGTGGCCGAGTGCATTGGGA

AGCTGGTCCTTGTGAACCCTTCGTTCCTTCTGCCCCGCTTGCGGAAGCAGCTTGCTGC

AGGTCGGCCACACACCCGGAGCACCGTCATCACAGCGGTCAAGTTCCTTATCTCGGAC

CAGCCCCATCCCAT_TG_ACCCCCTCCTGAAGAGCTTCATCGCTGTGCACAACAAGCCCT

CGCTAGTCCGGGAC_CTGC_TGGATGACATCCTGCCCCTCCTCTACCAGGAGACAAAGAT

CCGGCGGGACCTCA_TCCG_AGAGGTGGAGATGGGGCCCTTTAAACATACAGTGGACGAT JGGGCTGGACGTGCGGAAGGCGGCCTTTGAATGCATGTATTCACTGCTTGAGAGCTGCC ITGGGCCAGCTGGATATCTGTGAGTTCCTGAACCATGTGGAGGACGGGCTGAAGGACCA ICTACGACATCCGGATGCTGACCTTCATCATGGTTGCCCGGCTGGCCACCCTGTGTCCT JGCACCTGTCCTGCAGAGGGTGGACCGACTCATTGAGCCACTAAGGGCCACCTGCACTG ^'CCAAGGTCAAAGCTGGTTCTGTGAAGCAGGAGTTTGAAAAGCAAGATGAACTGAAGCG CTCTGCAATGAGGGCAGTGGCTGCCCTGCTGACCATCCCCGAGGTGGGGAAAAGCCCC ATCATGGCCGACTTCTCTTCCCAAATCAGATCCAACCCTGAACTTGCTGCCCTCTTTG AAAGCATCCAGAAGGATTCCGCTTCAGCCCCCAGCACAGACTCAATGGAGCTCAGCTA GTCCCCTCAGCACCAAG

ORF Start: ATG at 6 ORF Stop: TAG at 3363

SEQ ID NO: 46 ! H 19 aa jMW at 122680.0kD

NOV 16b, STAAFHISS LEKMTSSDKDFRFMATSDLMSELQKDSIQLDEDSERKWKM RLLE CG102061-02 DKNGΞVQNLAVKWLGVPLGAFHASLLHCLLPQLSSPRLAVRKRAVGA GHLATACSTD L'VELADH LDRLPGPRVPTSPTAIRTLIQCLGSVGRQAGHR GAHLDR VPLVEDFC Protein Sequence NLDDDE RESCLQAFEAF RKCPKE GPHVPNVTS CLQYIKHDPNYNYDSDEDΞEQM ETEDSEFSEQΞSEDEYSDDDDMSWKVRRAAAKCIAALISSRPDLLPDFHCTLAPVLIR RFKΞREENVKADVFTAYIVLLRQTRPPKG LEAMEEPTQTGSNLHMLRGQVPLW AL QRQLKDRSVRARQGCFS TE AGV PGS AEHMPVLVSGIIFS ADRSSSSTIRMDA AF QGLLGTEPAEAFHPHLPILLPPλMACVADSFYKIAAEA WLQELVRAL PLHR PRMLDPEPYVGΞMSAVTLARLRATDLDQEVKERAISCMGHLVGHLGDRLGDDLΞPTLL LLLDRLRNEITRLPAIKA TLVAVSPLQLDLQ ILAEALHI ASFLRKNQRALRLATL AALDALAQSQGLSLPPSAVQAVLAELPALVNESDMHVAQLAVDFLATVTQAQPASLVE VSGPVLSELLRLLRSPLLPAGVLAAAEGFLQALVGTRPPCVDYAKLISLLTAPVYEQA VDGGPGLHKQVFHSLARCVAALSAACPQEAASTASRLVCDARSPHSSTGVKVLAFLSL AEVGQVAGPGPQRELKAVLLEALGSPSEDVRAAASYALGRVGAGSLPDFLPFLLEQIE AEPRRQYLLLHSLREALGAAQPDSLKPYAEDIWALLFQRCEGAEEGTRGWAECIGKL VLVNPSFLLPRLRKQLAAGRPHTRSTVITAVKFLISDQPHPIDPLLKSFIAVHNKPSL VRDLLDDILPLLYQETKIRRDLIREVEMGPFKHT-VDDGLDVRKAAFECMYSLLESCLG QLDICΞFLNHVEDGLKDHYDIRMLTFIMVARLATLCPAPVLQRVDRLIΞPLRATCTAK VKAGSVKQEFEKQDΞLKRSAMRAVAALLTIPEVGKSPIMADFSSQIRSNPELAALFES j IQKDSASAPSTDS ELS

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 16B.

Table 16B. Comparison of NOVlόa against NOVlόb.

NOVlόa Residues/ ! Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOVlόb 166..1237 941/1074 (87%) 73..1119 949/1074 (87%)

Further analysis of the NOV 16a protein yielded the following properties shown in Table 16C.

Table 16C. Protein Sequence Properties NOVlόa

PSort 0.4590 probability located in mitochondrial matrix space; 0.3000 probability analysis: located in microbody (peroxisome); 0.1547 probability located in mitochondrial inner membrane; 0.1547 probability located in mitochondrial intermembrane space

SignalP No Known Signal Sequence Indicated analysis: A search of the NOVlόa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 16D.

In a BLAST search of public sequence databases, the NOVlόa protein was found to have homology to the proteins shown in the BLASTP data in Table 16E.

norvegicus (Rat). 1273 aa.

Q9R0L3 TIP 120-FAMILY PROTEIN ' 25..1237 1082/1217 (88%) 0.0 i TIP120B. SHORT FORM - Rattus 1..1211 1131/1217 (92%) ^' norvegicus (Rat), 1211 aa.

075155 ! KIAA0667 PROTEIN - Homo 166..1237 1026/1074 (95%) 0.0 j sapiens (Human), l l l l aa 65..1111 1034/1074 (95%) ; (fragment).

Q9P0H7 i TIP 120 PROTEIN - Homo sapiens 1..1237 763/1239 (61%) 0.0 j (Human), 1230 aa. 1..1230 985/1239 (78%)

PFam analysis indicates that the NOVlόa protein contains the domains shown in the Table 16F.

Table 16F. Domain Analysis of NOVlόa

Identities/ iPfam Domain NOVlόa Match Region i Similarities , Expect Value

, for the Matched Region

No Significant Matches Found

Example 17.

The NOV 17 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 17A.

NOV 17b, CCTTTGGTCTGATCCATGCACAAGGCGGGGCTGCTAGGCCTCTGTGCCCGGGCTTGGA

: CGI 02102-02 DNA ATTCGGTGCGGATGGCCAGCTCCGGGATGACCCGCCGGGACCCGCTCGCAAATAAGGT GGCCCTGGTAACGGCCTCCACCGACGGGATCGGCTTCGCCATCGCCCGGCGTTTGGCC

'Sequence CAGGACGGGGCCCATGTGGTCGTCAGCAGCCGGAAGCAGCAGAATGTGGGCCAGGCGG TGGCCACGCTGCAGGGGGAGGGGCTGAGCGTGACGGGCACCGTGTGCCATGTGGGGAA GGCGGAGGACCGGGAGCGGCTGGTGGCCACGCTCTGGATGGACAAGGAAAAAGAGGAA AGCATGAAAGAAACCCTGCGGATAAGAAGGTTAGGCGAGCCAGAGGATTGTGCTGGCA TCGTGTCTTTCCTGTGCTCTGAAGATGCCAGCTACATCACTGGGGAAACAGTGGTGGT GGGTGGAGGAACCCCGTCCCGCCTCTGAGGACCGGGAGACAGCCCACAGGCCAGAGTT

GGGCTCTAGCTCCTGGTGCTGTTCCTGCATTCACCCACTGGCCCTTCCCACCTCTGCT

CACTTA

ORF Start: ATG at 16 ORF Stop: TGA at 490

SEQ ID NO: 50 158 aa jMW at l6827.1kD

NOV 17b, MHKAGLLGLCARA NSVRMASSG TRRDPLANKVALVTASTDGIGFAIARRLAQDGAH j CGI 02102-02 VWSSR QQNVGQAVATLQGEGLSVTGTVCHVGKAEDRERLVATLWMDKΞKEESMKETj LRIRRLGEPΞDCAGIVSFLCSEDASYITGETVWGGGTPSRL Protein Sequence

SEQ ID NO: 51 1842 bp

NOV 17c, TGGTCTGATCCATGCACAAGGCGGGGCTGCTAGGCCTCTGTGCCCGGGCTTGGAATTC

CGI 02102-03 DNA GGTGCGGATGGCCAGCTCCGGGATGACCCGCCGGGACCCGCCCGCAAATAAGGTGGCC CTGGTAACGGCCTCCACCGACGGGATCGGCTTCGCCATCGCCCGGCGTTTGGCCCAGG

; Sequence ACGGGGCCCATGTGGTCGTCAGCAGCCGGAAGCAGCAGAATGTGGACCAGGCGGTGGC CACGCTGCAGGGGGAGGGGCTGAGCGTGACGGGCACCGTGTGCCATGTGGGGAAGGCG GAGGACCGGGAGCGGCTGGTGGCCACGACTCTGGACATTAATGTGAAGGCCCCAGCCC TGATGACAAAGGCAGTGGTGCCAGAAATGGAGAAACGAGGAGGCGGCTCAGTGGTGAT CGTGTCTTCCATAGCAGCCTTCAGTCCATCTCCTGGCTTCAGTCCTTACAATGTCAGT AAAACAGCCTTGCTGGGCCTGACCAAGACCCTGGCCATAGAGCTGGCCCCAAGGAACA TTAGGGTGAACTGCCTAGCACCTGGACTTATCAAGACTAGCTTCAGCAGGATGCTCTG GATGGACAAGGAAAAAGAGGAAAGCATGAAAGAAACCCTGCGGATAAGAAGGTTAGGC JGAGCCAGAGGATTGTGCTGGCATCGTGTCTTTCCTGTGCTCTGAAGATGCCAGCTACA 'TCACTGGGGAAACAGTGGTGGTGGGTGGAGGAACCCCGTCCCGCCTCTGAGGACCGGG iAGACAGCCCACAGGCCAGAGTTGGGCTCTAGCTCCTGGTGCTGTTCCTGCATTCACCC

ACTGGCCCTTCCCACCTCTGCTCACTTACT

ORF Start: ATG at 12 IORF Stop: TGA at 744

SEQ ID NO: 52 1244 aa MW at 25865.6kD

'NOV 17c, MHKAGL GLCARA NSVRMASSGMTRRDPPAN VA VTASTDGIGFAIARRLAQDGAH ICG102102-03 AΛ VSSRKQQNλ/DQAVAT QGEGLSVTGTVCHVG AEDRERLVATTLDINVKAPALMT AWPEMEKRGGGSWIVSS IAAFSPSPGFSPYNVSKTALLG TKTLAIELAPRNIRVN Protein Sequence CLAPGLIKTSFSRMLWMDKEKEESMKETLRIRRLGEPEDCAGIVSFLCSEDASYITGE TVWGGGTPSRL

SEQ ID NO: 53 (700 bp

NOV17d, GAACCCATACTTGCTGGTCTGATCCATGCAGATGGCCAGGCTGCTAGGCCTCTGTGCC

CGI 02102-04 DNA CGGGCACGGAATTCGGTGCGGATGGCCAGCTCCGGGATGACCCGCCGGGACCCGCTCG CAAATAGGGTGGCCCTGGTAACGGCCTCCACCGACGGGATCGGCTTCGCCATCGCCCG

Sequence GCGTTTGGCCCAGGACGGGGCCCATGTGGTCGTCAGCAGCCGGAAGCAGCAGAATGTG GACCAGGCGGTGGCCACGCTGCAGGGGGAGGGGCTGAGCGTGACGGGCACCGTGTGCC ATGTGGGGAAGGCGGAGGACCGGGAGCGGCTGGTGGCCACGGCTGTGAAGCTTCATGG AGGTATCGATATCCTAGTCTCCAATGCTGCTGTCAACCCTTTCTTTGGAAGCATAATG GATGTCACTGAGGAGGTGTGGGACAAGCTCTGGATGGACAAGGAAAAAGAGGAAAGCA TGAAAGAAACCCTGCGGATAAGAAGGTTAGGCGAGCCAGAGGATTGTGCTGGCATCGT GTCTTTCCTGTGCTCTGAAGATGCCAGCTACATCACTGGGGAAACAGTGGTGGTGGGT GGAGGAACCCCGTCCCGCCTCTGAGGACCGGGAGACAGCCCACAGGCCAGAGTTGGGC TCTAGCTCCTGGTGCTGTTCCTGCATTCACCCACTGGCCTTTCCCACCTCTGCTCACT TACT

ORF Start: ATG at 26 ORF Stop: TGA at 602 J SEQ ID N0: 54 [ 192 aa MW at 20631.4kD

NOV17d, MQMARL GLCARARNSVRMASSGMTRRDPLANRVA VTASTDGIGFAIARR AQDGAH : CGI 02102-04 λAASSRKQQ VDQAVATLQGEG SVTGTVCHVGKAEDRERLVATAVKLHGGIDI VSN AAVNPFFGSIMDVTEEWDKLWMDKEKEESMKETLRIRRLGEPEDCAGIVSFLCSEDA Protein Sequence SYITGETWVGGGTPSR

SEQ ID NO: 55 1579 bp

;NOV17e, TGATCCATGCACAAGGCGGGGCTGCTAGGCCTCTGTGCCCGGGCTTGGAATTCGGTGC j CGI 02102-06 DNA GGATGGCCAGCTCCGGGATGACCCGCCGGGACCCGCTCGCAAATAAGGTGGCCCTGGT AACGGCCTCCACCGACGGGATCGGCTTCGCCATCGCCCGGCGTTTGGCCCAGGACGGG

[Sequence GCCCATGTGGTCGTCAGCAGCCGGAAGCAGCAGAATGTGGACCAGGCGGTGGCCACGC TGCAGGGGGAGGGGCTGAGCGTGACGGGCACCGTGTGCCATGTGGGGAAGGCGGAGGA CCGGGAGCGGCTGGTGGCCACGCTCTGGATGGACAAGGAAAAAGAGGAAAGCATGAAA GAAACCCTGCGGATAAGAAGGTTAGGCGAGCCAGAGGATTGTGCTGGCATCGTGTCTT TCCTGTGCTCTGAAGATGCCAGCTACATCACTGGGGAAACAGTGGTGGTGGGTGGAGG AACCCCGTCCCGCCTCTGAGGACCGGGAGACAGCCCACAGGCTAGAGTTGGGCTCTAG

CTCCTGGTGCTGTTCCTGCATTCACCCACTGGCCCTTCCCACCTCTGCTCACTTACT

ORF Start: ATG at 7 IORF Stop: TGA at 481

SEQ ID NO: 56 158 aa jMW at 16885. lkD

NOV17e, MHKAGLLG CARAWNSVRMASSGMTRRDPLANKVA VTASTDGIGFAIARRLAQDGAH ■ CGI 02102-06 VWSSRKQQNVDQAVATLQGEGLSVTGTVCHVGKAEDRERLVATLWMDKEKΞESMKET LRIRRLGEPEDCAGIVSFLCSEDASYITGETWVGGGTPSRL ! Protein Sequence

SEQ ID NO: 57 789 bp

,NOV17f, TGGTCTGATCCATGCACAAGGCGGGGCTGCTAGGCCTCTGTGCCCGGGCTTGGAATTC j CGI 02102-07 DNA GGTGCGGATGGCCAGCTCCGGGATGACCCGCCGGGACCCGCCCGCAAATAAGGTGGCC CTGGTAACGGCCTCCACCGACGGGATCGGCTTCGCCATCGCCCGGCGTTTGGCCCAGG

! Sequence ACGGGGCCCATGTGGTCGTCAGCAGCCGGAAGCAGCAGAATGTGGACCAGGCGGTGGC ICACGCTGCAGGGGGAGGGGCTGAGCGTGACGGGCACCGTGTGCCATGTGGGGAAGGCG GAGGACCGGGAGCGGCTGGTGGCCACGACTCTGGACATTAATGTGAAGGCCCCAGCCC TGATGACAAAGGCAGTGGTGCCAGAAATGGAGAAACGAGGAGGCGGCTCAGTGGTGAT CGTGTCTTCCATAGCAGCCTTCAGTCCATCTCCTGGCTTCAGTCCTTACAATGTCAGT AAAACAGCCTTGCTGGGCCTGGCCAAGACCCTGGCCATAGAGCTGGCCCCAAGGAACA TTAGGGTGAACTGCCTAGCACCTGGACTTATCAAGACTAGCTTCAGCAGGATGCTCTG GATGGACAAGGAAAAAGAGGAAAGCATGAAAGAAACCCTGCGGATAAGAAGGTTAGGC GAGCCAGAGGATTGTGCTGGCATCGTGTCTTTCCTGTGCTCTGAAGATGCCAGCTACA TCACTGGGGAAACAGTGGTGGTGGGTGGAGGAACCCCGTCCCGCCTCTGAGGACCGGG AGACAGCCCACAGGCCAGAGTTGGGATCTAGCTAC

ORF Start: ATG at 12 {ORF Stop: TGA at 744 jSEQ ID NO: 58 1244 aa MW at 25835.6kD

NOV17f, I MH AGLLGLCARAWNSVRMAS SGMTRRDPPANKVALVTASTDGIGFAIARR AQDGAH |CG102102-07 jλAAtSSRKQQlNTVDQAVAT QGEGLSVTGTVCHVGKΑEDRERLVATTLDI VKAPALMT

JAλA/PEME RGGGSWIVSSIAAFSPSPGFSPYNVSKTALLGLAKTLAIELAPRNIRVN ; Protein Sequence CLAPGLIKTSFSRMLWMDKEKEESMKETLRIRRLGEPEDCAGIVSFLCSEDASYITGE

I TVWGGGTPSRL

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 17B.

1..158 146/192 (76%)

Further analysis of the NOV 17a protein yielded the following properties shown in Table 17C.

Table 17C. Protein Sequence Properties NOV17a

PSort 0.5500 probability located in endoplasmic reticulum (membrane); 0.5000 : analysis: probability located in microbody (peroxisome); 0.1900 probability located in lysosome (lumen); 0.1000 probability located in endoplasmic reticulum (lumen)

; SignalP Cleavage site between residues 23 and 24 i analysis:

A search of the NOVl 7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 17D.

AAU30722 j Novel human secreted protein #1213 - 1..136 136/136 (100%) 3e-72 Homo sapiens, 477 aa. I 1..136 136/136 (100%)

[WO200179449-A2, 25-OCT-2001] j

In a BLAST search of public sequence databases, the NOV 17a protein was found to have homology to the proteins shown in the BLASTP data in Table 17E.

PFam analysis indicates that the NOV 17a protein contains the domains shown in the Table 17F.

Example 18.

The NOVl 8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 18A.

Table 18A. NOV18 Sequence Analysis

SEQ ID NO: 59 j2559 bp iNOVlδa, ATGTCATCAGTGAGCCCCATCCAGATCCCCAGTCGCCTCCCGCTGCTGCTCACCCACG JCG102554-01 DNA AGGGCGTCCTGCTGCCCGGCTCCACCATGCGCACCAGCGTGGACTCGGCCCGCAACCT GCAGCTGGTGCGGAGCCGCCTTCTGAAGGGCACGTCGCTGCAAAGCACCATCCTGGGC

.Sequence , GTCATCCCCAACACGCCTGACCCCGCCAGCGACGCGCAGGACCTGCCGCCGCTGCACA GGATTGGCACAGCTGCACTGGCCGTTCAGGTTGTGGGCAGTAACTGGCCCAAGCCCCA CTACACTCTGTTGATTACAGGCCTATGCCGTTTCCAGATTGTACAGGTCTTAAAAGAG AAGCCATATCCCATTGCTGAAGTGGAGCAGTTGGACCGACTTGAGGAGTTTCCCAACA CCTGTAAAATGAGGGAGGAGCTAGGAGAACTATCAGAGCAGTTTTACAAATATGCAGT ACAATTGGTTGAAATGTTGGATATGTCTGTCCCTGCAGTTGCTAAATTGAGACGTCTT TTAGATAGTCTTCCAAGGGAAGCTTTACCAGACATCTTGACATCAATTATCCGAACAA GCAACAAAGAGAAACTCCAGATTTTAGATGCTGTGAGCCTAGAGGAGCGGTTCAAGAT GACTATACCACTGCTTGTCAGACAAATTGAAGGCCTGAAATTGCTTCAAAAAACCAGA AAACCCAAGCAAGATGATGATAAGAGGGTTATAGCAATACGCCCTATTAGGAGAATTA CACATATCTCAGGTACTTTAGAAGATGAAGATGAAGATGAAGATAATGATGACATTGT CATGCTAGAGAAAAAAATACGAACATCTAGTATGCCAGAGCAGGCCCATAAAGTCTGT GTCAAAGAGATAAAGAGACTCAAAAAAATGCCTCAGTCAATGCCAGAATATGCTCTGA CTAGAAATTATTTGGAACTTATGGTAGAACTTCCTTGGAACAAAAGTACAACTGACCG CCTGGACATTAGGGCAGCCCGGATTCTTCTGGATAATGACCATTACGCCATGGAAAAA TTGAAGAAAAGAGTACTGGAATACTTGGCTGTCAGACAGCTCAAAAATAACCTGAAGG GCCCAATCCTATGCTTTGTTGGCCCTCCTGGAGTTGGTAAAACAAGTGTGGGAAGATC AGTGGCCAAGACTCTAGGTCGAGAGTTCCACAGGATTGCACTTGGAGGAGTATGTGAT CAGTCTGACATTCGAGGACACAGGCGCACCTATGTTGGCAGCATGCCTGGTCGCATCA TCAACGGCTTGAAGACTGTGGGAGTGAACAACCCAGTGTTCCTATTAGATGAGGTTGA CAAACTGGGAAAAAGTCTACAGGGTGATCCAGCAGCAGCTCTGCTTGAGGTGTTGGAT CCTGAACAAAACCATAACTTCACAGATCATTATCTAAATGTGGCCTTTGACCTTTCTC AAGTTCTTTTTATAGCTACTGCCAACACCACTGCTACCATTCCAGCTGCCTTGTTGGA CAGAATGGAGATCATTCAGGTTCCAGGTTATACACAGGAGGAGAAGATAGAGATTGCC CATAGGCACTTGATCCCCAAGCAGCTGGAACAACATGGGCTGACTCCACAGCAGATTC AGATACCCCAGGTCACCACTCTTGACATCATCACCAGGTATACCAGAGAGGCAGGGGT TCGTTCTCTGGATAGAAAACTTGGGGCCATTTGCCGAGCTGTGGCCGTGAAGGTGGCA GAAGGACAGCATAAGGAAGCCAAGTTGGACCGTTCTGATGTGACTGAGAGAGAAGGTT GCAGAGAACACATCTTAGAAGATGAAAAACCTGAATCTATCAGTGACACTACTGACTT GGCTCTACCACCTGAAATGCCGATTTTGATTGATTTCCATGCTCTGAAAGACATCCTT GGGCCCCCGATGTATGAAATGGAGGTGTCTCAGCGTTTGAGTCAGCCAGGAGTAGCAA TAGGTTTGGCTTGGACTCCCTTAGGTGGAGAAATCATGTTCGTGGAGGCGAGTCGAAT GGATGGCGAGGGCCAGTTAACTCTGACCGGCCAGCTCGGGGACGTGATGAAGGAGTCC GCCCACCTCGCTATCAGCTGGCTCCGCAGCAACGCAAAGAAGTACCAGCTGACCAATG CTTTTGGAAGTTTTGATCTTCTTGACAACACAGACATCCATCTGCACTTCCCAGCTGG AGCTGTCACAAAAGATGGACCATCTGCTGGAGTTACCATAGTAACCTGTCTCGCCTCA CTTTTTAGTGGGCGGCTGGTACGTTCAGATGTAGCCATGACTGGAGAAATTACACTGA GAGGTCTTGTTCTTCCAGTAGGTGGAATTAAAGACAAAGTGCTGGCGGCACACAGAGC GGGACTGAAGCAAGTCATTATTCCTCGGAGAAATGAAAAAGACCTTGAGGGAATCCCA GGCAACGTACGACAGGATTTAAGTTTTGTCACAGCAAGCTGCCTGGATGAGGTTCTTA ATGCAGCTTTTGATGGTGGCTTTACTGTCAAGACCAGACCTGGTCTGTTAAATAGCAA ACTGTAG

ORF Start: ATG at 1 ORF Stop: TAG at 2557

SEQ ID NO: 60 852 aa M at 94615.4kD

NOVl 8a, MSSVSPIQIPSR PL LTHEGVLLPGSTMRTSλmSARNLQLVRSRLLKGTSLQSTI G CG102554-01 VIPNTPDPASDAQD PPLHRIGTAA AVQWGSN PKPHYTLLITGLCRFQIVQVLKE Protein Sequence KPYPIAEVEQ DRLEEFPNTCKMREELGE SEQFYKYAVQLVEM DMSVPAVAK RRL DSLPREALPDI TSIIRTSNKEKLQI DAVSLEERFKMTIPLLVRQIEGL LLQKTR PKQDDDKRVIAIRPIRRITHISGTLEDEDEDEDNDDIVM EKKIRTSSMPΞQAHKVC

VKEIKR KKMPQSMPEYA TRNYLELMVE P NKSTTDRLDIRAARIL DNDHYAMEK KKRVLEYLAVRQ K NLKGPILCFVGPPGVGKTSVGRSVAKT GRΞFHRIA GGVCD

QSDIRGHRRTYVGSMPGRIINGLKTVG-VrølPVFL DEVDK GKS QGDPAAA LEVLD

PEQNHNFTDHY NVAFDLSQV FIATANTTATIPAA LDRMEIIQVPGYTQEΞ IEIA

HRH IPKQLEQHG TPQQIQIPQVTTLDIITRYTRE GVRS DRKLGAICRAVAV VA

EGQHKEAK DRSDVTEREGCREHILEDE PΞSISDTTD ALPPEMPILIDFHALKDIIj

GPPMYE EVSQRLSQPGVAIGLAWTP GGEI FVEASRMDGEGQLTLTGQLGDVMKEsJ

AH AISWLRSNAK YQLTNAFGSFDL DNTDIH HFPAGAVTKDGPSAGVTIVTCLASJ FSGR VRSDVAMTGEIT RGLV PVGGIKDKVLAAHRAGLKQVIIPRRNEKDLEGIPJ

GVRQD SFVTASCLDEV NAAFDGGFTVKTRPGL NSK I

Further analysis of the NOV 18a protein yielded the following properties shown in Table 18B.

Table 18B. Protein Sequence Properties NOVlSa

PSort 0.8000 probability located in microbody (peroxisome); 0.3000 probability analysis: located in nucleus; 0.1740 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

SignalP I No Known Signal Sequence Indicated ; analysis:

A search of the NOVlSa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table ISC.

j NO:14730 - Homo sapiens, 571 aa. 1..571 570/571 (99%) ! [EP1074617-A2, 07-FEB-2001]

In a BLAST search of public sequence databases, the NOVlSa protein was found to have homology to the proteins shown in the BLASTP data in Table 18D.

PFam analysis indicates that the NOVl 8a protein contains the domains shown in the Table 18E.

Example 19.

The NOV 19 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 19 A.

Table 19A. NOV19 Sequence Analysis

SEQ ID NO: 61 3721 bp

■NOV 19a, GGGATGCACGTGAATGCCTCTGCCCGACGGTGGGGGCGGGGAGGGGCTGCAGCACTAC

' CGI 02605-01 DNA CAGGCCCGGCAGCCAGTCCGCGCAGACCCGCGCCCCGCACAGGCCCGGTGGGCAGGCC Sequence GACCCTGGCTCCGAGCCCCTCCCGCGCCCACGCCCACGCCAAGACCAACCTGCTGCCG

GGCCGTGCAGTCCAGGCCCCCGATGCCGTGCCCGGCGCCGGCTCCAGCCGCGCGCCCG

CGCGCTGGCGACCCAGAGACCCTGGAAGCTCCGCTCCGGACGCCTGGCAGCGCTTCCG

CCCTGCACCGCTGCGCGCGCAGCCCCGCCCCCCCCCCCGGCCCGCCCCCGGCCCGCCC

CCGCCGCGGAAGGGCGGCTGCGGCGGCCAATGGCGAGCTCCCCAGGACAGGACGCGGG

GGCTGCGGAGCAGGAACTCGCCCCGCCCACCCCTCGCGCAGCCCCGCCTCCGCCACGC

CAACCAATGGCGCGCGCCGCCGGGCACGCCGGCTGCTGATTGGCGGCGCCCGGCACGC

TCGGGGCGGGCAGTGCGCGACGGCGGCGGCGGCGCGGGAGGTTCGGAGCGGGAGCTCG

GGCTCGCGGACGGTATGGAGGACTACGAGCAGGAGCTGTGCGGCGTCGAGGATGATTT

CCACAACCAGTTCGCGGCCGAGCTGGAGGTGCTGGCAGAGCTGGAAGGGGCGTCGACT

CCGTCGCCCTCCGGGGTCCCCCTGTTCACCGCGGGCCGACCCCCGCGGACGTTCGAGG

AGGCCCTTGCCAGAGGGGACGCGGCCTCCAGTCCCGCCCCAGCCGCATCTGTGGGCAG

CAGCCAGGGCGGCGCCAGGAAGAGGCAGGTGGACGCCGACCTGCAGCCGGCCGGGTCC

CTGCCCCACGGTAGGTTGGCGGCATTGCCCCAGGGCCTCCGGAGTGGGCGCGAGGCTG

AGGAGGCCTCTGGTTCCCTGCATGTGTCTCCCCCAGCCCCCAGGATCAAACGGCCTAG

GCTGCAGGTGGTCAAGAGGCTGAACTTCAGGTCGGAGGAGATGGAGGAGCCGCCCCCT

CCCGACTCCTCGCCGACGGACATCACCCCGCCGCCGAGCCCTGAGGACCTCGCAGAGC

TTTGGGGCCACGGAGTCTCAGAAGCTGCTGCCGACGTGGGTCTCACACGGGCCTCACC

AGCTGCCCGCAATCCCGTCCTGAGGCGGCCCCCCATCTTGGAGGACTACGTCCACGTG

ACATCCACGGAGGGCGTCCGGGCTTATCTGGTGCTGCGTGCTGACCCCATGGCCCCGG

GGGTGCAGGGCTCTCTCCTCCACGTCCCATGGCGAGGCGGTGGCCAGCTGGACCTGC

GGGTGTGTCCTTAGCCTCCCTGAAGAAGCAGGTCGACGGCGAGCGGCGGGAGCGGCTG

CTTCAGGAGGCCCAGAAGCTTTCAGACACCCTGCACAGTCTCAGGTCGGGGGAGGAGG

AGGCAGCCCAGCCCTTGGGGGCCCCTGAGGAGGAGCCGACTGACGGTCAAGACGCCTC

CAGTCACTGCCTCTGGGTGGATGAGTTTGCACCCCGCCACTACACGGAGCTGCTCAGT

GATGACTTCACCAACCGCTGCCTGCTCAAGTGGCTGAAGTTGTGGGACCTGGTGGTGT

TTGGCCACGAGAGGCCTTCCCGGAAGCCCAGGCCCAGTGTTGAGCCGGCCCGGGTCAG

CAAGGAGGCCACAGCCCCAGGCAAGTGGAAGAGCCACGAACAGGTGCTGGAGGAGATG

CTGGAGGCTGGGCTGGACCCGAGCCAGCGACCGAAGCAGAAGGTGGCACTGCTCTGTG

GGCCCCCGGGGCTGGGGAAGACCACCCTGGCACACGTGATTGCGCGTCACGCGGGGTA

CTCTGTGGTGGAGATGAACGCCAGTGACGACCGTAGCCCGGAGGTCTTCCGCACACGC

ATCGAGGCGGCCACCCAGATGGAGTCGGTGCTGGGTGCTGGCGGGAAGCCCAACTGCC

TGGTCATCGATGAGATCGACGGGGCCCCCGTGGCCGCCATCAACGTCCTCCTGAGCAT

CCTGAACCGCAAGGGGCCACAGGAGGTGGGGCCACAGGGCCCGGCTGTGCCTTCGGGA

GGCGGCCGACGGCGCCGGGCAGAGGGGGGGCTCCTCATGAGGCCCATTATCTGCATTT

GCAATGACCAGTTCGCACCGTCCCTGCGGCAGCTGAAGCAGCAGGCCTTCCTGCTCCA

CTTCCCGCCGACTCTGCCCTCGAGGCTGGTGCAGCGGCTCCAGGAGGTCTCCCTGCGG

CAGGGCATGAGGGCCGACCCAGGGGTGCTGGCCGCCCTCTGTGAGAAAACTGACAATG

ACATCCGGGCCTGCATCAACACCCTGCAGTTCCTGTACAGCCGGGGCCAGCGGGAGCT

GAGCGTGCGGGACGTGCAGGCCACACGCGTGGGCCTCAAGGACCAGCGCAGAGGGCTC

TTCTCGGTGTGGCAGGAGGTCTTCCAGCTGCCTCGAGCCCAGAGGCGCCGTGTGGGCC

AGGACCCCGCCCTGCCTGCTGACACACTCCTGCTGGGTGACGGGGACGCGGGCTCCCT

CACCTCCGCCTCACAGCGATTCTACCGTGTCCTGCATGCCGCTGCCTCTGCGGGCGAG

CACGAGAAGGTGGTCCAGGGCTTGTTTGACAACTTCCTGCGTCTGCGGCTGCGAGACT

CCAGCCTGGGTGCTGTGTGTGTGGCCCTCGACTGGCTGGCCTTCGATGACCTGCTGGC

GGGGGCTGCTCATCACAGCCAGAGCTTCCAGCTGCTGCGCTACCCACCCTTCCTGCCC

GTGGCCTTCCATGTGCTGTTTGCTTCCAGCCACACACCCAGGATCACCTTCCCCAGCA

GCCAGCAGGAGGCCCAGAACCGGATGAGCCAGATGAGGAACCTGATCCAGACGCTGGT

Further analysis of the NOV 19a protein yielded the following properties shown in Table 19B.

Table 19B. Protein Sequence Properties NOV19a

PSort 0.8500 probability located in endoplasmic reticulum (membrane); 0.4400 analysis: probability located in plasma membrane; 0.3500 probability located in nucleus; 0.3000 probability located in microbody (peroxisome)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV 19a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 19C. Table 19C. Geneseq Results for NOV19a

In a BLAST search of public sequence databases, the NOV 19a protein was found to have homology to the proteins shown in the BLASTP data in Table 19D.

Table 19D. Public BLASTP Results for NOV19a

Q8WVB6 HYPOTHETICAL 107.4 KDA 198..1200 975/1003 (97%) 0.0

! PROTEIN - Homo sapiens 1..975 ' 975/1003 (97%)

; (Human), 975 aa.

AAH24142 SIMILAR TO HYPOTHETICAL 198..1200 : 740/1005 (73%) 0.0 PROTEIN C321D2.4 - Mus 1..969 ! 796/1005 (78%) j musculus (Mouse), 969 aa. !

PFam analysis indicates that the NOV 19a protein contains the domains shown in the Table 19E.

Table 19E. Domain Analysis of NOVl 9a

Identities/

Pfam Domain NOV19a Match Region Similarities ! Expect Value for the Matched Region i AAA 594..7S7 40/238 (17%) 2.7e-05 1 16/238 (49%)

Example 20.

The NOV20 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 20A.

Table 20A. NOV20 Sequence Analysis

SEQ ID NO: 63 ; i 880 bp

^<NOV20a, GCCATGGCCACCACGGTGACCTGCACCCGCTTCACCGACGAGTACCAGCTCTACGAGG

CG102909-01 DNA ATATTGGCAAGGGGGCTTTCTCTGTGGTCCGACGCTGTGTCAAGCTCTGCACCGGCCA TGAGTATGCAGCCAAGATCATCAACACCAAGAAGCTGTCAGCCAGAGATCACCAGAAG i Sequence CTGGAGAGAGAGGCTCGGATCTGCCGCCTTCTGAAGCATTCCAACATCGTGCGTCTCC ACGACAGCATCTCCGAGGAGGGCTTCCACTACCTGGTCTTCGATCTGGTCACTGGTGG GGAGCTCTTTGAAGACATTGTGGCGAGAGAGTACTACAGCGAGGCTGATGCCAGTCAC TGTATCCAGCAGATCCTGGAGGCCGTTCTCCATTGTCACCAAATGGGGGTCGTCCACA GAGACCTCAAGCCGGAGAACCTGCTTCTGGCCAGCAAGTGCAAAGGGGCTGCAGTGAA GCTGGCAGACTTCGGCCTAGCTATCGAGGTGCAGGGGGACCAGCAGGCATGGTTTGGT TTCGCTGGCACACCAGGCTACCTGTCCCCTGAGGTCCTTCGCAAAGAGGCGTATGGCA AGCCTGTGGACATCTGGGCATGTGGTGTGATCCTGTACATCCTGCTCGTGGGCTACCC ACCCTTCTGGGACGAGGACCAGCACAAGCTGTACCAGCAGATCAAGGCTGGTGCCTAT GACTTCCCGTCCCCTGAGTGGGACACCGTCACTCCTGAAGCCAAAAACCTCATCAACC AGATGCTGACCATCAACCCTGCCAAGCGCATCACAGCCCATGAGGCCCTGAAGCACCC GTGGGTCTGCCAACGCTCCACGGTAGCATCCATGATGCACAGACAGGAGACTGTGGAG TGTCTGAAAAAGTTCAATGCCAGGAGAAAGCTCAAGGGAGCCATCCTCACCACCATGC TGGCCACACGGAATTTCTCAGCAGCCAAGAGTTTACTCAACAAGAAAGCAGATGGAGT CAAGCCCCAGACGAATAGCACCAAAAACAGTGCAGCCGCCACCAGCCCCAAAGGGACG CTTCCTCCTGCCGCCCTGGAGCCTCAAACCACCGTCATCCATAACCCAGTGGACGGGA TTAAGGAGTCTTCTGACAGTGCCAATACCACCATAGAGGATGAAGACGCTAAAGCCCC CAGGATCTCTGACATCCTGAACTCTGTGAGAAGGGGTTCAGGAACCCCAGAAGCCGAG GGCCCCCTCTCAGCGGGGCCCCCGCCCTGCCTGTCTCCGGCTCTCCTAGGCCCCCTGT CCTCCCCGTCCCCCAGGATCTCTGACATCCTGAACTCTGTGAGGAGGGGCTCAGGGAC CCCAGAAGCCGAGGGCCCCTCGCCAGTGGGGCCCCCGCCCTGCCCATCTCCGACTATC CCTGGCCCCCTGCCCACCCCATCCCGGAAGCAGGAGATCATTAAGACCACGGAGCAGC TCATCGAGGCCGTCAACAACGGTGACTTTGAGGCCTACGCGAAAATCTGTGACCCAGG GCTGACCTCGTTTGAGCCTGAAGCACTGGGCAACCTGGTTGAAGGGATGGACTTCCAC

RKFNARRK KGAILTTMLVSRNFΞAAKSLLNK SDGGVKKRKSSSSVHLMPQSNNK S EPQTTWHNATDGIKGSTESCNTTTΞDEDLKVRKQΞI IKITEQLIEAINNGDFEAY TKICDPG TSFEPEA GNLVEGMDFHKFYFENLLSKNSKPIHTTILNPHVHVIGEDAA CIAYIRLTQYIDGQGRPRTSQSEETRV HRRDGK VHYHCSGAPAAPLQ

SEQ ID NO: 67 J2034 bp

|NOV20c, GCCGAGCCCGTCCGCCGCCGCCATGGCCACCACGGTGACCTGCACCCGCTTCCGCCGA

|CG102909-03 DNA GCCCGTCCGCCGCCGCCATGGCCACCACGGTGACCTGCACCCGCTTCACCGACGAGTA Sequence CCAGCTCTACGAGGATATTGGCAAGGGGGCTTTCTCTGTGGTCCGACGCTGTGTCAAG CTCTGCACCGGCCATGAGTATGCAGCCAAGATCATCAACACCAAGAAGCTGTCAGCCA GAGATCACCAGAAGCTGGAGAGAGAGGCTCGGATCTGCCGCCTTCTGAAGCATTCCAA CATCGTGCGTCTCCACGACAGCATCTCCGAGGAGGGCTTCCACTACCTGGTCTTCGAT CTGGTCACTGGTGGGGAGCTCTTTGAAGACATTGTGGCGAGAGAGTACTACAGCGAGG CTGATGCCAGTCACTGTATCCAGCAGATCCTGGAGGCCGTTCTCCATTGTCACCAAAT GGGGGTCGTCCACAGAGACCTCAAGCCGGAGAACCTGCTTCTGGCCAGCAAGTGCAAA GGGGCTGCAGTGAAGCTGGCAGACTTCGGCCTAGCTATCGAGGTGCAGGGGGACCAGC AGGCATGTGGTGCTGGCACACCAGGCTACCTGTCCCCTGAGGTCCTTCGCAAAGAGGC GTATGGCAAGCCTGTGGACATCTGGGCATGTGGTGTGATCCTGTACATCCTGCTCGTG GGCTACCCACCCTTCTGGGACGAGGACCAGCACAAGCTGTACCAGCAGATCAAGGCTG GTGCCTATGACTTCCCGTCCCCTGAGTGGGACACCGTCACTCCTGAAGCCAAAAACCT CATCAACCAGATGCTGACCATCAACCCTGCCAAGCGCATCACAGCCCATGAGGCCCTG AAGCACCCGTGGGTCTGCCAACGCTCCACGGTAGCATCCATGATGCACAGACAGGAGA CTGTGGAGTGTCTGAAAAAGTTCAATGCCAGGAGAAAGCTCAAGCCTGGCTGTCCCCA GACGAATAGCACCAAAAACAGTGCAGCCGCCACCAGCCCCAAAGGGACGCTTCCTCCT GCCGCCCTGGAGCCTCAAACCACCGTCATCCATAACCCAGTGGACGGGATTAAGGTAC TGCCCCACTTTCCTCCTCCCGCTTTCCCCAGGCAGGAGGCTCCAGGCCAGGAGAGAGG TCTGGGGCAGCATTTGTGCCAGAGTGGAGGGCAGATGTCCCATGGCCCTGGCCGCCCC TCCGCCTCAGCCCCCAGGGTCCCCGACATCCTGAGCTCAGTGAGGAGGGGCTCGGGAG CCCCAGAAGCCGAGGGGCCCCTGCCCTGCCCATCTCCGGCTCCCTTTAGCCCCCTGCC AGCCCCAGCCCCCAGGATCTCTGACATCCTGAACTCTGTGAGAAGGGGTTCAGGAACC CCAGAAGCCGAGGGCCCCCTCTCAGCGGGGCCCCCGCCCTGCCTGTCTCCGGCTCTCC TAGGCCCCCTGTCCTCCCCGTGTTCCACCCCAGCCCCCAGGATCTCTGACATCCTGAA CTCTGTGAGAAGGGGTTCAGGAACCCCAGAAGCCGAGCAGCAGACCCCACCCTCCTGC CCAGCCCCTACCCTCCCAGGCCCTTTGGGCTTTCCTAGCCGGAAGCAGGAGATCATTA AGACCACGGAGCAGCTCATCGAGGCCGTCAACAACGGTGACTTTGAGGCCTACGCGAA AATCTGTGACCCAGGGCTGACCTCGTTTGAGCCTGAAGCACTGGGCAACCTGGTTGAA GGGATGGACTTCCACAGATTCTACTTCGAGAACGTGCTGGCCAAGAACAGCAAGCCGA TCCACACGACCATCCTGAACCCACACGTGCACGTCATTGGAGAGGATGCCGCCTGCAT CGCTTACATCCGGCTCACGCAGTACATTGACGGGCAGGGCCGGCCCCGCACCAGCCAG TCTGAGGAGACCCGCGTGTGGCACCGCCGCGACGGCAAGTGGCAGAACGTGCACTTCC ACTGCTCGGGCGCGCCTGTGGCCCCGCTGCAGTGAAGGTGAGTGTTCTGTGCTAAGTG ACAG

ORF Start: ATG at 76 ORF Stop: TGA at 2005

SEQ ID NO: 68 643 aa MW at 70252.3kD

NOV20c, MATTVTCTRFTDEYQ YEDIGKGAFSWRRCVK CTGHEYAAKIINTKKLSARDHQKL CGI 02909-03 EREARICR LKHSNIVR HDSISEEGFHY VFD VTGGELFEDIVAREYYSEADASHC IQQILEAVLHCHQMGWHRDLKPENL ASKCKGAAVKLADFGLAIEVQGDQQACGAG Protein Sequence TPGYLSPEV RKEAYGKPVDIWACGVI YILLVGYPPF DEDQHK YQQIKAGAYDFP SPE DTVTPEAKNLINQMLTINPAKRITAHEALKHPWVCQRSTVASMMHRQETVECLK KFNARRKLKPGCPQTNSTKNSAAATSPKGTLPPAALEPQTTVIHNP^'VDGIKVLPHFPP PAFPRQEAPGQERG GQH CQSGGQMSHGPGRPSASAPRVPDILSSVRRGSGAPEAΞG PLPCPSPAPFSP PAPAPRISDILNSVRRGSGTPEAEGPLSAGPPPCLSPALLGPLSS PCSTPAPRISDI NSVRRGSGTPEAEQQTPPSCPAPT PGP GFPSRKQEIIKTTEQL IEAAi^NGDFEAYAJNlCDPGLTSFEPEALGNLVEGMDFHRFYFE VLAKNSKPIHTTI NPHλ/HVlGEDAACIAYIR TQYIDGQGRPRTSQSEETRλt HRRDGKWQNVHFHCSGAP VAPLQ

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 20B. Table 20B. Comparison of NOV20a against NOV20b and NOV2W.

NOV20a Residues/ Identities/

Protein Sequence ]

Match Residues j Similarities for the Matched Region

NOV20b 1..384 325/396 (82%) 1..381 343/396 (86%)

NOV20c 1..604 522/675 (77%) 1..643 530/675 (78%)

Further analysis of the NOV20a protein yielded the following properties shown in

Table 20C.

Table 20C. Protein Sequence Properties NOV20a

PSort i 0.8500 probability located in endoplasmic reticulum (membrane); 0.7900 analysis: j probability located in plasma membrane; 0.1000 probability located in

J mitochondrial inner membrane; 0.1000 probability located in Golgi body

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV20a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 20D.

Table 20D. Geneseq Results for NOV20a

Homo sapiens, 525 aa. 8..391 553/385 (90%) [WO200157190-A2, 09-AUG-2001]

In a BLAST search of public sequence databases, the NOV20a protein was found to have homology to the proteins shown in the BLASTP data in Table 20E.

PFam analysis indicates that the NOV20a protein contains the domains shown in the Table 20F.

Example 21.

The N0V21 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 21 A.

Table 21A. NOV21 Sequence Analysis

SEQ ID NO: 69 1200 bp

NOV21a, CTCAACGCTGGGACGTTACAGCCAGGGCCAATGGGCAGAGCGGGACTCGAGGCCCCGC j CGI 02920-01 DNA CCCCGCCTTGTGGCGTCACGGGGACGCCGGGGGCGCGCGGGCTGCAGGGCCGCGTAGG TCCCCGCCCCCAGAGTCTGGCTTTCCGCGGCTGCCCGCCTCGCGCGTCTTCCCTGCCC

Sequence GGGTCTCCTCGCTGTCGCCGCCGCTGCCACACCATGGCCTTCGTCACCAGGCAGTTCA TGCGTTCCGTGTCCTCCTCGTCCACCGCCTCGGCCTCGGCCAAGAAGATAATCGTCAA GCACGTGACGGTCATCGGCGGCGGGCTGATGGGCGCCGGCATTGCCCAGGTTGCTGCA GCAACTGGTCACACAGTAGTGTTGGTAGACCAGACAGAGGACATCCTGGCAAAATCCA AAAAGGGAATTGAGGAAAGCCTTAGGAAAGTGGCAAAGAAGAAGTTTGCAGAAAACCC TAAGGCCGGCGATGAATTTGTGGAGAAGACCCTGAGCACCATAGCGACCAGCACGGAT GCAGCCTCCGTTGTCCACAGCACAGACTTGGTGGTGGAAGCCATCGTGGAGAATCTGA AGGTGAAAAACGAGCTCTTCAAAAGGCTGGACAAGTTTGCTGCTGAACATACAATCTT TGCCAGCAACACTTCCTCCTTGCAGATTACAAGCATAGCTAATGCCACCACCAGACAA GACCGATTCGCTGGCCTCCATTTCTTCAACCCAGTGCCTGTCATGAAACTTGTGGAGG TCATTAAAACACCAATGACCAGCCAGAAGACATTTGAATCTTTGGTAGACTTTAGCAA AGCCCTAGGAAAGCATCCTGTTTCTTGCAAGGACACTCCTGGGTTTATTGTGAACCGC CTCCTGGTTCCATACCTCATGGAAGCAATCAGGCTGTATGAACGAGGTGACGCATCCA AAGAAGACATTGACACTGCTATGAAATTAGGAGCCGGTTACCCCATGGGCCCATTTGA GCTTCTAGATTATGTCGGACTGGATACTACGAAGTTCATCGTGGATGGGTGGCATGAA ATGGATGCAGAGAACCCATTACATCAGCCCAGCCCATCCTTAAATAAGCTGGTAGCAG AGAACAAGTTCGGCAAGAAGACTGGAGAAGGATTTTACAAATACAAGTGATGTGCAGC

TTCTCCGGCTCTGAGAAGAACACCTGAGAGCGCTTTCCAG j

ORF Start: ATG at 31 | ORF Stop: TGA at 1150 j

SEQ ID NO: 70 |373 aa 'MW at 40349. lkD |

NOV21a, GRAGLEAPPPPCGVTGTPGARGLQGRVGPRPQS AFRGCPPRASSLPGSPRCRRRCH J CG102920-01 TMAFVTRQFMRSVSSSSTASASAKKIIVKHVTVIGGG MGAGIAQVAAATGHTVVL\/D | QTEDILAKSKKGIEES R VAKKKFAENPKAGDΞFVEKTLSTIATSTDAASΛATHSTDL ; Protein Sequence ΛA^EAIVENLKVKNELFKR DKFAAEHTIFASNTSSLQITSIANATTRQDRFAG HFFNJ PVPVMK VEVIKTPMTSQKTFES VDFSKALGKHPVSCKDTPGFIΛ RL VPY MEAL J YERGDASKEDIDTAMKLGAGYP GPFE LDYVG DTTKFIVDGWHEMDAENPLHQP I SPS NKLVAENKFGKKTGEGFYKYK !

Further analysis of the NOV21a protein yielded the following properties shown in Table 2 IB.

Table 21B. Protein Sequence Properties NOV21a

PSort 0.7600 probability located in nucleus; 0.1000 probability located in analysis: mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.0785 probability located in microbody (peroxisome)

SignalP j No Known Signal Sequence Indicated analysis: A search of the NOV21a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 21 C.

In a BLAST search of public sequence databases, the NOV2 la protein was found to • have homology to the proteins shown in the BLASTP data in Table 2 ID.

JC4879 3-hydroxyacyI-CoA dehydrogenase j 60..373 313/314 (99%) e-l 76 (EC 1.1.1.35), short chain-specific, | 1..314 313/314 (99%) precursor - human, 314 aa.

PFam analysis indicates that the NOV2 la protein contains the domains shown in the Table 2 IE.

Example 22.

The NOV22 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 22A.

;AGCACCTGGAGCGGGCGGGCGAGAACCTGTCCCTCCTGACCTCCTTCTACTTCTGCATJ

ICGTCACCTTCTCCACCGTGGGCTACGGTGACGTCACGCCCAAGATCTGGCCATCGCAG]

JCTGCTGGTGGTCATCATGATCTGCGTGGCCCTCGTGGTGCTCCCACTGCAGTTCGAGGJ

'AGCTCGTCTACCTCTGGATGGAGCGGCAGAAGTCAGGGGGCAACTACAGCCGCCACCG!

TGCGCAGACGGAGAAGCACGTGGTCCTGTGTGTCAGCTCCCTCAAGATCGACCTTCTC

ATGGACTTCCTGAACGAGTTCTACGCCCACCCCCGGCTCCAGGACTATTACGTGGTCA

TCCTGTGCCCCACGGAGATGGATGTCCAGGTGCGCAGAGTCCTGCAGATCCCTCTGTG

GTCCCAGCGGGTCATCTACCTCCAGGGCTCTGCACTCAAAGACCAGGACCTCATGCGA

GCCAAGATGGACAATGGGGAGGCCTGCTTCATCCTCAGCAGCAGGAACGAGGTGGACC

GCACGGCTGCAGACCACCAGACCATCCTGCGCGCCTGGGCCGTGAAGGACTTCGCCCC

CAACTGCCCCCTCTACGTCCAGATCCTCAAACCTGAAAACAAGTTTCACGTCAAGTTT

GCTGACCACGTGGTGTGTGAGGAGGAGTGCAAGTACGCCATGCTGGCGCTGAACTGCA

TCTGCCCGGCGACCTCCACCCTCATCACCCTGCTGGTGCACACGTCCCGCGGCCAGGA

GGGACAGGAGTCTCCGGAGCAGTGGCAGCGCATGTATGGGCGCTGCTCCGGCAACGAG

GTGTACCACATCCGCATGGGTGACAGCAAGTTCTTCCGCGAGTACGAGGGCAAGAGCT

TCACCTACGCGGCCTTCCACGCCCACAAGAAGAGGTATGGCGTGTGCCTCATCGGGCT

GAAGCGGGAGGACAACAAGAGCATCCTGCTGAACCCGGGGCCCCGGCACATCCTGGCC

GCCTCTGACACCTGCTTCTACATCAACATCACCAAGGAGGAGAACTCGGCCTTCATCT

TCAAGCAGGAGGAGAAGCGGAAGAAGAGGGCCTTCTCGGGGCAGGGGCTGCACGAGGG

TCCGGCCCGCCTGCCCGTGCACAGCATCATCGCCTCCATGGTGGCCATGGACCTGCAG

GGCACAGAGCACCGGCCTACGCAGAGCGGCGGTGGGGGCGGGGGCAGCAAGCTGGCAC

ITGCCCACGGAGAACGGCTCGGGCAGCCGGCGGCCCAGCATCGCGCCCGTCCTGGAACT

JGGCCGACAGCTCAGCCCTGCTGCCCTGCGACCTGCTGAGCGACCAGTCGGAGGATGAG

JGTGACGCCGTCGGACGACGAGGGGCTCTCCGTGGTAGAGTATGTGAAGGGCTACCCTC

LCCAACTCGCCCTACATCGGCAGCTCCCCAACCCTGTGCCACCTCCTGCCTGTGAAAGC

JCCCCTTCTGCTGCCTGCGGCTGGACAAGGGCTGCAAGCACAACAGCTATGAAGACGCC

|AAGGCCTACGGGTTCAAGAACAAGCTGATCATCGTCTCGGCAGAGACGGCCGGCAATG

IGGCTGTACAACTTCATCGTGCCACTGCGGGCCTACTACAGATCCCGCAAGGAGCTGAA

JCCCCATCGTGCTGCTGCTGGACAACAAGCCCGACCACCACTTCCTGGAAGCCATCTGC

JTGCTTCCCCATGGTCTACTACATGGAGGGCTCTGTGGACAGCCTGGACAGCCTGCTGC

JAGTGTGGCATCATCTATGCGGACAACCTGGTGGTGGTGGACAAGGAGAGCACCATGAG

JCGCCGAGGAGGACTACATGGCGGACGCCAAGACCATCGTCAACGTGCAGACCATGTTC

ICGGCTCTTCCCCAGCCTCAGCATCACCACGGAGCTCACCCACCCTTCCAACATGCGCT

TCATGCAGTTCCGCGCCAAGGACAGCTACTCTCTGGCTCTTTCCAAACTAGAAAAGAG

GGAGCGAGAGAATGGCTCCAACCTGGCCTTCATGTTCCGCCTGCCGTTCGCCGCCGGC

CGCGTCTTCAGCATCAGCATGTTGGACACACTGCTCTACCAGTCCTTCGTGAAGGACT

ACATGATCACCATCACCCGGCTGCTGCTGGGCCTGGACACCACGCCGGGCTCGGGGTA

CCTCTGTGCCATGAAAATCACCGAGGGCGACCTGTGGATCCGCACGTACGGCCGCCTC

TTCCAGAAGCTCTGCTCCTCCAGCGCCGAGATCCCCATTGGCATCTACCGGACAGAGA

GCCACGTCTTCTCCACCCAGCCCCACGACCTCAGAGCCCAGTCCCAGATCTCGGTGAA

CGTGGAGGACTGTGAGGACACACGGGAAGTGAAGGGGCCCTGGGGCTCCCGCGCTGGC

ACCGGAGGCAGCTCCCAGGGCCGCCACACGGGCGGCGGTGACCCCGCAGAGCACCCAC

TGCTACGGCGCAAGAGCCTGCAGTGGGCCCGGAGGCTGAGCCGCAAGGCGCCCAAGCA

GGCAGGCCGGGCGGCGGCCGCGGAGTGGATCAGCCAGCAGCGCCTCAGCCTGTACCGG

CGCTCTGAGCGCCAGGAGCTCTCCGAGCTGGTGAAGAACCGCATGAAGCACCTGGGGC

TGCCCACCACCGGCTACGAGGACGTAGCAAATTTAACAGCCAGTGATGTCATGAATCG

GGTAAACCTGGGATATTTGCAAGACGAGATGAACGACCACCAGAACACCCTCTCCTAC

GTCCTCATCAACCCTCCGCCCGACACGAGGCTGGAGCCCAGTGACATTGTGTATCTCA

TCCGCTCCGAOCCCCTGGCTCACGTGGCCAGCAGCTCCCAGAGCCGGAAGAGCAGCTG

CAGCCACAAGCTGTCGTCCTGCAACCCCGAGACTCGCGACGAGACACAGCTCTGAGCC

AGCCCTGCACGG

ORF Start: ATG at 2 ORF Stop: TGA at 3707

SEQ ID NO: 72 1235 aa MW at l39111.3kD

NOV22a, MARAKLPRSPSEGKAGPGGAPAGAAAPEEPHGLSP PARGGGSVGSDVGQR PVEDF CG103051-01 SLDSSLSQVQVEFYVNΞNTFKERLKLFFIKNQRSS RIRLFNFSLKLLTCLLYIVRV DDPALGIGW GCPKQNYSFNDSSSEINWAPIL VERKMT AIQVIVAIISF ETM Protein Sequence IYLSYKGNI EQIFRVSFVLEMINTLPFIITVFWPPLRNLFIPVFLNC AKHALΞN MINDFHRAILRTQSAMFNQVLILFCTLLCLVFTGTCGIQHLERAGEN SLLTSFYFCI VTFSTVGYGDVTPKI PSQL λΛ/IMICVA W PLQFEE VYLWMERQKSGGNYSRHR ΪAQTΞKHWLCVSSLKIDLLMDF NEFYAHPRLQDYYΛΛ/I CPTEMDVQVRRVLQIPLW

ISQRVIYLQGSA KDQDLMRAKMDNGEACFI SSRNEVDRTAADHQTI RAWAVKDFAP

INCPLYVQILKPENKFHVKFADHWCΞEECKYAM ALNCICPATSTLIT LVHTSRGQE

IGQESPEQWQRMYGRCSGNEVYHIRMGDSKFFREYEGKSFTYAAFHAHKKRYGVCLIG

ΪKREDNKSILLNPGPRHILAASDTCFYINITKEΞNSAFIFKQEEKRKKRAFSGQGLHEG

PAR PVΉSIIASMVA DLQGTEHRPTQSGGGGGGSKA PTENGSGSRRPSIAPV EL

ADSSALLPCDLLSDQSEDEVTPSDDEG S EYVKGYPPNSPYIGSSPTLCHLLPVKA

PFCCLRLDKGC HNSYEDAKAYGFKNKLIIVSAETAGNGLY FIVPLRAYYRSRKELN

PIV L DN PDHHFI,EAICCFPMVYYMΞGSΛ^⁾SLDS LQCGIIYADNVA^DKESTMS

AEEDYMADAKTIVNVQTMFRLFPSLSITTE THPSNMRFMQFRAKDSYS A SKEKR

ERENGSNLAFMFRLPFAAGRVFSISM DTLLYQSFVDYMITITRL LGLDTTPGSGY

LCAMKITEGDL IRTYGRLFQKLCSSSAEIPIGIYRTESHVFSTQPHDLRAQSQISΛΠM

VEDCEDTREVKGP GSRAGTGGSSQGRHTGGGDPAEHPLLRRKSLQWARRLSRKAPKQ

AGRAAAAE ISQQRLSLYRRSERQELSELVKNRMKH GLPTTGYEDVALTASDΛ NR

VNGYLQDEMNDHQNTLSYV INPPPDTRLEPSDIVY IRSDPLAHVASSSQSRKSSC

SHKLSSCNPETRDETQL

Further analysis of the NOV22a protein yielded the following properties shown in

Table 22B.

Table 22B. Protein Sequence Properties NOV22a

PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3200 probability located in nucleus; 0.3000 probability located in endoplasmic reticulum (membrane)

I SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV22a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 22C.

In a BLAST search of public sequence databases, the NOV22a protein was found to have homology to the proteins shown in the BLASTP data in Table 22D.

PFam analysis indicates that the NOV22a protein contains the domains shown in the Table 22E.

Table 22E. Domain Analysis of NOV22a

Identities/

Pfam Domain NOV22a Match Region ! Similarities Expect Value for the Matched Region ion trans 157. J_H 36/224 (16%) 1.5e-18 130/224 (58%) Example 23.

The NOV23 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 23A.

Table 23A. NOV23 Sequence Analysis

SEQ ID NO: 73 5583 bp

,NOV23a, TTGTTGTTTGATGTTTCCCACTCTTAGAGGAAGGATGGTTGATTTGGAGAGCGAAGTG CG103061-01 DNA CCCCCTCTGCCTCCCAGGTACAGGTTTCGAGATTTGCTGCTAGGGGACCAAGGATGGC AAAACGACGACAGGGTACAAGTTGAATTCTATATGAATGAAAATACATTTAAAGAAAG 'Sequence ACTAAAATTATTTTTCATAAAAAACCAGAGATCAAGTCTAAGGATACGCCTGTTCAAT TTTTCTCTCAAATTACTAAGCTGCTTATTATACATAATCCGAGTACTACTAGAAAACC CTTCACAAGGAAATGAATGGAAAGGTACCTTTTCTGACCTTCAACAATATTATTTTGA TTATTTTGAGTTTTATAGGTCTCATATCTTTTGGGTGAACAGAAGTCTACCTTTGTGG GGCTTACAGGTTTCAGTGGCATTGATAAGTCTGTTTGAAACAATATTACTTGGTTATC TTAGTTATAAGGGAAACATCTGGGAACAGATTTTACGAATACCCTTCATCTTGGAAAT AATTAATGCAGTTCCCTTCATTATCTCAGTATTCTGGCCTTCCTTAAGGAATCTATTT GTCCCAGTCTTTCTGAACTGTTGGCTTGCCAAACATGCCTTGGAAAATATGATTAATG GCTTTATGAAATGTGCTTTGGCTTTCAAAAGAATAATGATGAGAAATTATGTGTCCAG TTTGAAAGATTTAATTGTAATGCATATTTGTTTCTTTAGCATTTGTGGGATCCAACAT CTGGAACGAATAGGAAAGAAGCTGAATCTCTTTGACTCCCTTTATTTCTGCATTGTGA CGTTTTCTACTGTGGGCTTCGGGGATGTCACTCCTGAAACATGGTCCTCCAAGCTTTT TGTAGTTGCTATGATTTGTGTTGCTCTTGTGGTTCTACCCTTACAGTTTGAACAGCTG GCTTATTTGTGGATGGAGAGACAAAAGTCAGGAGGAAACTATAGTCGACATAGAGCTC AAACTGAAAAGCATGTCGTCCTGTGTGTCAGCTCACTGAAGATTGATTTACTTATGGA TTTTTTAAATGAATTCTATGCTCATCCTAGGCTCCAGGATTATTATGTGGTGATTTTG TGTCCTACTGAAATGGATGTACAGGTTCGAAGGGTACTGCAGATTCCAATGTGGTCCC AACGAGTTATCTACCTTCAAGGTTCAGCCCTTAAAGATCAAGACCTATTGAGAGCAAA GGGATCCAATGGAAAGAAATGTAAATATTTAAGCTCCAAAAATAAAATAACTATATCA CAGAAGGATCACCAAACAATTTTGAGAGCATGGGCTGTGAAAGATTTTGCTCCAAATT GTCCTTTGTATGTCCAGATATTAAAGCCTGAAAATAAATTTCACATCAAATTTGCTGA TCATGTTGTTTGTGAAGAAGAGTTTAAATACGCCATGTTAGCTTTAAACTGTATATGC CCAGCAACATCTACACTTATTACACTACTGGTTCATACCTCTAGAGGGCAGGAAGGCC AGCAATCGCCAGAACAATGGCAGAAGATGTACGGTAGATGCTCCGGGAATGAAGTCTA CCACATTGTTTTGGAAGAAAGTACATTTTTTGCTGAATATGAAGGAAAGAGTTTTACA TATGCCTCTTTCCATGCACACAAAAAGTATGGCGTCTGCTTGATTGGTGTTAGGAGGG AGGATAATAAAAACATTTTGCTGAATCCAGGTCCTCGATACATTATGAATTCTACAGA CATATGCTTTTATATTAATATTACCAAAGAAGAGAATTCAGCATTTAAAAACCAAGAC CAGCAGAGAAAAAGCAATGTGTCCAGGTCGTTTTATCATGGACCTTCCAGATTACCTG TACATAGCATAATTGCCAGCATGGTGGCTATAGACTTGCAAGATACAAGCTGTAGATC AGCAAGTGGCCCTACCCTGTCTCTTCCTACAGAGGGAAGCAAAGAAATAAGAAGACCT AGCATTGCTCCTGTTTTAGAGGTTGCAGATACATCATCGATTCAAACATGTGATCTTC TAAGTGACCAATCAGAAGATGAAACTACACCAGATGAAGAAATGTCTTCAAACTTAGA GTATGTTAAAGGTTACCCACCTTATTCTCCATATATAGGAAGTTCACCCACTTTTTGT CATCTCCTTCATGAAAAAGTACCATTTTGCTGCTTAAGATTAGACAAGAGTTGCCAAC ATAACTACTATGAGGATGCAAAAGCCTATGGATTCAAAAATAAACTAATTATAGTTGC AGCTGAAACAGCTGGAAATGGATTATATAACTTTATTGTTCCTCTCAGGGCATATTAT AGACCAAAGAAAGAACTTAATCCCATAGTACTGCTATTGGATAACAGGCCAGATATGC ATTTTCTGGATGCAATCTGTTGGTTTCCAATGGTTTACTACATGGTGGGCTCTATTGA CAGCCTAGATGACTTACTCAGGTGTGGAGTGACTTTTGCTGCTAATATGGTGGTTGTG GATAAAGAGAGCACCATGAGTGCCGAGGAAGACTACATGGCAGATGCCAAAACCATTG: TGAACGTGCAGACACTCTTCAGGTTGTTTTCCAGTCTCAGTATTATCACAGAGCTAAC TCACCCCGCCAACATGAGATTCATGCAATTCAGAGCCAAAGACTGTTACTCTCTTGCT CTTTCAAAACTGGAAAAGAAAGAACGGGAGAGAGGCTCTAACTTGGCCTTTATGTTTC GACTGCCTTTTGCTGCTGGGAGGGTGTTTAGCATCAGTATGTTGGACACTCTGCTGTA^ TCAGTCATTTGTGAAGGATTATATGATTTCTATCACGAGACTTCTGTTGGGACTGGAC ACTACACCAGGATCTGGGTTTCTTTGTTCTATGAAAATCACTGCAGATGACTTATGGA,

GTTGTGAAGTGGATAGGACATCATCTGATCACCAAACAATTTTGAGAGCATGGGCTGT GAAAGATTTTGCTCCAAATTGTCCTTTGTATGTCCAGATATTAAAGCCTGAAAATAΆA TTTCACATCAAATTTGCTGATCATGTTGTTTGTGAΆGAAGAGTTTAAATACGCCATGT TAGCTTTAAACTGTATATGCCCAGCAACATCTACΆCTTATTACACTACTGGTTCATAC CTCTAGAGGGCAAGAAGGCCAGCAATCGCCAGAACAATGGCAGAAGATGTACGGTAGA TGCTCCGGGAATGAAGTCTACCΆCATTGTTTTGGAAGAAAGTACATTTTTTGCTGAAT ATGAΆGGAAAGAGTTTTACATATGCCTCTTTCCATGCACACAAAAAGTTTGGCGTCTG CTTGATTGGTGTTAGGAGGGAGGATAATAAAAACATTTTGCTGAATCCAGGTCCTCGA TACATTATGAATTCTACAGACATATGCTTTTATATTAATATTACCAAAGAAGAGAATT CAGCATTTAAAAACCAAGACCAGCAGAGAAAAAGCAATGTGTCCAGGTCGTTTTATCA GGACCTTCCAGATTACCTGTACATAGCATAΆTTGCCAGCATGGTGGCTATAGACTTG CAΆGATACAAGCTGTAGATCAGCAAGTGGCCCTACCCTGTCTCTTCCTACAGAGGGAA GCAAAGAAATAAGAAGACCTAGCATTGCTCCTGTTTTAGAGGTTGCAGATACATCATC GΆTTCAAACATGTGATCTTCTAAGTGACCAATCAGAAGATGAAACTACACCAGATGAA GAAΆTGTCTTCAAΆCTTAGAGTATGCTAAAGGTTACCCACCTTATTCTCCATATATAG GAAGTTCACCCACTTTTTGTCATCTCCTTCATGAAAAAGTACCATTTTGCTGCTTAAG ATTAGACAAGAGTTGCCAACATAΆCTACTATGAGGATGCAAAAGCCTATGGATTCAAA AATAAACTAATTATAGTTGCAGCTGAAACAGCTGGAAATGGATTATATAACTTTATTG TTCCTCTCAGGGCATATTATAGACCAAAGAAAGAACTTAATCCCATAGTACTGCTATT GGATAACCCGCCAGATATGCATTTTCTGGATGCAATCTGTTGGTTTCCAATGGTTTAC TACATGGTGGGCTCTATTGACAACCTAGATGACTTACTCAGGTGTGGAGTGACTTTTG CTGCTAATATGGTGGTTGTGGATAAAGAGAGCACCATGAGTGCCGAGGAAGACTACAT GGCAGATGCCAAAACCATTGTGAACGTGCAGACACTCTTCAGGTTGTTTTCCAGTCTC AGTATTATCACAGAGCTAACTCACCCCGCCAACATGAGATTCATGCAATTCAGAGCCA AAGACTGTTACTCTCTTGCTCTTTCAAAACTGGAAAAGAAAGAACGGGAGAGAGGCTC TAACTTGGCCTTTATGTTTCGACTGCCTTTTGCTGCTGGGAGGGTGTTTAGCATCAGT ATGTTGGACACTCTGCTGTATCAGTCATTTGTGAAGGATTATATGATTTCTATCACGA GACTTCTGTTGGGACTGGACACTACACCAGGATCTGGGTTTCTTTGTTCTATGAAAAT CACTGCAGATGACTTATGGATCAGAACTTATGCCAGACTTTATCAGAAGTTGTGTTCT TCTACTGGAGATGTTCCCATTGGAΆTCTACAGGACTGAGTCTCAGAAACTTACTACAT CTGAGTCTCAAATATCTATCAGTGTAGAAGAGTGGGAAGACACCAAAGACTCCAAAGA ACAAGGGCACCACCGCAGCAACCACCGCAACTCAACATCCAGTGACCAGTCGGACCAT CCCTTGCTGCGGAGAAAAAGCATGCAGTGGGCCCGAAGACTGAGCAGAAAAGGCCCAA AACACTCTGGTAAAACAGCTGAAAAAATAACCCAGCAGCGACTGAACCTCTACAGGAG GTCAGAAAGACAAGAGCTTGCTGAACTTGTGAAAAATAGAATGAAACACTTGGGTCTT TCTACAGTGGGATATGGTATGCTCTTTAAAAACTACTGTATATATGGACTCGTGATTT CTTGCCATTAGTAGTAATATAGTTGGTTCTAΆTTTAATAΆAGAATTGAATTTTTGCTT

ORF Start: ATG at 61 ORF Stop: TAG at 3373

SEQ ID NO: 76 ill04aa MWatl27357.4kD

NOV23b, VDLESEVPPLPPRYRFRDLLLGDQG QNDDRVQVEFYMNENTFKERLKLFFIINQRS CG103061-02 SLRIRLFNFSLKLLSCLLYIIRVLLENPSQGNEWKGTFSDLQQYYFDYFEFYRSHIF Protein Sequence λπsfRSLPL GLQVSVALISLFETILLGYLSYKGNIWEQILRIPFILEIINAVPFIISIF WPSLRNLFVPVFLNCWLAKHALENMINDLHRAIQRTQSAMFNQVLILISTLLCLIFTC ICGIQHLERIGKKLNLFDSLYFCIVTFSTVGFGDVTPETWSSKLFWAMICVALWLP IQFEQLAYL MERQKSGGNYSRHRAQTΞKHVVLCVSSLKIDLLMDFLNEFYAHPRLQD YYWILCPTEMDVQVRRVLQIPM SQRVIYLQGSALKDQD LRAKMDDAEACFILSSR CEVDRTSSDHQTILRA AVKDFAPNCPLYVQILKPΞNKFHIKFADHWCEEEFKYAML AL CICPATSTLITLLVHTSRGQEGQQSPEQ QKMYGRCSGNEVYHIVLEESTFFAEY EGKSFTYASFHAHKKFGVCLIGVRREDNKNILLNPGPRYIMNSTDICFYINITKEENS AFKNQDQQRKS VSRSFYHGPSRLPVHSIIASMVAIDLQDTSCRSASGPTLSLPTEGS KEIRRPSIAPVLEVADTSSIQTCDLLSDQSEDETTPDEEMSSNLEYAKGYPPYSPYIG SSPTFCHLLHEKVPFCCLRLDKSCQHNYYEDAKAYGFKNKLIIVAAETAGNGLY FIV PLRAYYRPKKELNPIVLLLDNPPDMHFLDAIC FP VYYMVGSIDNLDDLLRCGVTFA A_sW A KESTMSAEΞDYMADAKTIV_TVQTLFRLFSSLSIITELTHPANMRFMQFRAK DCYSLALSKLEKKΞRERGSNLAFMFRLPFAAGRVFSISMLDTLLYQSFVKDY ISITR LLLGLDTTPGSGFLCS KITADDLWIRTYARLYQKLCSSTGDVPIGIYRTESQKLTTS ESQISISVEEWEDTKDSKEQGHHRSNHRNSTSSDQSDHPLLRRKSMQ ARRLSRKGPK HSGKTAEKITQQRLNLYRRSERQELAELVIOvvR KHLGLSTVGYGMLFKNYCIYGLVIS CH

SEQ ID NO: 77 3444 bp

NOV23c, CTTTCTTTCTCCCTCCTCTCCTCCATTTGTTGTTTGATGTTTCCCACTCTTTGAGGAA;

CG103061-03 DNA GGATGGTTGATTTGGAGAGCGAAGTGCCCCCTCTGCCTCCCAGGTACAGGTTTCGAGAI TTTGCTGCTAGGGGACCAAGGATGGCAAAACGACGACAGGGTACAAGTTGAATTCTAT Sequence ATGAATGAAAATACATTTAAAGAAAGACTAAAΆTTATTTTTCATAAAAAACCAGAGAT CAAGTCTAAGGATACGCCTGTTCAATTTTTCTCTCAAATTACTAAGCTGCTTATTATA CATAATCCGAGTACTACTAGAAAACCCTTCACAAGGAAATGAATGGTCTCATATCTTT TGGGTGAACAGAAGTCTACCTTTGTGGGGCTTACAGGTTTCAGTGGCATTGATAAGTC TGTTTGAAACAATATTACTTGGTTATCTTAGTTATAAGGGAAACATCTGGGAACAGAT TTTACGAATACCCTTCATCTTGGAAATAATTAATGCAGTTCCCTTCATTATCTCAATA TTCTGGCCTTCCTTAAGGAATCTATTTGTCCCAGTCTTTCTGAACTGTTGGCTTGCCA AACATGCCTTGGAAAATATGATTAATGATCTACACAGAGCCATTCAGCGTACACAGTC TGCAATGTTTAATCAAGTTTTGATTTTAATATCTACATTACTATGCCTTATCTTCACC TGCATTTGTGGGATCCAACATCTGGAΆCGAATAGGAAAGΆAGCTGAATCTCTTTGACT CCCTTTATTTCTGCATTGTGACGTTTTCTACTGTGGGCTTCGGGGATGTCACTCCTGA AACATGGTCCTCCAAGCTTTTTGTAGTTGCTATGATTTGTGTTGCTCTTGTGGTTCTA CCCATACAGTTTGAACAGCTGGCTTATTTGTGGATGGAGAGACAAAAGTCAGGAGGAA ACTATAGTCGACATAGAGCTCAAACTGAAAAGCATGTCGTCCTGTGTGTCAGCTCACT GAAGATTGATTTACTTATGGATTTTTTAAATGAATTCTATGCTCATCCTAGGCTCCAG !GATTATTATGTGGTGATTTTGTGTCCTACTGAAΆTGGATGTACAGGTTCGAAGGGTAC TGCAGATTCCAATGTGGTCCCAACGAGTTATCTACCTTCAAGGTTCAGCCCTTAAAG TCAAGACCTATTGAGAGCAAAGATGGATGACGCTGAGGCCTGTTTTATTCTCAGTAGC iCGTTGTGAAGTGGATAGGACATCATCTGATCACCAAACAATTTTGAGAGCATGGGCTG ITGAAAGATTTTGCTCCAAATTGTCCTTTGTATGTCCAGATATTAAAGCCTGAAAATAA: jATTTCACATCAAATTTGCTGATCATGTTGTTTGTGAAGAΆGAGTTTAAATACGCCATG ^'TTAGCTTTAAACTGTATATGCCCAGCAACATCTACACTTATTACACTACTGGTTCATAI CCTCTAGAGGGCAAGAAGGCCAGCAATCGCCAGAACAATGGCAGAAGATGTACGGTAG

ATGCTCCGGGAATGAAGTCTACCACATTGTTTTGGAAGAAAGTACATTTTTTGCTGAA; ATGAAGGAAΆGAGTTTTACATATGCCTCTTTCCATGCACACAAAAAGTTTGGCGTCT GCTTGATTGGTGTTAGGAGGGAGGATAATAAAAACATTTTGCTGAATCCAGGTCCTCG

{ATACATTATGAATTCTACAGACATATGCTTTTATATTAATATTACCAAAGAAGAGAAT

|TCAGCATTTAAAAACCAAGACCAGCAGAGAAAΆAGCAATGTGTCCAGGTCGTTTTATC

JATGGACCTTCCAGATTACCTGTACATAGCATAATTGCCAGCATGGTGGCTATAGACTT

IGCAAGATACAAGCTGTAGATCAGCAAGTGGCCCTACCCTGTCTCTTCCTACAGAGGGA

JAGCAAAGAAATAAGAAGACCTAGCATTGCTCCTGTTTTAGAGGTTGCAGATACATCAT

ICGATTCAAACATGTGATCTTCTAAGTGACCAATCAGAAGATGAAACTACACCAGATGA

JAGAAATGTCTTCAAACTTAGAGTATGCTAAAGGTTACCCACCTTATTCTCCATATATA

^GGAAGTTCACCCACTTTTTGTCATCTCCTTCATGAAAAAGTACCATTTTGCTGCTTAA

!GATTAGACAAGAGTTGCCAACATAACTACTATGAGGATGCAAAAGCCTATGGATTCAA

'AAATAAACTAATTATAGTTGCAGCTGAAACAGCTGGAAATGGATTATATAACTTTATT

GTTCCTCTCAGGGCATATTATAGACCAAAGAAAGAACTTAATCCCATAGTACTGCTAT

TGGATAACCCGCCAGATATGCATTTTCTGGATGCAATCTGTTGGTTTCCAATGGTTTA

CTACATGGTGGGCTCTATTGACAACCTAGATGACTTACTCAGGTGTGGAGTGACTTTT

GCTGCTAATATGGTGGTTGTGGATAAAGAGAGCACCATGAGTGCCGAGGAAGACTACA

TGGCAGATGCCAAAACCATTGTGAΆCGTGCAGACACTCTTCAGGTTGTTTTCCAGTCT

CAGTATTATCACAGAGCTAACTCACCCCGCCAACATGAGATTCATGCAATTCAGAGCC

AAAGACTGTTACTCTCTTGCTCTTTCAAAACTGGAAAAGAAAGAACGGGAGAGAGGCT

CTAACTTGGCCTTTATGTTTCGACTGCCTTTTGCTGCTGGGAGGGTGTTTAGCATCAG

TATGTTGGACACTCTGCTGTATCAGTCATTTGTGAAGGATTATATGATTTCTATCACG

AGACTTCTGTTGGGACTGGACACTACACCAGGATCTGGGTTTCTTTGTTCTATGAAAA

TCACTGCAGATGACTTATGGATCAGAACTTATGCCAGACTTTATCAGAAGTTGTGTTC

TTCTACTGGAGATGTTCCCATTGGAATCTACAGGACTGAGTCTCAGAAACTTACTACA

TCTGAGTCTCAAATATCTATCAGTGTAGAAGAGTGGGAAGACACCAAAGACTCCAAAG

AACAAGGGCACCACCGCAGCAACCACCGCAACTCAACATCCAGTGACCAGTCGGACCA

TCCCTTGCTGCGGAGAAAAAGCATGCAGTGGGCCCGAAGACTGAGCAGAAAAGGCCCA

AAACACTCTGGTAAAACAGCTGAAAAAATAACCCAGCAGCGACTGAACCTCTACAGGG

ATGAAATGAATGATCATCAAAGTACCCTCTCCTACATCCTGATTAACCCATCTCCAGA

TACCAGAATAGAGCTGAATGATGTTGTATACTTAATTCGACCAGATCCACTGGCCTAC

CTTCCAAACAGTGAGCCCAG_TCGAAGAAACAGCATCTGCAATGTCACTGGTCAAGATT . CTCGGGAGGAAACTCAACTTTGATAAAAATAAAATGAGAAACTTTTTTCCTACAAAGAi JCCTTGCTTGAAACCACAAAAGT i

;ORF Start: ATG at 61 iORF Stop: TGA at 3385

SEQ ID NO: 78 i l lOS aa |MW at l27444.0kD _sNOV23c, MVDLESEVPPLPPRYRFRDLLLGDQG QNDDRVQVEFY NENTFKERL LFFIKNQRS JCG103061-03 SLRIRLFNFSLKLLSCLLYIIRVLLENPSQGNEWSHIFWVNRSLPLWGLQVSVALISL ^' Protein Sequence FETILLGYLSYKGNIWEQILRIPFILEIINAVPFIISIFWPSLRNLFVPVFLNCWLAK HALENMINDLHRAIQRTQSAMFNQVLILISTLLCLIFTCICGIQHLERIGKKLNLFDS LYFCIVTFSTVGFGDVTPETWSSKLFWAMICVALWLPIQFEQLAYLWMERQKSGGN YSRHRAQTEKHWLCVSSLKID LMDFLNEFYAHPRLQDYYWI CPTEMDVQVRRVL QIPM SQRVIYLQGSALKDQDLLRAKMDDAEACFILSSRCEVDRTSSDHQTILRAWAV KDFAPNCPLYVQILKPENKFHIKFADHVVCEEEFKYAMLALNCICPATSTLITLLVHT SRGQEGQQSPEQ QK YGRCSGNEVYHIVLEESTFFAEYEG SFTYASFHAHKKFGVC IGVRREDNKNI PGPRYIMNSTDICFYINITKEENSAFKNQDQQRKSNVSRSFYH GPSRLPVHSIIASMVAIDLQDTSCRSASGPTLSLPTEGSKEIRRPSIAPVLEVADTSS LQTCDLLSDQSEDETTPDEEMSSNLEYAKGYPPYSPYIGSSPTFCHLLHEKVPFCCLR LDKSCQHNYYEDAKAYGFKNKLIIVAAETAGNGLYNFIVPLRAYYRP KELNPIVLLL DNPPDMHFLDAICWFPMVYY VGSIDNLDDLLRCGVTFAAMWVDKESTMSAEEDYM ADAKTIVNVQTLFRLFSSLS11 ELTHPANMRFMQFRAKDCYSLALSKLEKKERERGS NLAFMFRLPFAAGRVFSISMLDTLLYQSFV DYMISITRLLLGLDTTPGSGFLCSMKI TADDLWIRTYARLYQKLCSSTGDVPIGIYRTESQKLTTSESQISISVEE EDTKDSKE QGHHRSNHRNSTSSDQSDHPLLRRKSMQ ARRLSRKGPKHSGKTAEKITQQRLNLYRD EMNDHQSTLSYILINPSPDTRIEL DWYLIRPDPLAYLPNSEPSRRNSICNVTGQDS REETQL

SEQ ID NO: 79 3519 bp

NOV23d, CTTTCTTTCTCCCTCCTCTCCTCCATTTGTTGTTTGATGTTTCCCACTCTTTGAGGAA

CG103061-04 DNA GGATGGTTGATTTGGAGAGCGAAGTGCCCCCTCTGCCTCCCAGGTACAGGTTTCGAGA TTTGCTGCTAGGGGACCAAGGATGGCAAAACGACGACAGGGTACAAGTTGAATTCTAT

Sequence ATGAATGAAAATACATTTAAAGAAAGACTAAAATTATTTTTCATAAAAAACCAGAGAT CAAGTCTAAGGATACGCCTGTTCAATTTTTCTCTCAAATTACTAAGCTGCTTATTATA CATAATCCGAGTACTACTAGAAAACCCTTCACAAGGAAATGAATGGTCTCATATCTTT TGGGTGAACAGAAGTCTACCTTTGTGGGGCTTACAGGTTTCAGTGGCATTGATAAGTC TGTTTGAAACAATATTACTTGGTTATCTTAGTTATAAGGGAAACATCTGGGAACAGAT TTTACGAATACCCTTCATCTTGGAAATAATTAATGCAGTTCCCTTCATTATCTCAATA TTCTGGCCTTCCTTAAGGAATCTATTTGTCCCAGTCTTTCTGAACTGTTGGCTTGCCA AACATGCCTTGGAAAATATGATTAATGATCTACACAGAGCCATTCAGCGTACACAGTC TGCAATGTTTAATCAAGTTTTGATTTTAATATCTACATTACTATGCCTTATCTTCACC TGCATTTGTGGGATCCAACATCTGGAACGAATAGGAAAGAAGCTGAATCTCTTTGACT CCCTTTATTTCTGCATTGTGACGTTTTCTACTGTGGGCTTCGGGGATGTCACTCCTGA AACATGGTCCTCCAAGCTTTTTGTAGTTGCTATGATTTGTGTTGCTCTTGTGGTTCTA CCCATACAGTTTGAACAGCTGGCTTATTTGTGGATGGAGAGACAAAAGTCAGGAGGAA ACTATAGTCGACATAGAGCTCAAACTGAAAAGCATGTCGTCCTGTGTGTCAGCTCACT GAAGATTGATTTACTTATGGATTTTTTAAATGAATTCTATGCTCATCCTAGGCTCCAG GATTATTATGTGGTGATTTTGTGTCCTACTGAAATGGATGTACAGGTTCGAAGGGTAC TGCAGATTCCAATGTGGTCCCAACGAGTTATCTACCTTCAAGGTTCAGCCCTTAAAGA TCAAGACCTATTGAGAGCAAAGATGGATGACGCTGAGGCCTGTTTTATTCTCAGTAGC CGTTGTGAAGTGGATAGGACATCATCTGATCACCAAACAATTTTGAGAGCATGGGCTG TGAAAGATTTTGCTCCAAATTGTCCTTTGTATGTCCAGATATTAAAGCCTGAAAATAA ATTTCACATCAAATTTGCTGATCATGTTGTTTGTGAAGAAGAGTTTAAATACGCCATG TTAGCTTTAAACTGTATATGCCCAGCAACATCTACACTTATTACACTACTGGTTCATA CCTCTAGAGGGCAAGAAGGCCAGCAATCGCCAGAACAATGGCAGAAGATGTACGGTAG ATGCTCCGGGAATGAAGTCTACCACATTGTTTTGGAAGAAAGTACATTTTTTGCTGAA' TATGAAGGAAAGAGTTTTACATATGCCTCTTTCCATGCACACAAAAAGTTTGGCGTC GCTTGATTGGTGTTAGGAGGGAGGATAATAAAAACATTTTGCTGAATCCAGGTCCTCG ATACATTATGAATTCTACAGACATATGCTTTTATATTAATATTACCAAAGAAGAGAAT TCAGCATTTAAAAACCAAGACCAGCAGAGAAAAAGCAATGTGTCCAGGTCGTTTTATC; ATGGACCTTCCAGATTACCTGTACATAGCATAATTGCCAGCATGGTGGCTATAGACT GCAAGATACAAGCTGTAGATCAGCAAGTGGCCCTACCCTGTCTCTTCCTACAGAGGGA AGCAAAGAAATAAGAAGACCTAGCATTGCTCCTGTTTTAGAGGTTGCAGATACATCAT

CGATTCAAACATGTGATCTTCTAAGTGACCAATCAGAAGATGAAACTACACCAGATGA

AGAAATGTCTTCAAACTTAGAGTATGCTAAAGGTTACCCACCTTATTCTCCATATATA

SGGAAGTTCACCCACTTTTTGTCATCTCCTTCATGAAAAAGTACCATTTTGCTGCTTAA

JGATTAGACAAGAGTTGCCAACATAACTACTATGAGGATGCAAAAGCCTATGGATTCAA

IAAATAAACTAATTATAGTTGCAGCTGAAACAGCTGGAAATGGATTATATAACTTTATT

IGTTCCTCTCAGGGCATATTATAGACCAAAGAAAGAACTTAATCCCATAGTACTGCTAT

JTGGATAACCCGCCAGATATGCATTTTCTGGATGCAATCTGTTGGTTTCCAATGGTTTA

ICTACATGGTGGGCTCTATTGACAACCTAGATGACTTACTCAGGTGTGGAGTGACTTTT

GCTGCTAATATGGTGGTTGTGGATAAAGAGAGCACCATGAGTGCCGAGGAAGACTACA

TGGCAGATGCCAAAACCATTGTGAACGTGCAGACACTCTTCAGGTTGTTTTCCAGTCT

CAGTATTATCACAGAGCTAACTCACCCCGCCAACATGAGATTCATGCAΆTTCAGAGCC

AAAGACTGTTACTCTCTTGCTCTTTCAAAACTGGΆAAAGAAAGAACGGGAGAGAGGCT

CTAACTTGGCCTTTATGTTTCGACTGCCTTTTGCTGCTGGGAGGGTGTTTAGCATCAG

TATGTTGGACACTCTGCTGTATCAGTCATTTGTGAAGGATTATATGATTTCTATCACG

AGACTTCTGTTGGGACTGGACACTACACCAGGATCTGGGTTTCTTTGTTCTATGAAAA

TCACTGCAGATGACTTATGGATCAGAACTTATGCCAGACTTTATCAGAAGTTGTGTTC TCTACTGGAGATGTTCCCATTGGAATCTACAGGACTGAGTCTCAGAAACTTACTACA

TCTGAGTCTCAAATATCTATCAGTGTAGAAGAGTGGGAAGACACCAAAGACTCCAAAG

AACAAGGGCACCACCGCAGCAACCACCGCAACTCAACATCCAGTGACCAGTCGGACCA

TCCCTTGCTGCGGAGAAAAAGCATGCAGTGGGCCCGAAGACTGΆGCAGAAAΆGGCCCA

JAAACACTCTGGTAAAACAGCTGAAAAAATAACCCAGCAGCGACTGAACCTCTACAGGA

IGGTCAGAAAGACAAGAGCTTGCTGAACTTGTGAAAAATAGAATGAAACACTTGGGTCT

JTTCTACAGTGGGATATGATGAAATGAATGATCATCAAAGTACCCTCTCCTACATCCTG

IATTAACCCATCTCCAGATACCAGAATAGAGCTGAATGATGTTGTATACTTAATTCGAC

'CAGATCCACTGGCCTACCTTCCAAACAGTGAGCCCAGTCGAAGAAACAGCATCTGCAA

;TGTCACTGGTCAAGATTCTCGGGAGGAAACTCAACTTTGATAAAAATAAAATGAGAAA

IC TTTTTCCTACAAAGACCTTGCTTGAAACCACAAAAGT jORF Start: ATG at 61 ORF Stop: TGA at 3460

JSEQ ID NO: 80 11133 aa MW at 130341.3kD

,NOV23d, (MVDLESEVPPLPPRYRFRDLLLGDQG QNDDRVQVEFYMNΞNTFKERLKLFFIKNQRS .CG103061-04 SLRIRLFNFSLKLLSCLLYIIRVLLENPSQGNE SHIF Λ RSLPL GLQVSVALISL FETILLGYLSYKGNIWEQILRIPFILEIINAVPFIISIF PSLRNLFVPVFLNC LAK I Protein Sequence HALENMINDLHRAIQRTQSAMFNQVLILISTLLCLIFTCICGIQHLERIGKKLNLFDS LYFCIVTFSTVGFGDVTPETWSSKLFWAMICVALWLPIQFEQLAYLWMERQKSGGN YSRHRAQTE HΛΛLCVSSLKIDLLMDFLNEFYAHPRLQDYYWILCPTEMDVQVRRVL QIPM SQRVIYLQGSALKDQDLLRAKMDDAEACFILSSRCEVDRTSSDHQTILRAWAV KDFAPNCPLYVQILKPEN FHIKFADHWCΞEEFKYAMLALNCICPATSTLITLLVHT SRGQΞGQQSPEQ QKMYGRCSGNEVYHIVLEESTFFAEYEGKSFTYASFHAHKKFGVC LIGVRREDNK ILLNPGPRYIMNSTDICFYINITKEENSAFKNQDQQRKSISTVSRSFYH GPSRLPVHS11ASMVAIDLQDTSCRSASGPTLSLPTEGSKEIRRPSIAPVLEVADTSS IQTCDLLSDQSEDETTPDEEMSSNLEYAKGYPPYSPYIGSSPTFCHLLHEKVPFCCLR LDKSCQHNYYEDAKAYGFKNKLIIVAAETAGNGLYNFIVPLRAYYRPKKELNPIVLLL DNPPDMHFLDAICWFPMVYYMVGSIDNLDDLLRCGVTFAANMVVVDKEST SAΞEDYM ADAKTIVNVQTLFRLFSSLSIITΞLTHPANMRF QFRAKDCYSLALSKLEK ERERGS NLAFMFRLPFAAGRVFSISMLDTLLYQSFVKDYMISITRLLLGLDTTPGSGFLCSMKI TADDLWIRTYARLYQKLCSSTGDVPIGIYRTESQKLTTSESQISISVEEWEDTKDSKE QGHHRSNHRNSTSSDQSDHPLLRRKSMQWARRLSRKGPKHSGKTAEKITQQRLNLYRR SERQELAELVKNRMKHLGLSTVGYDEMNDHQSTLSYILINPSPDTRIELNDWYLIRP DPLAYLPNSEPSRRNSICNVTGQDSREETQL

SEQ ID NO: 81 3459 bp

NOV23e, CTTTCTTTCTCCCTCCTCTCCTCCATTTGTTGTTTGATGTTTCCCACTCTTTGAGGAA

CGI03061-05 DNA GGATGGTTGATTTGGAGAGCGAAGTGCCCCCTCTGCCTCCCAGGTACAGGTTTCGAGA TTTGCTGCTAGGGGACCAAGGATGGCAAAACGACGACAGGGTACAAGTTGAATTCTAT

Sequence ATGAATGAAAATACATTTAAAGAAAGACTAAAATTATTTTTCATAAAAAACCAGAGAT CAAGTCTAAGGATACGCCTGTTCAATTTTTCTCTCAAATTACTAAGCTGCTTATTATA CATAATCCGAGTACTACTAGAAAACCCTTCACAAGGAAATGAATGGTCTCATATCTTT TGGGTGAACAGAAGTCTACCTTTGTGGGGCTTACAGGGAAACATCTGGGAACAGATTT TACGAATACCCTTCATCTTGGAAATAATTAATGCAGTTCCCTTCATTATCTCAATATT CTGGCCTTCCTTAAGGAATCTATTTGTCCCAGTCTTTCTGAACTGTTGGCTTGCCAAA CATGCCTTGGAAAATATGATTAATGATCTACACAGAGCCATTCAGCGTACACAGTCTG CAATGTTTAATCAAGTTTTGATTTTAATATCTACATTACTATGCCTTATCTTCACCTG CATTTGTGGGATCCAACATCTGGAACGAATAGGAAAGAAGCTGAATCTCTTTGACTCC CJ.'TTATTTCTGCATTGTGACGTTTTCTACTGTGGGCTTCGGGGATGTCACTCCTGAAA CATGGTCCTCCAAGCTTTTTGTAGTTGCTATGATTTGTGTTGCTCTTGTGGTTCTACC CATACAGTTTGAACAGCTGGCTTATTTGTGGATGGAGAGACAAAAGTCAGGAGGAAAC TATAGTCGACATAGAGCTCAAACTGAAAAGCATGTCGTCCTGTGTGTCAGCTCACTGA AGATTGATTTACTTATGGATTTTTTAAATGAATTCTATGCTCATCCTAGGCTCCAGGA TTATTATGTGGTGATTTTGTGTCCTACTGAAATGGATGTACAGGTTCGAAGGGTACTG CAGATTCCAATGTGGTCCCAACGAGTTATCTACCTTCAAGGTTCAGCCCTTAAAGATC AAGACCTATTGAGAGCAAAGATGGATGACGCTGAGGCCTGTTTTATTCTCAGTAGCCG TTGTGAAGTGGATAGGACATCATCTGATCACCAAACAATTTTGAGAGCATGGGCTGTG AAAGATTTTGCTCCAAATTGTCCTTTGTATGTCCAGATATTAAAGCCTGAAAATAAAT TTCACATCAAATTTGCTGATCATGTTGTTTGTGAAGAAGAGTTTAAATACGCCATGTT AGCTTTAAACTGTATATGCCCAGCAACATCTACACTTATTACACTACTGGTTCATACC TCTAGAGGGCAAGAAGGCCAGCAATCGCCAGAACAATGGCAGAAGATGTACGGTAGAT GCTCCGGGAATGAAGTCTACCACATTGTTTTGGAAGAAAGTACATTTTTTGCTGAATA TGAAGGAAAGAGTTTTACATATGCCTCTTTCCATGCACACAAAAAGTTTGGCGTCTGC TTGATTGGTGTTAGGAGGGAGGATAATAAAAACATTTTGCTGAATCCAGGTCCTCGAT ACATTATGAATTCTACAGACATATGCTTTTATATTAATATTACCAAAGAAGAGAATTC AGCATTTAAAAACCAAGACCAGCAGAGAAAAAGCAATGTGTCCAGGTCGTTTTATCAT GGACCTTCCAGATTACCTGTACATAGCATAATTGCCAGCATGGTGGCTATAGACTTGC AAGATACAAGCTGTAGATCAGCAAGTGGCCCTACCCTGTCTCTTCCTACAGAGGGAAG JCAAAGAAATAAGAAGACCTAGCATTGCTCCTGTTTTAGAGGTTGCAGATACATCATCG JATTCAAACATGTGATCTTCTAAGTGACCAATCAGAAGATGAAACTACACCAGATGAAG AAATGTCTTCAAACTTAGAGTATGCTAAAGGTTACCCACCTTATTCTCCATATATAGG AAGTTCACCCACTTTTTGTCATCTCCTTCATGAAAAAGTACCATTTTGCTGCTTAAGA TTAGACAAGAGTTGCCAACATAACTACTATGAGGATGCAAAAGCCTATGGATTCAAAA ATAAACTAATTATAGTTGCAGCTGAAACAGCTGGAAATGGATTATATAACTTTATTGT TCCTCTCAGGGCATATTATAGACCAAAGAAAGAACTTAATCCCATAGTACTGCTATTG GATAACCCGCCAGATATGCATTTTCTGGATGCAATCTGTTGGTTTCCAATGGTTTACT ACATGGTGGGCTCTATTGACAACCTAGATGACTTACTCAGGTGTGGAGTGACTTTTGC TGCTAATATGGTGGTTGTGGATAAAGAGAGCACCATGAGTGCCGAGGAAGACTACATG GCAGATGCCAAAACCATTGTGAACGTGCAGACACTCTTCAGGTTGTTTTCCAGTCTCA GTATTATCACAGAGCTAACTCACCCCGCCAACATGAGATTCATGCAATTCAGAGCCAA AGACTGTTACTCTCTTGCTCTTTCAAAACTGGAAAAGAAAGAACGGGAGAGAGGCTCT AACTTGGCCTTTATGTTTCGACTGCCTTTTGCTGCTGGGAGGGTGTTTAGCATCAGTA TGTTGGACACTCTGCTGTATCAGTCATTTGTGAAGGATTATATGATTTCTATCACGAG ACTTCTGTTGGGACTGGACACTACACCAGGATCTGGGTTTCTTTGTTCTATGAAAATC ACTGCAGATGACTTATGGATCAGAACTTATGCCAGACTTTATCAGAAGTTGTGTTCTT CTACTGGAGATGTTCCCATTGGAATCTACAGGACTGAGTCTCAGAAACTTACTACATC TGAGTCTCAAATATCTATCAGTGTAGAAGAGTGGGAAGACACCAAAGACTCCAAAGAA CAAGGGCACCACCGCAGCAACCACCGCAACTCAACATCCAGTGACCAGTCGGACCATC CCTTGCTGCGGAGAAAAAGCATGCAGTGGGCCCGAAGACTGAGCAGAAAAGGCCCAAA ACACTCTGGTAAAACAGCTGAAAAAATAACCCAGCAGCGACTGAACCTCTACAGGAGG TCAGAAAGACAAGAGCTTGCTGAACTTGTGAAAAATAGAATGAAACACTTGGGTCTTT CTACAGTGGGATATGATGAAATGAATGATCATCAAAGTACCCTCTCCTACATCCTGAT TAACCCATCTCCAGATACCAGAATAGAGCTGAATGATGTTGTATACTTAATTCGACCA GATCCACTGGCCTACCTTCCAAACAGTGAGCCCAGTCGAAGAAACAGCATCTGCAATG TCACTGGTCAAGATTCTCGGGAGGAAΆCTCAACTTTGATAAAAATAAAΆTGAGAAACT TTTTTCCTACAAAGACCTTGCTTGAAACCACAAAAGT

ORF Start: ATG at 61 ORF Stop: TGA at 3400

SEQ ID NO: 82 1113 aa MW at l28129.7kD

NOV23e, VDLESEVPPLPPRYRFRDLLLGDQGWQNDDRVQVEFYMNENTFKERLKLFFIKNQRS CG103061-05 SLRIRLFNFSLKLLSCLLYIIRVLLENPSQGNEWSHIF VNRSLPL GLQGNIWEQIL RIPFILEIINAVPFIISIFWPSLRNLFVPVFLNCWLAKHALENMINDLHRAIQRTQSA Protein Sequence MFNQVLILISTLLCLIFTCICGIQHLERIGKKLNLFDSLYFCIVTFSTVGFGDVTPET

^' _:NOV23f, iTRSL GLQVSVALISLFETILLGYLSYKGNIWEQILRIPFILEIINAVPFIISIF PS

^275630903 Protein ΪLRNLFVPVFLNC LAKHALENMINDLHRAIQRTQSAMFNQVLILISTLLCLIFTCICG

J IQHLERIGKKLNLFDSLYFCIVTFSTVGFGDVTPETWSSKLFWAMICVALWLPLQF

■Sequence EQLLEG

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 23B.

Further analysis of the NOV23a protein yielded the following properties shown in Table 23C.

Table 23C. Protein Sequence Properties NOV23a i PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3200 probability located in nucleus; 0.3000 probability located in endoplasmic reticulum (membrane)

^'. SignalP No Known Signal Sequence Indicated i analysis:

A search of the NOV23a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 23D.

In a BLAST search of public sequence databases, the NOV23a protein was found to have homology to the proteins shown in the BLASTP data in Table 23E.

Table 23E. Public BLASTP Results for NO 23a

Protein NOV23a Identities/

Expect

Accession Protein/Organism/Length Residues/ Similarities for Value

Number Residues Portion

AAM18770 j POTASSIUM CHANNEL 40..1 187 868/1 162 (74%) 0.0 ; SUBUNIT - Gallus gallus 64..1201 977/1162 (83%) ! (Chicken), 1201 aa.

Q9Z258 j POTASSIUM CHANNEL 40..1187 839/1174 (71%) 0.0

SUBUNIT - Rattus norvegicus 66..1237 963/1174 (81%) (Rat), 1237 aa.

Q8WX41 BA100C15.2 (POTASSIUM 40..1187 844/1210 (69%) 0.0 CHANNEL SUBUNIT PROTEIN 151..1349 963/1210 (78%) (KIAA1422) ) - Homo sapiens (Human), 1349 aa.

Q9P2C5 KIAA1422 PROTEIN - Homo 8..1066 j 792/1078 (73%) ' 0.0 sapiens (Human), 1 151 aa 75..1150 ! 897/1078 (82%) (fragment).

Q9BE94 HYPOTHETICAL 78.7 KDA 509..1187 488/708 (68%) 0.0 _ PROTEIN - Macaca fascicularis 1..705 574/708 (80%) ^J (Crab eating macaque)

(Cynomolgus monkey), 705 aa.

PFam analysis indicates that the NOV23a protein contains the domains shown in the Table 23F.

Table 23F. Domain Analysis of NOV23a

Identities/

Pfam Domain NOV23a Match Region Similarities ; Expect Value for the Matched Region

■ ion trans 131..306 36/226 (16%) .8e-10 135/226 (60%)

Example 24.

The NOV24 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 24A.

Further analysis of the NOV24a protein yielded the following properties shown in

Table 24B.

Table 24B. Protein Sequence Properties NOV24a

PSort 0.3077 probability located in microbody (peroxisome); 0.3000 probability analysis: located in nucleus; 0.1827 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Indicated i analysis:

A search of the NOV24a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 24C.

Table 24C. Geneseq Results for NOV24a

NOV24a Identities/

In a BLAST search of public sequence databases, the NOV24a protein was found to have homology to the proteins shown in the BLASTP data in Table 24D.

PFam analysis indicates that the NOV24a protein contains the domains shown in the Table 24E.

Example 25.

The NOV25 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 25A.

AAGAAGATTATCGAAGAAGAAAGTCTCATCCTAATTTTCTGGACCACATAAATGCTGA AAAAATGGTTCTCAAATTTGGAAAAAAGGCCAGAAAATTTGCAGCATACGTAGTTGCT GCTGGACTCCAGTATGGAGCGGAAGGAGGCATGTTACACACATTTTTTAAGATGGCTT GGTTGGGCGAGATTCCTGCATTACCAGTTTTTGGCGATGGAACAAATGTAATTCCAAC AATCCATGTTCTTGATCTAGCAGGAGTGATACAAAACGTCATAGATCACGTGCCAAAG CCTCACTACCTGGTTGCTGTGGATGAGTCTGTTCATACCCTGGAAGACATAGTCAAGT GTATCAGTAAAAATACTGGCCCTGGGAAAATCCAGAAAATACCCAGAGAAAATGCATA CCTAACCAAGGACTTAACGCAAGATTGTCTTGACCATTTACTGGTCAACTTAAGAATG GAAGCGCTCTTTGTGAAGGAGAATTTTAATATTCGATGGGCTGCCCAAACAGGATTTG TGGAAAATATCAACACTATCCTCAAGGAGTACAAGCAAAGCAGAGGATTGATGCCAAT CAAGATCTGCATTCTTGGTCCCCCTGCTGTGGGAAAATCCAGTATTGCTAAAGAATTG GCCAAGTACTACAAACTGCATCACATCCAACTGAAGGATGTCATTTCTGAAGCCATAG CAAAACTGGAGGCGATTGTTGCCCCTAACGATGTAGGGGAAGGAAAAAGAGAAGAAAG AGAATTACTGGAGGCTCAGTCAATTCCCCTGACAGAATATATAAAGACCTATGTGATG CCAACTCTTATTCAGGGCCTGAATGAATGTTGCAACGTCCGACCCGAAGACCCTGTTG ATTTTCTGGCAGAATATCTCTTCAAGAACAATCCTGAAGCACAGTGAAACTTGAAAGA TCTGGTATTAT

ORF Start: ATG at 28 JORF Stop: TGA at 1147

SEQ ID NO: 92 ]373 aa MW at 42189.4kD

_;NOV25c, MRLLECDVIIYNITESSQQMEEAIWAVSALSEEVSHFEKRKLFILLSTVMT ARSKAL ΪCG103229-03 DPEDSEVPFTEEDYRRRKSHPNFLDHINAEK VLKFG KARKFAAYWAAGLQYGAEG GMLHTFFKMA LGEIPALPVFGDGTNVIPTIHVLDLAGVIQNVIDHVPKPHYLVAVDE ; Protein Sequence SVHTLEDIVKCISK TGPGKIQKIPRENAYLTKDLTQDCLDHLLVWLRMΞALFVKENF ;NIR AAQTGFVENINTILKEYKQSRGLMPIKICILGPPAVGKSSIAKELAKYYKLHHI IQLKDVISEAIAKLEAIVAPNDVGEGKREERELLEAQSIPLTEYIKTYVMPTLIQGLNE j JCCNVRPEDPVDFLAEYLFKNNPEAQ I

SEQ ID NO: 93 ] 1299 bp iNOV25d, CAGGCCATCTCTCGAGAAGACCTTCTCATGCGCCTGCTGGAGTGTGATGTTATTATTT

I CGI 03229-04 DNA ATAACATCACTGAGAGCTCACAGCAAATGGAGGAAGCCATCTGGGCAGTCTCTGCACT

' Sequence CAGTGAAGAAGTCAGCCACTTTGAAAAGCGAAAGCTATTTATTTTACTGTCGACGGTG ATGACTTGGGCGCGCTCCAAAGCCCTGGACCCCGAGGATTCTGAGGTTCCATTCACTG AAGAAGATTATCGAAGAAGAAAGTCTCATCCTAATTTTCTGGACCACATAAATGCTGA AAAAATGGTTCTCAAATTTGGAAAAAAGGCCAGAAAATTTGCAGCATACGTAGTTGCT GCTGGACTCCAGTATGGAGCGGAAGGAGGCATGTTACACACATTTTTTAAGATGGCTT GGTTGGGCGAGATTCCTGCATTACCAGTTTTTGGCGATGGAACAAATGTAATTCCAAC AATCCATGTTCTTGATCTAGCAGGAGTGATACAAAACGTCATAGATCACGTGCCAAAG CCTCACTACCTGGTTGCTGTGGATGAGTCTGTTCATACCCTGGAAGACATAGTCAAGT GTATCAGTAAAAATACTGGCCCTGGGAAAATCCAGAAAATACCCAGAGAAAATGCATA CCTAACCAAGGACTTAACGCAAGATTGTCTTGACCATTTACTGGTCAACTTAAGAATG GAAGCGCTCTTTGTGAAGGAGAATTTTAATATTCGATGGGCTGCCCAAACAGGATTTG TGGAAAATATCGACGATGAGACTGTCTTCAACTATTTTGATGAACTTGAAATTCACCC GATACATATTGATGTAGGAAAACTTGAAGATGCTCAGAATAGACTTGCTATCAAACAG CTCATCAAAGAGATTGGGGAGCCTCGAAATTATGGTTTAACAGACGAAGAAAAGGCAG AAGAGGAGCGGAAGGCTGCGGAGGAGCGGCTGGCCAGGGAGGCTGCTGAGGAAGCAGA ACGCGAGCACCAGGAGGCCGTGGAGATGGCAGAGAAGATAGCTCGCTGGGAGGAGTGG AATAAACGACTGGAGGAAGTGAAAAGAGAAGAAAGAGAATTACTGGAGGCTCAGTCAA TTCCCCTGAGAAACTATTTAATGACCTATGTGATGCCAACTCTTATTCAGGGCCTGAA TGAATGTTGCAACGTCCGACCCGAAGACCCTGTTGATTTTCTGGCAGAATATCTCTTC AAGAACAATCCTGAAGCACAGTGAAACTTGAAAGATCTGGTATTATCTACCTTTACAG AACCACAGATCACTTATTATACT

ORF Start: ATG at 28 ORF Stop: TGA at 1240

SEQ ID NO: 94 404 aa MW at 46579.5kD

NOV25d, MRLLECDVIIYNITESSQQMEEAIWAVSALSEEVSHFEKR LFILLSTVMT ARSKAL CGI 03229-04 DPEDSEVPFTEEDYRRRKSHPNFLDHINAEKMVLKFGKKARKFAAYWAAGLQYGAEG GMLHTFFKMAWLGEIPALPVFGDGTNVIPTIHVLDLAGVIQNVIDHVPKPHYLVAλHDE Protein Sequence SVHTLEDIVKCISKNTGPGKIQKIPRENAYLTKDLTQDCLDHLLVNLRME LFVKENF NIR AAQTGFVENIDDETVFNYFDELEIHPIHIDVGKLEDAQNRLAIKQLIKEIGEPR

ICG103229-06 VLDLAGVIQNVIDHVPKPHYLVAVDESVHTLEDIVKCISK TGPGKIQKIPRENAYLT i Protein Sequence KDLTQDCLDHLLλ NLRMEALFVKENFNIR AAQTGFVENINTILKEYKQSRGLMPIKI CILGPPAVGKSSIAKELANYYKLHHIQLKDVISEAIAKLEAIVAPNDVGEGEEEVEΞE VKREERELLΞAQSIPLRNYLMTYVMPTLIQGLNECCNVRPEDPVDFLAEYLFfOrøPEA Q

!S£Q ID NO: 99 | 1098 bp

NOV25g, AAGACCTTCTCATGCGCCTGCTGGAGTGTGATGTTATTATTTATAACATCACTGAGAG

CGI 03229-07 DNA CTCACAGCAAATGGAGGAAGCCATCTGGGCAGTCTCTGCACTCAGTGAAGAAGTCAGC

Sequence CACTTTGAAAAGCGAAAGCTATTTATTTTACTGTCGACGGTGATGACTTGGGCGCGCT CCAAAGCCCTGGACCCCGAGGATTCTGAGGTTCCATTCACTGAAGAAGATTATCGAAG AAGAAAGTCTCATCCTAATTTTCTGGACCACATAAATGCTGAAAAAATGGTTCTCAAA TTTGGAAAAAAAATGGCTTGGTTGGGCGAGATTCCTGCATTACCAGTTTTTGGCGATG GAACAAATGTAATTCCAACAATCCATGTTCTTGATCTAGCAGGAGTGATACAAAACGT CATAGATCACGTGCCAAAGCCTCACTACCTGGTTGCTGTGGATGAGTCTGTTCATACC CTGGAAGACATAGTCAAGTGTATCAGTAAAAATACTGGCCCTGGGAAAATCCAGAAAA TACCCAGAGAAAATGCATACCTAACCAAGGACTTAACGCAAGATTGTCTTGACCATTT ACTGGTCAACTTAAGAATGGAAGCGCTCTTTGTGAAGGAGAATTTTAATATTCGATGG GCTGCCCAAACAGGATTTGTGGAAAATATCAACACTATCCTCAAGGAGTACAAGCAAA GCAGAGGATTGATGCCAATCAAGATCTGCATTCTTGGTCCCCCTGCTGTGGGAAAATC CAGTATTGCTAAAGAATTGGCCAAGTACTACAAACTGCATCACATCCAACTGAAGGAT GTCATTTCTGAAGCCATAGCAAAACTGGAGGCGATTGTTGCCCCTAACGATGTAGGGG AAGGAGAAGAAGAAGTCGAAGAGGAAGTGAAAAGAGAAGAAAGAGAATTACTGGAGGC TCAGTCAATTCCCCTGAGAAACTATTTAATGACCTATGTGATGCCAACTCTTATTCAG GGCCTGAATGAATGTTGCAACGTCCGACCCGAAGACCCTGTTGATTTTCTGGCAGAAT ATCTCTTCAAGAACAATCCTGAAGCACAGTGAAACTTGAAAGATCTGGTATTAT

IORF Start: ATG at 12 iORF Stop: TGA at 1074

SEQ ID NO: 100 354 aa !MW at 40319.1kD

NOV25g, MRLLECDVIIYNITESSQQMEEAIWAVSALSEEVSHFEKRKLFILLSTλ/MTWARSKAL ICG103229-07 DPEDSEVPFTEEDYRRRKSHPNFLDHINAEKMVLKFG KMA LGEIPALPVFGDGTNV IPTIHVLDLAGVIQNVIDHVPKPHYLVAVDESVHTLEDIVKCISKNTGPGKIQKIPRE Protein Sequence NAYLTKDLTQDCLDHLLVNLRMEALFVKENFNIRWAAQTGFVENINTILKEYKQSRGL MPIKICILGPPAVGKSSIAKELAKYYKLHHIQLKDVISEAIAKLEAIVAP DVGEGEE EVEEEVKREERELLEAQSI LRNYLMTYVMPTLIQGLNECC VRPEDPVDFLAΞYLFK NNPEAQ

SEQ ID NO: 101 2006 bp

|NOV25h, AAGACCTTCTCATGCGCCTGCTGGAGTGTGATGTTATTATTTATAACATCACTGAGAG

CG103229-08 DNA CTCACAGCAAATGGAGGAAGCCATCTGGGCAGTCTCTGCACTCAGTGAAGAAGTCAGC CACTTTGAAAAGCGAAAGCTATTTATTTTACTGTCGACGGTGATGACTTGGGCGCGCT

Sequence CCAAAGCCCTGGACCCCGAGGATTCTGAGGTTCCATTCACTGAAGAAGATTATCGAAG AAGAAAGTCTCATCCTAATTTTCTGGACCACATAAATGCTGAAAAAATGGTTCTCAAA TTTGGAAAAAAGTATCTCATGAGTTCTCAGTGTTTTACTCATGGTATCTCATGTCATC TTCAAGAGTCTCATAAACAATTCCCAGAATTCTGTGAGGCCAGAAAATTTGCAGCATA CGTAGTTGCTGCTGGGCTCCAGTATGGAGCGGAAGGAGGCATGTTACACACATTTTTT AAGATGGCTTGGTTGGGCGAGATTCCTGCATTACCAGTTTTTGGCGATGGAACAAATG TAATTCCAACAATCCATGTTCTTGATCTAGCAGGAGTGATACAAAACGTCATAGATCA CGTGCCAGAGCCTCACTACCTGGTTGCTGTGGATGAGTCTGTTCATACCCTGGAAGAC ATAGTCAAGTGTATCAGTAAAAATACTGGCCCTGGGAAAATCCAGAAAATACCCAGAG AAAATGCATACCTAACCAAGGACTTAACGCAAGATTGTCTTGACCATTTACTGGTCAA CTTAAGAATGGAAGCGCTCTTTGTGAAGGAGAATTTTAATATTCGATGGGCTGCCCAA ACAGGATTTGTGGAAAATATCAACACTATCCTCAAGGAGTACAAGCAAAGCAGAGGAT TGATGCCAATCAAGATCTGCATTCTTGGTCCCCCTGCTGTGGGAAAATCCAGTATTGC TAAAGAATTGGCCAACTACTACAAACTGCATCACATCCAACTGAAGGATGTCATTTCT GAAGCCATAGCAAAACTGGAGGCGATTGTTGCCCCTAACGATGTAGGGGAAGGAGAAG AAGAAGTCGAAGAGGAAGAGGAGGAGGAGAATGTGGAAGATGCACAGGAGCTCCTAGA TGGCATCAAGGAGAGCATGGAGCAGAATGCAGGTCAACTAGACGATCAATATATAATT AGATTTATGAAAGAAAAGCTAAAATCAATGCCTTGCAGGAATCAAGGTTATATTTTGG ATGGATTCCCAAAGACCTATGATCAAGCAAAAGACCTGTTCAATCAGGAAGATGAGGA GGAGGAAGATGATGTCAGAGGCAGAATGTTTCCCTTTGATAAATTAATTATACCTGAA

TTCGTTTGTGCACTGGATGCTTCGGATGAGTTTCTGAAGGΆGCGTGTGATAAACCTTC

JCTGAGAGCATCGTGGCGGGGACCCACTACAGCCAAGACCGATTCCTCCGGGCTCTGAG

JCAACTACCGGGACATCAATATCGACGATGAGACTGTCTTCAACTATTTTGATGAACTT

IGAAATTCACCCGATACATATTGATGTAGGAAAACTTGAAGATGCTCAGAATAGACTTG

CTATCAAACAGCTCATCAAAGAGATTGGGGAGCCTCGAAATTATGGTTTAACAGACGA

AGAAAAGGCAGAAGAGGAGCGGAAGGCTGCGGAGGAGCGGCTGGCCAGGGAGGCTGCT

GAGGAAGCAGAACGCGAGCACCAGGAGGCCGTGGAGATGGCAGAGAAGATAGCTCGCT

GGGAGGAGTGGAATAAACGACTGGAGGAAGTGAAAAGAGAAGAAAGAGAATTACTGGA

GGCTCAGTCAATTCCCCTGAGAAACTATTTAATGACCTATGTGATGCCAACTCTTATT

CAGGGCCTGAATGAATGTTGCAACGTCCGACCCGAAGACCCTGTTGATTTTCTGGCAG

SAATATCTCTTCAAGAACAATCCTGAAGCACAGTGAAACTTGAAAGATCTGGTATTATC

TACCTTTACAGAACCACAGATCACTTATTATACT

ORF Start: ATG at 12 ORF Stop: TGA at 1947

SEQ ID NO: 102 645 aa MWat74281.4kD

JNOV25L MRLLECDVIIYNITESSQQMEEAI AVSALSEEVSHFEKRKLFILLSTΛ/MT ARSKAL !cG103229-08 DPEDSEVPFTEEDYRRRKSHPNFLDHINAEKMVLKFGKKYLMSSQCFTHGISCHLQES

HKQFPEFCEARKFAAYVVAAGLQYGAEGGMLHTFFKMA LGEIPALPVFGDGTLSRVIPT Rrotein Sequence IHVLDLAGVIQNVIDHVPEPHYLVAVDESVHTLEDIVKCISKNTGPGKIQKIPRENAY

JLTKDLTQDCLDHLLVNLRMEALFVKENFNIRWAAQTGFVENINTILKEYKQSRGLMPI

IKICILGPPAVGKSSIAKELANYYKLHHIQLKDVISEAIAKLEAIVAP DVGEGEEEVE

JEEEEEENVEDAQELLDGIKESMΞQNAGQLDDQYIIRFMKEKLKSMPCRNQGYILDGFP

^'KTYDQAKDLFNQEDEEEEDDVRGRMFPFDKLIIPEFVCALDASDEFLKERVINLPΞSI

VAGTHYSQDRFLRALSNYRDINIDDETVFNYFDELEIHPIHIDVGKLEDAQNRLAIKQ

LIKEIGEPRNYGLTDEEKAEEERKAAEERLAREAAEEAEREHQEAVEMAEKIARWEE

NKRLEEVKREERELLEAQSIPLRNYL TYVMPTLIQGLNECCNVRPEDPVDFLAEYLF

KNNPEAQ

SEQ ID NO: 103 531 bp jNOV25i, CAGATTGTGGGCACGCTGTCCAAGCCTGACAGCCCGCGGCCTGACTTTGCGGTGGAGA

^!CG103229-09 DNA JCGTACTCTGCCATCTCTCGAGAAGACCTTCTCATGCGCCTGCTGGAGTGTGATGTTAT ^'TATTTATAACATCACTGAGAGCTCACAGCAAATGGAGGAAGCCATCTGGGCAGTCTCT

'Sequence GCACTCAGTGAAGAAGTCAGCCACTTTGAAAAGCGAAAGCTATTTATTTTACTGTCGA CGGTGATGACTTGGGCGCGCTCCAAAGCCTTGGACCCCGAGGATTCTGAGGTTCCATT CACTGAAGAAGATTATCGAAGAAGAAAGTCTCATCCTAATTTTCTGGACCACATAAAT GCTGAAAAAATGGTTCTCAAATTTGGAAAAAAGGCTGTTATCTACGCACATTGATGTC

CTCAGCGCATTTCCTGGCGTGGAGCTGAGATTCAGTCTGAGAGCCATCAGCCACCAAA

GCCTGCTGGGTTCGCTTTTTTTCTTTGGAATCCAAAACCCCATCATTCAATAGAATTT

'ATCTTGACA

ORF Start: ATG at 91 ORF Stop: TGA at 400

SEQ ID NO: 104 103 aa MW at l2087.7kD

NOV25i, MRLLECDVIIYNITESSQQMEEAIWAVSALSEEVSHFEKRKLFILLSTV TWARSKAL CG103229-09 DPEDSEVPFTEEDYRRRKSHPNFLDHINAEKMVLKFGKKAVIYAH Protein Sequence

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 25B.

Table 25B. Comparison of NOV25a against NOV25b through NOV25L ties/

Protein Sequence NOV25a Residues/ Identi Match Residues Similarities for the Matched Region

NOV25b 1..312 311/312 (99%) 1..312 311/312 (99%)

Further analysis of the NOV25a protein yielded the following properties shown in Table 25C.

Table 25C. Protein Sequence Properties NOV25a

PSort 0.3000 probability located in microbody (peroxisome); 0.3000 probability [ analysis: located in nucleus; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

: SignalP Cleavage site between residues 58 and 59 j analysis:

A search of the NOV25a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 25D.

In a BLAST search of public sequence databases, the NOV25a protein was found to have homology to the proteins shown in the BLASTP data in Table 25E.

Table 25E. Public BLASTP Results for NOV25a

NOV25a Identities/

Protein Residues/ Similarities for Expect

Accession Protein/Organism/Length

Match the Matched Value

Number Residues Portion

Q96M32 CDNA FLJ32864 FIS, CLONE 1..617 614/617 (99%) 0.0 TESTI2003625 - Homo sapiens 107..723 614/617 (99%) (Human), 723 aa.

Q9D2H2 4930502N02RIK PROTEIN - Mus 4..617 536/614 (87%) 0.0 musculus (Mouse), 614 aa. 1..614 590/614 (95%)

Q95JP6 i HYPOTHETICAL 60.8 KDA 90..617 511/528 (96%) 0.0 PROTEIN - Macaca fascicularis 1..528 520/528 (97%) (Crab eating macaque) (Cynomolgus monkey), 528 aa.

Q8WQ37 HYPOTHETICAL PREDICTED 68-328 78/300 (26%) 4e-17 PROTEIN P265.14, UNKNOWN 293..590 130/300 (43%)

FUNCTION - Leishmania major, 1146 aa.

Q962J2 PV1H14210_P - Plasmodium vivax, 308-612 74/321 (23%) 2e-E 894 aa. 559-865 141/321 (43%)

PFam analysis indcates that the NOV25a protein contains the domains shown in the Table 25F.

165/297 (56%)

Example 26.

The NOV26 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 26A.

Table 26A. NOV26 Sequence Analysis

SEQ ID NO: 105 1920 bp

NOV26a, CGCGCGTTTGTTCTCGGCGCCCAGGGCCTTGCAGTCACATGTCAGTCGCGCCGAGCAG

CG103285-01 DNA CCCCCACGCCGCGCTGGTCCGTCCTCGCCTCCCTCGCCGCCGCCCCCCGCGCGCGCGG

GCCTTTGCCACCATCGGTGTCCCGGCCAGAGCCNGAGGAGGGCGCCATCGGACGCCGA Sequence CGTCGGGGTNACGCCGCCGGGCTCGCTCGCACCTGGGCAGCTTCAAGGTGGACAACTG

GAAGCAGAACCTGCGGGCCATCTACCAGTGCTTCGTGTGGAGCGGCACGGCTGAGGCC CGCAAGCGCAAGGCCAAGTCCTGTATCTGCCATGTCTGTGGCGTCCACCTCAACAGGC TGCATTCCTGCCTCTACTGTGTCTTCTTCGGCTGTTTCACAAAGAAGCATATTCACGA GCATGCGAAGGCGAAGCGGCACAACCTGGCCATTGATCTGATGTATGGAGGCATCTAC TGTTTTCTGTGCCAGGACTACATCTATGACAAAGACATGGAAATAATCGCCAAGGAGG AGCAGCGAAAAGCTTGGAAAATGCAAGGCGTTGGAGAGAAGTTTTCAACTTGGGAACC AACCAAACGGGAGCTTGAACTGCTGAAGCACAACCCGAAAAGGAGAAAGATCACCTCG AACTGCACCATAGGTCTGCGTGGGCTGATCAACCTTGGGAACACATGCTTCATGAACT GCATCGTGCAGGCCCTGACCCACACGCCACTTCTGCGGGACTTCTTCCTGTCTGACAG GCACCGCTGTGAGATGCAGAGCCCCAGCTCCTGTCTGGTCTGTGAGATGTCCTCACTG 'TTTCAGGAGTTTTACTCTGGACACCGGTCCCCTCACATCCCGTATAAGTTGCTGCACC ITGGTGTGGACCCACGCGAGGCACCTAGCAGGCTACGAGCAGCAGGACGCCCACGAGTT JCCTCATCGCAGGACGCCCACGAGTTCCTCATCGCAGGACGCCCACGAGTTCCTCATCG ICAGGACGCCCACGAGTTCCTCATCGCGGCCCTGGACGTGCTCCACCGACACTGCAAAG _;GTGATGACAATGGGAAGAAGGCCAACAACCCCAACCACTGCAACTGCATCATAGACCA GATCTTCACAGGCGGGTTGCAGTCAGACGTCACCTGCCAAGTCTGCCATGGAGTCTCC ACCACCATCGACCCCTTCTGGGACATCAGCTTGGATCTCCCCGGCTCTTCCACCCCAT TCTGGCCCCTGAGCCCAGGGAGCGAGGGCAACGTGGTAAACGGGGAAAGCCACGTGTC GGGAACCACCACGCTCACGGACTGCCTGCGACGATTCACCAGACCAGAGCACTTGGGC JAGCAGCGCCAAGATCAAGTGCAGCGGTTGCCATAGCTACCAGGAGTCCACAAAGCAGC ^CACTATGAAGAAACTGCCCATCGTAGCCTGTTTTCATCTCAAACGATTTGAACACTC AGCCAAGCTGCGGCGGAAGATCACCACGTATGTGTCCTTCCCCCTGGAGCTGGACATG ACCCCTTTCATGGCCTCCAGCAAAGAGAGCAGGATGAATGGACAGTACCAGCAGCCCA CGGACAGTCTCAACAATGACAACAAGTATTCCCTGTTTGCTGTTGTTAACCATCAAGG GACCTTGGAGAGTGGCCACTACACCAGCTTTATCCGGCAGCACAAAGACCAGTGGTTC AAGTGTGACGATGCCATCATCACCAAGGCCAGCATCAAGGACGTCCTGGACAGCGAAG GGTACTTGCTGTTCTATCACAAACAGTTCCTGGAATACGAGTAGCCTTATCTGCAGCT GGTCAGAAAAACAAAGGCAATGCATTGGCAAGCCTCACAAAGTGATCCTCCCTGGCCC CCCCCCTCCCCCAAGCCTCCCACCGCCTCCCCGGCCTGGTGACACCACCTCCCATGCA

GATGTG

ORF Start: at 186 JORF Stop: end of sequence

SEQ ID NO: 106 581 aa MW at 66078.9kD

NOV26a, MSVAPSSPHAALVRPRLPRRRPPRARAFATIGVPARAXGGRHRTPTSGXRRRARSHLG CG103285-01 SFKVD QNLRAIYQCFV SGTAEARKRKAKSCICHVCGVHLNRLHSCLYCVFFGCF TKKHIHEHAKAKRHNLAIDLMYGGIYCFLCQDYIYDKDMΞIIAKEEQRKA KMQGVGE Protein Sequence KFSTWEPTKRELELLKHNPKRRKITSNCTIGLRGLINLGNTCFM CIVQALTHTPLLR DFFLSDRHRCEMQSPSSCLVCEMSSLFQEFYSGHRSPHIPYKLLHLV THARHLAGYE QQDAHEFLIAGRPRVPHRRTPTSSSSQDAHEFLIAALDVLHRHC GDDNGKKANPNH CNCIIDQIFTGGLQSDVTCQVCHGVSTTIDPF DISLDLPGSSTPF PLSPGSEGNW NGESHVSGTTTLTDCLRRFTRPEHLGSSAKIKCSGCHSYQESTKQLTMKKLPIVACFH LKRFEHSAKLRRKITTYVSFPLELD TPF ASSKESRMNGQYQQPTDSLNNDNKYSLF AλAnsTHQGTLESGHYTSFIRQHKDQ FKCDDAIITKASIKDVLDSEGYLLFYHKQFLEY SEQ ID NO: 107 11845 bp

;NOV26b, I CGCGCGTTTGTTCTCGGCGCCCAGGGCCTTGCAGTCACATGTCAGTCGCGCCGAGCAG

; CGI 03285 -02 DNA iCCCCCACGCCGCGCTGGTCCGTCCTCGCCTCCCTCGCCGCCGCCCCCCGCGCGCGCGG

JGCCTTTGCCACCATCGGTGTCCCGGCCAGAGCCNGAGGAGGGCGCCATCGGACGCCGA Sequence CGTCGGGGTNACGCCGCCGGGCTCGCTCGCACCTGGGCAGCTTCAAGGTGGACAACTG GAAGCAGAACCTGCGGGCCATCTACCAGTGCTTCGTGTGGAGCGGCACGGCTGAGGCC CGCAAGCGCAAGGCCAAGTCCTGTATCTGCCATGTCTGTGGCGTCCA.CCTCAACAGGC TGCATTCCTGCCTCTACTGTGTCTTCTTCGGCTGTTTCACAAAGAAGCATATTCACGA GCATGCGAAGGCGAAGCGGCACAACCTGGCCATTGATCTGATGTATGGAGGCATCTAC TGTTTTCTGTGCCAGGACTACATCTATGACAAAGACATGGAAATAATCGCCAAGGAGG AGCAGCGAAAAGCTTGGAAAATGCAAGGCGTTGGAGAGAAGTTTTCAACTTGGGAACC AACCAAACGGGAGCTTGAACTGCTGAAGCACAACCCGAAAAGGAGAAAGATCACCTCG AACTGCACCATAGGTCTGCGTGGGCTGATCAACCTTGGGAACACATGCTTCATGAACT GCATCGTGCAGGCCCTGACCCACACGCCACTTCTGCGGGACTTCTTCCTGTCTGACAG GCACCGCTGTGAGATGCAGAGCCCCAGCTCCTGTCTGGTCTGTGAGATGTCCTCACTG TTTCAGGAGTTTTACTCTGGACACCGGTCCCCTCACATCCCGTATAAGTTGCTGCACC TGGTGTGGACCCACGCGAAGCACCTAGCAGGCTACGAGCAGCAGGACGCCCACGAGTT CCTCATCGCGGCCCTGGACGTGCTCCACCGACACTGCAAAGGTGATGACAATGGGAAG AAGGCCAACAACCCCAACCACTGCAACTGCATCATAGACCAGATCTTCACAGGCGGGT TGCAGTCAGACGTCACCTGCCAAGTCTGCCATGGAGTCTCCACCACCATCGACCCCTT CTGGGACATCAGCTTGGATCTCCCCGGCTCTTCCACCCCATTCTGGCCCCTGAGCCCA GGGAGCGAGGGCAACGTGGTAAACGGGGAAAGCCACGTGTCGGGAACCACCACGCTCA CGGACTGCCTGCGACGATTCACCAGACCAGAGCACTTGGGCAGCAGCGCCAAGATCAA GTGCAGCGGTTGCCATAGCTACCAGGAGTCCACAAAGCAGCTCACTATGAAGAAACTG CCCATCGTAGCCTGTTTTCATCTCAAACGATTTGAACACTCAGCCAAGCTGCGGCGGA AGATCACCACGTATGTGTCCTTCCCCCTGGAGCTGGACATGACCCCTTTCATGGCCTC CAGCAAAGAGAGCAGGATGAATGGACAGTACCAGCAGCCCACGGACAGTCTCAACAAT GACAACAAGTATTCCCTGTTTGCTGTTGTTAACCATCAAGGGACCTTGGAGAGTGGCC ACTACACCAGCTTTATCCGGCAGCACAAAGACCAGTGGTTCAAGTGTGACGATGCCAT CATCACCAAGGCCAGCATCAAGGACGTCCTGGACAGCGAAGGGTACTTGCTGTTCTAT CACAAACAGTTCCTGGAATACGAGTAGCCTTATCTGCAGCTGGTCAGAAAAACAAAGG CAATGCATTGGCAAGCCTCACAAAGTGATCCTCCCTGGCCCCCCCCCTCCCCCAAGCC TCCCACCGCCTCCCCGGCCTGGTGACACCACCTCCCATGCAGATGTG

ORF Start: at 186 j ORF Stop: end of sequence

SEQ ID NO: 108 556 aa MW at 63265.9kD

NOV26b, MSVAPSSPHAALVRPRLPRRRPPRARAFATIGVPARAXGGRHRTPTSGXRRRARSHLG CG103285-02 SFKVD WKQNLRAIYQCFV SGTAEAR RKAKSCICHVCGVHLNRLHSCLYCVFFGCF TKKHIHEHAKAKRHNLAIDLMYGGIYCFLCQDYIYDKDMEIIAKEEQRKAWKMQGVGE Protein Sequence KFSTWEPTKRELELLKHNPKRRKITSNCTIGLRGLINLGNTCF CIVQALTHTPLLR DFFLSDRHRCEMQSPSSCLVCEMSSLFQEFYSGHRSPHIPYKLLHL THAKHLAGYE QQDAHEFLIAALDVLHRHCKGDDNGKKANNPNHCNCIIDQIFTGGLQSDVTCQVCHGV STTIDPF DISLDLPGSSTPFWPLSPGSEG WNGESHVSGTTTLTDCLRRFTRPEHL GSSAKI CSGCHSYQESTKQLTMKKLPIVACFHLKRFEHSAKLRRKITTYVSFPLELD MTPF^ SSKESRM GQYQQPTDSLN_roNKYSLFAV NHQGTLESGHYTSFIRQHI-DQW FKCDDAIITKASIKDVLDSEGYLLFYHKQFLΞYE

SEQ ID NO: 109 1857 bp

NOV26c, AATGCAGCTCTGTTGAGGTGGACGCCACAGACATGGCAGATACAGGACTTGGCCTTGC

CGI 03285-03 DNA GCTTGCGGGCCTCAGCCGTGCCGCTCCACACGAAGTACTGGTAGATGGCCCGCAGGTT

CTGCTTCCAGTTGTCCACCTTGAAGCTGCCCAGGTGCGAGCAGCCCGGCGGCTGGCCA

Sequence GGCTGGCCAAGGCCCGGGCGCCGAGAACAAAGCGCGGAGGCCGGACAAAGATGGGGCT GCGCGATCGCGCAGCCCCATCTTTGTCCGGCCTCCGCGCTTTGTTCTCGGCGCCCGGG CCTTGGCCAGCCTGGCCAGCCGCCGGGCTGCTCGCACCTGGGCAGCTTCAAGGTGGAC AACTGGAAGCAGAACCTGCGGGCCATCTACCAGTGCTTCGTGTGGAGCGGCACGGCTG AGGCCCGCAAGCGCAAGGCCAAGTCCTGTATCTGCCATGTCTGTGGCGTCCACCTCAA CAGGCTGCATTCCTGCCTCTACTGTGTCTTCTTCGGCTGTTTCACAAAGAAGCATATT CACGAGCATGCGAAGGCGAAGCGGCACAACCTGGCCATTGATCTGATGTACGGAGGCA

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 26B.

Further analysis of the NOV26a protein yielded the following properties shown in Table 26C.

Table 26C. Protein Sequence Properties NOV26a >■ analysis: mitochondrial matrix space; 0.5041 probability located in microbody I (peroxisome); 0.2292 probability located in mitochondrial inner membrane

; SignalP No Known Signal Sequence Indicated ! analysis:

A search of the NOV26a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 26D.

In a BLAST search of public sequence databases, the NOV26a protein was found to have homology to the proteins shown in the BLASTP data in Table 26E.

Q9JIG5 UBIQUITIN SPECIFIC PROTEASE 66..581 405/531 (76%) • 0.0 Mus musculus (Mouse), 525 aa 9..513 439/531 (82%) I (fragment).

Q9NSJ7 HYPOTHETICAL 29.8 KDA 318..581 264/264 (100%) i e-l 59 PROTEIN - Homo sapiens (Human), 1..264 264/264 (100%) ; 264 aa (fragment).

Q95TK9 j LD43147P - Drosophila melanogaster 56-581 269/548 (49%) ^; e-l 46 i (Fruit fly), 703 aa. 215-703 346/548 (63%) i

Q9U6Q9 UBIQUITIN-SPECIFIC PROTEASE 56..581 ! 269/548 (49%) I e-146 NONSTOP - Drosophila melanogaster 247-735 I 346/548 (63%) ! (Fruit fly), 735 aa.

PFam analysis indicates that the NOV26a protein contains the domains shown in the Table 26F.

Table 26F. Domain Analysis of NOV26a

Identities/

Pfam Domain NOV26a Match Region Similarities Expect Value for the Matched Resion zf-UBP 94..163 18/83 (22%) 0.00013 47/83 (57%)

UCH-1 207..238 18/32 (56%) 8.7e-16 31/32 (97%)

UCH-2 515-575 24/71 (34%) 7.5e-24 52/71 (73%)

Example 27.

The NOV27 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 27A.

^~ Table 27A. NOV27 Sequence Analysis

JTCGCCACCATGCTCAACATCCTTGCTTTGGTGTATCGGGACCAGAATAAGTATAAGGA AGCTGCCCACCTGCTGAATGATGCCCTTAGCATCCGGGAGAGCACCTTGGGACCTGAC

JCATCCTGCTGTGGCTGCCACACTCAACAATTTGGCTGTGCTCTATGGCAAAAGGGGCA

JAGTACAAGGAGGCAGAGCCTCTGTGCCAGCGGGCACTGGAGATTCGAGAAAAGGTACT

IGGGCACGAATCATCCAGATGTGGCAAAACAGCTGAACAACCTGGCCCTCTTGTGCCAA

JAACCAGGGCAAGTATGAGGCCGTGGAACGCTACTACCAGCGAGCACTGGCCATCTACG

LAGGGGCAGCTGGGGCCGGACAACCCTAATGTAGCCCGGACCAAGAACAACCTGGCTTC

^'CTGTTACCTGAAACAGGGCAAATATGCTGAGGCTGAGACACTATACAAAGAGATCCTG

ACCCGTGCCCATGTACAGGAGTTTGGGTCTGTGGATGATGACCACAAGCCCATCTGGA

TGCATGCAGAGGAGCGGGAGGAAATGAGCAAAAGCCGGCACCATGAGGGTGGGACACC

CTATGCTGAGTATGGAGGCTGGTACAAGGCCTGCAAAGTGAGCAGCCCCACAGTGAAC

ACTACTCTGAGAAACCTGGGAGCTCTGTATAGGCGCCAGGGAAAGCTGGAGGCTGCTG

AGACCCTGGAGGAATGTGCCCTGCGGTCCCGGAGACAGGGCACTGACCCTATCAGCCA

GACGAAGGTGGCAGAGCTGCTTGGGGAGAGTGATGGTAGAAGGACCTCCCAGGAGGGC

CCTGGAGACAGTGTGAAATTCGAGGGAGGTGAAGATGCTTCTGTGGCTGTGGAGTGGT

CCGGGGATGGCAGTGGGACCCTGCAGAGGAGTGGCTCTCTTGGCAAGATCCGGGATGT

GCTCCGCAGAAGCAGTGAACTCTTGGTGAGGAAGCTCCAGGGGACTGAGCCTCGGCCC

TCCAGCAGCAACATGAAGCGAGCAGCCTCCTTGAACTATCTGAACCAACCTAGTGCAG

CACCCCTCCAGGTGTCCCGGGGCCTCAGTGCCAGCACCATGGACCTCTCTTCAAGCAG

CTGACATTCAACCCGGCCCCCAG

ORF Start: ATG at 1 IORF Stop: TGA at 1858 jSEQ ID NO: 112 619 aa MW at 68668.9kD

|NOV27a, MSGLVLGQRDΞPAGHRLSQEEILGSTRLVSQGLEALRSEHQAVLQSLSQTIECLQQGG ICG103374-01 HEEGLVHEKARQLRRSMENIELGLSEAQλWlLALASHLSTVESEKQKLRAQVRRLCQΞN QWLRDELAGTQQRLQRSEQAVAQLΞEEKKHLEFLGQLRQYDEDGHΞEKEGDATKDSLD ! Protein Sequence DLFPNEEEEDPSNGCEVSRGQGATAAQQGGYEIPARLRTLHNLVIQYAAQGRYEVAVP LCKQALEDLΞRTSGRGHPDVATMLNILALVYRDQNKYKΞAAHLL DALSIRESTLGPD HPAVAATLNNLAVLYGKRGKYKEAEPLCQRALEIREKVLGT HPDVAKQLNNLALLCQ NQG YEAVERYYQRALAIYEGQLGPDNPNVARTKNNLASCYLKQGKYAEAETLYKEIL TRAHVQEFGSVDDDHKPI MHAEΞREEMSKSRHHEGGTPYAEYGG YKACKVSSPTVN TTLRNLGALYRRQGKLEAAETLEECALRSRRQGTDPISQTKVAELLGESDGRRTSQEG PGDSVKFEGGEDASVAVE SGDGSGTLQRSGSLGKIRDVLRRSSELLVRKLQGTEPRP SSS MKRAASLNYLNQPSAAPLQVSRGLSASTMDLSSSS

Further analysis of the NOV27a protein yielded the following properties shown in Table 27B.

A search of the NOV27a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 27C.

Table 27C. Geneseq Results for NOV27a

Geneseq NOV27a Identities/

Protein/Organism/Length [Patent Expect Identifier Residues/ Similarities for #, Date] Value Residues Region

AAM4E > 1 , Human polypeptide SEQ ID NO 1..564 561/566 (99%) 0.0 ] 6262 - Homo sapiens, 585 aa. 22-585 562/566 (99%) l [WO2001 53312-Al, 26-JUL-2001]

AAM39545 | Human polypeptide SEQ ID NO 1..509 ^■ 503/511 (98%) 0.0 ; 2690 - Homo sapiens, 581 aa. 1..509 ! 506/511 (98%) ! [WO200153312-A1, 26-JUL-2001]

AAU74330 Human cytoskeleton-associated 12-619 433/626 (69%) 0.0 protein (CYSKP) #1 - Homo sapiens, 7..618 485/626 (77%)

622 aa. [WO200185942-A2, 15- NOV-2001]

AAB95098 Human protein sequence SEQ ID 12..619 430/623 (69%) 0.0 NO: 17060 - Homo sapiens, 622 aa. 7..618 485/623 (77%) [EP1074617-A2, 07-FEB-2001] i AAB94338 Human protein sequence SEQ ID 12..619 430/623 (69%) 0.0 NO: 14840 - Homo sapiens, 622 aa. 7..618 485/623 (77%) [EP1074617-A2, 07-FEB-2001]

In a BLAST search of public sequence databases, the NOV27a protein was found to have homology to the proteins shown in the BLASTP data in Table 27D.

Table 27D. Public BLASTP Results for NOV27a

PFam analysis indicates that the NOV27a protein contains the domains shown in the Table 27E. Table 27E. Domain Analysis of NOV27a

Example 28.

The NOV28 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 28A.

Table 28A. NOV28 Sequence Analysis

I SEQ ID NO: 113 |5516 bp

NOV28a, ITCCGGACAAGGGGGACAACGCCTCCAACTGTGACTGCCGCGCATGGGACTACGGCATC CG10341 5-01 DNA I ^{G G C}G^GCCTCGTCCAGAACGTGGTCAGCAAGGGTCGGCCGGCGGCCTGTGCTGCTG ITTTTCCATCATCTTCATTCTGATCTTTGGACTGACTGTGGCACTGTCAGTGAATGTGA Sequence jCAATGTTCAGCACACTCAGGTTCTTTGAAGGACTTTGCCTGGCTGGAATCATTCTCAC JCTTGTATGCTTTACGAATAGAGCTGTGCCCCCCTGGAAAACGGTTCATGATTACGATG JGTGGCGAGCTTCGTGGCCATGGCGGGCCAGTTCCTCATGCCTGGGCTAGCCGCCCTGT JGCCGGGATTGGCAGGTGCTGCAGGCCCTCATCATCTGCCCCTTCCTGCTCATGCTGCT 'cTACTGGTCGATATTCCCCGAGTCCCTCCGGTGGCTAATGGCCACCCAGCAGTTTGAG TCTGCAAAGAGGCTGATCCTCCACTTCACACAGAAGAATCGCATGAACCCTGAGGGCG ACATCAAGGGTGTGATACCAGAGCTGGAGAAAGAGCTTTCCCGGAGGCCCAAGAAGGT CTGCATCGTGAAGGTGGTGGGGACACGGAACCTGTGGAAGAACATTGTGGTCCTGTGT GTGAACTCGCTGACGGGGTACGGGATCCACCACTGCTTTGCCAGGAGCATGATGGGCC ACGAGGTGAAGGTGCCGCTCCTGGAGAACTTCTATGCTGACTACTATACCACGGCCAG CATCGCGCTGGTGTCCTGCCTGGCCATGTGCGTGGTGGTCCGATTCCTCGGGCGCAGG GGAGGGCTGCTGCTCTTCATGATCCTCACCGCCCTGGCCTCACTCCTGCAGCTCGGCC TCCTCAACGTGATTGGAAAGTACAGCCAGCACCCAGACTCAGGGATGAGTGACAGCGT CAAGGACAAATTTTCCATCGCGTTTTCCATCGTGGGCATGTTTGCCTCCCATGCGGTG GGGAGCCTCAGCGTGTTCTTCTGTGCGGAGATCACCCCGACGGTGATAAGGTGCGGCG GGCTGGGGCTGGTGCTGGCCAGCGCGGGCTTCGGCATGCTGACGGCACCCATCATCGA GCTGCACAACCAGAAAGGCTACTTCCTGCACCACATCATCTTTGCCTGCTGCACGCTC ATCTGCATCATCTGCATCCTCCTGCTGCCCGAGAGCAGGGACCAGAACCTGCCTGAGA ACATTTCTAACGGGGAGCACAACACGCGCCAGCCGCTGCTGCCGCACAAGAAGGGGGA GCAGCCACTGCTGCTCACCAACGCCGAGCTCAAGGACTACTCGGGCCTCCACGATGCC GCAGCCGCGGGTGACACACTGCCCGAGGGTGCCACGGCCAACGGCATGAAGGCCATGT AGCCCGGCCTGCGGAACCCGGGGCTCCAGGGTCTGGGGCAGCTTGGGCACAGGTTTAC AGACCAGGGACCGAACACGCAGCCAGGGGTGGGAAAGCTGCCTCAGCCAAGCTGAGCC

TCTCAACTGGTGTGGGGAA_ATCCTGTCTTTCCAAAAGTCCAAGGAGCGCGGGTCGGAG GAGACAAACTCTTTGG_AA_ATAACCCTTTCAAGACTTTCTTTTCTGCCGTTAAATGTGT GTATTTATTTTGGTC_ATT_TTTACGAGAAGCACTTTATTCCCTCTCCCTCTCACTGATC ACAAATGGAATCAC_CTCCCTGGGC_AGCGAGACGCAGTTGCTCTGGGAAGATGCCACAG '^•TGACCAGGGCCATGGCCGGTCCCTCTGGGGAGATGGGACACGGCTCCTGGCAGCACCC jAGGAGCCCCCCAGGCTGCCTGCCTGCGTGCAGAGGCAGGAGAGGACCGTGGAGCGTTT iCCGGGACTGCATTTTAGACGGAGTGAAATGTACATGAATTTGGCTTTTGCTAGAGTCT jGTGTATGGTTTTTTAAGGTCCTTTTTCCCTTTCTGTTTGTAAGGTAAGAGCTTCTGTT CGTGTGCAGGGAAAGCAGCTCACAGACGCCGTTAAAACCAGCTTCATCTTTCCTTCAG

GATCATCCTTTTGTACTTGATGCTGGAAGCTCTTGGAGAAAAAGCTTAAACATTTCAC CAGAAATCTTAATTGAGCAGCAGTCATATCGCCACAGCTTTGTGAGTACACAGCTAAC

AGATGCGTCGAGACCTGAGATGTGCTCGTTTTTATTCCTCCTCTCCCAGATTGGCTCG

AGCAGAAAAGTCCCTCGTGCACAGGCAGCTCTTGTGCCGGCACTACTTGAAAACATGG

CTACTTTCTAAGCTACAAACCATTAGAAAATAACTCAAAAAGATGGCAGAGGCAAATC

CACAGAAGGGGGGCTGCCCTCCACACACACACGCCCGTCACCCACACCTTGAGCACAC

ACCATGAAGATCACCAGCTTGGATGGCCGTCACCTCAGACATCACTCCAGGGAGCACC

CGCAGGAGCTGGGCCCCCTCACGCCTGCCTTCCTGGGCCAGCTTCCTGCTTGCAGTCA

CTCGCATAGCACAGAGGTGGGGCTTCGGGCAGGGAGCGGAGATTCCTCATAGGTGAGT

CCAAATGACCTCCAGCCTCTCGAAGGCATCAAGACAAATTGAAAGAAAGCAATAACTC

ACCAAAGCTCAACGCTGCCCCTGCCTCGACCTCCATGGGTCTCTTCGTGTTCCTCGTT

TCACCCCAGAAAGTGGAGGTTTCCTCTTGGCATTTTCGGAGGAAACTTGTAGGACACC

CAAGGCGACTAAGAGACAGCCTCCTTGGCAAGGGCAGGCACCACTTTGTAGCAACTTG

GGCACCAGCTTTTCTGGACAGCCTGGCTTCTTACTGGCATTGTCCAACTCATCCCTTC

TCGAAGCATGTCTTTGCCATGGGCTGTGTCCTTCCAGGGAAATTGTGGTCTCCGGCCT

GGGTGAGACAATGAAGTGACTTCCAACCGACAGTTGCTAGAATTCACAGGGCAGAAAA

GGGGTTGACCTTCTCCCCTTCTGGCTTTCCACCCGGCCTGCTGCTTGCTGTCGCCACT

CATGTCTCCTCCACATGCGGTCCACACATCAGTAAGGGCCTGGAGATGTGTAAAGACA

CAGCAAGGGGCAAGCAGACTCTTGGCCACGTGTTTCCAGTGGCTGGACCACGCCGACA

CCTGGGATCTTGAGATACCCAGGAAGGGAGGCTGTCTGGCCAGCCTCTCCCTGCCTCC

ACTTGCTCCACGTCCAGCTCATCCTCACCTTCCCTCTTTTTTAAAGTCACATTTCCAT

GTTTCAACATTAGTTTGCATTCACCTTTACAAAGGCCTTTCTTTAGATCTGTGCAGCC

TTTGCGTGCCAAACTTGTGAAATTCCTTTTACCTTTTTTGGAGTACTTGCTATAAAGC

CACCTGTCAACAAACCCCCATTATGTACAGAATAGGACCTATCCAGTAGCCAGGCCAG

TAGGCAGTTGGGGAAGGTGGGAAGGATCCAGCGAGGCCCCTGAGCCTGCACCTGGACA

GGTGTACGTCTGCACCCATCACCCTCAGCACCAGGCCACCCTGCAGTCCACTTACTGT

ACTGTGTTGTGGAAGGATATGCTAAGTGATGAAAGTTGCGAGCAGTCTCACTGGTCGT

GTAAACTTTTTTTTTTTTTTGGAAATTGAAGCTGTAGAGTGCTGCCCGAAATCTCTAG

GAAGTTGGTGGCAAGGGACAGCACTCACACTCTTCTGGTCATGATCTCTGATCTCCAC

CTCAAATGACAATAAAAAACTGGTCCAACGAAGACACTGCTCAGCACTTCAGCCATCA

GGACTAATCCATCGATGACTGGAAAAGAGGCTAGCTTTGAGGAAAACAGCCTGGGCTC

TTGGGAGCAGAGTCCAGTGGGTGTGAGTGAGGCTGACTTGCCGACGGTCGGCAGGTAA

TGGCTCTCAGCCGGCGAGGCGGTCCCACAGCTCTCCTCCCAGGGCAGCCTGAGGAGGA

GGAGGCCGGGTGCCTGTTTGGTGGCAGCTTCAGCCTAGGGATACCTGAAGCTGTTGAG

CAACACCTTTATGAAATGTTGCCAGAGCAGCAACACTTCCCTGTGGGCACAGCCCCGG

GAAATCCGGTACCAAGTGAGCAAGGTGGCAGGACCCACCCAAGCCTGATACGCATCTG

GGCCCGCCGGGCTCAGCAGGGGAGGCTGCTACGGCTGCCCACTTCCCAGCACCGTCTG

TCAGGCTTGAACCCCTCTGTGCTGTTCCCTTCCTGGCTAATAGGGAGACCCTTCGCAG

GCACCCACTGTTTCAACTTGACCCTCCCACCCCCTGCTACTCTCCTCCACACACCCCT

CCGTTCCGCTAGCCTACCCTGTCAGCCTTTCAΆTAAAΆGTTATGCACAAATGTGAΆCA

CCTGAGATGGAGCTGAACATTTCTTCACTTTGTTCTTTTTCTGAAGTCAAACTCTTAT

CAAATGCCCTAAAATTATTACCACCCAAGAGAAACAGGAAAAAGGTTACATGTTTTTG

TTTACTGAGAGTAAGATCACCTGCATCTGGAAGACGGGCTGGTAAATTGGTTTGGCTA

CAGAACAGAAAGAAAACAAAAACAAACCTCGTAAGGGAAGTATCGCACTCAGACACCA

CCACTTCCTAGAGCCAAATGAGCAATCCCAAACTGCAAGTGCCGTAAGTGGGCCTGTG

ACGTCACACCGCCCGGCCCGAGGTATCGCATGTGCGGGGGAGGCCCACACTACAGCTG

TCCTCTCGTCTAGAAGGCACCACCTCGCTTTCATGTCCCGTGTGTTTTGGAAAAGCAG TATGGTGTGTCATGTCTAGCGGCGAACACTTCCCTCCCTCTGTCCTTGAGGTTGTAAT

ATAAAAACTGTGTTTCTGTACGTGTGGGTGGGAATTCTCTGACGGTGCTCGTTCATAG

CACAAGCTTACGCTGAGTTCTGAACTGTCGTTCACAGCTGCGTGTCTGCATGGTGTCG CATCTGTTGTACCTTTGGGGAAAATTTGTATGTAAATGTACAGAAATAAAAACGTTGC

CCCATTAACAGATTTCCTCTGGAATGTCTTCCCTACCTCACCTGATGGTATCCACCGA AGGGCATTTCACTACCATTAATGGTGAGTAATAAAATCCTCCGTGTTCATTCAGACCT CACTGCGTCACTACTTTGAACGCCTCTGTAAGCTGTGTCTTCACTCGCCCCGAGGTGG GTGGAGGGAGGCCTCTCACTCTGCTTCGAGTCCTGGTCTTAAAGGTAGTCAGAGGCAG AGGCTGGATTAAACACACACTGTTTACCAAGTGCCACTCTCAGACCACCTGAGAGACG ,GGGGGCCATCAGTAAAATTAAGAGGAATTTTTTTCCCTTGTTCGTGTATGTTCTGCTG

ATCCGTGGCCTGAAGGTTCCTAGAGACGTCAAGAAATGAATATCTTACACTGTGATTC

TGTGAGGAAAGACTGGTAACCCAAAACTCTCTTCTCTAATGTATTTTTTAACGAAAAT

GACAATATTTCTTTAATAAAGTATTTATACCAAAAAAAAAAAAAAAAAAAAAAAAAAA

AAAAAA

ORF Start: ATG at 177 iORF Stop: TAG at 1392

SEQ ID NO: 114 405 aa MW at 44686.6kD

NOV28a, MFSTLRFFEGLCLAGI ILTLYALRIELCPPGKRFMITMVASFVAMAGQFLMPGLAALC CG103415-01 RDWQV QA IICPFLLMLLY SIFPES RWL^'1ATQQFESAKR I HFTQK RM PEGD IKGVIPELE ELSRRPK VCIVKVVGTRNL KNIVVLC^'V SLTGYGIHHCFARSMMGH Protein Sequence EVKVPLLENFYADYYTTASIALVSCLAMCVWRFLGRRGGLLLFMILTALASLLQLGL LNVIGKYSQHPDSGMSDSVKDKFSIAFS IVGMFASHAVGSLSVFFCAEITPTVIRCGG LGLVLASAGFGr.LTAPIIELHNQKGYFLHHIIFACCTLICIICILLLPESRDQNLPEN I SNGEHNTRQPLLPHKKGEQPLLLTNAELKDYS GLHDAAAAGDTLPEGATANG KAM

SEQ ID NO: 115 1002 bp

;NOV28b, GCTGCTGTTTTCCATCATCTTCATTCTGATCTTTGGACTGACTGTGGCACTGTCAGTG

:CG103415-02 DNA AATGTGACAATGTTCAGCACACTCAGGTTCTTTGAAGGATTTTGCCTGGCTGGAATCA

TTCTCACCTTGTATGCTTTACGAATAGAGCTGTGCCCCCCTGGAAAACGGTTCATGAT I Sequence JTACGATGGTGGCGAGCTTCGTGGCCATGGCGGGCCAGTTCCTCATGCCTGGGCTAGCC

IGCCCTGTGCCGGGATTGGCAGGTGCTGCAGGCCCTCATCATCTGCCCCTTCCTGCTCA

|ΤGCTGCTCTACTGGTCGATATTCCCCGAGTCCCTCCGGTGGCTAATGGCCACCCAGCA

'GTTTGAGTCTGCAAAGAGGCTGATCCTCCACTTCACACAGAΆGAATCGCATGAACCCT

GAGGGCGACATCAAGGGTGTGATACCAGAGCTGGAGAAAGAGCTTTCCCGGAGGCCCA

AGAAGGTCTGCATCGTGAAGGTGGTGGGGACACGGAACCTGTGGAAGAACATTGTGGT

CCTGTGTGTGAACTCGCTGACGGGGTACGGGATCCACCACTGCTTTGCCAGGAGCATG

ATGGGCCACGAGGTGAAGGTGCCGCTCCTGGAGAACTTCTATGCTGACTACTATACCA

CGGCCAGCATCGCGCTGGTGTCCTGCCTGGCCTCGCTCCTGCAGCTCGGCCTCCTCAA

JCCTGATTGGAAAGTACAGCCAGCACCCAGACTCAGGGATGAGTGACAGCGTCAAGAAC

LATTTCTAACGGGGAGCACTACACGCGCCAGCCGCTGCTGCCGCACAAGAAGGGGGAGC

AGCCACTGCTGCTCACCAACGCCGAGCTCAAGGACTACTCGGGCCTCCACGATGCCGC

AGCCGCGGGTGACACACTGCCCGAGGGTGCCACGGCCAACGGCATGAAGGCCATGTAG

CCCGGCCTGCGGAACCCGGGGCTCCAGGGTCTGGGGCAGCTTGGGCACAGGTTTACAG

I ACCGGGACCGAACATC I ORF Start: ATG at 68 fORF Stop: TAG at 926

1 SEQ ID NO: 116 |286 aa MW at 31942.3kD iNOV28b, MFSTLRFFEGFCLAGIILTLYALRIELCPPGKRFMITMVASFVAMAGQFLMPGLAALC ICG103415-02 RD QVLQALIICPFLLMLLYVJSIFPESLR LMATQQFESAKRLILHFTQK R NPEGD IKGVIPELEKELSRRPKKVCIVKλΛGTRNL KNIWLCλπMSLTGYGIHHCFARSMMGH

Protein Sequence EVKVPLLENFYADYYTTASIALVSCLASLLQLGLLNLIGKYSQHPDSGMSDSVKNISN GEHYTRQPLLPHKKGEQPLLLTNAELKDYSGLHDAAAAGDTLPEGATANGMKAM

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 28B.

Further analysis of the NOV28a protein yielded the following properties shown in Table 28C. Table 28C. Protein Sequence Properties NOV28a

! PSort ! 0.6850 probability located in endoplasmic reticulum (membrane); 0.6400 ^! analysis: probability located in plasma membrane; 0.4600 probability located in Golgi body; 0.1000 probability located in endoplasmic reticulum (lumen) j SignalP Cleavage site between residues 23 and 24 j analysis:

A search of the NOV28a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 28D.

In a BLAST search of public sequence databases, the NOV28a protein was found to have homology to the proteins shown in the BLASTP data in Table 28E.

PFam analysis indicates that the NOV28a protein contains the domains shown in the Table 28F.

Table 28F. Domain Analysis of NOV28a

Identities/

Pfam Domain ; NOV28a Match Region Similarities Expect Value for the Matched Region sugar tr 1..35 75/508 (15%) 0.37 237/508 (47%)

Example 29.

The NOV29 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 29A.

! Table 29A. NOV29 Sequence Analysis

GGCAGGGTGCAGCCTTCAGCCCAGAGGGCCAGCCCATCGGGGGCTATACCGAGACAGA GCCACACGTGGCCTTCCGGCCTCCAGCATCAGTGGGGATGAGTTTGAACTTGGAAGGA IGAATGGCATTATCTATAGAGGCTGATGCGGGAGAGACCCAGCCTCCGC

! ORF Start: ATG at 4 |ORF Stop: TAG at 1060

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 29B.

Further analysis of the NOV29a protein yielded the following properties shown in Table 29C. Table 29C. Protein Sequence Properties NOV29a

PSort ; 0.5247 probability located in mitochondrial matrix space; 0.2532 probability analysis: ' located in mitochondrial inner membrane; 0.2532 probability located in

■ mitochondrial intermembrane space; 0.2532 probability located in mitochondrial outer membrane

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV29a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 29D.

In a BLAST search of public sequence databases, the NOV29a protein was found to have homology to the proteins shown in the BLASTP data in Table 29E.

j related protein 2) - Homo sapiens 44-382 310/339 (91%) j (Human), 382 aa (fragment).

PFam analysis indicates that the NOV29a protein contains the domains shown in the Table 29F.

Table 29F. Domain Analysis of NOV29a

Identities/

Pfam Domain ! NOV29a Match Region Similarities I Expect Value for the Matched Region i homeobox 264-297 15/34 (44%) 0.14 25/34 (74%)

Example 30.

The NOV30 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 30 A.

CAGATTCTGCTTGCTCTGTGTCTGTGCTTGATCCAAGTGAACCCCGAACACCTGTTGG IGAGTAGGAAAGCCAGCCGTAACATATTTTTAGAGGATGATTTGGCCTGGCAAAGTTTG JATTCATCCAGATTCCTCAAATACTCCTCTTTCAACAAGACTTGTATCTGTGCAAGAGG IATGCTGGGAAATCTCCTGCTCGAAATAGATCAGCCAGCATTACTAACCTGTCACTGGA ^'TAGATCTGGTTCTCCTATGGTACCTTCATATGAGACATCTGTCAGTCCCCAGGCTAAC CGAACATATGTTAGGACAGAGACCACTGAGGATGAACGCAAAATTCTTCTGGACAGTG GCAGTTAAAAGACCTGTGGAAAAAAATCTGCCATCACAGCAGTGGAATGGAGTTTCA GGATCACCGCTACTGGTTGAGAACGCATCCCAACTGCATTGTAGGAAAGGAATTAGTC AACTGGCTAATCCGAAATGGGCATATTGCCACAAGGGCACAAGCTATAGCAATTGGAC AAGCAATGGTTGATGGACGTTGGCTGGATTGTGTTAGTCATCACGACCAGCTTTTCAG AGATGAGTATGCGCTGTATAGACCACTGCAGAGTACAGAATTTTCTGAGACGCCTTCT CCCGACAGTGACTCAGTGAACTCCGTGGAAGGACACTCTGAGCCATCCTGGTTTAAAG ACATAAAGTTTGATGACAGTGACACAGAACAGATAGCTGAAGAAGGTGACGATAATTT GGCTAAGTATTTGATTTCTGACACTGGAGGACAACAGCTCTCAATAAGTGACGCTTTC ATCAAAGAATCCTTATTTAATCGCCGAGTAGAGGAAAAATCCAAAGAGCTGCCTTTCA CACCTTTGGGCTGGCATCATAACAACCTGGAGCTCCTGAGGGAGGAGAATGGGGAGAA ACAAGCCATGGAGAGGTTGCTTTCAGCTAATCATAACCACATGATGGCACTACTCCAG CAGTTGCTCCATAGTGACTCACTGTCATCATCTTGGAGGGACATCATCGTGTCATTGG TCTGCCAGGTTGTTCAGACAGTCCGACCTGATGTCAAGAACCAGGATGATGACATGGA TATCCGTCAGTTTGTCCACATCAAAAAAATCCCAGGTGGAAAGAAGTTTGATTCTGTG GTTGTCAATGGCTTTGTTTGTACCAAGAACATTGCACATAAAAAGATGAGTTCTTGTA TTAAAAACCCCAAAATTCTTCTGTTGAAGTGTTCCATTGAGTATCTCTACAGAGAAGA AACTAAGTTTACTTGCATTGATCCTATTGTGCTTCAGGAAAGGGAATTCTTGAAGAAT TATGTCCAGCGAATAGTTGATGTTCGACCCACCTTGGTTCTTGTTGAGAAAACAGTGT CTCGGATTGCCCAGGACATGTTATTGGAACATGGCATTACTTTGGTCATTAATGTAAA GTCACAAGTTTTGGAACGAATCAGTCGAATGACCCAAGGTGATTTAGTGATGTCAATG GACCAGCTGCTTACGAAACCACACCTGGGCACTTGTCACAAATTTTATATGCAGATAT TTCAGTTGCCTAATGAACAAACCAAGACACTGATGTTTTTTGAAGGTTGTCCACAGCA CCTAGGCTGTACAATCAAGCTAAGAGGAGGCTCTGATTATGAGCTGGCTCGAGTTAAG GAGATCCTAATATTTATGATCTGTGTTGCTTATCATTCTCAACTAGAAATATCCTTTC TCATGGATGAATTTGCTATGCCTCCCACATTAATGCAAAACCCTTCATTCCATTCCCT GATTGAGGGACGAGGGCATGAGGGGGCTGTCCAAGAGCAGTACGGTGGAGGTTCCATC CCCTGGGATCCTGACATCCCTCCTGAGTCTCTGCCCTGTGATGATAGCAGTTTGCTGG AATTGAGGATTGTGTTTGAGAAGGGTGAGCAGGAAAATAAAAATCTTCCGCAGGCTGT TGCCTCTGTGAAGCATCAAGAACATAGCACAACAGCTTGCCCGGCGGGTCTCCCTTGT GCTTTCTTTGCACCTGTACCGGAATCATTGTTGCCACTCCCTGTGGATGACCAACAAG ATGCTTTAGGCAGCGAGCAGCCAGAGACTTTGCAGCAAACAGTTGTGCTGCAGGATCC ICAAAAGCCAGATAAGAGCCTTTAGAGACCCTCTACAGGATGACACTGGATTATATGTT ACTGAGGAAGTCACCTCCTCTGAAGATAAACGAAAGACTTATTCTTTGGCCTTTAAGC AGGAATTAAAAGATGTGATCCTCTGTATCTCCCCAGTAATCACATTCCGAGAACCCTT TCTTTTAACTGAAAAGGGGATGAGATGCTCTACCCGAGATTATTTTGCAGAGCAGGTT TACTGGTCTCCTCTCCTCAATAAAGAATTCAAAGAAATGGAGAACAGGAGGAAGAAAC AGCTGCTCAGGGATCTCTCTGGACTTCAGGGCATGAATGGAAGTATTCAGGCCAAGTC TATTCAAGTCTTACCCTCACATGAGCTAGTGAGCACTAGAATTGCTGAGCATCTGGGC GATAGCCAGAGCTTGGGTAGAATGCTGGCCGATTATCGAGCCAGAGGAGGAAGAATTC AGCCCAAAAATTCAGACCCTTTTGCTCATTCAAAGGATGCATCAAGTACTTCAAGTGG CCAATCAGGAAGCAAAAATGAGGGTGATGAAGAGAGAGGGCTTATTCTGAGTGATGCT GTGTGGTCAACAAAGGTGGACTGTCTGAATCCCATTAATCACCAGAGACTTTGTGTGC TCTTCAGCAGCTCTTCTGCCCAGTCCAGCAATGCTCCTAGTGCCTGTGTCAGTCCTTG GATTGTAACAATGGAATTTTATGGAAAGAATGATCTTACATTAGGAATATTTTTAGAG AGATACTGTTTCAGGCCTTCTTATCAGTGTCCAAGCATGTTCTGTGATACCCCCATGG TACATCATATTCGGCGCTTTGTTCATGGCCAAGGCTGTGTGCAGATAATCCTGAAGGA GTTGGATTCTCCAGTACCTGGATATCAGCATACAATTCTTACATATTCCTGGTGTAGA ATCTGCAAACAGGTAACACCAGTTGTTGCTCTTTCCAATGAGTCCTGGTCTATGTCAT TTGCAAAATACCTTGAACTTAGGTTTTATGGGCACCAGTATACTCGCAGAGCCAACGC

TGAGCCCTGTGGTCACTCCATCCATCATGATTATCACCAGTATTTCTCCTATAACCAG ATGGTGGCGTCTTTCAGTTATTCTCCCATTCGGCTTCTTGAAGTATGTGTTCCACTCC CCAAAATATTCATTAAGCGTCAGGCCCCATTAAAAGTGTCCCTTCTTCAGGATCTGAA GGACTTCTTTCAAAAAGTTTCACAGGTATATGTTGCCATTGATGAAAGACTTGCATCT TTGAAAACTGATACATTTAGTAAAACAAGAGAGGAAAAAATGGAAGATATTTTTGCAC AGAAAGAGATGGAAGAAGGTGAGTTCAAGAACTGGATTGAGAAGATGCAAGCAAGGCT ICATGTCTTCCTCTGTAGATACCCCTCAGCAACTGCAGTCGGTCTTTGAGTCACTCATT ^'IGCCAAGAAACAAAGTCTCTGTGAAGTGCTGCAAGCTTGGAATAACAGGTTGCAGGACC !TTTTCCAACAGGAAAAGGGTAGAAAGAGACCTTCAGTTCCTCCAAGTCCTGGAAGACT ^'GAGACAAGGGGAAGAAAGCAAGATAAGTGCGATGGATGCATCTCCACGGAATATTTCT CCAGGACTTCAGAATGGAGAAAAAGAGGATCGCTTCTTAACAACTTTGTCCAGCCAGA GCTCCACCAGTTCTACTCATCTCCAATTGCCTACGCCACCTGAAGTCATGTCTGAACA GTCAGTGGGAGGGCCCCCTGAGCTAGATACAGCCAGCAGTTCCGAAGATGTGTTTGAT GGGCATTTGCTGGGATCCACAGACAGCCAAGTGAAGGAAAAGTCAACCATGAAAGCCA TCTTTGCAAATTTGCTTCCAGGAAATAGCTATAATCCTATTCCATTTCCTTTTGATCC AGATAAACACTACTTAATGTATGAACATGAACGAGTGCCCATTGCAGTCTGCGAGAAG GAACCCAGCTCCATCATTGCTTTTGCTCTCAGTTGTAAAGAATACCGAAATGCCTTAG AGGAATTGTCTAAAGCGACTCAGTGGAACAGTGCCGAAGAAGGGCTTCCAACAAATAG TACTTCAGATAGCAGACCAAAGAGTAGCAGCCCTATCAGATTACCTGAAATGAGTGGA GGACAGACAAATCGTACAACAGAAACAGAACCACAACCAACCAAAAAGGCTTCTGGAA TGTTGTCCTTCTTCAGAGGGACAGCAGGGAAAAGCCCCGATCTCTCTTCCCAGAAGAG AGAGACCTTACGTGGAGCAGATAGTGCTTACTACCAGGTTGGGCAGACGGGCAAGGAG GGGACCGAGAATCAAGGCGTTGAGCCTCAAGATGAAGTAGATGGAGGAGATACGCAAA AGAAGCAACTCATAAATCCTCATGTGGAACTTCAATTTTCAGATGCTAATGCCAAGTT TTACTGTCGGCTCTACTATGCGGGAGAGTTTCATAAGATGCGTGAAGTGATTCTGGAC AGCAGTGAGGAAGATTTCATTCGTTCCCTCTCCCACTCATCACCCTGGCAGGCCCGGG GAGGCAAATCAGGAGCTGCCTTCTATGCAACTGAGGATGATAGATTTATTTTGAAGCA AATGCCTCGTCTGGAAGTCCAGTCCTTCCTCGACTTTGCACCACATTACTTCAATTAT ATTACAAATGCTGTTCAACAAAAGAGGCCCACGGCGTTGGCCAAAATTCTTGGAGTTT ACAGAATTGGTTATAAGAACTCTCAGAACAACACTGAGAAGAAGTTAGATCTCCTTGT CATGGAAAATCTTTTCTACGGGAGAAAGATGGCACAGGTTTTTGATTTGAAGGGCTCT CTTAGGAATCGGAATGTAAAAACTGACACTGGAAAAGAGAGTTGTGATGTGGTCCTGC TAGATGAAAATCTCCTAAAGATGGTTCGAGACAACCCTCTATATATTCGTTCTCATTC CAAAGCTGTGCTGAGAACCTCGATCCATAGTGACTCCCATTTCCTTTCTAGCCACCTC ATTATAGATTATTCTTTGCTGGTTGGGCGAGATGATACTAGCAATGAGCTAGTAGTTG GAATTATAGATTATATTCGAACATTTACATGGGACAAAAAGCTTGAGATGGTTGTGAA ATCAACAGGAATTTTAGGTGGACAAGGTAAAATGCCAACAGTGGTGTCTCCGGAGTTG TACAGGACTAGGTTTTGTGAGGCAATGGACAAGTATTTCCTAATGGTACCAGACCACT GGACAGGCTTGGGTCTGAATTGCTGAAATCAAGCACATATTTTGAAATGGACTGTGAA

GGAAAAGGGGACAGGAACAAAGGACCAAAAATAAGCTACATGTTTTATTTCTTCATCG

TGTTCACCACTGTATGCCAAGGCTTTTCAGTTCTGTGTCTGTTTAGACTGTCCGTAAT

GGAATGGTAAAACTCCATGAATTTGCACTTTGGTTTTTGATACCTGTGGAGCTGTCTG

TACGTTGGGAAGTGGCATGAAAATTTTCTTAAGCTAAAATACAGACATGTTTCAAAGG

GCTAAAGTTGGAGATGAGTAGATAGGGTGAAAAATGGGTTAAATTTGCTAGCTTAATT

GTTTTAAGAAGAAAACAGTGTCTCATAAATTGACT

ORF Start: ATG at 13 jORF Stop: TGA at 6172

SEQ ID NO: 122 2053 aa MW at 232366.3kD

NOV30a, ATDDKTSPTLDSANDLPRSPTSPSHLTHFKPLTPDQDEPPFKSAYSSFVNLFRFNKE CG103900-01 RAEGGQGEQQPLSGS TSPQLPSRTQSVRSPTPYKKQLNEELQRRSSALDNSLQHPQE

NTDTRRKAEPTFGGHDPRTAVQLRSLSTVLKRLKEIMEGKSQDSDLKQYWMPDSQCKE Protein Sequence CYDCSEKFTTFRRRHHCRLCGQIFCSRCCNQEIPGKFMGYTGDLRACTYCRKIALSYA

HSTDSNSIGEDLNALSDSACSVSVLDPSΞPRTPVGSRKASRNIFLEDDLA QSLIHPD

SSNTPLSTRLVSVQEDAGKSPARNRSASITNLSLDRSGSPMVPSYETSVSPQANRTYV

RTETTEDERKILLDSVQLKDLWKKICHHSSGMEFQDHRYWLRTHPNCIVGKELVNWLI

RNGHIATRAQAIAIGQAMVDGRWLDCVSHHDQLFRDEYALYRPLQSTEFSETPSPDSD

SVNSVEGHSEPS FKDIKFDDSDTΞQIAEEGDDNLAKYLISDTGGQQLSISDAFIKES

LFNRRVEEKSKELPFTPLG HHNNLELLRΞENGEKQAMERLLSANHNHMMALLQQLLH

SDSLSSSWRDIIVSLVCQWQTVRPDVKNQDDDMDIRQFVHIK IPGGKKFDSVWNG

FVCTKNIAHKKMSSCIK PKILLLKCSIEYLYREETKFTCIDPIVLQEREFLKNYVQR

IVDVRPTLVLVEKTVSRIAQDMLLEHGITLVINVKSQVLERISRMTQGDLVMSMDQLL

TKPHLGTCHKFYMQIFQLPNEQTKTL FFEGCPQHLGCTIKLRGGSDYELARVKEILI

FMICVAYHSQLEISFLMDEFAMPPTLMQNPSFHSLIEGRGHEGAVQEQYGGGSIP DP

DIPPESLPCDDSSLLELRIVFEKGEQENKNLPQAVASVKHQEHSTTACPAGLPCAFFA!

PVPESLLPLPVDDQQDALGSEQPETLQQTWLQDPKSQIRAFRDPLQDDTGLYVTEEv'

TSSEDKRKTYSLAFKQELKDVILCISPVITFREPFLLTE GMRCSTRDYFAEQVY SP LLNKEFKEMΞNRRK QLLRDLSGLQGMNGSIQAKSIQVLPSHELVSTRIAEHLGDSQS LGRMLADYRARGGRIQPKNSDPFAHSKDASSTSSGQSGSK EGDEERGLILSDAV ST J KVDCLNPINHQRLCVLFSSSSAQSSNAPSACVSP IVTMEFYGKNDLTLGIFLERYCF RPSYQCPSMFCDTPMVHHIRRFλraGQGCVQIILKELDSPVPGYQHTILTYSWCRIC Q VTPWALSNES SMSFAKYLELRFYGHQYTRRANAEPCGHSIHHDYHQYFSY Q VAS FSYSPIRLLEVCVPLPKIFIKRQAPLKVSLLQDLKDFFQKVSQVYVAIDERLASLKTD TFSKTREEKMEDIFAQKE EEGEFK IEKMQARLMSSSλπ TPQQLQSVFESLIAKKQ SLCEVLQAWNNRLQDLFQQEKGRKRPSVPPSPGRLRQGEESKISAMDASPRNISPGLQ NGEKEDRFLTTLS SQS STS STHLQLPTPPEVMSEQS GGPPELDTAS S SEDVFDGHLL GSTDSQVKEKSTMINAIFANLLPGNSYNPIPFPFDPDKHYLMYEHERVPIAVCEKEPSS

IIAFALSCKEYRNALEELSKATQ NSAEΞGLPTNSTSDSRPKSSSPIRLPEMSGGQTN RTTETEPQPTKKASGMLSFFRGTAGKSPDLSSQKRETLRGADSAYYQVGQTGKEGTEN QGVEPQDEΛ/DGGDTQKKQLINPHVELQFSDANAKFYCRLYYAGEFHK REVILDSSEE DFIRSLSHSSP QARGGKSGAAFYATEDDRFILKQMPRLEVQSFLDFAPHYFNYITNA VQQKRPTALAKILGVYRIGYKNSQ NTEKKLDLLVMENLFYGRKMAQVFDLKGSLRNR VKTDTGKESCDWLLDENLLKMVRDNPLYIRSHS AVLRTSIHSDSHFLSSHLI IDY SLLVGRDDTSNELΛ/VGIIDYIRTFT DKKLEMWKSTGILGGQGKMPTΛA/^'SPELYRTR FCEAMDKYFLMVPDHWTGLGLNC

Further analysis of the NOV30a protein yielded the following properties shown in

Table 3 OB.

Table 30B. Protein Sequence Properties NOV30a

, PSort 0.7000 probability located in nucleus; 0.3000 probability located in microbody ^' analysis: (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen) j SignalP No Known Signal Sequence Indicated < analysis:

A search of the NOV30a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 30C.

j [WO200175067-A2, l l-OCT-2001]

ABG16883 Novel human diagnostic protein 1..31 1 280/312 (89%) e-161 #16874 - Homo sapiens, 612 aa. 174-474 285/312 (90%) [WO200r5067-A2, l l-OCT-2001]

ABG27219 Novel human diagnostic protein 1767-2015 248/249 (99%) e-141 #27210 - Homo sapiens, 864 aa. 532-780 249/249 (99%) [WO200175067-A2, l l-OCT-2001]

In a BLAST search of public sequence databases, the NOV30a protein was found to have homology to the proteins shown in the BLASTP data in Table 30D.

PFam analysis indicates that the NOV30a protein contains the domains shown in the

Table 30E.

Table 30E. Domain Analysis of NOV30a

Identities/

Pfam Domain NOV30a Match Region Similarities Expect Value for the Matched Region

FYVE 164-224 8.9e-20 46/66 (70%)

DEP 376-451 17/89 (19%) 0.15 48/89 (54%) cpn60_TCPl 620..670 18/56 (32%) 7.3e-06 38/56 (68%)

PIP5K 1802-2039 98/360 (27%) 2.2e-l l l 227/360 (63%)

Example 31.

The N0V31 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 31 A.

jSEQ ID NO: 125 { 1403 bp

NOV31b, ■CGGCGGCGTGGCGCAGCGGCGACATGGCCGTTGTCTCAGAGGACGACTTTCAGCACAG

CGI 04220-02 DNA TTCAAACTCCACCTACGGAACCACAAGCAGCAGTCTCCGAGCTGACCAGGAGGCACTG CTTGAGAAGCTGCTGGACCGCCCGCCCCCTGGCCTGCAGAGGCCCGAGGACCGCTTCT

Sequence GTGGCACATACATCATCTTCTTCAGCCTGGGCATTGGCAGTCTACTGCCATGGAACTT C TTATCACTGCCAAGGAGTACTGGATGTTCAAACTCCGCAACTCCTCCAGCCCAGCC ACCGGGGAGGACCCTGAGGGCTCAGACATCCTGGTTGCAGTCCACATCCGTGTCCTGG CCTCACTGACGGTCATCCTGGCCATCTTCATGGTGATAACTGCACTGGTGAAGGTGGA CACTTTCTCCTGGACCCGTGGCTTTTTTGCGGTCACCATTGTCTGCATGGTGATCCTC AGCGGTGCCTCCACTGTCTTCAGCAGCAGCATCTACGGCATGACCGGCTCCTTTCCTA TGAGGAACTCCCAGGCACTGATATCAGGAGGAGCCATGGGCGGGACGGTCAGCGCCGT GGCCTCATTGGTGGACTTGGCTGCATCCAGTGATGTGAGGAACAGCGCCCTGGCCTTC TTCCTGACGGCCACCATCTTCCTCGTGCTCTGCATGGGACTCTACCTGCTGCTGTCCA GGCTGGAGTATGCCAGGTACTACATGAGGCCTGTTCTTGCGGCCCATGTGTTTTCTGG TGAAGAGGAGCTTCCCCAGGACTCCCTCAGTGCCCCTTCGGTGGCCTCCAGATTCATT GATTCCCACACACCCCCTCTCCGCCCCATCCTGAAGAAGACGGCCAGCCTGGGCTTCT GTGTCACCTACGTCTTCTTCATCACCAGCCTCATCTACCCCGCCGTCTGCACCAACAT CGAGTCCCTCAACAAGGGCTCGGGCTCACTGTGGACCACCAAGTTTTTCATCCCCCTC ACTACCTTCCTCCTGTACAACTTTGCTGACCTATGTGGCCGGCAGCTCACCGCCTGGA TCCAGGTGCCAGGGCCCAATAGCAAGGCGCTCCCAGGGTTCGTGCTCCTCCGGACCTG CCTCATCCCCCTCTTCGTGCTCTGTAACTACCAGCCCCGCGTCCACCTGAAGACTGTG GTCTTCCAGTCCGATGTGTACCCCGCACTCCTCAGCTCCCTGCTGGGGCTCAGCAACG GCTACCTCAGCACCCTGGCCCTCCTCTACGGGCCTAAGATTGTGCCCAGGGAGTCTTC TGCTGAGGCCACGGGAGTGGTGATGTCCTTTTATGTGTGCTTGGGCTTAACACTGGGC TCAGCCTGCTCTACCCTCCTGGTGCACCTCATCTAGAAGGGAGGACACAAGGACATGC AGAGTGGTGAG

ORF Start: ATG at 24 ORF Stop: TAG at 1368

SEQ ID NO: 126 448 aa MW at 48718. lkD

'NOV31b, MAWSEDDFQHSSNSTYGTTSSSLRADQEALLEKLLDRPPPGLQRPEDRFCGTYIIFF JCG104220-02 jSLGIGSLLPWNFFITAKEYWMFKLRNSSSPATGEDPEGSDILVAVHIRVLASLTVILA JIFMVITALVKVDTFS TRGFFAVTIVC VILSGASTVFSSSIYGMTGSFPMRNS ALI {Protein Sequence SGGAMGGTVSAVASLVDLAASSDVRNSALAFFLTATIFLVLC GLYLLLSRLEYARYY MRPVLAAHVFSGEEELPQDSLSAPSVASRFIDSHTPPLRPILKKTASLGFCVTYVFFI TSLIYPAVCTNIESLNKGSGSL TTKFFIPLTTFLLYNFADLCGRQLTA IQVPGPNS KALPGFVLLRTCLIPLFVLCNYQPRλ/HLKTWFQSDVYPALLSSLLGLSNGYLSTLAL LYGPKIVPRESSAEATGWMSFYVCLGLTLGSACSTLLVHLI

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 3 IB.

Further analysis of the NOV3 la protein yielded the following properties shown in Table 3 IC.

Table 31C. Protein Sequence Properties NOV31a

PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: 0.3000 probability located in microbody (peroxisome)

^" SignalP Cleavage site between residues 16 and 17 ' analysis:

A search of the NOV3 la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3 ID.

In a BLAST search of public sequence databases, the NOV3 la protein was found to have homology to the proteins shown in the BLASTP data in Table 3 IE.

PFam analysis indicates that the NOV31 a protein contains the domains shown in the Table 3 IF.

Example 32.

The NOV32 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 32A.

Table 32A. NOV32 Sequence Analysis

SEQ ID NO: 127 1967 bp

NOV32a, GGCCAGAGCCGGGGAGCTGGGAGGGGTCTACCGGGGCTCGACTCTAGGAGTTGGGCTG

CG104693-01 DNA AGGATTTCCACCCGATCCTCGAACCTCCGGCCCATCTCATGGACGCCCCTCCCCCTTC AAACACCCTCCCCCACATTTATTCCCGCGTCTGTTTTAAAGATGGGTAAACTGAGGCA Sequence CAGGGAGCCGGGCCGGGGAGCACTGACAGAACCAGAAGCAGGTTCTGCCTCCCGTCCC CTCGGAGGGCCGACTTGCCCCTTCTGGGTTTCGTCGGGGGTCTCAGATACGAGGAGGC CCAGCTGGAAGCCACCTGAGGGTGTCCCCCGCTAAGATGCGCAAATGGGAAAAGCGAG GCCGGGGTTGGGGAAAGAACTTGCCCGAGCCGCAGAGCGCGTCAGCCGGGGAGGTCGG GGCGGGGGCGACCCGCGCGACCGAGGATCGGGTATCTGGGCCCGGCGCGGAGCCTGCA

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 32B.

Table 32B. Comparison of NOV32a against NO V32b.

NOV32a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV32b 76..510 435/491 (88%) 1..491 435/491 (88%)

Further analysis of the NOV32a protein yielded the following properties shown in Table 32C.

Table 32C. Protein Sequence Properties NOV32a

I PSort 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody . analysis: (peroxisome); 0.2695 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV32a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 32D.

Table 32D. Geneseq Results for NOV32a

NOV32a Identities/

Geneseq Protein/Organism/Length [Patent Residues/ Similarities for 1 Expect Identifier #, Date] Match the Matched j Value Residues Region

In a BLAST search of public sequence databases, the NOV32a protein was found to have homology to the proteins shown in the BLASTP data in Table 32E.

; cress), 588 aa.

PFam analysis indicates that the NOV32a protein contains the domains shown in the Table 32F.

Example 33.

The NOV33 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 33A.

Further analysis of the NOV33a protein yielded the following properties shown in

Table 33 B.

Table 33B. Protein Sequence Properties NOV33a

PSort 0.7600 probability located in nucleus; 0.1000 probability located in analysis: mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Indicated analysis: A search of the NOV33a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 33C.

In a BLAST search of public sequence databases, the NOV33a protein was found to have homology to the proteins shown in the BLASTP data in Table 33D.

PFam analysis indicates that the NOV33a protein contains the domains shown in the

Table 33E.

Table 33E. Domain Analysis of NOV33a

Identities/

Pfa Domain NOV33a Match Region Similarities ; Expect Value for the Matched Region

No Significant Matches Found

Example 34.

The NOV34 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 34A.

Table 34A. NOV34 Sequence Analysis

ISEQ ID NO: 133 1790 bp

NOV34a, TCACAGTAGCATTTGTCTTCAATCTGTGTGTTAACTAGAAATCAAGGAAAGACATGAG

CGI 04800-01 DNA GAGATTTGTCTACTGCAAGGTGGTTCTAGCCACTTCGCTGATGTGGGTTCTTGTTGAT GTCTTCTTACTGCTGTACTTCAGTGAATGTAACAAATGTGATGACAAGAAGGAGAGAT

Sequence CTCTGCTGCCTGCATTGAGGGCTGTTATTTCAAGAAACCAAGAAGGGCCAGGAGAAAT GGGAAAAGCTGTGTTGATTCCTAAAGATGACCAGGAGAAAATGAAAGAGCTGTTTAAA ATCAATCAGTTTAACCTTATGGCCAGTGATTTGATTGCCCTTAATAGAAGTCTGCCAG ATGTAAGATTAGAAGGATGTAAGACAAAAGTCTACCCTGATGAACTTCCAAACACAAG TGTAGTCATTGTGTTTCATAATGAAGCTTGGAGCACTCTCCTTAGAACTGTTTACAGT GTGATAAATCGTTCCCCACACTATCTACTCTCAGAGGTCATCTTGGTAGATGATGCCA GTGAAAGAGATTTTCTCAAGTTGACATTAGAGAATTACGTGAAAAATTTAGAAGTGCC AGTAAAAATTATTAGGATGGAAGAACGCTCTGGGTTAATACGTGCCCGTCTTCGAGGA GCAGCTGCTTCAAAAGGGCAGGTCATAACTTTTCTTGATGCACACTGTGAATGCACGT TAGGATGGCTGGAGCCTTTGCTGGCAAGAATAAAGGAAGACAGGAAAACGGTTGTCTG CCCTATCATTGATGTGATTAGTGATGATACTTTTGAATATATGGCTGGGTCAGACATG ACTTATGGGGGTTTTAACTGGAAACTGAATTTCCGCTGGTATCCTGTTCCCCAAAGAG AAATGGACAGGAGGAAAGGAGACAGAACATTACCTGTCAGGACCCCTACTATGGCTGG TGGCCTATTTTCTATTGACAGAAACTACTTTGAAGAGATAGGAACTTACGATGCAGGA ATGGATATCTGGGGTGGAGAGAATCTTGAAATGTCTTTTAGGATTTGGCAATGTGGAG GCTCCTTGGAGATTGTTACTTGCTCCCATGTTGGTCATGTTTTTCGGAAGGCAACTCC

ATACACTTTTCCTGGTGGCACTGGTCATGTCATCAACAAGAACAACAGGAGACTGGCA_,

GAAGTTTGGATGGATGAATTTAAAGATTTCTTCTACATCATACCAGGTGTTGTCAAAG!

TGGATTATGGAGATGTGTCAGTCAGAAAAACACTAAGAGAAAATCTGAAGTGTAAGCC^'

CTTTTCTTGGTACCTAGAAAACATCTATCCGGACTCCCAGATCCCAAGACGTTATTAC

TCACTTGGTGAGATAAGAAATGTTGAAACCAATCAGTGTTTAGACAACATGGGCCGCA

AGGAAAATGAAAAAGTGGGTATATTCAACTGTCATGGTATGGGAGGAAATCAGGTATT

TTCTTACACTGCTGACAAAGAAATCCGAACCGATGACTTGTGCTTGGATGTTTCTAGA

CTCAATGGACCTGTAATCATGTTAAAATGCCACCATATGAGAGGAAATCAGTTATGGG

AATATGATGCTGAGAGACTCACGTTGCGACATGTTAACAGTAACCAATGTCTCGATGA

ACCTTCTGAAGAAGACAAAATGGTGCCTACAATGCAGGACTGTAGTGGAAGCAGATCC

CAACAGTGGCTGCTAAGGAACATGACCTTGGGCACATGAAGATCATGTCCTCCAAGCC

ATGAAAGTGTCTACGCTTTTGTTTTTCCATTATTTCAATTGGGGGAAAAT

ORF Start: ATG at 54 ORF Stop: TGA at 1719

SEQ ID NO: 134 555 aa MW at 63962.9kD iNOV34a, MRRFVYC WLATSLMWVLVDVFLLLYFSECNKCDDKKERSLLPALRAVISRNQEGPG CG104800-01 EMGKAVLIPKDDQEK KELFKINQFNLMASDLIALNRSLPDVRLEGCKTKVYPDELPN TSWIVFHNEAWSTLLRTVYSVINRSPHYLLSEVILVDDASERDFLKLTLENYVKNLE .Protein Sequence VPVKIIRMEERSGLIRARLRGAAASKGQVITFLDAHCECTLG LEPLLARIKEDRKTV VCPIIDVISDDTFEYMAGSDMTYGGFNWKLNFRWYPVPQREMDRRKGDRTLPVRTPTM AGGLFSIDRNYFEEIGTYDAGMDI GGENLEMSFRI QCGGSLEIVTCSHVGHVFR A TPYTFPGGTGHVIN NNRRLAEV MDEFKDFFYIIPGWKVDYGDVSVR TLRENLKC KPFSWYLENIYPDSQIPRRYYSLGEIRNVETNQCLDNMGRKENEKVGIFNCHG GGNQ VFSYTADKEIRTDDLCLDVSRLNGPVIMLKCHHMRGNQL EYDAERLTLRHλ/ SNQCL DEPSEEDKMVPTMQDCSGSRSQQ LLRiMMTLGT

ISEQ ID NO: 135 1956 bp

^■NOV34b, TCACAGTAGCATTTGTCTTCAATCTGTGTGTTAACTAGAAATCAAGGAAAGACATGAG

;CG104800-02 DNA GAGATTTGTCTACTGCAAGGTGGTTCTAGCCACTTCGCTGATGTGGGTTCTTGTTGAT GTCTTCTTACTGCTGTACTTCAGTGAATGTAACAAATGTGATGACAAGAAGGAGAGAT ^'Sequence CTCTGCTGCCTGCATTGAGGGCTGTTATTTCAAGAAACCAAGAAGGGCCAGGAGAAAT GGGAAAAGCTGTGTTGATTCCTAAAGATGACCAGGAGAAAATGAAAGAGCTGTTTAAA ATCAATCAGTTTAACCTTATGGCCAGTGATTTGATTGCCCTTAATAGAAGTCTGCCAG ATGTAAGATTAGAAGGATGTAAGACAAAAGTCTACCCTGATGAACTTCCAAACACAAG TGTAGTCATTGTGTTTCATAATGAAGCTTGGAGCACTCTCCTTAGAACTGTTTACAGT GTGATAAATCGTTCCCCACACTATCTACTCTCAGAGGTCATCTTGGTAGATGATGCCA GTGAAAGAGATTTTCTCAAGTTGACATTAGAGAATTACGTGAAAAATTTAGAAGTGCC AGTAAAAATTATTAGGATGGAAGAACGCTCTGGGTTAATACGTGCCCGTCTTCGAGGA GCAGCTGCTTCAAAAGGGCAGGTCATAACTTTTCTTGATGCACACTGTGAATGCACGT TAGGATGGCTGGAGCCTTTGCTGGCAAGAATAAAGGAAGACAGGAAAACGGTTGTCTG CCCTATCATTGATGTGATTAGTGATGATACTTTTGAATATATGGCTGGGTCAGACATG ACTTATGGGGGTTTTAACTGGAAACTGAATTTCCGCTGGTATCCTGTTCCCCAAAGAG AAATGGACAGGAGGAAAGGAGACAGAACATTACCTGTCAGGACCCCTACTATGGCTGG TGGCCTATTTTCTATTGACAGAAACTACTTTGAAGAGATAGGAACTTACGATGCAGGA ATGGATATCTGGGGTGGAGAGAATCTTGAAATGTCTTTTAGGATTTGGCAATGTGGAG GCTCCTTGGAGATTGTTACTTGCTCCCATGTTGGTCATGTTTTTCGGAAGGCAACTCC ATACACTTTTCCTGGTGGCACTGGTCATGTCATCAACAAGAACAACAGGAGACTGGCA GAAGTTTGGATGGATGAATTTAAAGATTTCTTCTACATCATATCCCCAGGTGTTGTCA AAGTGGATTATGGAGATGTGTCAGTCAGAAAAACACTAAGAGAAAATCTGAAGTGTAA GCCCTTTTCTTGGTACCTAGAAAACATCTATCCGGACTCCCAGATCCCAAGACGTTAT TACTCACTTGGTGAGATAAGAAATGTTGAAACCAATCAGTGTTTAGACAACATGGGCC GCAAGGAAAATGAAAAAGTGGGTATATTCAACTGTCATGGTATGGGAGGAAATCAGGT ATTTTCTTACACTGCTGACAAAGAAATCCGAACCGATGACTTGTGCTTGGATGTTTCT AGACTCAATGGACCTGTAATCATGTTAAAATGCCACCATATGAGAGGAAATCAGTTAT GGGAATATGATGCTGAGACCCACACTCTTCTTCATATAATCACCCAGTCTTGTCTCTC AGTGAACAAAGTAGCTGATGGCTCCCAGCATCCTACTGTGGAAACCTGTAATGATAGC ACTTTGCAAAAATGGCTACTAAGAAACTATACAAGAATGGAAATTTTTAGAAATATTT TTGGGAATTCTACTGATTACATTCTCTAATGATTTTTGGAGAGACTCACGTTGCGACA TGTTAACAGTAACCAATGTCTCGATGAACCTTCTGAAGAAGACAAAATGGTGCCTACA JATGCAGGACTGTAGTGGAAGCAGATCCCAACAGTGGCTGCTAAGGAACATGACCTTGG iGCACATGAAGATCATGTCCTCCAAGCCATGAAAGTGTCTACG iORF Start: ATG at 54 JORF Stop: TAA at 1767

SEQ ID NO: 136 _>71 aa JMW at 65781.9kD

;NOV34b, MRRFVYCKWLATSL WVLVDVFLLLYFSECNKCDDKKERSLLPALRAVISRNQEGPG JCGI 04800-02 EMGKAVLIP DDQEKMKELFKINQFNLMASDLIALNRSLPDVRLEGCKTKVΥPDΞLPN TSλA^IVFHNEAWSTLLRTATYSVINRSPHYLLSEVIL^'VDDASERDFLKLTLENYVKNLΞ 'Protein Sequence VPVKIIRMΞERSGLIRARLRGAAASKGQVITFLDAHCECTLGWLEPLLARIKEDRKTV VCPIIDVISDDTFEYMAGSDMTYGGFNWKLNFRWYPVPQREMDRRKGDRTLPVRTPTM AGGLFSIDRNYFΞEIGTYDAGMDI GGENLEMSFRI QCGGSLEIVTCSHVGHVFRKA TPYTFPGGTGHVINKNNRRLAEV MDEFKDFFYIISPGWKVDYGDVSVRKTLRENLK CKPFSWYLENIYPDSQIPRRYYSLGEIRNVETNQCLDNMGRKENEKVGIFNCHG GGN QVFSYTADKEIRTDDLCLDVSRLNGPVIMLKCHHMRGNQLWEYDAETHTLLHIITQSC LSV VADGSQHPTVETCNDSTLQK LLRNYTRMEIFRNIFGNSTDYIL

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 34B.

Table 34B. Comparison of NOV34a against NOV34b.

NOV34a Residues/ I Identities/

^• Protein Sequence Match Residues Similarities for the Matched Region

NOV34b 1..552 511/554 (92%) 1..554 517/554 (93%)

Further analysis of the NOV34a protein yielded the following properties shown in

Table 34C.

Table 34C. Protein Sequence Properties NOV34a

PSort 0.8200 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 32 and 33 analysis:

A search of the NOV34a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 34D.

; APR- 1997]

In a BLAST search of public sequence databases, the NOV34a protein was found to have homology to the proteins shown in the BLASTP data in Table 34E.

acetylgalactosaminyltransferase) (UDP-

, GalNAc:polypeptide, N- < ^' ! : _t acetylgalactosaminyitransferase) {

(GalNAc-Tl) - Rattus norvegicus (Rat), j j

559 aa. . ! i

Q29121 Polypeptide N- 1 1. .553 | 471/556 (84%) 0.0 acetylgalactosaminyltransferase (EC j 1. .555 ; 516/556 (92%)

2.4.1.41) (Protein- UDP { i

! acetylgalactosaminyltransferase) (UDP- |

GalNAc:polypeptide, N- 1 , acetylgalactosaminyltransferase) 1 j

(GalNAc-Tl) - Sus scrofa (Pig), 559 aa. | |

PFam analysis indicates that the NOV34a protein contains the domains shown in the Table 34F.

Table 34F. Domain Analysis of NOV34a

Identities/

Pfam Domain NOV34a Match Region Similarities Expect Value for the Matched Region

Glycos_transf_2 118.306 47/191 (25%) 4.8e-37 153/191 (80%)

Ricin B lectin 430..471 16/44 (36%) 5.7e-10 34/44 (77%)

Ricin B lectin 472..507 16/44 (36%) 1.4e-06 29/44 (66%)

Ricin B lectin 511..551 12/44 (27%) 5.6e-05 33/44 (75%)

Example 35.

The NOV35 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 35 A.

: ORF Start: ATG at 3 JORF Stop: TAG at 564

! |SEQ ID NO: 138 187 aa |MW at 21186.1kD

.NOV35a, MPDLSKRSRPLSLQEVDGQPQHSLHVAYARATVDELGKVLTPTKVNRPTSIS DDLES ;CG104813-01 RKLYTLVLTDPDAPGRKKPQYTE RHFLVλ/NMKG DVSSGPVIS ITRGLGPPEGTDLH RYV LATYKQDRLLKCDEPILSNGSGGHSGKFKMASFKKKYELVLVAPVARKRYQAE D jProtein Sequence DYVPKLQEQLSGK

Further analysis of the NOV35a protein yielded the following properties shown in

Table 35B.

Table 35B. Protein Sequence Properties NOV35a i PSort 0.9400 probability located in nucleus; 0.1127 probability located in microbody analysis: (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV35a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several

_> homologous proteins shown in Table 35C.

In a BLAST search of public sequence databases, the NOV35a protein was found to have homology to the proteins shown in the BLASTP data in Table 35D.

PFam analysis indicates that the NOV35a protein contains the domains shown in the Table 35E.

Table 35E. Domain Analysis of NOV35a

Identities/

Pfam Domain NOV35a Match Region Similarities j Expect Value for the Matched Region

PBP 1..172 76/203 (37%) l.le-43 138/203 (68%)

Example 36.

The NOV36 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 36A.

'AGGAATGTTTTCATCCTTACAATACATGCATTACTGATTTAAGGACTTCACATTGGGA LAGAAGCAATCCAGGAAACAAAAGGTGGTGCAGCCAATAGAAAATTGGCTGAAGAATGT ^'TATTTCCTTTGGAAATCTACACGTTTACAGCATATGACACTAGCAGAAGACGTCAAAG CCATGCTTACTGAACTTCGAAAGGAGGTCCGCCTACTTCTATTAACGAATGGGGACAG ACAGACCCAGAGGGAGAAGATTGAGGCTTGTGCCTGTCAGTCCTATTTTGACGCTGTT GTTGTAGGTGGAGAGCAGAGAGAGGAGAAACCAGCACCGTCCATATTTTATTACTGCT GCAATCTTCTCGGAGTACAACCTGGGGACTGTGTGATGGTCGGTGACACATTAGAAAC CGACATCCAAGGAGGCCTCAATGCAGGATTGAAAGCAACAGTCTGGATCAATAAAAAT GGAATAGTGCCACTGAAGTCCTCCCCAGTTCCGCATTACATGGTTTCTTCTGTGCTAG AGTTACCTGCTCTCTTACAAAGTATAGACTGCAAAGTCAGTATGTCCACTTAAAGCAC ATAAAAGGGCATGATTATGAATGTTAGAATCAATTTGCTGAGTATGAAA

ORF Start: ATG at 61 ORF Stop: TAA at 805

SEQ ID NO: 140 248 aa MW at 27812.8kD

;NOV36a, MGLSRVRAVFFDLDNTLIDTAGASRRGMLEVIKLLQSKYHYKEEAEIICDKVQVKLSK JCG104892-01 ECFHPYNTCITDLRTSHWEEAIQETKGGAA RKLAEECYFL KSTRLQHMTLAEDVKA MLTELRKEVRLLLLTNGDRQTQREKIEACACQSYFDA WGGEQREEKPAPSIFYYCC i Protein Sequence NLLGVQPGDCV VGDTLETDIQGGLNAGLKATV INK GIVPLKSSPVPHYMVSSVLE LPALLQSIDCKVSMST

SEQ ID NO: 141 796 bp

;NOV36b, CGGCGGTGGCAAGGCTACGGTTCGCGCCAGCGGCCGGCGCTATGGGGCTGAGCCGCGT

'.CG104892-02 DNA GCGGGCGGTTTTCTTTGACTTGGACAACACTCTCATCGACACGGCCGGGGCGAGCAGG AGAGGCATGTTGGAGGTGATAAAACTCTTACAATCAAAATACCATTATAAAGAAGAGG

'Sequence CTGAAATCATCTGTGATAAAGTTCAAGTTAAACTCAGCAAGGAATGTTTTCATCCTTA CAATACATGCATTACTGATTTAAGGACTTCACATTGGGAAGAAGCAATCCAGGAAACA AAAGGTGGTGCAGCCAATAGAAAATTGGCTGAAGAATGTTATTTCCTTTGGAAATCTA CACGTTTACAGCATATGACACTAGCAGAAGACGTCAAAGCCATGCTTACTGAACTTCG AAAGGAGGTCCGCCTACTTCTATTAACGAATGGGGACAGACAGACCCAGAGGGAGAAG ATTGAGGCTTGTGCCTGTCAGTCCTATTTTGACGCTGTTGTTGTAGGTGGAGAGCAGA GAGAGGAGAAACCAGCACCGTCCATATTTTATTACTGCTGCAATCTTCTCGGAGTACA ACCTGGGGACTGTGTGATGGTCGGTGACACATTAGAAACCGACATCCAAGGAGGCCTC AATGCAGGATTGAAAGCAACAGTCTGGATCAATAAAAATGGAATAGTGCCACTGAAGT CCCCCCCAGTTCCGCATTACATGGTTTCTTCTGTGCTAGAGTTACCTGCTCTCTTACA AAGTATAGACTGCAAAGTCAGTATGTCCACTTAAΆGCAΆAGG

ORF Start: ATG at 42 {ORF Stop: TAA at 786

SEQ ID NO: 142 Ϊ24S aa MW at 27822.8kD

<NOV36b, MGLSRVRAVFFDLDNTLIDTAGASRRG LEVIKLLQSKYHYKEEAEI ICDKVQVKLSK • CG104892-02 ECFHPYNTCITDLRTSHWEEAIQETKGGAANRKLAEECYFL KSTRLQHMTLAEDVKA MLTΞLRKEVRLLLLTNGDRQTQREKIEACACQSYFDAWVGGEQREEKPAPSIFYYCC ! Protein Sequence NLLGVQPGDCλ/ VGDTLETDIQGGLNAGLKATV INKNGIVPLKSPPVPHYMVSSVLΞ LPALLQS IDCKVSMST

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 36B.

Further analysis of the NOV36a protein yielded the following properties shown in Table 36C. Table 36C. Protein Sequence Properties NOV36a

1 PSort j 0.4814 probability located in mitochondrial matrix space; 0.4500 probability ^: analysis: j located in cytoplasm; 0.1897 probability located in mitochondrial inner membrane: 0.1897 probability located in mitochondrial intermembrane space

I SignalP No Known Signal Sequence Indicated j analysis:

A search of the NOV36a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 36D.

In a BLAST search of public sequence databases, the NOV36a protein was found to have homology to the proteins shown in the BLASTP data in Table 36E.

PFam analysis indicates that the NOV36a protein contains the domains shown in the Table 36F.

Example 37.

The NOV37 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 37 A.

GCCATGGTTGTAGAAGCTGTCCAACTCATAGCTGATGGAAAAGCTCCTCGTATACCCC

AGCCAGAAGAAGGGGCAACATATGAAGGTATCCAGAAAAAGGAAAATGCTGAGATTTC

TTGGGACCAGTCTGCCGAAGTTTTACATAACTGGATTCGAGGTCATGATAAAGTCCCT

GGAGCTTGGACAGAGGTCACTTTCTATGGCTCGACATTACTGAATAGCTCTGTGCCTC

CTGGAGAACCACTGGAAATTAAAGGTGCCAAGAAGCCTGGTCTCGTTACCAAAAATGG

ACTTGTTCTTTTTGGTAACGATGGAAAAGCAGTGAGTGTTAAAAATCTGCAGTTTGAA

GATGGAAAAATGATCCCTGCCTCTCAGTACTTTTCAACGGGTGAGACGTCAGTGGTAG

AACTGACAGCTGAAGAGGTGAAAGTGGCAGAGACCATCAAGATCTGGGCTGGAATTTT

AAGCAATGTCCCCATTATTGAAGACTCAACAGACTTCTTTAAATCTGGAGCAAGCTCA

ATGGATGTTTTAAGGCTGGTTGAAGAGATCAGACAGAAATGTGGTGGGCTTCAGTTGC

AGAATGAAGATGTCTATATGGCCACCAAGTTTGAAGGCTTTATCCAAAAGGTCGTGAG

GAAACTGAGAGGAGAAGATCAAGAGGTGGAGCTGGTTGTAGATTATGTATCAAAGGAG

GTCAATGAAATCATGGTAAAAATGCCATACCAGTGTTTCATAAATGGACAGTTCACAG

ATGCAGACGATGGAAAGACTTACGACACTATCAACCCAACAGATGGATCTGTGATATG

CAAAGTATCCTACGCTTCTTTGGCGGATGTTGATAAAGCAGTAGCAGCAGCAAAAGAT

GCTTTTGAAAACGGTGAATGGGGAAGAATGAATGCAAGAGAAAGAGGAAGATTGATGT

ATAGGAGACTTGCAGACCTACTGGAAGAGAACCAAGAAGAGCTGGCAACTATTGAAGC

ACTTGATTCAGGGCCTGTCTATACCTTGGCCCTGAAGACACACATTGGAATGTCTGTG

CAAACATTCAGATATTTTGCTGGCTGGTGCGACAAAATTCAGGGTTCTACTATTCCAA

TCAGCCAGGCCCGTCCAAATCGCAATCTGACCTTCACCAAGAAAGAGCCACTCGGTGT

CTGTGCCATTATTATTCCCTGGAACTACCCGCTGATGATGCTGGCATGGAAGAGTGCT

IGCGTGTTTGGCAGCAGGCAATACCTTAGTGCTCAAGCCAGCACAGGTCACACCCTTGA

!CTGCTTTGAAGTTTGCAGAACTGTCTGTGAAAGCAGGCTTTCCAAAGGGGGTCATCAA

JCATCATTCCAGGCTCAGGTGGCATAGCAGGACAACGTCTGTCTGAACATCCTGACATC

^■CGCAAACTTGGTTTCACTGGATCCACTCCTATTGGCAAACAGATCATGAAGAGCTGTG

SCTGTTAGCAACTTGAAGAAAGTTTCCCTTGAGCTTGGTGGCAAGTCTCCACTTATAAT

JATTTAATGACTGTGAACTTGACAAGGCTGTGCGAATGGGCATGGGAGCAGTATTTTTC

|AACAAAGGAGAGAACTGTATTGCTGCTGGGCGGTTGTTCGTGGAAGAATCCATCCACG

^'IACGAATTTGTGACAAGAGTGGTAGAAGAAATTAAAAAGATGAAAATTGGTGATCCACT GACAGATCCACTGATCATGGGCCCCAAAATCATAAGGCTCATCTGGAAAAGCTGCTG jCAATACTGTGAAACTGGAGTGAAAGAAGGGGCCACTTTGGTGTACGGGGGAAGACAAG iTCCAAAGGCCAGGCTTTTTCATGGAGCCGACCGTGTTCACAGATGTGGAAGACTACAT

IGTACCTCGCCAAAGAGGAATCCTTTGGGCCTATTATGGTCATTTCTAAATTCCAAAAT ⁼GGGGACATCGATGGAGTGTTGCAGCGAGCAAATAGTACAGAGTATGGTTTGGCCTCAG GGGTTTTTACAAGAGACATAAACAAAGCTATGTATGTGAGTGAAAAACTGGAAGCAGG AACTGTTTTTATTAACACATACAACAAGACAGATGTGGCGGCCCCATTTGGCGGAGTT AAACAATCTGGCTTTGGAAAAGACCTAGGTGAGGAAGCTCTAAATGAATATCTCAAAA CCAAGACGGTGACACTGGAATATTAGAGCAACACCATCATCAGGAAAGCCTTGACAGA ' CAGCCCTTTACAAC

ORF Start: ATG at 1 ORF Stop: TAG at 2692

SEQ ID NO: 144 897 aa MW at 98676.2kD

NOV37a, MKLALIGQSLFGQEVYSHLRKEGHRWGVFTVPDKDGKADPLGLAAEKDGTPVFKLPK CG104955-01 RVKGKTIKEVAEAYRSVGAΞLNVLPFCTQFIPMDIIDSPKHGSIIYHPSILPRHRGA SAINWTLI GDKKAGFSVF ADDGLDTGPILLQRSCDVEPNDTΛTOALYNRFLFPEGIK Protein Sequence AMΛΛEAVQLIADGKAPRIPQPΞEGATYΞGIQKKENAEIS DQSAEVLHNWIRGHDKVP GA TEVTFYGSTLLNSSVPPGEPLEIKGAKKPGLVTKNGLVLFGNDGKAVSVKNLQFE DGKMIPASQYFSTGETSWELTAEEVKVAETIKIWAGILSNVPIIEDSTDFFKSGASS MDVLRLVEEIRQKCGGLQLQNEDΛTYMATKFEGFIQKΛAARKLRGEDQEVELWDYVSKE Λ EIIWKMPYQCFINGQFTDADDGKTYDTINPTDGSVICKVSYASLADVDKAVAAAKD AFENGEWGRMNARERGRLMYRRLADLLEENQEELATIEALDSGPVΎTLALKTHIGMSV QTFRYFAG CDKIQGSTIPISQARPNRNLTFTKKEPLGVCAIIIPWNYPLMMLAWKSA ACLAAGNTLVLKPAQVTPLTALKFAΞLSVKAGFPKGVINIIPGSGGIAGQRLSΞHPDI RKLGFTGSTPIGKQIM SCAVSNLKKVSLΞLGG SPLIIFHDCELDKAΛΛRMGMGAVFF NKGENCIAAGRLFVEESIHDEFVTRWEΞIKKMKIGDPLDRSTDHGPQNHKAHLEKLL QYCETGVKEGATLΛTYGGRQVQRPGFFMEPTVFTDVEDYMYLA EESFGPIMVISKFQN GDIDGVLQRANSTEYGLASGVFTRDINKAMYVSEKLEAGTVFINTYNKTDVAAPFGGV KQSGFGKDLGEEALNEYLKTKTVTLEY

222 Further analysis of the NOV37a protein yielded the following properties shown in Table 37B.

Table 37B. Protein Sequence Properties NQV37a PSort 0.4500 probability located in cytoplasm; 0.4094 probability located in microbody analysis: (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV37a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 37C.

In a BLAST search of public sequence databases, the NOV37a protein was found to have homology to the proteins shown in the BLASTP data in Table 37D.

Table 37D. Public BLASTP Results for NOV37a

Protein/Organism/Length

PFam analysis indicates that the NOV37a protein contains the domains shown in the Table 37E.

Example 38.

The NOV38 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 38 A.

I Table 38A. NOV38 Sequence Analysis iSEQ ID NO: 145 i649 bp

Further analysis of the NOV38a protein yielded the following properties shown in Table 38B.

Table 38B. Protein Sequence Properties NOV38a

PSort 0.5500 probability located in endoplasmic reticulum (membrane); 0.2419 analysis: probability located in lysosome (lumen); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP j Cleavaae site between residues 20 and 21 analysis:

A search of the NOV38a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 38C.

In a BLAST search of public sequence databases, the NOV38a protein was found to have homology to the proteins shown in the BLASTP data in Table 38D.

PFam analysis indicates that the NOV38a protein contains the domains shown in the

Table 38E.

Table 38E. Domain Analysis of NOV38a Identities/

Pfam Domain ι NOV38a Match Region Similarities Expect Value | for the Matched Region adh short 1..156 46/276 (17%) 0.025 117/276 (42%)

Example 39.

The NOV39 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 39A.

Table 39A. NO 39 Sequence Analysis

SEQ ID NO: 147 >05 bp

NOV39a, GACAAGAGCTCAGACCTGAGGAGAGTGACTAGCTTCTCTGTGTCCCAGGTGGCCACCT

CG105^01 -01 DNA I^{TCCACTG GGAAGCTCATGGACTCCATTGGCT}

JACCCTGAGTTGCTCTGAGGAGGGCTTGCCCGGGCCCTCAGACAGCTCAGAGCTGGTGC

Sequence (AGGAGTGCCTGCAGCAGTTCAAGGTGACAAGGGCACAGCTACAGCAGATCCAAGCCAG ICCTCTTGGGTTCCATGGAGCAGGCGCTGAGGGGACAGGCCAGCCCTGCCCCTGCGGTC CGGATGCTGCCTACATACGTGGGGTCCACCCCACATGGCACTGAGCAAGGAGACTTCG TGGTGCTGGAGCTGGGGGCCACAGGGGCCTCACTGCGTGTTTTGTGGGTGACTCTAAC TGGCATTGAGGGGCATAGGGTGGAGCCCAGAAGCCAGGAGTTTGTGATCCCCCAAGAG GTGATGCTGGGTGCTGGCCAGCAGCTCTTTGACTTTGCTGCCCACTGCCTGTCTGAGT TCCTGGATGCGCAGCCTGTGAACAAACAGGGTCTGCAGCTTGGCTTCAGCTTCTCTTT CCCTTGTCACCAGACGGGCTTGGACAGGAGCACCCTCATTTCCTGGACCAAAGGTTTT AGGTGCAGTGGTGTGGAAGGCCAGGATGTGGTCCAGCTGCTGAGAGATGCCATTCGGA .GGCAGGGGGCCTACAACATCGACGTGGTTGCTGTGGTGAACGACACAGTGGGCACCAT JGATGGGCTGTGAGCCGGGGGTCAGGCCGTGTGAGGTTGGGCTAGTTGTAGACACGGGC IACCAACGCGTGTTACATGGAGGAGGCACGGCATGTGGCAGTGCTGGACGAAGACCGGG ^CCGCGTCTGCGTCAGCGTCGAGTGGGGCTCCTTAAGCGATGATGGGGCGCTGGGACC AGTGCTGACCACCTTCGACCATACCCTGGACCATGAGTCCCTGAATCCTGGTGCTCAG AGGTTTGAGAAGATGATCGGAGGCCTGTACCTGGGTGAGCTGGTGCGGCTGGTGCTGG CTCACTTGGCCCGGTGTGGGGTCCTCTTTGGTGGCTGCACCTCCCCTGCCCTGCTGAG CCAAGGCAGCATCCTCCTGGAACACGTGGCTGAGATGGAGGAGTGAGTCGGGGAGATG

GTGGTTTAGTGGGGGATTCTTGGCTTGGAGGAAGGGGATGATACTCTGTTCCCAAGGT

AGCCATGGGGCTTTAGTGGGATGGGGAGCTTCTGGGCTGAGCCCCAAACCACTTCCCT

TTCCCCTCCAGCCCCTCTACTGGGGCAGCCCGTGTCCATGCTATCCTGCAGGACTTGG

GCCTGAGCCCTGGGGCTTCGGATGTTGAGCTTGTGCAGCACGTCTGTGCGGCCGTGTG

CACGCGGGCTGCCCAGCTCTGTGCTGCCGCCCTGGCCGCTGTTCTCTCCTGCCTCCAG

CACAGCCGGGAGCAACAAACACTCCAGGTTGCTGTGGCCACCGGAGGCCGAGTGTGTG

AGCGGCACCCCAGGTTCTGCAGCGTCCTGCAGGGGACAGTGATGCTCCTGGCCCCGGA

ATGCGATGTCTCCTTAATCCCCTCTGTGGATGGTGGTGGCCGGGGAGTGGCGATGGTG

ACTGCTGTGGCTGCCCGTCTGGCTGCCCACCGGCGCCTGCTGGAGGAGACCCTGGCCC

CATTCCGGTTGAACCATGATCAACTGGCTGCGGTTCAGGCACAGATGCGGAAGGCCAT

GGCCAAGGGGCTCCGAGGGGAGGCCTCCTCCCTTCGCATGCTGCCCACTTTCGTCCGG

GCCACCCCTGACGGCAGCGAGCGAGGGGATTTCCTGGCCCTGGACCTCGGGGGCACGA

ACTTCCGTGTCCTCCTGGTACGTGTGACCACAGGCGTGCAGATCACCAGCGAGATCTA

CTCCATTCCCGAGACTGTGGCCCAGGGTTCTGGGCAGCAGCTCTTTGACCACATCGTG

GACTGCATCGTGGACTTCCAGCAGAAGCAGGGCCTGAGCGGGCAGAGCCTCCCACTGG

GTTTTACCTTCTCCTTCCCATGTAGGCAGCTTGGCCTAGACCAGGGCATCCTCCTGAA

CTGGACCAAGGGTTTCAAGGCATCAGACTGCGAGGGCCAAGATGTCGTGAGTCTGTTG

CGGGAAGCCATCACTCGCAGACAGGCAGTGGAGCTGAATGTGGTTGCCATTGTCAATG

ACACGGTGGGGACCATGATGTCCTGTGGCTATGAGGACCCCCGTTGCGAGATAGGCCT

CATTGTCGGAACCGGCACCAATGCCTGCTACATGGAGGAGCTCCGGAATGTGGCGGGC

GTGCCTGGGGACTCAGGCCGCATGTGCATCAACATGGAGTGGGGCGCCTTTGGGGACG ATGGCTCTCTGGCCATGCTCAGCACCCGCTTTGATGCAAGTGTGGACCAGGCGTCCAT CAACCCCGGCAAGCAGAGGTTTGAAAAGATGATCAGCGGCATGTACCTGGGGGAGATC

GTCCGCCACATCCTTTTACATTTAACCAGCCTTGGCGTTCTCTTCCGGGGCCAGCAGA

TCCAGCGCCTTCAGACCAGGGACATCTTCAAGACCAAGTTCCTCTCTGAGATCGAAAG TGACAGCCTGGCCCTGCGGCAGGTCCGAGCCATCCTAGAGGATCTGGGGCTACCCCTG

ACCTCAGATGACGCCCTGATGGTGCTAGAGGTGTGCCAGGCTGTGTCCCAGAGGGCTG

CCCAGCTCTGTGGGGCGGGTGTAGCTGCCGTGGTGGAGAAGATCCGGGGGAACCGGGG

CCTGGAAGAGCTGGCAGTGTCTGTGGGGGTGGATGGAACGCTCTACAAGCTGCACCCG

CGCTTCTCCAGCCTGGTGGCGGCCACAGTGCGGGAGCTGGCCCCTCGCTGTGTGGTCA

CGTTCCTGCAGTCAGAGGATGGGTCCGGCAAAGGTGCGGCCCTGGTCACCGCTGTTGC

CTGCCGCCTTGCGCAGTTGACTCGTGTCTGAGGAAACCTCCAGGCTGAGGAGGTCTCC

GCCGCAGCCTTGCTGGAGCCGGGTCGGGGTCTGCCTGTTTCCCAGCCAGGCCCAGCCA

CCCAGGACTCCTGGGACATCCCATGTGTGACCCCTCTGCGGCCATTTGGCCTTGCTCC

CTGGCTTTCCCTGAGAGAAGTAGCACTCAGGTTAGCAATATATATATATAATTTATTT

ACAAAAAAAAAAAAA

ORF Start: ATG at 75 ORF Stop: TGA at 1146

SEQ ID NO: 148 357 aa MW at 38361. lkD

NOV39a, MDSIGSSGLRQGEETLSCSEEGLPGPSDSSELVQECLQQFKVTRAQLQQIQASLLGSM |CG105201-01 EQALRGQASPAPAVRMLPTYVGSTPHGTEQGDFWLELGATGASLRVL VTLTGIEGH RVEPRSQΞFVIPQEV LGAGQQLFDFAAHCLSEFLDAQPWKQGLQLGFSFSFPCHQT i Protein Sequence GLDRSTLISWTKGFRCSGVEGQDWQLLRDAIRRQGAYNIDWA NDTVGTMMGCEP GVRPCEVGLWDTGTNACYMEEARHVAVLDEDRGRVCVSVEWGSLSDDGALGPVLTTF DHTLDHESLNPGAQRFEK IGGLYLGELVRLVLAHLARCGVLFGGCTSPALLSQGSIL LEHVAE EE

Further analysis of the NOV39a protein yielded the following properties shown in

Table 39B.

Table 39B. Protein Sequence Properties NOV39a

; PSort j 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody analysis: • (peroxisome); 0.1646 probability located in lysosome (lumen); 0.1000 I ! probability located in mitochondrial matrix space

; SignalP j No Known Signal Sequence Indicated j analysis: I

A search of the NOV39a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 39C.

In a BLAST search of public sequence databases, the N0V39a protein was found to have homology to the proteins shown in the BLASTP data in Table 39D.

PFam analysis indicates that the NOV39a protein contains the domains shown in the Table 39E.

Table 39E. Domain Analysis of NOV39a

Identities/

Pfam Domain NOV39a Match Region Similarities Expect Value for the Matched Region hexokinase 27.357 164/357 (46%) 7.6e-197 319/357 (89%)

Example 40.

The NOV40 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 40A. Table 40A. NOV40 Sequence Analysis

SEQ ID NO: 149 15053 bp

NOV40a, GGCCATGGCCGGCCAGGGGGACTGCTGCGTCAAGGTGGCCGTCAGGATCCGGCCCCAG

;CG105294-01 DNA CTGTCGAAGGAGAAGATTGAGGGCTGTCACATCTGTACCTCTGTTACCCCGGGAGAGC CCCAGGTCCTGCTGGGGAAGGACAAGGCCTTCACCTATGACTTTGTCTTCGACCTGGA j Sequence CACCTGGCAAGAACAGATCTATTCCACCTGTGTGAGCAAGCTCATCGAGGGCTGCTTC GAGGGCTATAATGCCACGGTGCTGGCCTATGGGCAGACGGGGGCCGGGAAGACGTACA CCATGGGCACTGGCTTTGACATGGCAACGTCGGAGGAGGAGCAGGGCATCATCCCGAG GGCCATCGCACACCTCTTTGGGGGCATTGCCGAGCGCAAGCGCCGGGCACAGGAGCAG GGCGTGGCTGGACCTGAGTTCAAAGTCAGCGCCCAGTTTCTGGAGCTCTACAACGAGG AGATCCTTGACCTGTTTGACAGCACCCGTGACCCTGACACCCGCCACCGCAGGTCCAA CATCAAGATCCACGAGGACGCAAACGGTGGCATCTACACCACTGGCGTCACTTCTCGC CTCATCCACTCCCAGGAGGAGCTGATCCAGTGCCTGAAGCAGGGGGCCCTGTCCCGCA CCACAGCCAGCACCCAGATGAACGTGCAGAGCTCACGCTCCCACGCCATCTTCACCAT CCACCTGTGCCAGATGCGCGTGAATGAGGCGGTGACTGGGCTTCCTGATGGTACACCT CCCTCGAGTGAGTATGAGACACTCACTGCTAAGTTTCACTTTGTGGACCTGGCCGGCT CAGAGCGGCTGAAGCGGACAGGGGCTACTGGCGAGCGGGCCAAGGAGGGCATCTCCAT CAACTGTGGCCTGCTGGCCTTGGGCAATGTGATCAGCGCCTTAGGGGACCAGAGCAAG ^!AAGGTGGTGCACGTTCCCTACAGGGACTCCAAGCTCACTCGGCTCCTCCAGGATTCGC JTGGGGGGCAACAGCCAGACCATCATGATCGCCTGTGTGAGCCCCTCAGACCGAGATTT CATGGAGACCCTCAACACACTCAAATATGCCAATCGGGCCCGCAACATCAAGAACAAG JGTGGTAGTGAACCAGGACAAGACCAGCCAGCAAATCAGTGCACTGCGGGCTGAGATTG {CTCGGCTGCAGATGGAGCTGATGGAGTATAAGGCGGGCAAGCGAGTGATAGGAGAGGA ITGGCGCTGAGGGCTATAGTGATCTGTTCCGAGΆGAATGCCATGCTACAGAAGGAGAAT JGGGGCCCTGCGGCTGCGGGTGAAAGCCATGCAGGAGGCCATCGATGCCATCAACAACC JGCGTCACCCAGCTCATGAGCCAGGAGGCCAACCTGCTGCTAGCCAAGGCCGGTGATGG CAATGAGGCCATTGGTGCGCTGATCCAGAACTACATCCGGGAGATCGAGGAGCTACGG ACTAAGCTTCTAGAGAGTGAAGCCATGAACGAGTCCCTGCGCCGCAGCCTCTCACGGG CCTCGGCTAGGAGCCCCTACTCCCTGGGTGCTTCTCCAGCCGCCCCGGCCTTCGGGGG CAGCCCTGCCAGCTCCATGGAGGATGCCTCGGAGGTGATCCGCAGGGCCAAGCAGGAC CTGGAGCGGCTAAAGAAGAAGGAGGTCAGGCAGCGGAGGAAGAGCCCCGAGAAGGAAG CCTTCAAAAAGAGGGCAAAACTCCAACAGGAGAACAGCGAGGAGACGGATGAGAACGA GGCGGAGGAGGAGGAGGAAGAGCGAGACGAGAGTGGCTGTGAGGAGGAGGAAGGGCGC GAGGATGAAGATGAGGACTCGGGCAGTGAAGAGAGCCTGGTGGACTCAGACTCAGACC CCGAGGAGAAGGAGGTGAACTTCCAGGCGGACCTGGCCGACCTGACTTGTGAGATCGA AATCAAGCAGAAGCTGATCGACGAGCTGGAGAACAGCCAGCGGCGGTTGCAGACGCTC AAGCACCAGTATGAGGAAAAGCTGATTCTGCTGCAGAACAAGATCCGAGACACACAGC TGGAGCGCGACCGTGTGCTGCAGAACCTCAGTACCATGGAGTGCTATACTGAGGAGAA GGCCAACAAGATCAAGGCAGACTATGAGAAGAGGCTGCGGGAGATGAACCGGGACCTG CAGAAGCTGCAGGCCGCCCAGAAAGAGCACGCCCGGCTGCTTAAGAACCAGTCGCGCT ACGAGAGGGAGCTGAAGAAGCTACAGGCCGAGGTGGCTGAGATGAAGAAGGCCAAGGT AGCCCTGATGAAGCAGATGCGTGAGGAGCAACAGCGGCGGCGGCTAGTGGAGACCAAG AGGAACCGGGAGATCGCACAGCTCAAGAAGGAGCAGCGGCGACAGGAGTTTCAGATCC GAGCTCTGGAGTCCCAGAAGCGGCAGCAGGAGATGGTCCTGAGGAGGAAGACCCAGGA GGTGAGCGCACTGAGGCGCCTGGCCAAGCCCATGTCTGAGCGGGTGGCAGGGCGTGCA GGACTAAAGCCACCCATGCTGGACTCTGGGGCTGAGGTGTCGGCCAGCACTACCTCAT CTGAGGCTGAATCAGGGGCCCGCTCTGTCTCCAGCATCGTGCGCCAGTGGAACCGCAA AATCAACCACTTCTTGGGGGACCATCCTGCGCCCACTGTCAATGGCACCCGTCCTGCC CGAAAGAAGTTCCAGAAGAAGGGGGCCAGCCAGAGCTTCAGTAAGGCGGCAAGGCTCA AGTGGCAGTCCCTGGAGCGACGGATCATTGACATCGTCATGCAGAGAATGACCATTGT CAACCTGGAGGCTGACATGGAGCGGCTCATCAAGAAAAGGGAGGAGCTGTTCCTCCTG CAGGAGGCACTGCGGAGGAAGCGGGAGCGGCTGCAGGCTGAGAGCCCCGAGGAAGAGA AGGGGCTGCAGGAGCTGGCTGAGGAGATCGAGGTGCTGGCAGCCAACATTGACTACAT CAATGACGGCATCACCGACTGCCAGGCCACCATCGTGCAGCTGGAGGAGACCAAGGAG GAGCTGGACTCCACAGACACATCCGTGGTCATCAGCTCCTGCTCCCTGGCTGAAGCCC GCCTCCTGCTAGACAACTTCCTCAAGGCATCCATTGACAAGGGGCTGCAAGTGGCACA AAAGGAAGCCCAGATCCGGCTGTTGGAGGGCCGACTGAGGCAGACGGATATGGCAGGC TCCTCCCAGAACCATCTGCTCCTGGACGCCCTGCGTGAGAAGGCTGAAGCTCACCCCG AGCTGCAGGCCCTCATCTACAATGTGCAGCAGGAGAATGGCTACGCCAGCACAGATGA GGAGATCTCAGAGT_TCTC_TGAGGGCAGCTTCTCCCAGTCATTCACCATGAAAGGCTCC ACCAGCCATGACGATTTCAAGTTCAAGAGCGAGCCCAAACTGTCTGCCCAAATGAAAG CTGTGTCGGCTGAGTGCCTGGGCCCCCCACTGGATATCTCCACCAAGAACATCACCAA GTCCCTGGCCTCCCTCGTTGAGATCAAAGAGGACGGAGTGGGCTTCTCTGTCCGAGAC CCCTATTACCGGGACAGGGTCTCGCGCACCGTCAGTCTGCCTACCCGGGGCAGCACTA GCCCTAGGCAATCTCGAGCCACAGAGACGTCCCCGCTGACGAGAAGGAAGTCCTACGA CCGAGGGCAGCCCATTAGGTCCACAGATGTGGGATTCACACCCCCATCATCCCCTCCC ACTCGGCCCCGCAATGACCGCAATGTCTTCTCTCGTCTCACCAGTAATCAGAGCCAGG

! GGTCAGCGCTGGACAAGTCTGATGACAGCGACTCCTCTTTGTCGGAGGTCCTGAGGGG i 1 CATCATCTCCCCGGTTGGAGGAGCCAAGGGTGCACGGACGGCCCCACTGCAGTGTGTC

: TCCATGGCCGAAGGCCACACCAAGCCCATCCTCTGCCTGGATGCCACAGATGAGTTGC TATTCACAGGGTCCAAAGACCGAAGCTGCAAGATGTGGAACTTGGTTACGGGACAGGA GATCGCAGCTCTAAAGGGCCACCCCAACAACGTGGTCTCCATCAAGTACTGCAGCCAC

! TCGGGGCTTGTGTTCTCCGTGTCCACCTCCTACATCAAGGTGTGGGACATCCGGGACT

! CAGCCAAGTGCATTCGGACTCTCACGTCCTCGGGCCAGGTGATCTCAGGGGATGCCTG j TGCCGCCACATCCACCCGTGCCATCACCAGTGCTCAGGGCGAGCATCAGATCAACCAG ATCGCCCTCAGCCCTTCGGGCACCATGCTGTACGCCGCCTCGGGCAATGCCGTCCGCA TCTGGGAGCTTAGCAGGTTCCAGCCTGTCGGCAAGCTGACTGGCCACATCGGCCCTGT

( GATGTGCCTGACGGTCACCCAGACGGCCAGCCAGCATGACCTCGTGGTGACTGGCTCC AAGGACCACTACGTTAAGATGTTCGAGCTGGGCGAGTGTGTGACGGGCACCATCGGCC CCACTCACAACTTCGAGCCCCCGCACTACGATGGCATCGAGTGTCTCGCCATCCAGGG i

1 AGACATCCTGTTCAGTGGCTCCCGAGATAACGGCATCAAGAAGTGGGACCTAGACCAG 1 CAGGAGCTCATCCAGCAAATCCCCAATGCGCACAAGGACTGGGTGTGCGCCCTGGCCT TCATCCCGGGCCGCCCCATGCTGCTCAGCGCCTGCCGTGCGGGTGTCATCAAGGTCTG ii GAACGTGGACAACTTCACACCCATCGGTGAGATCAAGGGCCACGACAGTCCCATCAAT GCCATCTGCACCAATGCCAAGCATATCTTCACAGCCTCCAGTGACTGCCGGGTAAAGT TGTGGAATTACGTCCCTGGACTCACCCCCTGCCTTCCTCGCCGAGTCCTGGCCATAAA GGGCCGCGCCACCACCCTGCCCTTTCCCTCCCCAACTCTCCCTGTCTCCTCTTTCATT CTTCCCCTCTTTCCTTTTCCCTCTCTTTCCCCACTTCGATCTGAGCTGCTTCTTAACG TGACCTGACGGTGAAGTTCTGGAGTGTCCGGCGGTTACCCCACAGCGGCCCACCCTAG

; GAGTGAG s ORF Start: ATG at 5 |ORF Stop: TGA at 4994

SEQ IDNO: 150 11663 aa |MW at 185419.6kD jNOV40a, MAGQGDCCVKVAVRIRPQLSKE IΞGCHICTSVTPGEPQVLLGKDKAFTYDFVFDLDT CG105294-01 QEQIYSTCVSKLIEGCFEGYNATVLAYGQTGAGKTYTMGTGFDMATSEEEQGIIPRA IAHLFGGIAERKRRAQEQGVAGPEFKVSAQFLELYNEEILDLFDSTRDPDTRHRRSNI Protein Sequence KIHEDANGGIYTTGVTSRLIHSQEELIQCL QGALSRTTASTQMNVQSSRSHAIFTIH

1 LCQ RVNEAVTGLPDGTPPSSEYETLTAKFHFVDLAGSERLKRTGATGERAKEGISIN

1 CGLLALG VISALGDQSKKWHVPYRDSKLTRLLQDSLGG SQTIMIACVSPSDRDFM

; ETLNTLKYANRARNIKNKVVVNQDKTSQQISALRAEIARLQMELMEYKAGKRVIGEDG AEGYSDLFRENAMLQKENGALRLRVKAMQEAIDAI NRVTQLMSQEA LLLAKAGDGN

: EAIGALIQNYIREIEELRTKLLESEAMNESLRRSLSRASARSPYSLGASPAAPAFGGS PASSMEDASEVIRRAKQDLERLK KEVRQRRKSPEKEAFKKRAKLQQENSEETDENEA EEEEEERDESGCEEEEGREDEDEDSGSEESLλTDSDSDPEEKEVNFQADLADLTCEIEI KQKLIDΞLΞNSQRRLQTL HQYEEKLILLQNKIRDTQLERDRVLQNLSTMECYTEEKA NKIKADYEKRLREMNRDLQKLQAAQKEHARLLKNQSRYERELKKLQAEVAEMK AKVA LMKQMREEQQRRRLVETKRNREIAQLKKEQRRQEFQIRALESQKRQQEMVLRRKTQEV

I SALRRLAKPMSERVAGRAGLKPPMLDSGAEVSASTTSSEAESGARSVSSIVRQ NR I NHFLGDHPAPT\ GTRPARKKFQKKGASQSFSIO_ARLKWQSLERRIIDIVMQRMTIVN LEADMERLIKKREELFLLQEALRRKRERLQAESPEEEKGLQELAEEIEVLAANIDYIN DGITDCQATIVQLEET EELDSTDTSWISSCSLAEARLLLDNFLKASID GLQVAQK ΞAQIRLLEGRLRQTDMAGSSQNHLLLDALREKAEAHPELQALIYNVQQENGYASTDEE ISEFSEGSFSQSFTMKGSTSHDDFKFKSEP LSAQMKAVSAECLGPPLDISTKNITKS LASLVEIKEDGVGFSVRDPYYRDRVSRTVSLPTRGSTSPRQSRATETSPLTRRKSYDR GQPIRSTDVGFTPPSSPPTRPRNDRNVFSRLTSNQSQGSALDKSDDSDSSLSΞVLRGI ISPVGGAKGARTAPLQCVSMAEGHT PILCLDATDELLFTGSKDRSCKM NLVTGQEI AALKGHPNNWSIKYCSHSGLVFSVSTSYI VWDIRDSAKCIRTLTSSGQVISGDACA ATSTRAITSAQGEHQINQIALSPSGTMLYAASGNAVRI ELSRFQPVGKLTGHIGPVM CLTVTQTASQHDLWTGSKDHYVKMF_.ELGECVTGTIGPTHNFEPPHYDGIECLAIQGD ILFSGSRDNGI K DLD_QQELIQQIPNAHKDWVCALAFIPGRPMLLSACRAGVIKV N VDNFTPIGEIKGHDSPINAICTNAKHIFTASSDCRVKLWNYVPGLTPCLPRRVLAIKG RATTLPFPSPTLPVSSFILPLFPFPSLSPLRSELLL VT

Further analysis of the NOV40a protein yielded the following properties shown in Table 40B.

Table 40B. Protein Sequence Properties NOV40a j PSort j 0.9800 probability located in nucleus; 0.3000 probability located in microbody j analysis: I (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 j probability located in lysosome (lumen)

SignalP j No Known Signal Sequence Indicated ' analysis:

A search of the NOV40a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 40C.

In a BLAST search of public sequence databases, the NOV40a protein was found to have homology to the proteins shown in the BLASTP data in Table 40D.

Table 40D. Public BLASTP Results for NOV40a

Protein/Organism/Length

PFam analysis indicates that the NOV40a protein contains the domains shown in the Table 40E.

Example 41.

The NOV41 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 41 A. Table 41A. NOV41 Sequence Analysis

Further analysis of the NOV41a protein yielded the following properties shown in Table 4 IB.

Table 41B. Protein Sequence Properties NO 41a

PSort 0.8500 probability located in endoplasmic reticulum (membrane); 0.4400 analysis: probability located in plasma membrane; 0.1000 probability located in mitochondrial inner membrane; 0.1000 probability located in Golgi body

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV4 la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 41 C.

Table 41C. Geneseq Results for NOV41a

NOV41a Identities/

Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier ] Date] Match the Matched Value Residues Region

In a BLAST search of public sequence databases, the NOV4 la protein was found to have homology to the proteins shown in the BLASTP data in Table 4 ID.

PFam analysis indicates that the N0V4 la protein contains the domains shown in the Table 4 IE.

Example 42.

The NOV42 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 42A.

Further analysis of the NOV42a protein yielded the following properties shown in Table 42B.

Table 42B. Protein Sequence Properties NOV42a

PSort 0.4566 probability located in microbody (peroxisome); 0.4500 probability analysis: located in cytoplasm; 0.1574 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV42a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 42C.

In a BLAST search of public sequence databases, the NOV42a protein was found to have homology to the proteins shown in the BLASTP data in Table 42D.

PFam analysis indicates that the NOV42a protein contains the domains shown in the Table 42E.

Table 42E. Domain Analysis of NOV42a

Identities/

Pfa Domain NOV42a Match Region Similarities Expect Value for the Matched Region

Acetyltransf 48..129 22/84 (26%) 5.1e-l l 57/84 (68%)

Example 43.

The NOV43 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 43 A.

Table 43A. NOV43 Sequence Analysis

SEQ ID NO: 155 2076 bp

*NOV43a, ATTGGTGGGGGGTAAATAAAGGAGACGCGGGCGGAGCTAACTCCGTGTGCAGAGCAGG

:CG105550-01 DNA ACATGGAAGAACGCGGGTCACCCGACGGGGATCTCGCGCGGAGCCTGGAGCAAGGGCC ! Sequence AGAGGGGCCGGAAACGCCCATCCAGGTGGTGCTCAGGGTACGTCCCATGAGCGCGGCC GAGCTGCGTCGAGGGCAGCAGAGCGTGCTGCACTGCTCAGGGACCCGGACTCTGCAGG GCGGGGGTCCAGAAGTGGCGTTCCGCTTCGGTGCGGTGCTAGACGCGGCGCGCACGCA GGAGGACGTGTTCCGGGCGTGCGGCGTGCGGCGCCTGGGGGAGCTGGCGCTGCGCGGT TTCTCCTGCACTGTTTTCACCTTTGGCCAGACGGGCTCTGGGAAGACCTACACCCTGA CTGGACCCCCTCCCCAGGGGGAGGGGGTGCCTGTACCCCCCAGCCTGGCTGGCATCAT GCAGAGGACCTTCGCCTGGCTGTTGGACCGCGTGCAGCACCTGGGTGCCCCTGTCACC CTTCGCGCCTCTTATCTGGAGATCTACAATGAGCAGGTTCGGGACTTGCTGAGCCTGG GGTCTCCCCGGCCCCTCCCTGTTCGCTGGAACAAGACTCGGGGCTTCTATGTGGAGCA GCTGCGGGTGGTGGAATTTGGGAGTCTGGAGGCCCTGATGGAACTTTTGCAAACGGGT CTCAGCCGTCGAAGGAACTCAGCCCACACCCTGAACCAGGCCTCCAGCCGAAGCCATG CCCTGCTCACCCTTTACATCAGCCGTCAAACTGCCCAGCAGATGCCTTCTGTGGACCC TGGGGAGCCCCCTGTTGGTGGGAAGCTGTGCTTTGTGGACCTGGCAGGCAGTGAGAAG GTAGCAGCCACGGGATCCCGTGGGGAGCTGATGCTTGAGGCTAACAGCATCAACCGAA GCCTGCTGGCCCTGGGTCACTGCATCTCCCTGCTGCTGGACCCACAGCGGAAGCAGAG CCACATCCCTTTCCGGGACAGCAAGCTCACCAAGTTGCTGGCAGACTCACTGGGAGGG CGCGGGGTCACCCTCATGGTGGCCTGCGTGTCCCCCTCAGCCCAGTGCCTTCCTGAGA CTCTCAGCACCCTGCGATATGCAAGCCGAGCTCAGCGGGTCACCACCCGACCACAGGC CCCCAAGTCTCCTGTGGCAAAGCAGCCCCAGCGTTTGGAGACAGAGATGCTGCAGCTC CAGGAGGAGAAGCGTCGCCTGCAGTTGCAGCTGGACCAAATGGACTGCAAGGGGCTCA GTGGAGCCCGGGTGGCCTGGGCCCAGCGGAACCTGTACGGGATGCTACAGGAGTTCAT GCTAGAGAATGAGAGGCTCAGGAAAGAAAAGAGCCAGCTGCAGAATAGCCGAGACCTG GCCCAGAATGAGCAGCGCATCCTGGCCCAGCAGGTCCATGCACTAGAGAGGCGTCTCC TCTCTGCCTGCTACCATCACCAGCAGGGTCCTGGCCTGACCCCACCGTGTCCCTGCTT GATGGCCCCAGCTCCCCCTTGCCATGCACTGCCACCCCTCTACTCCTGCCCCTGCTGC CACATCTGCCCACTGTGTCGAGTGCCCCTGGCCCACTGGGCCTGCCTGCCAGGGGAGC ACCACCTGCCCCAGGTGTTGGACCCTGAGGCCTCAGGTGGCAGGCCCCCATCTGCCCG GCCCCCACCCTGGGCACCCCCATGCAGCCCTGGCTCTGCCAAGTGCCCAAGAGAGAGG AGTCACAGTGACTGGACTCAGACCCGAGTCCTGGCAGAGATGTTGACGGAGGAGGAGG TGGTACCTTCTGCACCTCCCCTGCCTGTGAGGCCCCCGAAGACATCACCA.GGGCTCAG AGGTGGGGCCGGGGTTCCAAACCTGGCCCAGAGACTGGAGGCCCTCAGAGACCAGATT GGCAGCTCCCTGCGACGTGGCCGCAGCCAGCCACCCTGCAGTGAGGGCGCACGGAGCC CAGGCCAAGTCCTCCCTCCCCATTGAAGGCCAAGTGGGAACCCAGGAGACTGCTGTGT

GACCTCAGACTGGGCTCCACACTCTTGGGCTTCAGTCTGCCCATCT

ORF Start: ATG at 61 ORF Stop: TGA at 1996

SEQ ID NO: 156 645 aa MW at 70558. lkD

NOV43a, MEERGSPDGDLARSLEQGPEGPETPIQWLRVRPMSAAELRRGQQSVLHCSGTRTLQG CG105550-01 GGPEVAFRFGAVLDAARTQED FRACGVRRLGELALRGFSCTVFTFGQTGSGKTYTLT GPPPQGΞGVPVPPSLAGIMQRTFAWLLDRVQHLGAPVTLRASYLEIY EQVRDLLSLG j Protein Sequence SPRPLPVRWN TRGFYVEQLRWEFGSLEALMELLQTGLSRRRNSAHTLNQASSRSHA LLTLYISRQTAQQMPSVDPGEPPVGGKLCFVDLAGSEKVAATGSRGELMLEANSINRS LLALGHCISLLLDPQRKQSHIPFRDSKLTKLLADSLGGRGVTLMVACVSPSAQCLPET LSTLRYASRAQRVTTRPQAPKSPVAKQPQRLETEMLQLQEENRRLQFQLDQMDCKGLS GARVA AQRNLYGMLQEFMLENERLRKEKSQLQNSRDLAQNEQRILAQQVHALERRLL SACYHHQQGPGLTPPCPCLMAPAPPCHALPPLYSCPCCHICPLCRVPLAHWACLPGEH HLPQVLDPEASGGRPPSARPPP APPCSPGSAKCPRERSHSD TQTRVLAEMLTEEEV VPSAPPLPVRPPKTSPGLRGGAGVPNLAQRLEALRDQIGSSLRRGRSQPPCSEGARSP GQVLPPH

Further analysis of the NOV43a protein yielded the following properties shown in

Table 43B.

A search of the NOV43a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 43 C.

In a BLAST search of public sequence databases, the NOV43a protein was found to have homology to the proteins shown in the BLASTP data in Table 43D.

PFam analysis indicates that the NOV43a protein contains the domains shown in the Table 43E.

Table 43E. Domain Analysis of NOV43a

Pfam Domain NOV43a Match Region Expect Value

Example 44.

The NOV44 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 44A.

Table 44A. NOV44 Sequence Analysis

SEQ ID NO: 157 1662 bp

!NOV44a, GCGTTAGAGGCGGGTGGCGGCGCGGGTGTTTACGTCAGGTCGCAGGGTGTCGCTGGCA

JCG105559-01 DNA GCATGGCGGACTACCTCATCAGCGGCGGCACCCGCTACCAGCCCGAGGATGGGCTCAC CGCACAGCAGCTCTTTGCCAGCGCTGACGACCTCACCTACAACGATTTCCTGATTCTC ! Sequence CCAGGATTCATAGACTTCCTAGCTGGTGAGGTGGACCTGACCTCAGCCCTGACCCGGA AGATCACGCTGAAGACGCCACTGATCTCCTTTCCCACGGACACTGTGATAGAGGCCGA CATGGCCATCGCGATGGCTCTGATGGGAGGTATTGGTTTCATTCACCACAACTGCACC CCAGAGTTCCAGGCCAACAAGGTGCAGAAGGTCAAGAAGTTTGAACAGGGCTTCATCA CAGACCCTGTGGTACTGAGCCCCTTGCACACTGTGGGTGATGTGCTGGAGGCCAAGAT GCGGCATGGCTTCTCTGGCATCCCCATTACTGAGACCGGCACCATCGGCAGCAAGCTG GTGGGCATCCTCACCTCCCGAGACATCGACTTCCTTGCTGAGAAGGACCACACCACCC TCCTCAGTGAGGTGATGACGCCAAGGATGGAGCTAGTGGTGGCTCCAGCAGGCGTGAC GTTCAAAGAGGCAAATGAGATCCTGCAGCGTAGCAAGAAAGGGAAGCTGCCTGTTGTC AATGATCATGATGAGCTGGTGGCCATCATCGCCCGCACGGACCTGAAGAAGAACCGAG ACTACCCTCTGGCCTCCAAGGATTCCCACAAGCAGCTGCTGTGCGGGGCAGTTGTGGG CACCTGTGAAGATGACAAATTCCGCCTGGGCCTGCTCACCCAGGCGGGCGTCGATGTC ATAGTCTTGGACTCGTCCCAAGGGAACTCGGTGTATCAGATTGCCATGGTGCGTTACA TCAAACAGAAGTACCCCCACCTCCAGGTGATTGGGAGGAATGTGGTGACAGCAGCCCA GGCCAAGAACCTGATTGACGCTGGTGTGGATGGGCTGCACGTGGGCATGGGCTGCGGC TCCATCTGCATCACCCTGGAAATGATGGCCTGTGGTCGGACCCACGGCACTGCTGTGT ACAAGGTGGCCGAGTATGCCTGGCGTTTTGGTGTGCCCATCATAGCTGATGGTGGCAT CCAGACCGTGGGGCACGTGGTCAAGGCCCTGGCCCTTGGAGCCTCCACAGTGATGATG GGCTCCCTGCTGGCCACCACCACGGAGGCCTCCGGTGAATACTTCTTCTCAGACGGGG TGCCGCTCAAGAAGTATCAGGGCATGGGCTCTGTGGATGCCATGGAGAAGAGCAGTAG CAGCCAGAAACGATACTTCAGCGAGGCGGATAAGGTGAAGTTCTCGCAGGGTATCTTG GGCTCCATCCAGGACAAAGGGTCCATTCAGAAGTTCGTGCCCTACCTCATAGCGGGCA TCCAGCACAGTTGCCAGGATATCGGGGCCCGAAGCCTGGCTGTCCTTCGGTCCATGAT GTACTCAGGAGAGCTCAAGTTTGAGAAGGGGACCGTGTCGGCCCAGATCGAGGGTGGC GTTCATGGCCTGCACTCTTACGAGAGGTGGCTGTACTGAGGAGAGTGGTGGAGGCCGA GGTGGTTGAAGGGGCGTGCCCCGCTTTCCCCCTTTGGG

ORF Start: ATG at 61 ORF Stop: TGA at 1603

SEQ ID NO: 158 514 aa MW at 55673.6kD

NOV44a, AD LISGGTRYQPEDGLTAQQLFASADDLTY DFLILPGFIDFLAGEVDLTSALTRK CG105559-01 ITLKTPLISFPTDTVIEAD AIAMALMGGIGFIHHNCTPEFQANKVQKVKKFEQGFIT DPλTVLSPLHTVGDVLEAKMRHGFSGIPITETGTIGSKLVGILTSRDIDFLAEKDHTTL Protein Sequence LSEVMTPRMELVVAPAGVTF EANEILQRSKKG LPVVNDHDELVAIIARTDLKKNRD YPLAS DSHKQLLCGAWGTCEDDKFRLGLLTQAGVDVIVLDSSQGNSVYQIAMVRYI KQKYPHLQVIGR-T TvJTAAQAKNLIDAGVDGLHVGMGCGSICITLEMMACGRTHGTAVY KVAEYAWRFGVPIIADGGIQTVGHWKALALGASTVMMGSLLATTTEASGEYFFSDGV PLK YQGMGSVDAMEKSSSSQKRYFSEADKVKFSQGILGSIQDKGSIQKFVPYLIAGI QHSCQDIGARSLAVLRS MYSGELKFEKGTVSAQIEGGVHGLHSYER LY Further analysis of the NOV44a protein yielded the following properties shown in Table 44B.

Table 44B. Protein Sequence Properties NOV44a

PSort 0.4580 probability located in microbody (peroxisome); 0.4500 probability analysis: located in cytoplasm; 0.1852 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

I SignalP j No Known Signal Sequence Indicated I analysis:

A search of the NOV44a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 44C.

In a BLAST search of public sequence databases, the NOV44a protein was found to have homology to the proteins shown in the BLASTP data in Table 44D.

Table 44D. Public BLASTP Results for NOV44a

PFam analysis indicates that the NOV44a protein contains the domains shown in the Table 44E.

Example 45.

The NOV45 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 45A.

Table 45A. NOV45 Sequence Analysis

SEQ ID NO: 159 5595 bp

NOV45a, TACAACTTTTCCTTTTCCCAGACTGTGGTTTTGTGCTTGCTCACCAAAGCTAACCTCA

CGI 05597-01 DNA GCATGCTCAAAAGGAAGCAGAGTTCCAGGGTGGAAGCCCAGCCAGTCACTGACTTTGG TCCTGATGAGTCTCTGTCGGATAATGCTGACATCCTCTGGATTAACAAACCATGGGTT

Sequence CACTCTTTGCTGCGCATCTGTGCCATCATCAGCGTCATTTCTGTTTGTATGAATACGC CAATGACCTTCGAGCACTATCCTCCACTTCAGTATGTGACCTTCACTTTGGATACATT ATTGATGTTTCTCTACACGGCAGAGATGATAGCAAAAATGCACATCCGGGGCATTGTC AAGGGGGATAGTTCCTATGTGAAAGATCGCTGGTGTGTTTTTGATGGATTTATGGTCT TTTGCCTTTGGGTTTCTTTGGTGCTACAGGTGTTTGAAATTGCTGATATAGTTGATCA GATGTCACCTTGGGGCATGTTGCGGATTCCACGGCCACTGATTATGATCCGAGCATTC CGGATTTATTTCCGATTTGAACTGCCAAGGACCAGAΆTTACAAATATTTTAAΆGCGAT CGGGAGAACAAATATGGAGTGTTTCCATTTTTCTACTTTTCTTTCTACTTCTTTATGG AATTTTAGGAGTTCAGATGTTTGGAACATTTACTTATCACTGTGTTGTAAATGACACA AΆGCCAGGGAATGTAACCTGGAATAGTTTAGCTATTCCAGACACACACTGCTCACCAG AGCTAGAAGAAGGCTACCAGTGCCCACCTGGATTTAAATGCATGGACCTTGAAGATCT GGGACTTAGCAGGCAAGAGCTGGGCTACAGTGGCTTTAATGAGATAGGAACTAGTATA TTCACCGTCTATGAGGCCGCCTCACAGGAAGGCTGGGTGTTCCTCATGTACAGAGCAA |TTGACAGCTTTCCCCGTTGGCGTTCCTACTTCTATTTCATCACTCTCATTTTCTTCCT ICGCCTGGCTTGTGAAGAACGTGTTTATTGCTGTTATCATTGAAACATTTGCAGAAATC JAGAGTACAGTTTCAACAAATGTGGGGATCGAGAAGCAGCACTACCTCAACAGCCACCA JCCCAGATGTTTCATGAAGATGCTGCTGGAGGTTGGCAGCTGGTAGCTGTGGATGTCAA CAAGCCCCAGGGACGCGCCCCAGCCTGCCTCCAGAAAATGATGCGGTCATCCGTTTTC CACATGTTCATCCTGAGCATGGTGACCGTGGACGTGATCGTGGCGGCTAGCAACTACT ACAAAGGAGAAAACTTCAGGAGGCAGTACGACGAGTTCTACCTGGCGGAGGTGGCTTT TACAGTACTTTTTGATTTGGAAGCACTTCTGAAGATATGGTGTTTGGGATTTACTGGA TATATTAGCTCATCTCTCCACAAATTCGAACTACTACTCGTAATTGGAACTACTCTTC ATGTATACCCAGATCTTTATCATTCACAATTCACGTACTTTCAGGTTCTCCGAGTAGT TCGGCTGATTAAGATTTCACCTGCATTAGAAGACTTTGTGTACAAGATATTTGGTCCT GGAAAAAAGCTTGGGAGTTTGGTTGTATTTACTGCCAGCCTCTTGATTGTTATGTCAG CAATTAGTTTGCAGATGTTCTGCTTTGTCGAΆGAACTGGACAGATTTACTACGTTTCC GAGGGCATTTATGTCCΆTGTTCCAGATCCTCACCCAGGAAGGATGGGTGGACGTAATG GACCAAACTCTAAATGCTGTGGGACATATGTGGGCACCCGTGGTTGCCATCTATTTCA TTCTCTATCATCTTTTTGCCACTCTGATCCTCCTGAGTTTGTTTGTTGCTGTTATTTT GGACAACTTAGAACTTGATGAAGACCTAAAGAAGCTTAAACAATTAAAGCAAAGTGAA GCAAATGCGGACACCAAAGAAAAGCTCCCTTTACGCCTGCGAATCTTTGAAAAATTTC CAAACAGACCTCAAATGGTGAAAATCTCΆAAGCTTCCTTCAGATTTTACAGTTCCTAΆ AATCAGGGAGAGTTTTATGAAGCAGTTTATTGACCGCCAGCAACAGGACACATGTTGC CTCCTGAGAAGCCTCCCGACCACCTCTTCCTCCTCCTGCGACCACTCCAAACGCTCAG CAATTGAGGACAΆCAAATACATCGACCAAAAACTTCGCAΆGTCTGTTTTCAGCATCAG GGCAAGGAACCTTCTGGAAΆAGGAGACCGCAGTCACTAAAATCTTAAGAGCTTGCACC CGΆCAGCGCATGCTGAGCGGATCATTTGAGGGGCAGCCCGCAAAGGAGAGGTCAATCC TCAGCGTGCAGCATCATATCCGCCAAGAGCGCAGGTCACTAAGACATGGATCAAACAG CCAGAGGATCAGCAGGGGAAAATCTCTTGAAACTTTGACTCAAGATCATTCCAATACA GTGAGATATAGΆAΆTGCACAAAGAGAΆGACAGTGAAATAAAGΆTGATTCAGGAAAAAA

AGGAGCAAGCAGAGATGAAAAGGAAAGTGCAAGAAGAGGAACTCAGAGAGAACCACCC

ATACTTCGATAAGCCACTGTTCATTGTCGGGCGAGAACACAGGTTCAGAAACTTTTGC CGGGTGGTGGTCCGAGCACGCTTCAACGCATCTAAAACAGACCCTGTCACAGGAGCTG TGAAAAATACAAAGTACCATCAACTTTATGATTTGCTGGGATTGGTCACTTACCTGGA CTGGGTCATGATCATCGTAACCATCTGCTCTTGCATTTCCΆTGATGTTTGAGTCCCCG TTTCGAAGAGTCATGC_ATGCACCTACTTTGCAGATTGCTGAGTATGTGTTTGTGATAT TCATGAGCATTG_AGC_TTAATCTGAAGATTATGGCAGATGGCTTATTTTTCACTCCAΆC =TGCTGTCATCAGGGACTTCGGTGGAGTAATGGACATATTTATATATCTTGTGAGCTTG IATATTTCTTTGTTGGATGCCTCAAAATGTACCTGCTGAATCGGGAGCTCAGCTTCTAA JTGGTCCTTCGGTGCCTGAGACCTCTGCGCATATTCAAACTGGTGCCCCAGATGAGGAA JAGTTGTTCGAGAACTTTTCAGCGGCTTCAAGGAAATTTTTTTGGTCTCCATTCTTTTG CTGACATTAATGCTCGTTTTTGCAAGCTTTGGAGTTCAGCTTTTTGCTGGAAAACTGG CCAAGTGCAATGATCCCAACATTATTAGAAGGGAAGATTGCAATGGCATATTCAGAAT AATGTCAGTGTGTCAAAGAACTTAAATTTAAAATTGAGGCCTGGAGAGAAAAAACCT GGATTTTGGGTGCCCCGTGTTTGGGCGAATCCTCGGAACTTTAATTTCGACAATGTGG GAAACGCTATGCTGGCGTTGTTTGAAGTTCTCTCCTTGAAAGGCTGGGTGGAAGTGAG AGATGTTATTATTCATCGTGTGGGGCCGATCCATGGAATCTATATTCATGTTTTTGTA TTCCTGGGTTGCATGATTGGACTGACCCTTTTTGTTGGAGTAGTTATTGCTAATTTCA ATGAAAACAAGGGGACGGCTTTGCTGACCGTCGATCAGAGAAGATGGGAAGACCTGAA GAGCCGACTGAAGATCGCACAGCCTCTTCATCTTCCGCCTCGCCCGGATAATGATGGT TTTAGAGCTAAAATGTATGACATAACCCAGCATCCATTTTTTAAGAGGACAATCGCAT TACTCGTCCTGGCCCAGTCGGTGTTGCTCTCTGTCAAGTGGGACGTCGAGGACCCGGT GACCGTACCTTTGGCAACAATGTCAGTTGTTTTCACCTTCATCTTTGTTCTGGAGGTT ACCATGAAGATCATAGCAATGTCGCCTGCTGGCTTCTGGCAAAGCAGAAGAAACCGAT ACGATCTCCTGGTGACGTCGCTTGGCGTTGTATGGGTGGTGCTTCACTTTGCCCTCCT GAATGCATATACTTACATGATGGGCGCTTGTGTGATTGTATTTAGGTTTTTCTCCATC TGTGGAAAACATGTAACGCTAAAGATGCTCCTCTTGACAGTGGTCGTCAGCATGTACA AGAGCTTCTTTATCATAGTAGGCATGTTTCTCTTGCTGCTGTGTTACGCTTTTGCTGG AGTTGTTTTATTTGGTACTGTGAAATATGGGGAGAATATTAACAGGCATGCAAATTTT TCTTCGGCTGGAAAAGCTATTACCGTACTGTTCCGAATTGTCACAGGTGAAGACTGGA ACAAGATTATGCATGACTGTATGGTTCAGCCTCCGTTTTGTACTCCAGATGAATTTAC ;ATACTGGGCAACAGACTGTGGAAATTATGCTGGGGCACTTATGTATTTCTGTTCATTT ITATGTCATCATTGCCTACATCATGCTAAATCTGCTTGTAGCCATAATTGTGGAGAATT JTCTCCTTGTTTTATTCCACTGAGGAGGACCAGCTTTTAAGTTACAATGATCTTCGCCA _JCTTTCAAATAATATGGAACATGGTGGATGATAAAAGAGAGGGGGTGATCCCCACGTTC

CGCGTCAAGTTCCTGCTGCGGCTACTGCGTGGGAGGCTGGAGGTGGACCTGGACAAGG ACAAGCTCCTGTTTAAGCACATGTGCTACGAAATGGAGAGGCTCCACAATGGCGGCGA CGTCACCTTCCATGATGTCCTGAGCATGCTTTCATACCGGTCCGTGGACATCCGGAAG AGCTTGCAGCTGGAGGAACTCCTGGCGAGGGAGCAGCTGGAGTACACCATAGAGGAGG AGGTGGCCAAGCAGACCATCCGCATGTGGCTCAAGAAGTGCCTGAAGCGCATCAGAGC TAAACAGCAGCAGTCGTGCAGTATCATCCACAGCCTGAGAGAGAGTCAGCAGCAAGAG CTGAGCCGGTTTCTGAACCCGCCCAGCATCGAGACCACCCAGCCCAGTGAGGACACGA ATGCCAACAGTCAGGACAACAGCATGCAACCTGAGACAAGCAGCCAGCAGCAGCTCCT GAGCCCCACGCTGTCGGATCGAGGAGGAAGTCGGCAAGATGCAGCCGACGCAGGGAAA CCCCAGAGGAAATTTGGGCAGTGGCGTCTGCCCTCAGCCCCAAAACCAATAAGCCATT CAGTGTCCTCAGTCAACTTACGGTTTGGAGGAAGGACAACCATGAAATCTGTCGTGTG CAAAATGAACCCCATGACTGACGCGGCTTCCTGCGGTTCTGAAGTTAAGAAGTGGTGG ACCCGGCAGCTGACTGTGGAGAGCGACGAAAGTGGGGATGACCTTCTGGATATTTAGG TGGATGTCAATGTAGATGAATTTCTAGTGGTGGAAACCGTTTTCTAATAATGTCCTTG

ATTGTCCAGTGAGCAATCTGTAATTGATCTATAACTGAATTCCAGCTTGTCACAAGAT

GTTTATAAATTGATTTTCATCCTGCCACAGAAAGGCATAAGCTGCATGTATGATGGGT

TACTATCAATCATTGCTCAAAAAAATTTTTGTATAATGACAGTACTGATAATATTAGA

AATGATACCGCAAGCAAATGTATATCACTTAAAAATGTCATATATTCTGTCTGCGTAA

ACTAAGGTATATATTCATATGTGCTCT

ORF Start: ATG at 61 ORF Stop: TAG at 5275

SEQ ID NO: 160 1738 aa MW at 200329. lkD

NOV45a, LKRKQSSRVEAQPVTDFGPDESLSDNADIL INKP VHSLLRICAIISVISVCMNTP CG105597-01 MTFEHYPPLQYVTFTLDTLLMFLYTAEMIAKMHIRGIVKGDSSYVKDRWCVFDGFMVF CLWVSLVLQVFEIADIΛ7DQMSP G LRIPRPLIMIRAFRIYFRFELPRTRITNILKRS Protein Sequence GEQI SVSIFLLFFLLLYGILGVQMFGTFTYHCWNDTKPGNVT NSLAIPDTHCSPE LEEGYQCPPGFKC DLΞDLGLSRQELGYSGFNEIGTSIFTVYEAASQEG VFLMYRAI DSFPRWRSYFYFITLIFFLA LVKNVFIAVIIΞTFAEIRVQFQQMWGSRSSTTSTATT QMFHED AGGWQLVA DV KPQGRAPACLQKIWRSSVFH FILSIVT^πDVIVAASl^_^ KGENFRRQYDEFYLAEVAFTVLFDLEALLKI CLGFTGYISSSLHKFELLLVIGTTLH VYPDLYHSQFTYFQVLRWRLIKISPALEDFVYKIFGPGK LGSLWFTASLLIVMSA ISLQMFCFVEELDRFTTFPRAFMSMFQILTQEGWλTOVMDQTLNAVGHM APλVAIYFI LYHLFATLILLSLFVAVILDNLELDEDLKKLKQLKQSEANADTKEKLPLRLRIFEKFP NRPQ VKI SKLPSDFTVPKIRESFMKQFIDRQQQDTCCLLRSLPTTS S S SCDHSKRSA IEDNKYIDQKLRKSVFS IRARNLLE ETAVTKILRACTRQRMLSGSFEGQPAKΞRSIL SVQHHIRQERRSLRHGSNSQRISRGKSLETLTQDHSNTVRYRNAQREDSEIKMIQEKK EQAEMKRKVQEEELRENHPYFDKPLFIVGREHRFRNFCRWVRARFNASRTDPVTGAV lαsTTKYHQLYDLLGLVTYLDWVMI IVTICSCISMMFESPFRRλπ iHAPTLQIAEYVFVIF MSIELNLKIMADGLFFTPTAVIRDFGGV DIFIYLVSLIFLC MPQNVPAESGAQLL VLRCLRPLRI FKLVPQMRKWRELFS GFKE I FLVS I LLLTLMLVFAS FG VQLFAGKLA KCNDPNIIRREDCNGIFRINVSVSKNLNLKLRPGEKKPGFWVPR n'7ANPRNFNFDl'JVG NAMLALFEVLSLKGWVEVRDVI IHRVGP IHGIYIHVFVFLGCMIGLTLFVGWIANFN ENKGTALLT^'/DQRR EDLKSRLKIAQPLHLPPRPDNDGFRAKMYDITQHPFFKRTIAL LVLAQSVLLSVKWDVEDPVTVPLATMSWFTFIFVLΞVTMKIIAMSPAGFWQSRRNRY DLLVTSLGWWWLHFALLNAYTYMMGACVIVFRFFSICGKHVTLKMLLLTVWSMYK SFFIIVGMFLLLLCYAFAGWLFGTVKYGENINRHANFSSAG AITVLFRIVTGEDWN KIMHDCMVQPPFCTPDEFTYWATDCGNYAGALMYFCSFYVIIAYIMLNLLVAIIVENF SLFYSTEEDQLLSYNDLRHFQII NMλ/DDKRΞGVIPTFRVKFLLRLLRGRLEλ DLDKD KLLFKHMCYE ERLHNGGDVTFHDVLSMLSYRSλ DIRKSLQLEELLAREQLEYTIEEΞ VAKQTIRMWLKKCLKRIRA QQQSCSI IHSLRESQQQELSRFLNPPSIETTQPSEDTN A SQDNSMQPETSSQQQLLSPTLSDRGGSRQDAADAGKPQR FGQWRLPSAPKPISHS IVSSV LRFGGRTTMKSWCK NP TDAASCGSEVKK TRQLTVESDESGDDLLDI

Further analysis of the NOV45a protein yielded the following properties shown in Table 45B.

Table 45B. Protein Sequence Properties NOV45a

PSort 0.8000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

' SignalP Cleavage site between residues 57 and 58 ^: analysis:

A search of the NOV45a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 45C.

In a BLAST search of public sequence databases, the NOV45a protein was found to have homology to the proteins shown in the BLASTP data in Table 45D.

PFam analysis indicates that the NOV45a protein contains the domains shown in the Table 45E.

Table 45E. Domain Analysis of NOV45a

Identities/

Pfam Domain NOV45a Match Region Similarities Expect Value for the Matched Region ion trans 70..321 45/278 (16%) 1.3e-20 186/278 (67%)

Example 46.

The NOV46 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 46A.

GACGGTCACCTTTGGGGTGGTGACAAGTGTGAGGCTTATCTTCACCATCATGATTGTT TATTTTCTCTTCTGGGCTCCCTACAACATTGTCCTTCTCCTGAACACCTTCCAGGAAT !TCTTTGGCCTGAATAATTGCAGTAGCTCTAACAGGTTGGACCAAGCTATGCAGGTGAC AGAGACTCTTGGGATGACGCACTGCTGCATCAACCCCATCATCTATGCCTTTGTCGGG GAGAAGTTCAGAAACTACCTCTTAGTCTTCTTCCAAAAGCACATTGCCAAACGCTTCT GCAAATGCTGTTCTATTTTCCAGCAAGAGGCTCCCGAGCGAGCAAGCTCAGTTTACAC CCGATCCACTGGGGAGCAGGAAATATCTGTGGGCTTGTGACACGGACTCAAGTGGGCT

GGTGACCCAGTCAGAGTTGTGCACATGGCTTAGTTTTCATACACAGCCTGGGCT

ORF Start: ATG at 46 ORF Stop: TGA at 850

SEQ ID NO: 164 268 aa IMW at 30754.9kD

NOV46b, DYQVSSPIYDINYYTSEPCQKI VKQIAARLPPPLYSLVFIFGFVGNMLVILILINC CGI 05627-04 KRLKSMTDIYLLNLAISDLFFLLTVPFWAHYAAAQWDFGNTMCQLLTGLYFIGFFSGI FFIILLTIDRYLA HAVFALKARTVTFGWTSVRLIFTIMIVYFLFWAPYNIVLLLN Protein Sequence TFQEFFGLNNCSSSNRLDQAMQVTETLGMTHCCINPIIYAFVGΞKFRNYLLVFFQKHI AKRFCKCCSIFQQEAPERASSVYTRSTGEQEISVGL

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 46B. r Table 46B. Comparison of NOV46a against NOV46b.

NOV46a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV46b 1..268 246/268 (91%) 1..268 247/268 (91%)

Further analysis of the NOV46a protein yielded the following properties shown in Table 46C.

j Table 46C. Protein Sequence Properties NOV46a

1 PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in I analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

[ SignalP Cleavage site between residues 64 and 65 1 analysis:

A search of the NOV46a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 46D.

In a BLAST search of public sequence databases, the NOV46a protein was found to have homology to the proteins shown in the BLASTP data in Table 46E.

PFam analysis indicates that the NOV46a protein contains the domains shown in the Table 46F.

Example 47.

The NOV47 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 47A.

Further analysis of the NOV47a protein yielded the following properties shown in Table 47B.

Table 47B. Protein Sequence Properties NOV47a ! PSort 0.5500 probability located in endoplasmic reticulum (membrane); 0.3880 , analysis: probability located in microbody (peroxisome); 0.3253 probability located in lysosome (lumen); 0.1000 probability located in endoplasmic reticulum (lumen) j SignalP Cleavage site between residues 32 and 3: j analysis:

A search of the NOV47a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 47C.

In a BLAST search of public sequence databases, the NO V47a protein was found to have homology to the proteins shown in the BLASTP data in Table 47D.

Table 47D. Public BLASTP Results for NOV47a

Protein NOV47a Identities/

Accession Residues/ Similarities for Expect

Protein/Organism/Length

Number Match the Matched Value

Residues Portion

PFam analysis indicates that the NOV47a protein contains the domains shown in the Table 47E.

Table 47E. Domain Analysis of NOV47a

Identities/

Pfam Domain NOV47a Match Region Similarities Expect Value for the Matched Region

I hemopexin 59-102 16/50 (32%) 6.3e-08 32/50 (64%) hemopexin 104..149 14/50 (28%) 4.5e-07 37/50 (74%)

Example 48.

The NOV48 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 48A.

Table 48A. NOV48 Sequence Analysis

SEQ ID NO: 167 6028 bp

;NOV48a, AAAATATTTCACGGTATGTTCACCTTTCTTTCTTTTTTCTTTTTTTTTTTTTTTTGTT

|CG105942-01 DNA TTCTTTTTCAGGCTCAGAAATCCTGGATAGAAAGAGCATTTTATAAAAGAGAATGTGT CCACATCATACCCAGCACCAAAGACCCCCATAGGATACCAGGGGTTCACTTTAACCTC Sequence TTCTGTTATAGGTGTTGCTGTGGGCGTCTGATAGGCCAGCATGTTGGCCTCACCCCCA GTATCTCCGTGCTTCAGAATGAGAAAAATGAAAGTCGCCTCTCCCGAAATGACATCCA GTCTGAAAAGTGGTCCATCAGCAAACACACTCAACTCAGCCCTACGGATGCTTTTGGG ACCATTGAGTTCCAAGGAGGTGGCCATTCCAACAAAGCCCAGTATGTGCGAGTATCTT TTGATACAAAACCTGATCTCCTCTTACACCTGATGACCAAGGAATGGCAGTTGGAGCT TCCCAAGCTTCTCATCTCTGTCCATGGGGGCCTGCAGAACTTTGAACTCCAGCCAAAA CTCAAGCAAGTCTTTGGGAAAGGGCTCATCAAAGCAGCAATGACAACTGGAGCGTGGA TATTCACTGGAGGGGTTAACACAGGTGTTATTCGTCATGTTGGCGATGCCTTGAAGGA TCATGCCTCTAAGTCTCGAGGAAAGATATGCACCATAGGTATTGCCCCCTGGGGAATT GTGGAAAACCAGGAGGACCTCATTGGAAGAGATGTTGTCCGGCCATACCAGACCATGT CCAATCCCATGAGCAAGCTCACTGTTCTCAACAGCATGCATTCCCACTTCATTCTGGC {TGACAACGGGACCACTGGAAΆATATGGAGCAGAGGTGAAACTTCGAAGACAΆCTGGAA IAAGCATATTTCACTCCAGAAGATAAACACAAGATGCCTGCCGTTTTTCTCTCTTGACT ICCCGCTTGTTTTATTCATTTTGGGGTAGTTGCCAGTTAGACTCAGTTGGAATCGGTCA IAGGTGTTCCTGTGGTGGCACTCATAGTGGAAGGAGGACCCAATGTGATCTCGATTGTT JTTGGAGTACCTTCGAGACACCCCTCCCGTGCCAGTGGTTGTCTGTGATGGGAGTGGAC ^'GGGCATCGGACATCCTGGCCTTTGGGCATAAATACTCAGAAGAAGGCGGACTGATAAA TGAATCTTTGAGGGACCAGCTGTTGGTGACTATACAGAAGACTTTCACATACACTCGA ACCCAΆGCTCAGCATCTGTTCATCATCCTCATGGAGTGCATGAAGAAGAAGGAATTGA TTACGGTATTTCGGATGGGATCAGAAGGACACCAGGACATTGATTTGGCTATCCTGAC AGCTTTACTCAAAGGAGCCAATGCCTCGGCCCCAGACCΆACTGAGCTTAGCTTTAGCC TGGAACAGAGTCGACATCGCTCGCAGCCAGATCTTTATTTACGGGCAACAGTGGCCGG TGGGATCTCTGGAGCAAGCCATGTTGGATGCCTTAGTTCTGGACAGAGTGGATTTTGT GAAATTACTCATAGAGAATGGAGTAAGCATGCACCGTTTTCTCACCATCTCCAGACTA GAGGAATTGTACAATACGAGACATGGGCCCTCAAATACATTGTACCACTTGGTCAGGG ATGTCAAAAAGGGGAACCTGCCCCCAGACTACAGAATCAGCCTGATTGACATCGGCCT GGTGATCGAGTACCTGATGGGCGGGGCTTATCGCTGCAACTACACGCGCAAGCGCTTC CGGACCCTCTACCACAACCTCTTCGGCCCCAAGAGGCCCAAAGCCTTGAAACTGCTGG GAATGGAGGATGATATTCCCTTGAGGCGAGGAAGAAAGACAACCAAGAAACGTGAAGA AGAGGTGGACATTGACTTGGATGATCCTGAGATCAACCACTTCCCCTTCCCTTTCCAT GAGCTCATGGTGTGGGCTGTTCTCATGAAGCGGCAGAAGATGGCCCTGTTCTTCTGGC AGCACGGTGAGGAGGCCATGGCCAAGGCCCTGGTGGCCTGCAAGCTCTGCAAAGCCAT GGCTCATGAGG^'CCTCTGAGAACGACATGGTTGACGACATTTCCCAGGAGCTGAATCAC AATTCCAGAGACTTTGGCCAGCTGGCTGTGGAGCTCCTGGACCAGTCCTACAAGCAGG ACGAACAGCTGGCCATGAAACTGCTGACGTATGAGCTGAAGAACTGGAGCAACGCCAC GTGCCTGCAGCTTGCCGTGGCTGCCAAACACCGCGACTTCATCGCGCACACGTGCAGC CAGATGCTGCTCACCGACATGTGGATGGGCCGGCTCCGCATGCGCAAGAACTCAGGCC TCAAGGTAATTCTGGGAATTCTACTTCCTCCTTCAATTCTCAGCTTGGAGTTCAAGAA CAAAGACGACATGCCCTATATGTCTCAGGCCCAGGAAATCCACCTCCAAGAGAAGGAG GCAGAAGAACCAGAGAAGCCCACAAAGGAAAAAGAGGAAGAGGACATGGAGCTCACAG CAATGTTGGGACGAAACAACGGGGAGTCCTCCAGGAAGAAGGATGAAGAGGAAGTTCA GAGCAAGCACCGGTTAATCCCCCTCGGCAGAAAAATCTATGAATTCTACAATGCACCC ATCGTGAAGTTCTGGTTCTACACACTGGCGTATATCGGATACCTGATGCTCTTCAACT ATATCGTGTTAGTGAAGATGGAACGCTGGCCGTCCACCCAGGAATGGATCGTAATCTC CTATATTTTCACCCTGGGAATAGAAAAGATGAGAGAGATTCTGATGTCAGAGCCAGGG AAGTTGCTACAGAAAGTGAAGGTATGGCTGCAGGAGTACTGGAATGTCACGGACCTCA TCGCCATCCTTCTGTTTTCTGTCGGAATGATCCTTCGTCTCCAAGACCAGCCCTTCAG GAGTGACGGGAGGGTCATCTACTGCGTGAACATCATTTACTGGTATATCCGTCTCCTA GACATCTTCGGCGTGAACAAGTATTTGGGCCCGTATGTAATGATGATTGGAAAAATGA TGATAGACATGATGTACTTTGTCATCATTATGCTGGTGGTTCTGATGAGCTTTGGGGT CGCCAGGCAAGCCATCCTTTTTCCCAATGAGGAGCCATCATGGAAACTGGCCAAGAAC ATCTTCTACATGCCCTATTGGATGATTTATGGGGAAGTGTTTGCGGACCAGATAGACC CTCCCTGTGGACAGAATGAGACCCGAGAGGATGGTAAAATAATCCAGCTGCCTCCCTG CAAGACAGGAGCTTGGATCGTGCCGGCCATCATGGCCTGCTACCTCTTAGTGGCAAAC ATCTTGCTGGTCAACCTCCTCATTGCTGTCTTTAACAATACATTTTTTGAAGTAAAAT CGATATCCAACCAAGTCTGGAAGTTTCAGAGGTATCAGCTCATCATGACTTTCCATGA AAGGCCAGTTCTGCCCCCACCACTGATCATCTTCAGCCACATGACCATGATATTCCAG CACCTGTGCTGCCGATGGAGGAAACACGAGAGCGACCCGGATGAAAGGGACTACGGCC TGAAACTCTTCATAACCGATGATGAGCTCAAGAAAGTACATGACTTTGAAGAGCAATG CATAGAAGAATACTTCAGAGAAAAGGATGATCGGTTCAACTCATCTAATGATGAGAGG ATACGGGTGACTTCAGAAAGGGTGGAGAACATGTCTATGCGGCTGGAGGAAGTCAACG AGAGAGAGCACTCCATGAAGGCTTCACTCCAGACCGTGGACATCCGGCTGGCGCAGCT GGAAGACCTTATCGGGCGCATGGCCACGGCCCTGGAGCGCCTGACAGGTCTGGAGCGG GCCGAGTCCAACAAAATCCGCTCGAGGACCTCGTCAGACTGCACGGACGCCGCCTACA TTGTCCGTCAGAGCAGCTTCAACAGCCAGGAAGGGAACACCTTCAAGCTCCAAGAGAG TATAGACCCTGCAGGTGAGGAGACCATGTCCCCAACTTCTCCAACCTTAATGCCCCGT ATGCGAAGCCATTCTTTCTATTCGGTCAATATGAAAGACAAAGGTGGTATAGAAAAGT TGGAAAGTATTTTTAAAGAAAGGTCCCTGAGCCTACACCGGGCTACTAGTTCCCACTC TGTAGCAAAAGAACCCAAAGCTCCTGCAGCCCCTGCCAACACCTTGGCCATTGTTCCT GATTCCAGAAGACCATCATCGTGTATAGACATCTATGTCTCTGCTATGGATGAGCTCC ACTGTGATATAGACCCTCTGGACAATTCCGTGAACATCCTTGGGCTAGGCGAGCCAAG CTTTTCAACTCC_AGT_ACC_TTCC_AC_AGCCCCTTC_AAGTAGTGCCTATGCAACACTTGCA jCCCACAGACAGACCTCCAAGCCGGAGCATTGATTTTGAGGACATCACCTCCATGGACA jCTAGATCTTTTTCTTCAGACTACACCCACCTCCCAGAATGCCAAAACCCCTGGGACTC SAGAGCCTCCGATGTACCACACCATTGAGCGTTCCAAAAGTAGCCGCTACCTAGCCACC ACACCCTTTCTTCTAGAAGAGGCTCCCATTGTGAAATCTCATAGCTTTATGTTTTCCC CCTCAAGGAGCTATTATGCCAACTTTGGGGTGCCTGTAAAAACAGCAGAATACACAAG TATTACAGACTGTATTGACACAAGGTGTGTCAATGCCCCTCAAGCAATTGCGGACAGA GCTGCCTTCCCTGGAGGTCTTGGAGACAAAGTGGAGGACTTAACTTGCTGCCATCCAG AGCGAGAAGCAGAACTGAGTCACCCCAGCTCTGACAGTGAGGAGAATGAGGCCAAAGG CCGCAGAGCCACCATTGCAATATCCTCCCA.GGAGGGTGATAACTCAGAGAGAACCCTG TCCAACAACATCACTGTTCCCAAGATAGAGCGCGCCAACAGCTACTCGGCAGAGGAGC CAAGTGCGCCATATGCACACACCAGGAAGAGCTTCTCCATCAGTGACAAACTCGACAG GCAGCGGAACACAGCAAGCCTGCGAAATCCCTTCCAGAGAAGCAAGTCCTCCAAGCCG GAGGGCCGAGGGGACAGCCTGTCCATGAGGAAACTGTCCAGAACATCGGCTTTCCAAA GCTTTGAAAGCAAGCACACCTAAACCTTCTTAATATCCGCCACAGAAGGCTCAAGAAT

CCAGCCCTAAAATTCTCTCCAACTCCAGTTTTTCCCCTTTCCTTGAATCATACCTGCT

TTATTCTTAGCTGAGCAAAACAAGCAATGCTTTGGGAGGTGTTAACTCAAAGGTGACT

TCTGGGCCACAGATCAAGAAAGCATTTGATCTGACCCAGTGCCAGACACAGGGGATTT

AAGGCATGTTCACACTTGCTGGGCAGGGAGGGGGAAGAGAGGGAGAAGGAAGGGTTAG lAGATGAATGTGTATCCGCAGTCACAGCAGAAAGCCATGAGAGCAGGGGAAACAAGGGG

CTTCGAGCACGCTCCATGCCAGGAGGCATCTGTTGATTTCTGACCATTATCAAGAGTT

GTAGGATGCAGGGCTAAATTGCAAAATAAAATAAAATAGCCAGCGTACACAATGAGAT

ATTCTAAACTTCCATTCTGTTTTCTTTTCACATTGGCTCCATCACTGGTGACTGATGA

AGAGCATCCTCTTTATTCAGTATAAGCCGGCAGCAAGCAGTTCTACCTAACGTCCCAC

ATCCTTCTCATGCCAACACTTCTGTAATTGATCATTATAAAGAAAAAACAAGGTAACA

GTCATAGTTCACCTGTCTCTTATCTATTCACTTCTGGTGCCACAACTGTTTATCCTTT

TTTGAAGAAAATAAGGGAACAGAAATGCCTTTTTGTATTGCAATCGAAATGAAAGAAG

AGTTGATGTTAAAAAAACAAAAGTCAAGTGATTTATTATATACAGTGGGCGTTCAAGT

CTAGTCGAGCAAGCTCAGGAGAATGTAATTAAATAATTTTATATTTTTTAATTTATTT

TGTATCTCACCTGTCATGGATGAATTCATTCACTGAATATGTAATATTGAACTT

ORF Start: ATG at 16 ORF Stop: TAA at 5125

SEQ ID NO: 168 11703 aa MW at 194521.2kD

;NOV48a, FTFLSFFFFFFFCFLFQAQKS IERAFYKRECVHIIPSTKDPHRIPGVHFNLFCYRC j CGI 05942-01 CCGRLIGQHVGLTPSISVLQNEKNESRLSRNDIQSΞKWSIS HTQLSPTDAFGTIEFQ GGGHSNKAQYVRVSFDTKPDLLLHLMTKEWQLELPKLLISVHGGLQNFELQP LKQVP I Protein Sequence GKGLIKAAMTTGAWIFTGGVNTGVIRHVGDALKDHASKSRGKICTIGIAP GIVENQE DLIGRDWRPYQTMSNPMSKLTVLNSMHSHFILADNGTTGKYGAEVKLRRQLEKHISL QKINTRCLPFFSLDSRLFYSFWGSCQLDSVGIGQGVPWALIVEGGPNVISIVLEYLR DTPPVPWVCDGSGRASDILAFGHKYSEEGGLINESLRDQLLVTIQRTFTYTRTQAQH LFIILMECMKKKELITVFRMGSEGHQDIDLAILTALLKGANASAPDQLSLALAWNRVD IARSQIFIYGQQWPVGSLEQAMLDALVLDRVDFV LLIENGVS HRFLTISRLEΞLYN TRHGPSNTLYHLVRDVKKGNLPPDYRISLIDIGLVIEYL GGAYRCNYTRKRFRTLYH NLFGPKRPKALKLLGMEDDIPLRRGRKTTKKREEEVDIDLDDPEINHFPFPFHELMVW AVLMKRQ-x-vlALFF QHGEEAMAKALVACKLCKAMAHEASΞNDMλπDDISQELNHNSRDF GQLAVELLDQSYKQDEQLAMKLLTYELKN SNATCLQLAVAAKHRDFIAHTCSQ LLT DMWMGRLRMRKNSGLKVILGILLPPSILSLEFKNKDDMPYMSQAQEIHLQΞKEAEΞPE KPTKEKEEEDMELTAMLGRNNGESSRKKDEEEVQSKHRLIPLGR I EFYNAPIVKF FYTLAYIGYL LFNYIVLVKMER PSTQE IVISYIFTLGIEIvMREILMSEPGKLLQK VKVWLQEYWNVTDLIAILLFSVGMILRLQDQPFRSDGRVIYCVNIIYWYIRLLDIFGV NKYLGPYλTM IGKMMIDlWYFVIIMLVVL SFGVARQAILFPNEEPSWKLAKNIFYMP Y IYGEVFADQIDPPCGQNETREDGKIIQLPPCKTGAWIVPAI ACYLLVANILLVN LLIAVF NTFFEVKSISNQV KFQRYQLIMTFHERPVLPPPLIIFSHMTMIFQHLCCR RKHESDPDERDYGLKLFITDDEL KVHDFEEQCIEEYFREKDDRFNSSNDERIRVTS ERVENMSMRLEEVNEREHSMKASLQTAHDIRLAQLEDLIGR ATALERLTGLERAESNK IRSRTSSDCTDAAYIVRQSSFNSQEGNTF LQESIDPAGEETMSPTSPTLMPR RSHS FYSVNMKD GGIE LESIFKERSLSLHRATSSHSVAKEPKAPAAPANTLAIVPDSRRP SSCIDIYVSAMDELHCDIDPLDNSVNILGLGEPSFSTPVPSTAPSSSAYATLAPTDRP PSRSIDFEDITSMDTRSFSSDYTHLPECQNPWDSEPPMYHTIERSKSSRYLATTPFLL EEAPIVKSHSFMFSPSRSYYANFGVPVKTAEYTSITDCIDTRCVNAPQAIADRAAFPG GLGDPVEDLTCCHPEREAELSHPSSDSEENEAKGRRATIAISSQEGDNSΞRTLS NIT jVPKIERANSYSAEEPSAPYAHTRKSFSISDKLDRQRNTASLRNPFQRSKSSKPEGRGD -JSLSMRKLSRTSAFQSFESKHT

Further analysis of the NOV48a protein yielded the following properties shown in Table 48B.

A search of the NOV48a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 48C.

In a BLAST search of public sequence databases, the NOV48a protein was found to have homology to the proteins shown in the BLASTP data in Table 48D. Table 48D. Public BLASTP Results for NOV48a

PFam analysis indicates that the NOV48a protein contains the domains shown in the Table 48E.

Table 48E. Domain Analysis of NOV48a

Identities/

^: Pfam Domain NOV48a Match Region Similarities I Expect Value for the Matched Region ion trans 897-1108 36/252 (14%) 1.8e-13 159/252 (63%)

Example 49.

The NOV49 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 49 A.

CCGGTTTGCTCTACCCGGGAACAGCCAGCTTGGCCTGCGGCCCGGCCAGCACCTGATA CTCAGAGGGATAGTAGATGACTTAGAAATTCAGAGAGCCTATACGCCCATCAGCCCTG CCAACGCAGAAGGATACTTTGAAGTGTTAATTAAGTATGGTGAGCTCCTCTTGCTGGC TGCGGGCACGGGCCTGGCCCCCATGGTGCCTATCCTGCAGAGCATCACAGACAATGAG AATGACGAGACTTTTGTCACTCTGGTCGGTTGCTTCAAGACCTTTGAGAGCATCTACC TGAAAACCTTCCTCCAAGAGCAGGCCCGTTTCTGGAATGTCCGTACCTTCTTTGTACT CAGCCAGGAGAGCTCCTCAGAGCAGCTTCCCTGGAGTTACCAAGAGAAAACCCACTTT GGCCACCTGGGCCAGGACCTAATTAAAGAGCTGGTCAGCTGCTGTCGGAGAAAGCCAT TCGCACTGGTCTGTGGCTCGGCTGAGTTCACCAAAGACATAGCCAGGTTTTCTGCTGA GTTCCTGAGGACCCTGACTCGAGGAGTCCACCGTCTCCTGGGGGCTGCAGATGCTGTC AAAACAAATGTGAAAGGTCTGGTGCTCGGCCTGCTACCCAGTAGACACTCAGACCCTC TTCCATCCGACTCCCCTGGCGGCCCGATCTGGTGGCTCAGAGGACCAGCATTGCAGCT GGACAGTCCCGGATTTGAATCCTGGTTCTGCCACTTAGAGGATGTGAGGTCAGCCCAG ACCTCTGTGGACAAGGAGGTGTTAGGCAGCACCTTGCTATCCCCTGGGCACCACCCCT GGACCCGGGAACCAGTGACAGGATACAGATATGAAGACAAAACGTGCTTAGAGAGAGC CCCAGCTATAGAGGTGCACCCTTGGAGACCTCCACAGACATGCACAGAGGTATGCAGA TGTGTACCCCAGAGCTTTGTGACCATCTATACTCAAAGCTCCACACACTCGGGCACAG ATCTATACACCAGCAGAAGCTGTGTACCCATGGAATAG

ORF Start: ATG at 35 jORF Stop: TAG at 1544

SEQ ID NO: 170 503 aa MW at 56300.2kD

NOV49a, MPVISAL ETEMRRSLEARSSRPDWQHSETLSLQNAGQGAGPAPRGLIEPGLF KSTS CGI 06074-01 CSFYAAQAPLM AEREEDDDTΞEA MQLRPTEPLPSQCCGSGCSPCVFDLYHRDLARW EAAQASKDRSLLRGPEΞQSCPSKLNPETFVAFCIIA DRLTKDTYRVRFALPGNSQLG Protein Sequence LRPGQHLILRGIVDDLEIQRAYTPISPANAEGYFΞVLIKYGELLLLAAGTGLAP VPI LQSITDNENDETFVTLVGCFKTFESIYLKTFLQEQARFWNVRTFFVLSQESSSEQLPW SYQEKTHFGHLGQDLIKELVSCCRRKPFALVCGSAEFTKDIARFSAΞFLRTLTRGVHR LLGAADAVKTNVKGLVLGLLPSRHSDPLPSDSPGGPIW LRGPALQLDSPGFES FCH LEDVRSAQTSVDKEVLGSTLLSPGHHPWTREPVTGYRYEDKTCLERAPAIEVHP RPP QTCTEVCRCVPQSFVTIYTQSSTHSGTDLYTSRSCVPMΞ

Further analysis of the NOV49a protein yielded the following properties shown in Table 49B.

! Table 49B. Protein Sequence Properties NOV49a

PSort 0.6731 probability located in mitochondrial imier membrane; 0.5309 probability analysis: located in microbody (peroxisome); 0.4400 probability located in plasma membrane; 0.3207 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV49a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 49C.

In a BLAST search of public sequence databases, the NOV49a protein was found to have homology to the proteins shown in the BLASTP data in Table 49D.

PFam analysis indicates that the NOV49a protein contains the domains shown in the Table 49E.

r j \ Identities/ [

Pfam Domain j NOV49a Match Region , Similarities Expect Value

I I for the Matched Region

Example 50.

The NOV50 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 50A.

TTGGCTAAGAGCATTTGCAGCCAATTCCGGACTCGGCTCAATAGTTCCCACGAGGCTT TTGCAGCCTCCTTGCGGCAGCTGGAAGCTGGCCACTCAGGCCGGTTAGAGAAAACGGA AGATCTATGGCTGAGGGTTCGGAAAGATCATGCTCCCCGCCTGGCCCGCCTTTCTCTG GAAAGCCGTTCTTTACAGGATGTCTTGCTTCATCGTAAACCTAAACTGGGACAGGAAC TGGGCCGGGGCCAGTATGGTGTGGTATACCTGTGTGACAACTGGGGAGGACACTTCCC TTGTGCCCTGAAATCAGTTGTCCCTCCAGATGAGAAGCACTGGAATGATCTGGCTTTG GAATTTCACTATATGAGGTCTCTGCCGAAGCATGAGCGATTGGTGGATCTCCATGGTT CAGTCATTGACTACAACTATGGTGGTGGCTCCAGCATTGCTGTGCTCCTCATTATGGA GCGGCTACACCGGGATCTCTACACAGGGCTGAAGGCTGGGCTGACCCTGGAGACACGT TTGCAGATAGCACTAGATGTGGTGGAGGGAATCCGCTTCCTGCACAGCCAGGGACTTG TCCATCGTGATATCAAACTGAAAAATGTGCTGCTGGATAAGCAGAACCGTGCCAAGAT CACTGACTTAGGATTCTGCAAGCCAGAGGCCATGATGTCAGGCAGCATTGTGGGGACA CCAATCCATATGGCCCCTGAACTTTTCACAGGGAAGTACGATAATTCCGTGGATGTCT ACGCTTTTGGAATTCTTTTCTGGTATATCTGCTCAGGCTCTGTCAAGCTCCCTGAGGC ATTTGAGAGGTGTGCTAGCAAAGACCATCTCTGGAACAATGTGCGGAGGGGGGCTCGC CCAGAACGTCTTCCTGTGTTTGATGAGGAGTGCTGGCAGTTGATGGAAGCCTGTTGGG ATGGCGACCCCTTGAAGAGGCCTCTCTTGGGCATTGTCCAGCCCATGCTCCAGGGCAT CATGAATCGGCTCTGCAAGTCCAATTCTGAGCAGCCAAACAGAGGACTAGATGATTCT ACTTGAAAGCAAAG

ORF Start: ATG at 1 ORF Stop: TGA at 2788

SEQ ID NO: 174 '929 aa |MW at l05257.5kD

NOV50b, EGDGVP GSEPVSGPGPGGGGMIRΞLCRGFGRYRRYLGRLRQNLRETQKFFRDIKCS ICG106166-02 HNHTCLSSLTGGGGAERGPAGDVAETGLQAGQLSCISFPPKEEKYLQQIVDCLPCILI LGQDCNV CQLLNLLLGV VLPTTKLGSEESC LRRLRFTYGTQTRVSLALPGQYELV Trotein Sequence HTLVAHQGlvWETIPΞEDLEVQENNEDAAHVLAELEVTMHHALLQEλDλΛλVAPCQGLRP TVDVLGDLVNDFLPVITYALHKDELSERDEQΞLQEIRKYFSFPVFFFKVP LGSEIID SSTRRMESERSPLYRQLIDLGYLSSSH NCGAPGQDTKAQS LVEQSEKLRHLSTFSH QVLQTRLVDAAKALNLλ/HCHCLDIFINQAFDMQRDLQITPKRLEYTRKKENELYESLM NIANRKQEEMKDMIVETLNTMKEELLDDATNMEFKDVIVPENGEPVGTREIKCCIRQI QELIISRLNQAVA KLISSVDYLRESFVGTLΞRCLQSLΞKSQDVSVHITSNYL QILN AAYHVEVTFHSGSSVTRML EQIKQIIQRITWVSPPAITLE KRKVAQEAIESLSASK LAKSICSQFRTRLNSSHEAFAASLRQLEAGHSGRLEKTEDLWLRVRKDHAPRLARLSL ESRSLQDVLLHR PKLGQELGRGQYG\ΛΛTLCDN GGHFPCALKSWPPDE HWNDLAL EFHYMRSLPKHERLVDLHGSVIDYNYGGGSSIAVLLIMERLHRDLYTGLKAGLTLETR LQIALDWEGIRFLHSQGLVHRDIKLKNVLLDKQNRAKITDLGFCKPEAMMSGSIVG PIH^ PE FTGKYD Sλπ^VYAFGILF YICSGSVKLPEAFERCASKDHLWNNVRRGAR PERLPVFDEEC QLMEACWDGDPLKRPLLGIVQPMLQGIMNRLCKSNSEQPNRGLDDS T

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 50B.

Table 50B. Comparison of NOV50a against NOV50b.

NOV50a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV50b 1..921 836/930 (89%) 1..929 837/930 (89%)

Further analysis of the NOV50a protein yielded the following properties shown in Table 50C.

Table 50C. Protein Sequence Properties NOVSOa analysis: located in nucleus; 0.1000 probability located in mitochondrial matrix space; j 0.1000 probability located in lysosome (lumen)

' SignalP No Known Signal Sequence Indicated j analysis:

A search of the NOV50a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 50D.

In a BLAST search of public sequence databases, the NOVSOa protein was found to have homology to the proteins shown in the BLASTP data in Table 50E.

PFam analysis indicates that the NOV50a protein contains the domains shown in the Table 50F.

Table 50F. Domain Analysis of NOVSOa

! Identities/

Pfam Domain NOVSOa Match Reεion Similarities j Expect Value for the Matched Region _i pkinase 644-889 74/280 (26%) 1.5e-39 173/280 (62%)

Example 51.

The NOV51 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 51 A.

Table 51A. NOV51 Sequence Analysis

SEQ ID NO: 175 | 1602 bp

NOV51a, ATGGCTTCGACCACCACCTGCACCAGGTTCACGGACGAGTATCAGCTTTTCGAGGAGC

CG106773-01 DNA TTGGAAAGGGGGCATTCTCAGTGGTGAGAAGATGTATGAAAATTCCTACTGGACAAGG ATATGCTGCCAAAATTATCAACACCAAAAAGCTTTCTGCTAGGGATCATCAGAAACTA Sequence GAAAGAGAAGCTAGAATCTGCCGTCTTTTGAAGCACCCTAATATTGTGCGACTTCATG ATAGCATATCAGAAGAGGGCTTTCACTACTTGGTGTTTGATTTAGTTACTGGAGGTGA ACTGTTTGAAGACATAGTGGCAAGAGAATACTACAGTGAAGCTGATGCCAGTCATTGT ATACAGCAGATTCTAGAAAGTGTTAATCATTGTCACCTAAATGGCATAGTTCACAGGG ACCTGAAGCCTGAGAATTTGCTTTTAGCTAGCAAATCCAAGGGAGCAGCTGTGAAATT GGCAGACTTTGGCTTAGCCATAGAAGTTCAAGGGGACCAGCAGGCGTGGTTTGGTTTT GCTGGCACACCTGGATATCTTTCTCCAGAAGTTTTACGTAAAGATCCTTATGGAAAGC CAGTGGATATGTGGGCATGTGGTGTCATTCTCTATATTCTACTTGTGGGGTATCCACC CTTCTGGGATGAAGACCAACACAGACTCTATCAGCAGATCAAGGCTGGAGCTTATGAT TTTCCATCACCAGAATGGGACACGGTGACTCCTGAAGCCAAAGACCTCATCAATAAAA TGCTTACTATCAACCCTGCCAAACGCATCACAGCCTCAGAGGCACTGAAGCACCCATG GATCTGTCAACGTTCTACTGTTGCTTCCATGATGCACAGACAGGAGACTGTAGACTGC TTGAAGAAATTTAATGCTAGAAGAAAACTAAAGGGTGCCATCTTGACAACTATGCTGG CTACAAGGAATTTCTCAGCAGCCAAGAGTTTGTTGAAGAAACCAGATGGAGTAAAGAT AAACAACAAAGCCAACGTGGTAACCAGCCCCAAAGAAAATATTCCTACCCCAGCGCTG GAGCCCCAAACTACTGTAATCCACAACCCTGATGGAAACAAGGAGTCAACTGAGAGTT

Further analysis of the NOV5 la protein yielded the following properties shown in Table 5 IB.

Table SIB. Protein Sequence Properties NOV51a i PSort 0.6500 probability located in plasma membrane; 0.2312 probability located in analysis: mitochondrial inner membrane; 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in Golgi body

^' SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV5 la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 51 C.

In a BLAST search of public sequence databases, the NOV5 la protein was found to have homology to the proteins shown in the BLASTP data in Table 5 ID.

PFam analysis indicates that the N0V51 a protein contains the domains shown in the Table 5 IE.

Table 51E. Domain Analysis of NOVSla

Identities/

Pfam Domain NOV51a Match Region Similarities j Expect Value for the Matched Region pkinase 14..272 103/294 (35%) 2.2e-90 212/294 (72%)

Example 52.

The NOV52 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 52A.

Table 52A. NOV52 Sequence Analysis

SEQ ID NO: 177 3084 bp

!NOV52a, AGCAGCTTAGTTTTTGAATCGGTTGTGGCGGCCGCCGGCGAGGAATGGCGGTATTTGT

|CG108211-01 DNA GAGAGGAGTCGGCGTTTGAAGAGGTGGAACTCCTAGGGCTTTTTTGAGAGTGCTGATT

TAGAAGAATACAAATCATGGCTGAAAATAGTGTATTAACATCCACTACTGGGAGGACT '; Sequence AGCTTGGCAGACTCTTCCATTTTTGATTCTAAAGTTACTGAGATTTCCAAGGAAAACT TACTTATTGGATCTACTTCATATGTAGAAGAAGAGATGCCTCAGATTGAAACAAGAGT GATATTGGTTCAAGAAGCTGGAAAACAAGAAGAACTTATAAAAGCCTTAAAGGACATT AAAGTGGGCTTTGTAAAGATGGAGTCAGTGGAAGAATTTGAAGGTTTGGATTCTCCGG AATTTGAAAATGTATTTGTAGTCACGGACTTTCAGGATTCTGTCTTTAATGACCTCTA CAAGGCTGATTGTAGAGTTATTGGACCACCAGTTGTATTACATTGTTCACAAAAAGGA GAGCCTTTGCCATTTTCATGTCGCCCGTTGTATTGTACAAGTATGATGAATCTAGTAC TATGCTTTACTGGATTTAGGAAAAAAGAAGAACTAGTCAGGTTGGTGACATTGGTCCA TCACATGGGTGGAGTTATTCGAAAAGACTTTAATTCAAAAGTTACACATTTGGTGGCA AATTGTACACAAGGAGAAAAATTCAGGGTTGCTGTGAGTCTAGGTACTCCAATTATGA AGCCAGAATGGATTTATAAAGCTTGGGAAAGGCGGAATGAACAGGATTTCTATGCAGC AGTTGATGACTTTAGAAATGAATTTAAAGTTCCTCCATTTTCAGATTGTATTTTAAGT TTCCTGGGATTTTCAGATGAAGAGAAAACCAATATGGAAGAAATGACTGAAATGCAAG GAGGTAAATATTTACCGCTTGGAGATGAAAGATGCACTCACCTTGTAGTTGAAGAGAA TATAGTAAAAGATCTTCCCTTTGAACCTTCAAAGAAACTTTATGTTGTCAAGCAAGAG TGGTTCTGGGGAAGCATTCAAATGGATGCCCGAGCTGGAGAAACTATGTATTTATATG AAAAGGCAAATACTCCTGAGCTCAAGAAATCAGTGTCAATGCTTTCTCTAAATACCCC TAACAGCAATCGCAAACGACGTCGTTTAAAAGAAACACTTGCTCAGCTTTCAAGAGAG ACAGACGTGTCACCATTTCCACCCCGTAAGCGCCCATCAGCTGAGCATTCCCTTTCCA TAGGGTCACTCCTAGATATCTCCAACACACCAGAGTCTAGCATTAACTATGGAGACAC CCCAAAGTCTTGTACTAAGTCTTCTAAAAGCTCCACTCCAGTTCCTTCAAAGCAGTCA GCAAGGTGGCAAGTTGCAAAAGAGCTTTATCAAACTGAAAGTAATTATGTTAATATAT TGGCAACAATTATTCAGTTATTTCAAGTACCATTGGAAGAGGAAGGACAACGTGGTGG ACCTATCCTTGCACCAGAGGAGATTAAGACTATTTTTGGTAGCATCCCAGATATCTTT GATGTACACACTAAGATAAAGGATGATCTTGAAGACCTTATAGTTAATTGGGATGAGA GCAAAAGCATTGGTGACATTTTTCTGAAATATTCAAAAGATTTGGTAAAAACCTACCC TCCCTTTGTAAACTTCTTTGAAATGAGCCAGGAAACCATTATTAAATGTGAAAAACCG AAACCACGATTTCCTGGTTTTCTCAAGATAAACCAAGCGAAACCAGAATGTGGGGGGC AGAGCCTTGTTGAACTTCTTATCGGACCAGTACAGAGGTTACCCAGTGTTGCGTTTCT TTTAAATGATCTTAAGAAGCATACAGCTGATGAAAATCCAGACAAAAGCCCTTTAGAAj AAAGCTATTGGATCACTGAAGGAAGTAATGACGCATATTAATGAGGATAAGAGAAAAA: CAGAAGCTCAAAAGCAAATTTTTGATGTTGTTTATGAAGTAGATGGATGCCCAGCTAA TCTTTTATCTTCTCACCGAAGCTTAGTACAGCGGGTTGAAACAATTTCTCTAGGTGAG' CACCCCTGTGACAGAGGAGAACAAGTAACTCTCTTCCTCTTCAATGATTGCCTAGAGA

TAGCAAGAAAACGGCACAAGGTTATTGGCACTTTTAGGAGTCCTCATGGCCAAACCCG

ACCCCCAGCTTCTCTTAAGCATATTCACCTAATGCCTCTTTCTCAGATTAAGAAGGTA

TTGGACATAAGAGAGACAGAAGATTGCCATAATGCTTTTGCCTTGCTTGTGAGGCCAC

CAACAGAGCAGGCAAATGTGCTACTCAGTTTCCAGATGACATCAGATGAACTTCCAAA

AGAAAACTGGCTAAAGATGCTGTGTCGACATGTAGCTAACACCATTTGTAAAGCAGAT

GCTGAGAATCTTATTTATACTGCTGATCCAGAATCCTTTGAAGTAAATACAAAAGATA

TGGACAGTACATTGAGTAGAGCATCAAGAGCAATAAAAAAGACTTCAAAAAAGGTTAC

AAGAGCATTCTCTTTCTCCAAAACTCCAAAAAGAGCTCTTCGAAGGGCTCTTATGACAI

TCCCACGGCTCAGTGGAGGGAΆGAAGTCCTTCCAGCAATGATAAGCATGTAATGAGTC

GTCTTTCTAGCACATCATCATTAGCAGGTATCCCTTCTCCCTCCCTTGTCAGCCTTCC

TTCCTTCTTTGAAAGGAGAΆGTCATACGTTAAGTAGATCTACAACTCATTTGATATGA

AGCGTTACCAAAATCTTAAATTATAGAAΆTGTATAGACACCTCATACTCAAATAAGAA

ACTGACTTAAATGGTACTTGTAATTAGCACTTGGTGAAAGCTGGAAGGAAGATAAATA

ACACTAAACTATGCTATTTGATTTTTCTTCTTGAAAGAGTAAGGTTTACCTGTTACAT

TTTCAAGTTAATTCATGTAAAΆAATGATAGTGATTTTGATGTAATTTATCTCTTGTTT

GAATCTGTCATTCAAAGGCCAATAATTTAAGTTGCTATCAGCTGATATTAGTAGCTTT

GCAACCCTGA

ORF Start: ATG at 133 SORF Stop: TGA at 2782

SEQ ID NO: 178 1883 aa MW at 99778. lkD

NOV52a, MAENSVLTSTTGRTSLADSS IFDSKVTEISKΞNLLIGSTSYVEEEMPQIETRVILVQE ;CG108211-01 AGKQEELIKALKDIKVGFVKMESVEEFEGLDSPEFENVFWTDFQDSVFNDLYKADCR

VIGPPWLHCSQKGEPLPFSCRPLYCTSMMNLVLCFTGFRKKEELVRLVTLΛ HMGGV IProtein Sequence IRKDFNSKVTHLVANCTQGEKFRVAVSLGTPI KPEWIYKAWERRNEQDFYAAVDDFR

SNEF VPPFSDCILSFLGFSDΞEKTNMEΞ TEMQGGKYLPLGDERCTHLWEENIVKDL

{ PFEPSKKLYWKQΞ F GSIQMDARAGETMYLYEKANTPΞLKKSVSMLSLNTPNSNRK

J RRRLKETLAQLSRETDVSPFPPRKRPSAEHSLSIGSLLDISNTPESSINYGDTPKSCT

KSSKSSTPVPSKQSARWQVAKELYQTESNYΛ/NILATIIQLFQVPLEEEGQRGGPILAP

J EEIKTIFGS IPDIFDVHTKIKDDLEDLIV DESKSIGDIFLKYSKDLVKTYPPFVNF FEMSQETIIKCEKP PRFPGFLKINQAKPECGGQSLVELLIGPVQRLPSVAFLLNDLK

| ΚHTADENPDKSPLEKAIGSLKEV THINEDKRKTEAQKQIFDVVYEΛ DGCPA LLSSH

RSLVQRVETISLGEHPCDRGEQVTLFLFNDCLEIARKRHKVIGTFRSPHGQTRPPASL

.SΗIHLMPLSQIKKVLDIRETEDCHNAFALLV^PPTEQANVLLSFQMTSDELPKEIVΠ'.LK

MLCRHVANTICKADAENLIYTADPESFEVNTKD DSTLSRASRAIKKTSKKVTRAFSF

SKTPKRALRRAL TSHGSVEGRSPSSNDKHV SRLSSTSSLAGIPSPSLVSLPSFFER

RSHTLSRSTTHLI

Further analysis of the NOV52a protein yielded the following properties shown in Table 52B.

Table 52B. Protein Sequence Properties NOV52a

PSort 0.5247 probability located in mitochondrial matrix space; 0.4900 probability analysis: located in nucleus; 0.3000 probability located in microbody (peroxisome); 0.2532 probability located in mitochondrial inner membrane

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV52a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 52C.

Table 52C. Geneseq Results for NOV52a

In a BLAST search of public sequence databases, the NOV52a protein was found to have homology to the proteins shown in the BLASTP data in Table 52D.

PFam analysis indicates that the NOV52a protein contains the domains shown in the Table 52E.

Example 53.

The NOV53 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 53A.

TTTCTCTGCCTTATTGCCCTGGCAAAACATTAGTGGTGGGTGCCTCTTATGTTGCCCT GGAGTGTGCAGGGTTTCTGGCTGGCTTTGGCCTAGATGTCACAGTTATGGTACGCTCA ATCCTTCTCCGTGGCTTCGACCAAGAAATGGCAGAAAAAGTGGGTTCCTACATGGAGC AGCATGGTGTGAAGTTCCTACGGAAATTCATACCTGTGATGGTTCAACAGTTGGAGAA AGGTTCACCTGGAAAGCTGAAAGTGTTGGCTAAATCCACTGAAGGAACAGAAACAATT GAAGGAGTCTATAACACAGTTTTGTTAGCTATTGGTCGTGACTCCTGTACAAGGAAAA TAGGCTTGGAGAAGATTGGTGTCAAAATTAATGAGAAGAGTGGAAAAATACCTGTAAA TGATGTGGAACAGACCAATGTGCCATATGTCTATGCTGTTGGTGATATTTTGGAGGAT AAGCCAGAGCTCACTCCTGTCGCCATACAGTCAGGCAAGCTGCTAGCTCAGAGACTTT TTGGGGCCTCTTTAGAAAAGTGTGATTATATTAATGTTCCGACTACAGTGTTTACTCC TCTGGAGTATGGTTGCTGTGGATTATCTGAAGAGAAAGCTATTGAAGTATATAAAAAA GAGAATCTAGAAATATATCATAC.TTTGTTCTGGCCTCTTGAATGGACAGTAGCTGGCA GAGAGAACAACACTTGTTACGCAAAGATAATCTGCAATAAATTCGACCATGATCGGGT GATAGGATTTCATATTCTTGGACCAAACGCCGGTGAGGTTACCCAAGGATTTGCAGCT GCAATGAAATGTGGGCTCACAAAACAGCTACTTGATGACACCATTGGAATTCACCCCA CATGTGGGGAGGTGTTCACGACTTTGGAAATCACAAAGTCGTCAGGACTAGACATCAC TCAGAAAGGCTGCTGAGGCTAGGCCTGCTGCTGTTTAGTTCTCCTTGTCATATTCTCA

TTTCTCTCAAAGATAAGAATGCTCTCGGATAAAATGAGCCTGTGCTCATGACAGCTGC

TCTGTTACTCAGGGACCAGTGCAGGGCTGTCTTACGACACTTAGATGAGAAAGTAGAC iAAGGAAAGAGGACAGCAGTGGGCATCTGCCTTGTGGTCTTGCTGACAGCGAGAAGCAG

TGGGACTGCTTCCTTGACGCCTTAGCTTGGAGCCCCGTTATGAGGTGAGCCAAGGCTG

ACTCTCGCAAGCCAGGACTGAGCTTCCCTCGGAAAGACCTTTGAGTGGCACCATTCAC

CTAAGTTAGCTTTTCTGGTCGCTATTGTTTTTATCCCCTTTGCTTTGTTGTTTCTGTG

AAAATATATTTTCAGTTAAGAAATGCTATAAAGTAGTGGTTTTCTAGTGCGTGGGCCT

AGAATTCACACATGCTCACTGGTGAACAGTGTCTGTGGGCTGCTGTGGGCTGCATTTG

GATAGCTGTCTGCATTAGCAGGAAGCTGTACACACTGTGTAGGGTTAGTCATCTCTTT

TCTTTTTTGAGGCACATTTAACCTACTGTCAAAACGCTGACTCATGCTTCACCCTCAC

ACTCACTACTTGGTGGTGATAACCTTGAAGCTATTCTCCCCTAATTAATATCTCGAGA

CTGAGCAAAATATCTCATGTAAGATAAAAGTACTTGAATTGCTTTTTCATGTTCATCT

TAATAGTATTATTTCCAAAAGTTTTTAATACTGTATTATGTGAAATCTAACTAATTTA

TCTGTGAAATAATTCCATCACAGTCTGTTTAATGATGATAAAGTTCCATAAATGAATA

CAGGT

ORF Start: ATG at 31 ORF Stop: TGA at 2044

SEQ ID NO: 180 1671 aa iMW at 73388.4kD

!NOV53a, MRGAVLGGGASGCLADSRG PGRARSESETLERSPPQSPGPGKAGDAPNRRSGHVRGA CG108351-01 RVLSPPGRRARLSSPGPSRSSEAREELRRHLVGLIEAERWIFSKSYCPHSTRVKELF SSLGVEC VLELDQ-VDDGARVQEVLSEITNQKTVPNIFVNKVHVGGCDQTFQAYQSGL Protein Sequence LQKLLQEDLAYDYDLIIIGGGSGGLSCAKEAAILGKKVMVLDFWPSPQGTSWGLGGT CVNVGCIP KLMHQAALLGQALCDSRKFG EYNQQVRHNWETMTKAIQNHISSLN GY RLSLREKAVAYVNSYGΞFVΞHHKIKATNKKGQETYYTAAQFVIATGERPRYLGIQGDK EYCITSDDLFSLPYCPG TLWGASYVALECAGFLAGFGLDVTVMVRSILLRGFDQEM AEKVGSYMEQHGVKFLRKFIPλ/MVQQLEKGSPGKLKVLAKSTEGTETIEGVYNTVLLA IGRDSCTRKIGLE IGVKINEKSGKIPVNDVEQTNVPYVYAVGDILEDKPELTPVAIQ SGKLLAQRLFGASLEKCDYI VPTTVFTPLEYGCCGLSEEKAIEVYKKENLΞIYHTLF WPLEWTVAGRElslTTTCYAKIICNKFDHDRVIGFHILGPNAGEVTQGFAAAMKCGLTKQL LDDTIGIHPTCGEVFTTLEITKSSGLDITQKGC

Further analysis of the NOV53a protein yielded the following properties shown in

Table 53B.

Table 53B. Protein Sequence Properties NO 53a

PSort 0.3000 probability located in microbody (peroxisome); 0.3000 probability analysis: located in nucleus; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen) j No Known Signal Sequence Indicated analysis:

A search of the NOV53a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 53C.

In a BLAST search of public sequence databases, the NOV53a protein was found to have homology to the proteins shown in the BLASTP data in Table 53D.

r i Mus musculus (Mouse). 615 aa. 61. 582/61 1 (94%)

¹ Q9CZE5 j THIOREDOXIN REDUCTASE 1 62..671 536/611 (87%) 0.0 ; Mus musculus (Mouse), 613 aa. 3..613 582/61 1 (94%)

Q99475 I KM-102-DERIVED REDUCTASE- 132-671 387/546 (70%) 0.0 j LIKE FACTOR (THIOREDOXIN 4..549 460/546 (83%) j REDUCTASE) - Homo sapiens I (Human), 549 aa.

PFam analysis indicates that the NOV53a protein contains the domains shown in the Table 53 E.

Table 53E. Domain Analysis of NOV53a

Identities/

Pfam Domain j NOV53a Match Region Similarities Expect Value for the Matched Region glutaredoxin 97..157 27/69 (39%) 4.4e-20 52/69 (75%) pyr_redox 188-519 103/367 (28%) 7e-71 256/367 (70%) pyr_redox_dim 544-657 39/118 (33%) 5.8e-41 98/118 (83%)

Example 54.

The NOV54 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 54A.

Table 54A. NOV54 Sequence Analysis

SEQ ID NO: 181 4181 bp

NOV54a. GGACCATGTTTGATGGTGCCAGATTGGCCTCACTTTTTGGACTGGATCAGGCAGCTGC

CG108462-01 DNA TGGCCATGGAAATGAATTTTTCCAGTACACAGCCCCAAAACAGCCTAAGAAAGGCCAG GGAACGGCAGCAACAGGAAATCAGGCAACACCAAAAACAGCACCAGCCACCATGAGCA Sequence CTCCCACAATACTGGTCGCAACAGCAGTCCATGCATATCGATACACAAATGGTCAATA TGTAAAGCAGGGCAAATTTGGTGCTGCAGTTCTGGGGAACCACACAGCCAGAGAGTAT AGGATTCTTCTTTATATCAGTCAACAACAGCCAGTTACGGTTGCTAGGATTCATGTGA ACTTTGAGCTAATGGTTCGGCCCAATAACTATAGCACCTTTTATGATGACCAGAGACA GAACTGGTCCATCATGTTTGAGTCGGAAAAGGCTGCTGTGGAGTTCAATAAGCAGGTG TGCATTGCTAAGTGCAACAGTACCTCTTCCCTGGATGCAGTGCTCTCCCAGGACCTCA TTGTGGCAGACGGCCCTGCTGTAGAAGTTGGAGATTCTTTGGAAGTGGCCTATACCGG CTGGCTCTTTCAGAATCATGTGCTGGGCCAGGTTTTCGACTCCACTGCTAACAAAGAT AAGTTGCTTCGCTTGAAGTTAGGATCAGGAAAAGTCATCAAGGGCTGGGAGGATGGAA TGCTGGGCATGAAAAAAGGAGGAAAGCGATTGCTTATTGTCCCTCCAGCCTGTGCTGT TGGCTCAGAAGGGGTAATAGGCTGGACTCAAGCAACGGACTCGATCCTGGTGTTCGAG GTGGAGGTTAGGCGGGTGAAGTTTGCCAGAGATTCTGGCTCTGATGGTCACAGTGTTA GTTCCCGCGATTCTGCAGCTCCGTCTCCCATCCCTGGTGCTGACAACCTCTCTGCTGA TCCTGTTGTGTCACCACCCACATCAATACCTTTCAAATCAGGGGAGCCAGCTCTTCGT ACCAAATCTAACTCCCTCAGTGAACAACTTGCAATAAATACAAGTCCCGATGCAGTCA AAGCCAAGTTGATCTCTCGGATGGCTAAAATGGGCCAGCCCATGCTGCCCATCCTTCC ACCACAGCTGGATTCCAATGATTCAGAAATCGAAGATGTGAACACTCTGCAAGGAGGT GGGCAGCCTGTGGTGACTCCGTCCGTCCAGCCCTCTCTTCAGCCGGCCCATCCAGCGT TACCACAGATGACCTCACAGGCACCTCAGCCATCTGTTACTGGGCTCCAGGCACCTTC TGCTGCCTTAATGCAAGTGTCATCTCTCGATTCCCACTCAGCTGTATCTGGAAATGCC CAATCCTTTCAGCCCTATGCAGGTATGCAAGCCTACGCTTATCCCCAGGCATCTGCCG TCACCTCCCAGCTGCAGCCCGTTCGGCCTTTGTACCCAGCACCGCTCTCTCAGCCTCC CCATTTCCAAGGATCAGGTGATATGGCTTCATTTCTCATGACTGAAGCCCGGCAACAT AACACTGAAATTCGAATGGCAGTCAGCAAAGTGGCTGATAAAATGGATCATCTCATGA CTAAGGTTGAAGAGTTACAGAAACATAGTGCTGGCAATTCCATGCTTATTCCTAGCAT GTCAGTTACAATGGAAACAAGCATGATTATGAGCAACATCCAGCGAATCATTCAGGAA AATGAAAGATTGAAGCAAGAGATCCTTGAAAAGAGCAATCGGATAGAAGAACAGAATG ACAAGATTAGTGAACTAATTGAACGAAATCAGAGGTATGTTGAGCAGAGTAACCTGAT GATGGAGAAGAGGAACAACTCACTTCAGACAGCCACAGAAAACACACAGGCAAGAGTA TTGCATGCTGAACAAGAGAAGGCCAAGGTGACAGAGGAGTTAGCAGCGGCCACTGCGC AGGTCTCTCATCTGCAGCTGAAAATGACTGCTCACCAAAAAAAGGAAACAGAGCTGCA GATGCAGCTGACAGAAAGCCTGAAGGAGACAGATCTTCTCAGGGGCCAGCTCACCAAA GTGCAGGCAAAGCTCTCAGAGCTCCAAGAAACCTCTGAGCAAGCACAGTCCAAATTCA AAAGTGAAAAGCAGAACCGGAAACAACTGGAACTCAAGGTGACATCCCTGGAGGAGGA ACTGACTGACCTTCGAGTTGAGAAGGAGTCCTTGGAAAAGAACCTCTCAGAAAGGAAA AAGAAGTCAGCTCAAGAGCGTTCTCAGGCCGAGGAGGAGATAGATGAAATTCGCAAGT CATACCAGGAGGAATTGGACAAACTTCGACAGCTCTTGAAAΆAGACTCGΆGTGTCCAC AGACCAAGCAGCTGCAGAGCAGCTGTCTTTAGTACAGGCTGAGCTACAGACCCAGTGG GAAGCAAAATGTGAACATTTGTTGGCCTCCGCCAAGGATGAGCACCTGCAGCAGTACC AGGAGGTGTGCGCACAGAGAGATGCCTACCAGCAGAAGCTGGTACAACTTCAGGAAAA GTGTTTAGCCCTCCAGGCCCAAATCACAGCTCTCACCAAGCAAAATGAACAGCACATC AAGGAACTAGAGΆAGAACAAGTCCCAGATGTCTGGGGTTGAAGCTGCTGCATCTGACC CCTCAGAGAAGGTCAAGAAGATCATGAACCAGGTGTTCCAGTCCTTACGGAGAGAGTT TGAGCTGGAGGAATCTTACAATGGCAGGACCATTCTGGGAACCATCATGAATACGATC AAGATGGTGACTCTTCAGCTGTTAAACCAACAGGAGCAAGAGAAGGAAGAGAGCAGCA GTGAAGAAGAAGΆAGAAAAAGCAGAAGAGCGGCCACGAAGACCTTCCCAGGAGCAGTC AGCCTCAGCCAGTTCTGGGCAGCCTCAAGCACCCCTGAATAGGGAGAGGCCAGAGTCC CCCATGGTGCCCTCAGAGCAGGTGGTCGAGGAAGCTGTCCCGTTGCCTCCTCAGGCCC TCACCACTTCCCAGGATGGACACAGAAGGAAAGGGGACTCAGAAGCTGAGGCACTCTC AGAGATAAAAGATGGTTCCCTTCCACCCGAACTGTCTTGCATCCCATCCCACAGAGTT CTAGGGCCCCCGACTTCAATTCCACCTGAGCCCCTAGGCCCTGTATCCATGGACTCTG AGTGTGAGGAGTCACTTGCTGCCAGCCCAATGGCAGCTAAGCCCGACAACCCATCAGG AAAGGTCTGTGTCAGGGAAGTAGCACCAGATGGCCCACTACAAGAAAGCTCCACAAGA CTGTCCCTGACTTCAGACCCCGAGGAGGGGGACCCACTGGCCTTAGGGCCTGAAAGCC CAGGAGAGCCTCAGCCTCCACAGCTCAAGAAAGATGATGTCACTAGCTCCACCGGTCC CCACAAGGAGCTGTCAAGCACAGAGGCAGGTTCCACAGTTGCAGGAGCAGCCCTCAGA CCCAGCCATCATTCCCAGCGTTCCAGTCTCTCTGGGGATGAAGAGGATGAACTGTTTA AAGGGGCAACTCTGAAAGCTCTGAGGCCCAAAGCACAGCCTGAGGAGGAGGATGAAGA CGAGGTGAGCATGAAGGGACGCCCGCCCCCAACGCCCCTTTTTGGAGATGATGATGAT GACGATGACATTGACTGGCTGGGATGAAGACCCAGGAAACTGGTGCAAAGGTTTCTCT

GCAACCCTTCCCTAAGCATGATTTTGCACAGCCAACCCTGGGTCTAGGCGAGCCACAG

GGTGAGGTCAAGGTGAGCATTCTGGGAACAATATTTGGGCTCAGAGGGTGGGTTGGCC

ACCTTCTGAGCCCCACCCCCGCCAGACCTGGTGAAGAGGATCATAACCCTGTCTTCAA

GAACACTGGGATTTCAGCAGCAAGTTGGAAGAAGGACTGGTAGGTTCCCCTCCAAGCC

AGTCACCTGTAAGAGTCCTGTCCTCTGCCAGACTTTTTAATCTCTTCATTAACTCTCA

GACTGACCTGGGAGCCCTCCTCTACCTGAATCCAGTGCTCAACTGTGCCCCGGCAACA

AGACCTGGGCTGAGGTCTCCCTGGTAGAACTAAGGGAGATTACACCATCTAAATCCCA

GTGCAGTCAACAGCCTGGCCTATAGTCCTGGGACATGTATCTTCTTCTTTGCCTTAAA

TCTGATACAAGAGGTCAATGACTTTGAAAATAAAACTAAAATAAATGTCTATAATGAA

ACTTG

ORF Start: ATG at 6 ORF Stop: TGA at 3621

SEQ ID NO: 182 1205 aa MW at l32270.0kD

NOV54a, MFDGARLASLFGLDQAAAGHGNEFFQYTAPKQPKKGQGTAATGNQATPKTAPATMSTP CGI 08462-01 ILVATAVHAYRYTNGQYVKQG FGAAVLGNHTAREYRILLYISQQQPVTVARIHVWF ELMVRP NYSTFYDDQRQNWSIMFESEKAAVEFN QVCIAKCNSTSSLDAVLSQDLIV Protein Sequence ADGPAVEVGDSLEVAYTGWLFQNHVLGQVFDSTANKD LLRLKLGSGKVI GWEDGML

GMKKGGKRLLIVPPACAVGSEGVIG TQATDSILVFEVEVRRVKFARDSGSDGHSVSS

RDSAAPSPIPGADNLSADPWSPPTSIPFKSGEPALRTKSNSLSEQLAINTSPDAVKA

KLISRMAKMGQPMLPILPPQLDSNDSEIΞDV TLQGGGQPWTPSVQPSLQPAHPALP

QMTSQAPQPSVTGLQAPSAALMQVSSLDSHSAVSGNAQSFQPYAGMQAYAYPQASAVT

SQLQPVRPLYPAPLSQPPHFQGSGDMASFLMTEARQHNTEIRMAVSKVADKMDHLMTK

VΞELQKHSAGNSMLIPSMSVTMETSMIMSNIQRIIQΞNERLKQEILΞ SNRIEEQNDK

ISELIERNQRYVEQSNLM^EKRN SLQTATENTQARVLHAEQEKAKVTEELAAATAQV

SHLQLK TAHQKKETELQMQLTESLKETDLLRGQLTKVQAKLSΞLQETSEQAQSKF S

EKQNRKQLELKVTSLΞEELTDLRVEKESLE NLSERK KSAQERSQAEEEIDEIRKSY

QEELDKLRQLLKKTRVSTDQAAAEQLSLVQAELQTQWEA CEHLLASAKDEHLQQYQE

JVCAQRDAYQQKLVQLQEKCLALQAQITALTKQNEQHIKELEKNKSQMSGVEAAASDPS

JE VKKIMNQVFQSLRREFELEESYNGRTILGTIMNTIKMVTLQLLNQQEQE EESSSE

JEΞΞEKAEERPRRPSQEQSASASSGQPQAPLNRERPESP VPSEQΛ/EEAVPLPPQALT

STSQDGHRRKGDSEAEALSEIKDGSLPPELSCIPSHRVLGPPTSIPPEPLGPVSMDSEC

IEESLAASP AAKPDNPSGKVCVREVAPDGPLQESSTRLSLTSDPEEGDPLALGPESPG

EPQPPQLKKDDVTSSTGPHKELSSTEAGSTVAGAALRPSHHSQRSSLSGDEEDELFKG

ATLKALRPKAQPEEEDEDEVSMKGRPPPTPLFGDDDDDDDID LG

Further analysis of the NOV54a protein yielded the following properties shown in Table 54B.

Table 54B. Protein Sequence Properties NOV54a

PSort 0.7000 probability located in nucleus; 0.3000 probability located in microbody analysis: (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV54a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 54C.

In a BLAST search of public sequence databases, the NOV54a protein was found to have homology to the proteins shown in the BLASTP data in Table 54D.

PFam analysis indicates that the NOV54a protein contains the domains shown in the Table 54E.

Example 55.

The NOV55 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 55 A.

Table 55A. NOV55 Sequence Analysis

SEQ ID NO: 182 11821 bp

NOV55a, GTGGGATGGATAGCAGGGTCTCAGGCACAACCAGTAATGGAGAGACAAAACCAGTGTA

CG108723-01 DNA TCCAGTCATGGAAAAGAAGGAGGAAGATGGCACCCTGGAGCGGGGGCACTGGAACAAC

AAGATGGAGTTTGTGCTGTCAGTGGCTGGGGAGATCATTGGCTTAGGCAACGTCTGGA Sequence GGTTTCCCTATCTCTGCTACAAAAATGGGGGAGGTGCCTTCTTCATCCCCTACCTCGT

CTTCCTCTTTACCTGTGGCATTCCTGTCTTCCTTCTGGAGACAGCACTAGGCCAGTAC

ACTAGCCAGGGAGGCGTCACAGCCTGGAGGAAGATCTGCCCCATCTTTGAGGGCATTG

GCTATGCCTCCCAGATGATCGTCATCCTCCTCAACGTCTACTACATCATTGTGTTGGC

CTGGGCCCTGTTCTACCTCTTCAGCAGCTTCACCATCGACCTGCCCTGGGGCGGCTGC

TACCATGAGTGGAACACAGAACACTGTATGGAGTTCCAGAAGACCAACGGCTCCCTGA

ATGGTACCTCTGAGAATGCCACCTCTCCTGTCATCGAGTTCTGGGAGCGGCGGGTCTT

GAAGATCTCTGATGGGATCCAGCACCTGGGGGCCCTGCGCTGGGAGCTGGCTCTGTGC

CTCCTGCTGGCCTGGGTCATCTGCTACTTCTGCATCTGGAAGGGGGTGAAGTCCACAG

GCAAGGTGGTGTACTTCACGGCCACATTTCCTTACCTCATGCTGGTGGTCCTGTTAAT

TCGAGGGGTGACGTTGCCTGGGGCAGCCCAAGGAATTCAGTTTTACCTGTACCCAAAC

CTCACGCGTCTGTGGGATCCCCAGGTGTGGATGGATGCAGGCACCCAGATATTCTTCT

CCTTCGCCATCTGTCTTGGGTGCCTGACAGCCCTGGGCAGCTACAACAAGTACCACAA

CAACTGCTACAGGGACTGCATCGCCCTCTGCTTCCTCAACAGCGGCACCAGCTTTGTG

JGCCGGCTTTGCCATCTTCTCCATCCTGGGCTTCATGTCTCAGGAGCAGGGGGTGCCCA

_JTTTCTGAGGTGGCCGAGTCAGGCCCTGGCCTGGCTTTCATCGCTTACCCGCGGGCTGT

JGGTGATGCTGCCCTTCTCTCCTCTCTGGGCCTGCTGTTTCTTCTTCATGGTCGTTCTC

JCTGGGACTGGATAGCCAGTTTGTGTGTGTAGAAAGCCTGGTGACAGCGCTGGTGGACA

!TGTACCCTCACGTGTTCCGCAAGAAGAACCGGAGGGAAGTCCTCATCCTTGGAGTATC

JTGTCGTCTCCTTCCTTGTGGGGCTGATCATGCTCACAGAGGGCGGAATGTACGTGTTC

[CAGCTCTTTGACTACTATGCAGCCAGTGGCATGTGCCTCCTGTTCGTGGCCATCTTCG

JAGTCCCTCTGTGTGGCTTGGGTTTACGGAGCCAAGCGCTTCTACGACAACATCGAAGA

;CATGATTGGGTACAGGCCATGGCCTCTTATCAAATACTGTTGGCTCTTCCTCACACCA

JGCTGTGTGCACAGCCACCTTTCTCTTCTCCCTGATAAAGTACACTCCGCTGACCTACA

IACAAGAAGTACACGTACCCGTGGTGGGGCGATGCCCTGGGCTGGCTCCTGGCTCTGTC

^'CTCCATGGTCTGCATTCCTGCCTGGAGCCTCTACAGACTCGGAACCCTCAAGGGCCCC

TTCAGAGAGAGAATCCGTCAGCTCATGTGCCCAGCCGAGGACCTGCCCCAGCGGAACC

CAGCAGGACCCTCGGCTCCCGCCACCCCCAGGACCTCACTGCTCAGACTCACAGAGCT

AGAGTCTCACTGCTAGGGGGCAG

ORF Start: ATG at 6 ORF Stop: TAG at 1812

SEQ ID NO: 184 602 aa MW at 68008.0kD

NOV55a, MDSRVSGTTSNGETKP\r_^"PVME KEEDGTLERGHWNNK EFVLSVAGEIIGLGNVWRF CG108723-01 PYLCYKNGGGAFFIPYLVFLFTCGIPVFLLΞTALGQYTSQGGVTAWRKICPIFEGIGY ASQMIVILL VYYIIVLAWALFYLFSSFTIDLPWGGCYHEWNTEHC EFQKTNGSLNG Protein Sequence TSENATSPVIEF ERRVLKISDGIQHLGALR ELALCLLLA VICYFCI KGVKSTGK WYFTATFPYLMLWLLIRGVTLPGAAQGIQFYLYPNLTRLWDPQVWMDAGTQIFFSF AICLGCLTALGSYN YHNNCYRDCIALCFLNSGTSFVAGFAIFSILGFMSQEQGVPIS EVAESGPGLAFIAYPRAλA7MLPFSPLWACCFFFMWLLGLDSQFVCVESLVTALλtDMY PHVFRKKNRREVLILGVSWSFLVGLIMLTEGGMYVFQLFDYYAASGMCLLFVAIFES LCVAWVYGAKRFYDNIEDMIGYRPWPLIKYCWLFLTPAVCTATFLFSLI YTPLTYNK KYTYP WGDALG LLALSSMVCIPA SLYRLGTLKGPFRERIRQLMCPAEDLPQRNPA GPΞAPATPRTSLLRLTELESHC SEQ ID NO: 185 (2092 bp

NOV55b, GTGTGCTGGAATCGCCCTTGTGGGATGGATAGCAGGGTCTCAGGCACAACCAGTAATG

:CG108723-02 DNA GAGAGACAAAACCAGTGTATCCAGTCATGGAAAAGAAGGAGGAAGATGGCACCCCTGG AGCGGGGGCACTGGAACAACAAGATGGAGTTTGTGCTGTCAGTGGCTGGGGAGATCAT ! Sequence TGGCTTAGGCAACGTCTGGAGGTTTCCCTATCTCTGCTACAAAAATGGGGGAGGTGCC TTCTTCATCCCCTACCTCGTCTTCCTCTTTACCTGTGGCATTCCTGTCTTCCTTCTGG AGACAGCACTAGGCCAGTACACTAGCCAGGGAGGCGTCACAGCCTGGAGGAAGATCTG CCCCATCTTTGAGGGCATTGGCTATGCCTCCCAGATGATCGTCATCCTCCTCAACGTC TACTACATCATTGTGTTGGCCTGGGCCCTGTTCTACCTCTTCAGCAGCTTCACCATCG ACCTGCCCTGGGGCGGCTGCTACCATGAGTGGAACACAGAACACTGTATGGAGTTCCA GAAGACCAACGGCTCCCTGAATGGTACCTCTGAGAATGCCACCTCTCCTGTCATCGAG TTCTGGGAGCGGCGGGTCTTGAAGATCTCTGATGGGATCCAGCACCTGGGGGCCCTGC GCTGGGAGCTGGCTCTGTGCCTCCTGCTGGCCTGGGTCATCTGCTACTTCTGCATCTG GAAGGGGGTGAAGTCCACAGGCAAGGTGGTGTACTTCACGGCCACATTTCCTTACCTC ATGCTGGTGGTCCTGTTAATTCGAGGGGTGACGTTGCCTGGGGCAGCCCAAGGAATTC AGTTTTACCTGTACCCAAACCTCACGCGTCTGTGGGATCCCCAGGTGTGGATGGATGC AGGCACCCAGATATTCTTCTCCTTCGCCATCTGTCTTGGGTGCCTGACAGCCCTGGGC AGCTACAACAAGTACCACAACAACTGCTACAGGGACTGCATCGCCCTCTGCTTCCTCA ACAGCGGCACCAGCTTTGTGGCCGGCTTTGCCATCTTCTCCATCCTGGGCTTCATGTC TCAGGAGCAGGGGGTGCCCATTTCTGAGGTGGCCGAGTCAGGCCCTGGCCTGGCTTTC ATCGCTTACCCGCGGGCTGTGGTGATGCTGCCCTTCTCTCCTCTCTGGGCCTGCTGTT TCTTCTTCATGGTCGTTCTCCTGGGACTGGATAGCCAGTTTGTGTGTGTAGAAAGCCT GGTGACAGCGCTGGTGGACATGTACCCTCACGTGTTCCGCAAGAAGAACCGGAGGGAA GTCCTCATCCTTGGAGTATCTGTCGTCTCCTTCCTTGTGGGGCTGATCATGCTCACAG AGGGCGGAATGTACGTGTTCCAGCTCTTTGACTACTATGCAGCCAGTGGCATGTGCCT CCTGTTCGTGGCCATCTTCGAGTCCCTCTGTGTGGCTTGGGTTTACGGAGCCAAGCGC TTCTACGACAACATCGAAGACATGATTGGGTACAGGCCATGGCCTCTTATCAAATACT GTTGGCTCTTCCTCACACCAGCTGTGTGCACAGCCACCTTTCTCTTCTCCCTGATAAA GTACACTCCGCTGACCTACAACAAGAAGTACACGTACCCGTGGTGGGGCGATGCCCTG GGCTGGCTCCTGGCTCTGTCCTCCATGGTCTGCATTCCTGCCTGGAGCCTCTACAGAC TCGGAACCCTCAAGGGCCCCTTCAGAGAGAGAATCCGTCAGCTCATGTGCCCAGCCGA GGACCTGCCCCAGCGGAACCCAGCAGGACCCTCGGCTCCCGCCACCCCCAGGACCTCA CTGCTCAGACTCACAGAGCTAGAGTCTCACTGCTAGGGGGCAGGCCCTTGGATGGTGC

CTGTGTGCCTGGCCTTGGGGATGGCTGTGGAGGGAACGTGGCAGAAGCAGCCCCATGT

GCTTCCCTGCCCCCGACCTGGAGTGGATAAGACAAGAGGGGTATTTTGGAGTCCACCT

GCTGAGCTGGAGGCCTCCCACTGCAACTTTTCAGCTCAGGGGTTGTTGAACAGATGTG

AAAGGCCAGTGCCAAGAGTGTCCCTCTGAGACCCTTGGGAAGCTGGGTGGAGGCTCCA

TGCG

ORF Start: ATG at 56 ORF Stop: TAG at 1832

SEQ ID NO: 186 592 aa MW at 67281.5kD

NOV55b, MERQNQCIQSWKRRRKMAPLERGH NNKMEFVLSVAGEIIGLGNV RFPYLCYKNGGG CG108723-02 AFFIPYLVFLFTCGIPVFLLETALGQYTSQGGVTA RKICPIFEGIGYASQMIVILLN VYYIIVLA ALFYLFSSFTIDLP GGCYHEW TEHCMEFQKTNGSLNGTSΞNATSPVI Protein Sequence EFWERRVLKISDGIQHLGALRWELALCLLLAWVICYFCI KGVKSTGKWYFTATFPY LMLWLLIRGVTLPGAAQGIQFYLYPNLTRLWDPQVWMDAGTQIFFSFAICLGCLTAL GSYNKYHNNCYRDCIALCFLNSGTSFVAGFAIFSILGFMSQEQGVPISEVAESGPGLA FIAYPRAWMLPFSPLWACCFFFMWLLGLDSQFVCVESLVTALVDMYPHVFR KNRR EVLILGVSWSFLVGLIMLTEGGMYVFQLFDYYAASGMCLLFVAIFES CVAWVYGAK RFYDNIED IGYRP PLIKYCWLFLTPAVCTATFLFSLIKYTPLTYNKKYTYP GDA LGWLLALSSMVCIPA SLYRLGTLKGPFRERIRQLMCPAEDLPQRNPAGPSAPATPRT SLLRLTELESHC

SEQ ID NO: 187 1799 bp

NOV55c, GTGGGATGGATAGCAGGGTCTCAGGCACAACCAGTAATGGAGAGACAAAACCAGTGTA

CGI 08723-03 DNA TCCAGTCATGGAAAAGAAGGAGGAAGATGGCACCCTGGAGCGGGGGCACTGGAACAAC AAGATGGAGTTTGTGCTGTCAGTGGCTGGGGAGATCATTGGCTTAGGCAACGTCTGGA

Sequence GGTTTCCCTATCTCTGCTACAAAAATGGGGGAGGTGCCTTCTTCATCCCCTACCTCGT CTTCCTCTTTACCTGTGGCATTCCTGTCTTCCTTCTGGAGACAGCACTAGGCCAGTAC ACTAGCCAGGGAGGCGTCACAGCCTGGAGGAAGATCTGCCCCATCTTTGAGGGCATTG iGCTATGCCTCCCAGATGATCGTCATCCTCCTCAACGTCTACTACATCATTGTGTTGGC ⁱCTGGGCCCTGTTCTACCTCTTCAGCAGCTTCACCATCGACCTGCCCTGGGGCGGCTGC TACCATGAGTGGAACACAGAACACTGTATGGAGTTCCAGAAGACCAACGGCTCCCTGA

ATGGTACCTCTGAGAATGCCACCTCTCCTGTCATCGAGTTCTGGGAGCGGCGGGTCTT

GAAGATCTCTGATGGGATCCAGCACCTGGGGGCCCTGCGCTGGGAGCTGGCTCTGTGci

CTCCTGCTGGCCTGGGTCATCTGCTACTTCTGCATCTGGAAOGGGGTGAAGTCCACAGj

GCAAGGTGGTGTACTTCACGGCCACATTTCCTTACCTCATGCTGGTGGTCCTGTTAAT

TCGAGGGGTGACGTTGCCTGGGGCAGCCCAAGGAATTCAGTTTTACCTGTACCCAAAcl

CTCACGCGTCTGTGGGATCCCCA.GGTGTGGATGGATGCAGGCACCCAGATATTCTTCT

CCTTCGCCATCTGTCTTGGGTGCCTGACAGCCCTGGGCAGCTACAACAAGTACCACAA

CAACTGCTACAGGGACTGCATCGCCCTCTGCTTCCTCAACAGCGGCACCAGCTTTGTG

GCCGGCTTTGCCATCTTCTCCATCCTGGGCTTCATGTCTCAGGAGCAGGGGGTGCCCA

TTTCTGAGGTGGCCGAGTCAGGCCCTGGCCTGGCTTTCATCGCTTACCCGCGGGCTGT

GGTGATGCTGCCCTTCTCTCCTCTCTGGGCCTGCTGTTTCTTCTTCATGGTCGTTCTCJ

CTGGGACTGGATAGCCAGTTTGTGTGTGTAGAAAGCCTGGTGACAGCGCTGGTGGACA

TGTACCCTCACGTGTTCCGCAAGAAGAACCGGAGGGAAGTCCTCATCCTTGGAGTATC

TGTCGTCTCCTTCCTTGTGGGGCTGATCATGCTCACAGAGGGCGGAATGTACGTGTTC

CAGCTCTTTGACTACTATGCAGCCAGTGGCATGTGCCTCCTGTTCGTGGCCATCTTCG

AGTCCCTCTGTGTGGCTTGGGTTTACGGAGCCAAGCGCTTCTACGACAACATCGAAGA

CATGATTGGGTACAGGCCATGGCCTCTTATCAAATACTGTTGGCTCTTCCTCACACCA

GCTGTGTGCACATACACTCCGCTGACCTACAACAAGAAGTACACGTACCCGTGGTGGG

GCGATGCCCTGGGCTGGCTCCTGGCTCTGTCCTCCATGGTCTGCATTCCTGCCTGGAG

CCTCTACAGACTCGGAACCCTCAAGGGCCCCTTCAGAGAGAGAATCCGTCAGCTCATG

TGCCCAGCCGAGGACCTGCCCCAGCGGAACCCAGCAGGACCCTCGGCTCCCGCCACCC

CCAGGACCTCACTGCTCAGACTCACAGAGCTAGAGTCTCACTGCTAGGGGGCAGGCTA

G

ORF Start: ATG at 6 ORF Stop: TAG at 1785

ISEQ ID NO: 188 1593 aa MW at 66986.8kD

NOV55c, MDSRVSGTTSNGETKPλT_-pλ MEKKEEDGTLERGHWIvTNKMEFVLSVAGEIIGLGNλ RF ;CG108723-03 PYLCYKNGGGAFFIPYLVFLFTCGIPVFLLETALGQYTSQGGVTA RKICPIFEGIGY ^: Protein Sequence ASQMIVILLKTVYYIIVLAWALFYLFSSFTIDLP GGCYHEWNTEHCMΞFQKTNGSLNG TSENATSPVIEF ERRVL ISDGIQHLGALRWELALCLLLAWVICYFCI KGVKSTGK WYFTATFPYLMLWLLIRGVTLPGAAQGIQFYLYPNLTRLWDPQVWMDAGTQIFFSF AICLGCLTALGSYNKYHNNCYRDCIALCFLNSGTSFVAGFAIFSILGFMSQEQGVPIS EVAESGPGLAFIAYPRAλATMLPFSPLWACCFFFMWLLGLDSQFVCVESLVTALλTDMY PHVFRK NRREVLILGVSWSFLVGLIMLTEGGMYVFQLFDYYAASGMCLLFVAIFΞS LCVA VYGAKRFYDNIEDMIGYRP PLIKYC LFLTPAVCTYTPLTYNKKYTYP GD ALG LLALSSMVCIPA SLYRLGTLKGPFRERIRQLMCPAEDLPQRNPAGPΞAPATPR TSLLRLTELESHC

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 55B.

Further analysis of the NOV55a protein yielded the following properties shown in Table 55C. Table SSC. Protein Sequence Properties NOV55a

\ PSort 0.8000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane): 0.0300 probability located in mitochondrial inner membrane

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV55a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 55D.

In a BLAST search of public sequence databases, the NOV55a protein was found to have homology to the proteins shown in the BLASTP data in Table 55E.

■ (Human).602 aa.

CAD10548 ! SEQUENCE 1 FROM PATENT 1..602 589/602 (97%) 0.0 | WO0177321 - Homo sapiens 1..602 594/602 (97%) J (Human\ 602 aa.

P31649 1 Sodium- and chloride-dependent 1..602 548/602 (91%) 0.0 ! GABA transporter 3 (GAT3) - Mus 1..602 574/602 (95%) • musculus (Mouse), 602 aa.

P31646 j Sodium- and chloride-dependent 1..602 551/602(91%) 0.0 GABA transporter 2 - Rattus 1..602 574/602 (94%) j norvegicus (Rat), 602 aa.

Q9NSD5 ¹ Sodium- and chloride-dependent 1..554 514/554(92%) 0.0 J GABA transporter 2 - Homo 1..520 516/554(92%) ' sapiens (Human), 569 aa.

PFam analysis indicates that the NOV55a protein contains the domains shown in the Table 55F.

Table 55F. Domain Analysis of NOVSSa

Identities/

Pfam Domain j NOVSSa Match Region Similarities Expect Value for the Matched Region

SNF 52-570 345/625 (55%) 522/625 (84%)

Example 56.

The NOV56 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 56 A.

jGAGGGCCCACACCCAGCCTCAGCCACAGGGACGCCTCCAAGGAACTGTTCAGAGTTGA ⁽AGAGGACTTGGACCAGATTCTGAACCTGGGAGCTGAGCCCAAAGCCAAGCCCCAGCTT AAGCCCAAGCCACCAGTGGCAGCTAAGCCGGTGATACCCAGAAAACCAGCTGTTCCCC CCAAAGCGGGCCCGGCTGAAGCTGTGGCTGGGCAGCAGAAGCCGCAGGAGCAGATCCA AGCCATGGACGAGATGGACATCTTGCAGTACATCCAGGACCACGATACACCAGCCCAG GCCGCCCCCAGCCTCTTCTGACCCTTCCATGCTGGCCCCTGGCCCAGCAGGCCTGTCT GT

ORF Start: ATG at 61 ORF Stop: TGA at 1237

SEQ ID NO: 190 392 aa |MW at 42785.8kD

NOV56a, MQSPAVLVTSRRLQNAHTGLDLTVPQHQEVRGKMMSGHVEYQILWTRLAAFKSAKHR CG108870-01 PEDWQFLVSKKYSEIEEFYQKLSSRYAAASLPPLPRKVLFVGESDIRERRAVFNEIL RCVS DAELAGSPELLEFLGTRSPGAAGLTSRDSSVLDGTDSQTGNDEEAFDFFEΞQD Protem Sequence QVAEEGPPVQSLKGEDAEESLEEEEALDPLGIMRSKKPKKHPKVAVKAKPSPRLTIFD EΞVDPDEGLFGPGRKLSPQDPSEDVSSMDPLKLFDDPDLGGAIPLGDSLLLPAACESG GPTPSLSHRDASKELFRVEEDLDQILNLGAΞPKAKPQLKP PPVAAKPVIPRKPAVPP KAGPAEAVAGQQKPQEQIQAMDEMDILQYIQDHDTPAQAAPSLF

Further analysis of the NOV56a protein yielded the following properties shown in Table 56B.

Table 56B. Protein Sequence Properties NOV56a

! PSort 0.6000 probability located in nucleus; 0.4532 probability located in j analysis: mitochondrial matrix space; 0.1457 probability located in mitochondrial inner membrane; 0.1457 probability located in mitochondrial intermembrane space signalP No Known Signal Sequence Indicated ! analysis:

A search of the NOV56a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 56C.

AAU 17426 Novel signal transduction pathway 27-170 1 18/144 (81%) 5e-57 protein, Seq ID 991 - Homo sapiens, 1..144 1 19/144 (81%) 144 aa. [WO200154733-A1 , 02- AUG-2001]

AAW77094 j Sorting nexin 1 - Homo sapiens, 522 21..178 50/182 (27%) 2e-06 aa. [US5804412-A, 08-SEP-1998] 144-317 78/182 (42%)

In a BLAST search of public sequence databases, the NOV56a protein was found to have homology to the proteins shown in the BLASTP data in Table 56D.

PFam analysis indicates that the NOV56a protein contains the domains shown in the Table 56E.

Example 57.

The NOV57 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 57 A.

Further analysis of the NOV57a protein yielded the following properties shown in Table 57B.

Table 57B. Protein Sequence Properties NO 57a

PSort 0.6438 probability located in microbody (peroxisome); 0.1000 probability ! analysis: located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV57a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 57C.

In a BLAST search of public sequence databases, the NOV57a protein was found to have homology to the proteins shown in the BLASTP data in Table 57D.

PFam analysis indicates that the NOV57a protein contains the domains shown in the Table 57E.

j Identities/ j

Pfam Domain NOV57a Match Region j Similarities j Expect Value j for the Matched Region j

Euk_porin 17..297 133/290 (46%) 7.2e-117 238/290 (82%)

Example 58.

The N0V58 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 58A.

Table 58A. NOV58 Sequence Analysis

SEQ ID NO: 193 1604 bp

;NOV58a, AGTGATGGGGTCTCAGGCCTCCACCTTACTGCACGATGAAGAGTTTGAGGAGATCAAG

JCG109514-01 DNA AAGGAGACTGGCTTTTCCCACAGTCAAATCACACGTCTGTACAGCCGGTTCAGCAACC TGGACAAAGGAGAGAACAGGACGATTTCCAGGGACGATTTCCAGGGGATTCCAGAACT . Sequence TGCCATCAACCCAGTGGGGGACTGGATCATCAATGCCTTCCTTCCAGAGGGΆGAGGAC CAGGTAAACTTCCGTGGATTCCTGCAAACTCTGGCTCATTTCCAAACCATTGAGGATA ATGAAAAGAGCAAAGTTGTGAATGGACCTGAACCACTCAACAGCCGAAGCAACAAΆCT GCAGTTTGCTTTTCGACTATATGATTTGGATAAAGATAACAAGATCTCTCGTGATGAG CTGTTAAGGGTGCTGTGCATGATGGTCCAAATAAATATCTCAGATAAGCAGCTGGGCA GTATCGCAGACAGGACCATTCAGGAGGCTGATCAGCATGGGGACAGTGCCATATCTTT TATCACAGACTTTGCTAAGGTTTTGGAGAAGGTGGATGTAGAACAGAAAATGAGCATC TGATTTCTTCACTAAAGGACAGAC

IORF Start: ATG at 5 IORF Stop: TGA at 581 iSEQ ID NO: 194 I 92 aa MW at 21912.3kD jNOV58a, jMGSQASTLLHDEΞFEEIKKETGFSHSQITRLYSRFSNLDKGΞNRTISRDDFQGIPΞLA JCG109514-01 JINPVGDWIINAFLPEGEDQ FRGFLQTLAHFQTIEDNEKSKWNGPEPLNSRSNKLQ JFAFRLYDLDKDNKISRDELLRVLCMMVQINISDKQLGSIADRTIQEADQHGDSAISFI •Protein Sequence jTDFAKVLΞKVDVEQKMSI

Further analysis of the NOV58a protein yielded the following properties shown in Table 58B.

I Table 58B. Protein Sequence Properties NOV58a

PSort 0.6500 probability located in cytoplasm; 0.1000 probability located in analysis: : mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.1000 probability located in plasma membrane

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV58a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 58C.

Table 58C. Geneseq Results for NOV58a

In a BLAST search of public sequence databases, the NOV58a protein was found to have homology to the proteins shown in the BLASTP data in Table 58D.

PFam analysis indicates that the NOV58a protein contains the domains shown in the Table 58E.

Table 58E. Domain Analysis of NOVSSa

Identities/

Pfam Domain NOV58a Match Region Similarities Expect Value

¹ for the Matched Region i efliand 114..142 11/29 (38%) 6.9e-05 25/29 (86%)

Example 59.

The NOV59 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 59A.

Table S9A. NOV59 Sequence Analysis

(SEQ ID NO: 195 1138 bp ιNOV59a ΆTGACTAGATCCAGAACACTAACGACACCAAATGCTGGCGAAGACATGGAGCAACAGG

' CG I 09594-01 DNA j ACTTCCACTCATTAATGCTGCAAAGACTGACACCGAGTCTGCAATAAGGCACCCAGG

AGCTCAACTGACCGCTGATGGCAAGCTGATTATACAGGACCCCTTCTGTCCTGAAAAG

.Sequence GACAATTCATACTTACTGAAATGGACACACATTCTGTATGTGGATTACCTTTCCGGCT TCCTGCACCTCAGCAAGCACGACAATCCAACGACTTACACAATGTCTAATCTACATAT GACTGTGCATAACAGCAACTTAGAAACCCTGCGGCTCTCTTCAAGTGGGGGGTATCCA CGTGTGACCCATCGAGCAATGGTTTTCCATCTTTTTCAAACTCTTTTTGAGAATCTGA TTAAAGCTATAGACCTGAGCTCTCTGCCTCAGGGGAACCAGCTTCCTGCCACCACTCC TGGGACTCGTCTGCCTCCCCCTGGCTGCATCTTCTGTCCTGAAACTCCAGGTCTGGAA GAGGTGCTCCGCCTGCAGGTCCTGGAGCCCTGCCAGAGGTTTCTGGAGATGCTGGTTG ACCCAGCCTCTTGGGGAAGAGGGGCAGGGCGCCAGTGCCAGCAGACGACAGGGGCACC GGTGCTAGCAGGGAACAGGGCGGGTCTGCTCATTTCCCTCTTCCTGTCAAAGAGGGAC TTTGGCATGAAGGATGTGAAGCTGTTTTCTGGGGAGGCCTCTACCTGCTGGCAGCTCA CAGTGAGGGTCCTGGAGGCGCGGAACCTGCGCTGGGCTGACCTGTTGAGTGAGGCCGA CCCTTACGTGATCCTACAGCTGTCGACCGCACCTGGAATGAAGTTTAAGACCAAGACG CTCACCGACACCAGTCATCCTGTGTGGAATGAGGCCTTCCGTTTCCTTATCCAAAGTC AGGTCAAGAATGTTCTGGAGCTTAGCATCTATGATGAGGACTCAGTCACGGAGGATGA CATCTGCTTCAAGGTTCTCTATGACATCTCAGAAGTCCTCCCTGGCAAGCTGCTCCGG AAAACCTTCTCCCAGAGTCCCCAGGGAGAGGAGGAGCTGGATGTGGAGTTCCTGATGG AAGAAACGTCAGATCGCCCAGAAAACCTCATCACCAACAAAGTCATTGTGGCCCGAGA GCTGTCATGCCTGGATGTGCATCTGGACAGCACAGGGAGCACCGCTGTGGTTGCAGAT CAGGACAAGCTGGAGCTGGAGCTGGTGCTGAAGGGGTCCTATGAGGACACACAGACAT CCTTCCTGGGCACAGCCTCTGCCTTCCGCTTCCACTACATGGCAGCCCTAGAGACAGA GCTGAGCGGGCGCCTGAGGAGCTCCAGAAGCAATGGCTGGAATGGGGACAACTCAGCT GGGTACCTCACTGTGCCCCTGAGGCCCTTGACCATTGGGAAGGAGGTGACTATGGATG TTCCTGCTCCAAATGCCCCAGGAGTGAGGCTGCAGCTCAAGGCAGAGGGCTGCCCTGA GGAGCTGGCCGTGCACCTGGGCTTCAATCTCTGTGCAGAGGAGCAGGCCTTCCTGAGC AGGAGGAAGCAGGTGGTGGCCAAGGCCCTGAAGCAGGCCCTGCAGCTGGACAGAGACC

Further analysis of the NOV59a protein yielded the following properties shown in Table 59B.

_, SignalP j No Known Signal Sequence Indicated I analysis:

A search of the NOV59a protein against the Geneseq database, a proprietary database that contains sequences-published in patents and patent publication, yielded several homologous proteins shown in Table 59C.

In a BLAST search of public sequence databases, the NOV59a protein was found to have homology to the proteins shown in the BLASTP data in Table 59D.

Table 59D. Public BLASTP Results for NOV59a

NOV59a Identities/

Protein Residues/ Similarities for Expect

Accession Protein/Organism/Length

Match the Matched Value

Number Residues Portion

095712 CYTOSOLIC PHOSPHOLIPASE A2 244-1034 403/795 (50%) 0.0 BETA - Homo sapiens (Human), 1012 236..1006 531/795 (66%) aa. Q9UKV7 CYTOSOLIC PHOSPHOLIPASE A2 244..1034 i 402/795 (50%) 0.0 BETA - Homo sapiens (Human), 1012 236-1006 530/795 (66%) aa.

Q9TT38 PHOSPHATIDYL CHOLINE 2- 461 -1034 180/624 (28%) 7e-68 ACYLHYDROLASE CPLA2 - 99..718 315/624 (49%) Oryctolagus cuniculus (Rabbit), 748 aa.

P47712 ] Cytosolic phospholipase A2 (CPLA2) 461-1034 183/627 (29%) 2e-67 [Includes: Phospholipase A2 (EC 99-719 310/627 (49%) 3.1.1.4) (Phosphatidylcholine 2- acylhydrolase); Lysophospholipase (EC 3.1.1.5)] - Homo sapiens (Human), 749 aa.

P50392 Cytosolic phospholipase A2 (CPLA2) 461 -1031 179/616 (29%) le-66 [Includes: Phospholipase A2 (EC 93..705 296/616 (47%) 3.1.1.4) (Phosphatidylcholine 2- acylhydrolase); Lysophospholipase (EC 3.1.1.5)] - Brachydanio rerio (Zebrafish) (Zebra danio), 741 aa.

PFam analysis indicates that the NOV59a protein contains the domains shown in the Table 59E.

Example 60.

The NOV60 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 60A.

Table 60A. NOV60 Sequence Analysis

SEQ ID NO: 197 2096 bp

NOV60a, CACACACGCATGCGGAACATTCATGTTTTCAATTCGAAGTTGCTTGTCAAGATCAGAA

CG109733-01 DNA ACTCTCACAGTTTGTACTTGCATGTGGTCTGTAGAAAAAATTCTGAAGAGTTGCAATC Sequence TCTCCAATAGTGATTGGGATGAGAATTTTGAATTAGTTACAGAATGTTGTGATTTGGT GATGGTCGCTTCTTTAAAAATATAAAATGTTCTTTCCTTTCTAGAAACGGCTTACAAA ATATACAGATCTTGGTAGACAACGTGGCTGCAGGCTGTTGAATTGGAATTCCCTGTGG CTGTCCGAAGGCAGGGTGTCCGGAGAGCGGTGGGCTGACCTGTTCCTACACCTTGCAT jCATGCCAGCTTTGTCAACGGGATCTGGGAGTGACACTGGTCTGTATGAGCTGTTGGCT GCTCTGCCAGCCCAGCTGCAGCCACATGTGGATAGCCAGGAAGACCTGACCTTCCTCT GGGATATGTTTGGTGAAAAAAGCCTGCATTCATTGGTAAAGATTCATGAAAAACTACA CTACTATGAGAAGCAGAGTCCGGTGCCCATTCTCCATGGTGCGGCGGCCTTGGCCGAT GATCTGGCCGAAGAGCTTCAGAACAAGCCATTAAACAGTGAGATCAGAGAGCTGTTGA AACTACTGTCAAAACCCAATGTGAAGGCTTTGCTCTCTGTACATGATACTGTGGCTCA GAAGAATTACGACCCAGTGTTGCCTCCTATGCCTGAAGATATTGACGATGAGGAAGAC TCAGTAAAAATAATCCGTCTGGTCAAAAATAGAGAACCACTGGGAGCTACCATTAAGA AGGATGAACAGACCGGGGCGATCATTGTGGCCAGAATCATGAGAGGAGGAGCTGCAGA TAGAAGTGGTCTTATTCATGTTGGTGATGAACTTAGGGAAGTCAACGGGATACCAGTG GAGGATAAAAGGCCTGAGGAAATAATACAGATTTTGGCTCAGTCTCAGGGAGCAATTA CATTTAAGATTATACCCGGCAGCAAAGAGGAGACACCATCAAAAGAAGGCAAGATGTT TATCAAAGCCCTCTTTGACTATAATCCTAATGAGGATAAGGCAATTCCATGTAAGGAA GCTGGGCTTTCTTTCAAAAAGGGAGATATTCTTCAGATTATGAGCCAAGATGATGCAA CTTGGTGGCAAGCGAAACACGAAGCTGATGCCAACCCCAGGGCAGGCTTGATCCCCTC AAAGCATTTCCAGGAAAGGAGATTGGCTTTGAGACGACCAGAAATATTGGTTCAGCCC CTGAAAGTTTCCAACAGGAAATCATCTGGTTTTAGAAAAAGTTTTCGTCTTAGTAGAA AAGATAAGAAAACAAATAAATCCATGTATGAATGCAAGAAGAGTGATCAGTACGACAC AGCTGACGTACCCACATACGAAGAAGTGACACCGTATCGGCGACAAACTAATGAAAAA TACAGACTCGTTGTCTTGGTTGGTACCACCAGAGCAAGAAGAAGCCAGGAGAGTGATG GTGTTGAATACATTTTCATTTCCAAGCATTTGTTTGAGACAGATGTACAAAATAACAA GTTTATTGAATATGGAGAATATAAAAACAACTACTACGGCACAAGTATAGACTCAGTT CGGTCTGTCCTTGCTAAAAACAAAGTTTGTTTGTTGGATGTTCAGCCTCATACAGTGA AGCATTTAAGGACACTAGAATTTAAGCCCTATGTGATATTTATAAAGCCTCCATCAAT AGAGCGTTTGAGAGAAACAAGAAAAAATGCAAAGATTATTTCAAGCAGAGATGACCAA GGTGCTGCAAAACCCTTCACAGAAGAAGATTTTCAAGAAATGATTAAATCTGCACAGA TAATGGAAAGTCAATATGGTCATCTTTTTGACAAAATTATAATAAATGATGACCTCAC TGTGGCATTCAATGAGCTCAAAACAACTTTTGACAAATTAGAGACAGAGACCCATTGG GTGCCAGTGAGCTGGTTACATTCATAACTAAGAGAAATTTCCATAATTGTCTTTTTCT ATAGAGTGCATGATGAAATCAATTACAGTTTTGGTAGTAGGGTTTTTAAATCTATATC

ACTGTCAT

ORF Start: ATG at 350 ORF Stop: TAA at 1997

SEQ ID NO: 198 549 aa MW at 62569.6kD

NOVόOa, MPALSTGSGSDTGLYELLAALPAQLQPHVDSQEDLTFL DMFGΞKSLHSLVKIHEKLH CG1097 m2 -01 YYEKQSPVPILHGAAALADDLAEELQNKPLNSEIRELLKLLSKPNVKALLSVHDTVAQ .slvYDPVLPPMPEDIDDEEDSVKIIRLVKNREPLGATIKKDEQTGAIIVARIMRGGAAD Protein Sequence RSGLIHVGDELREVNGIPVEDKRPEEIIQILAQSQGAITFKIIPGS EETPSKEGKMF IKALFDYNPNEDKAIPCKEAGLSFKKGDILQIMSQDDAT QAKHEADANPRAGLIPS KHFQΞRRLALRRPΞILVQPLKVSNRKSSGFRKSFRLSRKDKKTNKSMYΞCKKSDQYDT ADVPTYEEVTPYRRQTNEKYRLWLVGTTRARRSQESDGVEYIFISKHLFETDVQNNK FIEYGEYK NYYGTSIDSVRSVLAKNKVCLLDVQPHTVKHLRTLEFKPYVIFIKPPSI ERLRETRKNAKIISSRDDQGAAKPFTEEDFQEMIKSAQIMESQYGHLFDKIIINDDLT VAFNELKTTFDKLETETH VPVS LHS

Further analysis of the NOVόOa protein yielded the following properties shown in Table 60B.

Table 60B. Protein Sequence Properties NOVόOa

SignalP No Known Signal Sequence Indicated analysis: A search of the NOVόOa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 60C.

Table 60C. Geneseq Results for NOVόOa

NOVόOa Identities/

AAE 16270 Human kinase PKIN-16 protein - 1..549 549/576 (95%) 0.0

Homo sapiens, 576 aa. 1..576 549/576 (95%)

[WO200196547- A2, 20-DEC-2001]

AAU0712_ Human novel human protein, NHP 1..549 548/576 (95%) 0.0 i #23 - Homo sapiens, 576 aa. 1..576 549/576 (95%) j [WO200161016-A2, 23-AUG-2001]

AAU07119 Human novel human protein, NHP 1..529 525/556 (94%) 0.0 #19 - Homo sapiens, 560 aa. 1..556 527/556 (94%) [WO200161016-A2, 23-AUG-2001]

AAU07115 i Human novel human protein, NHP 1..491 489/518 (94%) 0.0 #15 - Homo sapiens, 520 aa. 1..518 491/518 (94%) [WO200161016-A2, 23-AUG-2001]

AAU071 1 1 Human novel human protein, NHP 1..445 442/472 (93%) 0.0 #11 - Homo sapiens, 473 aa. 1..472 443/472 (93%) [WO200161016-A2, 23-AUG-2001]

In a BLAST search of public sequence databases, the NOVόOa protein was found to have homology to the proteins shown in the BLASTP data in Table 60D.

PFam analysis indicates that the NOVόOa protein contains the domains shown in the Table 60E.

Table 60E. Domain Analysis of NOVόOa

Identities/

Pfam Domain NOVόOa Match Region Similarities j Expect Value for the Matched Region

! L27 10..68 15/59 (25%) 7.2e-07 49/59 (83%)

^ L27 72..125 26/56 (46%) 6.6e-l l 42/56 (75%)

PDZ 139-219 26/84 (31%) 5e-15 62/84 (74%)

SH3 231..296 19/66 (29%) 1.8e-05 49/66 (74%)

Guanvlate kin 377-473 47/108 (44%) 1.7e-33 73/108 (68%)

Example 61.

The NOV61 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 61 A.

^!NOV61c, MPVPYKHQLRRAQAVDELDWPPQASSSGSSDSLGSGEAAPAQKDGIFKVMLVGESGVG CG109835-03 KSTLAGTFGGLQGDSAHEPENPEDTYERRIMVDKEEVTLλΛ/YDIVJΞQGDAGGWL DHC LQTGDAFLIVFSVTDRRSFSKVPETLLRLRAGRPHHDLPVILVGNKSDLARSREVSLΞ Protein Sequence EGRHLAGTLSCKHIETSAALHHNTRELFEGAVRQIRLRRGR HAGGQRPDPGSPEGPA PPARRESLTKKAKRFLANLVPRlvAKFFKQRPRSCHDLSVL

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 6 IB.

Further analysis of the NOVόla protein yielded the following properties shown in Table 6 IC.

Table 61C. Protein Sequence Properties NOVόla

PSort I 0.6500 probability located in cytoplasm; 0.1000 probability located in analysis: j mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); i 0.0604 probability located in microbody (peroxisome)

SignalP :No Known Signal Sequence Indicated analysis:

A search of the NOVόl protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6 ID.

In a BLAST search of public sequence databases, the NOVόla protein was found to have homology to the proteins shown in the BLASTP data in Table 6 IE.

PFam analysis indicates that the NOVόla protein contains the domains shown in the Table 6 IF.

Example 62.

The NOV62 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 62A.

Table 62A. NOV62 Sequence Analysis

SEQ ID NO: 205 971 bp

NOV62a, AATCATTTCCGCACCAACCATGGCCACGTTTGTGGAGCTCAGTACAAAAGCCAAGATG

CGI 10114-01 DNA CCCATTGTGGGCCTGGGCACTTGGAGGTCTCTTCTCGGCAAAGTGAAAGAAGCGGTGA AGGTGGCCATTGATGCAGAATATCGCCACATTGACTGTGCCTATTTCTATGAGAATCA

Sequence ACATGAGGTGGGAGAAGCCATCCAAGAGAAGATCCAAGAGAAGGCTGTGATGCGGGAG GACCTGTTCATCGTCAGCAAGGTGTGGCCCACTTTCTTTTATATACCCCTTGTGAGGA AAGCCTTTGAGAAGACCCTCAAGGACCTGAAGCTGAGCTATCTGGACGTCTATCTTAT TCACTGGCCACAGGGATTCAAGACTGGGGATGACTTTTTCCCCAAAGATGATAAAGGT AATATGATCAGTGGAAAAGGAACGTTCTTGGATGCCTGGGAGGCCATGGAGGAGCTGG TGGACGAGGGGCTGGTGAAAGCCCTTGGGGTCTCAAATTTCAACCACTTCCAGATCGA GAGGCTCTTGAACAAACCTGGACTGAAATATAAACCAGTGACTAACCAGGTTGAGTGT CACCCATACCTCACGCAGGAGAAACTGATCCAGTACTGCCACTCCAAGGGCATCACCG TTACGGCCTACAGCCCCCTGGGCTCTCCGGATAGACCTTGGGCCAAACCTGAGGACCC TTCCCTGCTGGAGGATCCCAAGATTAAGGAGATTGCTGCAAAGCACAAAAAAACCACA GCCCAGGTTCTGATCCGTTTCCATATCCAGAGGAATGTGACAGTGATCCCCAAGTCTA TGACACCAGCACACATTGTTGAGAACATTCAGGTCTTTGACTTTAAATTGAGTGATGA GGAGATGGCAACCATACTCAGCTTCAACAGAAACTGGAGGGCCTTTGACTTCAAGGAA TTCTCTCATTTGGAGGACTTTCCCTTCGATGCAGAATATTGAG

ORF Start: ATG at 20 iORF Stop: TGA at 968

SEQ ID NO: 206 ilό aa MW at 36527.7kD

;NOV62a, MATFVELSTKAKMPIVGLGTWRSLLGKVKEAVKVAIDAEYRHIDCAYFYENQHEVGEA JCG1 10114-01 IQEKIQEKAVMREDLFIVSKλWPTFFYIPLVRKAFEKTLKDLKLSYLDVYLIH PQGF KTGDDFFPKDDKGNMISGKGTFLDAWEAMEELVDEGLVKALGVSNF HFQIERLLN P j Protein Sequence GLKYKPVTNQVECHPYLTQEKLIQYCHSKGITVTAYSPLGSPDRPWAKPEDPSLLΞDP KIKEIAA HKKTTAQVLIRFHIQRNVTVIPKSMTPAHIVENIQVFDFKLSDEEMATIL SFNRNWRAFDFKEFSHLEDFPFDAEY

SEQ ID NO: 207 966 bp

!NOV62b, ATTTCCGCACCAACCATGGCCACGTTTGTGGAGCTCAGTACAAAAGCCAAGATGCCCA

JCG1 10114-02 DNA TTGTGGGCCTGGGCACTTGGAGGTCTCTTCTCGGCAAAGTGAAAGAAGCGGTGAAGGT GGCCATTGATGCAGAATATCGCCACATTGACTGTGCCTATTTCTATGAGAATCAACAT

'Sequence GAGGTGGGAGAAGCCATCCAAGAGAAGATCCAAGAGAAGGCTGTGATGCGGGAGGACC TGTTCATCGTCAGCAAGGTGTGGCCCACTTTCTTTGAGAGACCCCTTGTGAGGAAAGC CTTTGAGAAGACCCTCAAGGACCTGAAGCTGAGCTATCTGGACGTCTATCTTATTCAC TGGCCACAGGGATTCAAGACTGGGGATGACTTTTTCCCCAAAGATGATAAAGGTAATA TGATCAGTGGAAAAGGAACGTTCTTGGATGCCTGGGAGGCCATGGAGGAGCTGGTGGA CGAGGGGCTGGTGAAAGCCCTTGGGGTCTCAAATTTCAACCACTTCCAGATCGAGAGG CTCTTGAACAAACCTGGACTGAAATATAAACCAGTGACTAACCAGGTTGAGTGTCACC CATACCTCACGCAGGAGAAACTGATCCAGTACTGCCACTCCAAGGGCATCACCGTTAC GGCCTACAGCCCCCTGGGCTCTCCGGATAGACCTTGGGCCAAACCTGAGGACCCTTCC CTGCTGGAGGATCCCAAGATTAAGGAGATTGCTGCAAAGCACAAAAAAACCACAGCCC AGGTTCTGATCCGTTTCCATATCCAGAGGAATGTGACAGTGATCCCCAAGTCTATGAC ACCAGCACACATTGTTGAGAACATTCAGGTCTTTGACTTTAAATTGAGTGATGAGGAG ATGGCAACCATACTCAGCTTCAACAGAAACTGGAGGGCCTTTGACTTCAAGGAATTCT CTCATTTGGAGGACTTTCCCTTCGATGCAGAATATTGA

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 62B.

Table 62B. Comparison of NOV62a against NOV62b.

NOV62a Residues/ Identities/

I Protein Sequence Match Residues Similarities for the Matched Region

NOV62b .316 314/316 (99%) .316 314/316 (99%)

Further analysis of the NOV62a protein yielded the following properties shown in Table 62C.

Table 62C. Protein Sequence Properties NOV62a

PSort 0.7480 probability located in microbody (peroxisome); 0.3000 probability analysis: located in nucleus; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen) j SignalP No Known Signal Sequence Indicated ; analysis:

A search of the NOV62a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 62D.

ABG04421 Novel human diagnostic protein 1..316 288/316 (91%) e-l 70 #4412 - Homo sapiens, 339 aa. 24-339 299/316 (94%) [WO200175067-A2, l l-OCT-2001]

AAB 10872 Human ARL- 1 protein - Homo 1..316 288/316 (91%) e-l 70 sapiens, 316 aa. [DE19910394-A1, 1..316 299/316 (94%) 07-SEP-2000]

AAB53383 Human colon cancer antigen protein 1..316 288/316 (91%) e-l 70 sequence SEQ ID NO: 923 - Homo 43-358 299/316 (94%) sapiens, 358 aa. [WO200055351-AL 21-SEP-2000]

In a BLAST search of public sequence databases, the NOV62a protein was found to have homology to the proteins shown in the BLASTP data in Table 62E.

PFam analysis indicates that the NOV62a protein contains the domains shown in the Table 62F.

Table 62F. Domain Analysis of NOV62a

Identities/

Pfam Domain NOV62a Match Region Similarities Expect Value for the Matched Region

Example 63.

The NOV63 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 63A.

jGCACACAGCAGGGAATCCCAGGCCCCCCCGCCAAGTGGTTACCCAAGTCACCACTCCT jGACCCAAAAATCAGGCATGGCATTAAAACGTTGCAAATTCCTTTACTGTTATCCCCCC iCACCACCAGGACCATGTAGGGTGCAGTCTTTACTCCCTAACCCGTTTCCCGAAAAAGG

ITGCTACCTCCTTTCCAGACAGATGAGAGAGGGCAGGACTTCAGGCTGGATCCACCACT

GGGCTCTCCCTCCCCCAGCCTGGAGCACGGGAGGGGAGGTGACGGCTGGTGACTGATG

GATGGGTAGTGGGCTGAGAAGAGGGGACTAGGAAGGGCTATTCCAGGCTCAGCCCTGC

TCCTGCAGCTTTGCCGCTGAGTGTAGGAAAAACAGGCATGACAGACCAGGGTGAGGGT

TGTGCCCAGCTGGGCCACGGCCATGCGTGGGGTGGCCCAATAAACACCGTGGACTCCC

AAAAAA

ORF Start: ATG at 28 JORF Stop: TAG at 2404

SEQ ID NO: 210 792 aa !MW at S4796.8kD

NOV63a, MYAFYSLLIYIFYSLFRRDGGAAAAAEPGDPAQVSGAGRAARRLPDLPAPELWTELTG CGI 10123-01 LAGRCSEPEDGSEGAAΞGRAAAVSLEΞALLRLAEFLSVQLGAEESCGGPADLGQGEVP

SLLTVTSQLLALLAWLRSPRGRQALLQGTQPAPRVRPPSPDGSTSQEESPSHFTAVPG Protein Sequence EPLGDETQGQQPLQLEEDQRAWQRLEQLILGQLEΞLKQQLEQQEEELGRLRLGVGATD

SEKRVQHLTLENEALKQSLSLMRDLLLH GPGPPIRAPQEEAEALLELQGRLQΞAQDT

TEALRAQLGVQEVQLQGLQGALQQLQQETEQNCRRELQQMHGQLAGLRARMASLRQGC

GDLRGLVSTFTQSCQGSLSEARGQVS ALGALSSGGPGTQLPEGQQGPPAGCPGRLPE

LKGNIRVLCRLRPGTSSSLVSVEPGPGGTVTTCYRGRHRRFRLD VFPPDASQEEVFR

JELEPAVLSCLRGYSVCIFTYGQTGTGKTYSMEGPPEDPGIVPRALQSLFREMGAGRQH

JRVTLSMVEIYNEAVRDLLAPGPPERLAVRQGPEGQGGIQVAGLTHWDVPNLETLHQML

JKLGRSNRATAATAMNQRSSRSHALVTLTLRAASPPRAPGTAGTLHLVDLAGSERARKA

IGAVGPPRRDPDGARRLREAQTINRSLLALGGΛΠIAALRAHRPHVPFRDSQLTRLLQPAL

IGPGTTAVLLLQISTRPEDLGETVCSLKFADRVGQVELGPARRRRVPRSSGTPSSLSTD

JTPLTGTPCTPTPSPGSPPCPSPDNGSGSALAPAEGLPL

Further analysis of the NOV63a protein yielded the following properties shown in

Table 63B.

Table 63B. Protein Sequence Properties NOV63a

PSort 0.5500 probability located in endoplasmic reticulum (membrane); 0.3225 analysis: probability located in lysosome (lumen); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP Cleavage site between residues 23 and 24 analysis:

A search of the NOV63a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 63C.

i^' [US6335189-Bl_; 01-JAN-2002]

AAM38739 j Human polypeptide SEQ ID NO 1884 ] 149-740 214/638 (33%) 8e-64 j - Homo sapiens, 673 aa. 93-672 296/638 (45%)

[WO200l 53312-Al, 26-JUL-2001]

AAM40525 Human polypeptide SEQ ID NO 5456 149..740 214/639 (33%) 7e-62

- Homo sapiens, 776 aa. 141..721 295/639 (45%)

[WO200153312-A 1 , 26- UL-2001 ]

ABB 11348 Human kinesin related protein 149-740 214/639 (33%) 7e-62 homologue, SEQ ID NO: 1718 - 147-727 295/639 (45%) Homo sapiens, 782 aa. [WO200157188-A2, 09-AUG-2001]

In a BLAST search of public sequence databases, the NOλ όSa protein was found to have homology to the proteins shown in the BLASTP data in Table 63D.

PFam analysis indicates that the NOV63a protein contains the domains shown in the

Table 63E.

Table 63E. Domain Analysis of NOV63a

Pfam Domain NOV63a Match Region Identities/ Expect Value : for the Matched Region kinesin 416..728 134/394 (34%) 4.2e-78 234/394 (59%)

Example 64.

The NOV64 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 64A.

Table 64A. NOV64 Sequence Analysis

SEQ ID NO: 211 5694 bp

NOV64a, CTCTGGTCCCGTTGGTCCTGGGCGCGGCGCCATGGCCTCCGAGGCGGTGAAGGTTGTC

CGI 10132-01 DNA JGTGCGCTGCCGTCCCATGAACCAGCGGGAGCGAGAGCTGCGCTGCCAGCCCGTGGTGΆ

Sequence ICTGTGGACTGCGCGCGCGCCCAGTGCTGCATCCAGAACCCGGGCGCCGCCGACGAGCC

JGCCCAAGCAGTTCACCTTCGACGGCGCCTACCACGTGGACCACGTCACCGAGCAGATC

STACAACGAGATCGCCTATCCGCTGGTGGAGGGCGTCACTGAGGGCTACAATGGCACCA

TCTTTGCCTACGGCCAGACAGGCAGCGGGAAGTCCTTCACCATGCAGGGCCTGCCGGA

TCCGCCCTCCCAGAGAGGCATCATCCCCAGGGCCTTCGAGCACGTGTTCGAGAGCGTC

CAGTGTGCAGAGAACACTAAGTTCCTGGTCCGGGCCTCCTACCTGGAGATCTACAATG

AAGATGTCCGGGACCTCCTTGGGGCTGACACCAAGCAGAAGCTGGAGCTGAAGGAGCA

CCCAGAGAAGGGCGTGTACGTGAAGGGGCTGTCCATGCACACGGTGCACAGCGTGGCC

ICAGTGTGAGCACATCATGGAGACTGGCTGGAAGAACCGTTCGGTCGGCTACACGCTGA

ITGAACAAGGATTCCTCACGCTCGCACTCCATCTTCACCATCAGCATCGAGATGTCTGC

JCGTGGATGAGCGGGGCAAGGACCACCTCCGGGCGGGCAAGCTGAACCTGGTGGACCTG

IGCGGGCAGCGAGCGGCAGTCCAAGACCGGGGCCACGGGCGAGCGGCTCAAGGAGGCCA

JCCAAGATCAACCTGTCGCTCTCGGCACTGGGCAATGTCATCTCGGCGCTGGTGGACGG

JGCGCTGTAAGCACGTCCCCTACCGTGACTCGAAGCTGACGCGGCTGCTGCAGGACTCA

JCTGGGCGGCAACACCAAGACGCTCATGGTGGCCTGCCTGTCGCCTGCGGACAACAACT

JACGATGAGACACTCAGCACGCTGCGCTACGCCAACCGGGCCAAGAACATCAGGAACAA

GCCGCGCATCAATGAGGACCCCAAGGATGCGCTGCTTCGCGAGTACCAGGAGGAGATC

AAGAAGCTCAAGGCCATCCTGACACAGCAGATGAGCCCCAGCAGCCTGTCAGCCCTGC

TGTCCAGGCAGGTGCCCCCAGACCCTGTGCAGGTGGAGGAGAAGCTGTTGCCCCAACC

TGTGATCCAGCATGACATGGAGGCCGAGAAGCAGCTGATCCGGGAGGAGTATGAAGAG

CGCCTGGCCCGGCTGAAAGCCGACTATAAGGCCGAGCAGGAGTCTCGGGCCAGGCTGG

AGGAAGACATCACTGCCATGCGCAACTCATATGACGTCAGGCTGTCCACGCTGGAGGA

JGAACCTGCGGAAGGAGACAGAGGCTGTCCTGCAGGTGGGAGTCCTCTACAAGGCTGAG

GTCATGTCCAGGGCTGAGTTTGCCAGCAGCGCTGAGTACCCGCCTGCTTTTCAGTATG

AGACAGTGGTGAAACCCAAGGTCTTCTCCACGACTGACACTCTGCCCAGTGACGATGT

CTCCAAGACTCAGGTTTCCTCCAGGTTTGCGGAGCTGCCCAAGGTGGAACCCTCCAAA

TCTGAGATTTCTCTGGGCTCCAGTGAGTCATCCTCGCTCGAAGAAACCTCTGTGTCCG

AGGCTTTCCCTGGGCCTGAGGAGCCCTCCAACGTGGAGGTCTCCATGCCCACTGAGGA

GTCCAGGAGCAGATACTTCCTGGATGAGTGCCTCGGGCAGGAGGCCGCTGGGCACCTG

CTGGGGGAACAGAACTACCTCCCGCAAGAGGAGCCGCAGGAGGTGCCCCTGCAGGGGT

TACTAGGCCTGCAGGACCCGTTTGCCGAGGTGGAAGCCAAGCTGGCCAGACTCTCCTC

CACCGTGGCCAGGACAGATGCACCCCAGGCAGACGTCCCCAAGGTCCCTGTGCAGGTC

CCTGCGCCGACAGACCTGCTGGAGCCCAGTGATGCCAGGCCCGAAGCCGAGGCGGCTG

ATGACTTCCCGCCCAGGCCTGAGGTAGATCTGGCCTCGGAAGTGGCCTTAGAGGTGGT

GCGGACAGCAGAGCCTGGCGTGTGGTTGGAGGCTCAGGCCCCGGTGGCCCTGGTGGCT

CAGCCTGAGCCCCTGCCGGCCACAGCTGGTGTGAAGAGGGAGAGCGTGGGCATGGAGG

TGGCAGTGCTGACTGATGACCCGCTGCCCGTTGTGGACCAGCAGCAGGTGCTGGCCCG

TCTGCAGCTGTTGGAGCAGCAGGTTGTGGGTGGAGAGCAGGCCAAGAACAAGGACCTG

AAGGAGAAGCACAAGCGGCGCAAGCGCTACGCAGACGAGCGCAGGAAGCAGCTGGTGG

CTGCCCTGCAGAACTCGGATGAGGACAGCGGGGACTGGGTGCTGCTTAACGTCTACGA

CTCCATCCAGGAGGAAGTGCGGGCCAAGAGCAAGCTGCTGGAGAAGATGCAGAGGAAG

CTTCGGGCAGCAGAGGTGGAGATCAAAGATCTGCAGTCCGAGTTTCAGCTGGAGAAGA

505 TCGATTACTTGGCCACCATCCGCCGGCAGGAGCGTGKCTeeAT^'GCTCTTG^'CASCAGCT CCTGGAGCAGGTGCAGCCCCTGATTCGCAGGGACTGTAACTACAGCAACCTGGAGAAG ATTCTGCGTGAGTCCTGCTGGGACGAAGATAACGGCTTCTGGAAGATCCCACATCCCG TCATCACAAAAACCAGCCTCCCAGTAGCAGTTTCAACTGGGCCACAGAACAAACCAGC CCGCAAAACCTCTGCAGCAGACAATGGCGAGCCGAACATGGAGGAGGACCGCTACAGG CTCATGCTCAGTCGGAGCAACAGTGAAAACATTGCCAGCAACTACTTCCGATCTAAGT GGGCCAGCCAGATCCTCAGCACAGACGCCAGGAAGAGCCTCACACATCACAACTCGCC ACCAGGCCTCAGCTGCCCACTCAGCAACAACTCTGCCATCCCACCCACCCAGGCCCCT GAAATGCCCCAGCCCCGGCCCTTCCGCCTCGAGTCCCTCGACATCCCTTTCACCAAGG CCAAGCGTAAGAAAAGCAAAAGCAACTTTGGCAGTGAGCCTCTGTGAGCACAGCTGCT

TGCCATTGCCTGCCTTATAGGCATGTAGAGACTGCCAGGCCCTCCCAGGGCAGCCCCA

ACCAGGTCTCCTCCCACCTGCCACACAGCGCTCCGGGGCCTGAGGGCTCCCTCAGCCC

TGGGAAGACACATTCCCTTCCCTGTTCCCCAGAGAGCCCACCTCTGCCCTGGGCAGGA

GCCCCTCGGAGGCTGTATAGTCCTCCTTAGAGAGGCCTGCTCCAGCTGTTCATACCAC

ATCAGTGTTTCCGTCTGCTCACCTGCCACGGAGCCCACACCCATGCCCACCAGTGTTG

GTCTTTGCCTCAAAGCCTGAGACCTGCTTCACGGCCTTCACCAGCCCTGATGGAGAGG

GCAGCAGCTGCCACGTGGAGGAAGCTCAATATCAGCTGGGAAGGAACTGTGCCTCTGT

CTGACTGGCCCCACTTCCTAAGCACTGCCCTGCCCCATGGGGTGGCACAGGGGTCCCA

CAGCAGGTCTTCCTGCACTGCCCACCCCTGGCTGGTCTGTGGCCCAAGGAAGGCCACT

CCACATTAAGCTGCCCAATAAACTGCTTTTAAGATAAAAA j ORF Start: ATG at 32 IORF Stop: TGA at 31 19 |SEQ ID NO: 212 11029 aa MW at l l5142.6kD

NOV64a, MASEAVKWVRCRPMNQRERELRCQPWTVDCARAQCCIQNPGAADEPPKQFTFDGAY CG1 10132-01 HVDHVTEQIYNEIAYPLVEGVTEGYNGTIFAYGQTGSGKSFT QGLPDPPSQRGIIPR AFEHVFESVQCAENTKFLVRASYLEIYNEDVRDLLGADTKQKLELKEHPEKGVYVKGL Protein Sequence S HTΛ SVAQCEHIMETGWKNRSVGYTLMNKDS SRSHS FTI S IE S AVDERGKDHLR AGKLNLVDLAGSERQSKTGATGERLKEATKINLSLSALG1WISALVDGRCKHVPYRDS KLTRLLQDSLGGNTKTLMVACLSPAD WYDETLSTLRYA RAKNIRNKPRINEDPKDA LLREYQEΞIKKLKAILTQQMSPSSLSALLSRQVPPDPVQVEE LLPQPVIQHDMEAEK QLIREEYEERLARL ADYKAEQESRARLEEDITAMRNSYDVRLSTLEENLR ΞTEAVL QVGVLY AEVMSRAEFASSAEYPPAFQYETWKPKVFSTTDTLPSDDVSKTQVSSRFA ELPKVEPSKSEISLGSSΞSSSLEETSVSEAFPGPEEPSNVEVSMPTEESRSRYFLDEC LGQEAAGHLLGEQNYLPQEEPQEVPLQGLLGLQDPFAEVEAKLARLSSTVARTDAPQA DVP VPVQVPAPTDLLEPSDARPEAEAADDFPPRPEVDLASEVALEWRTAEPGVWLE AQAPVALVAQPEPLPATAGVKRESVGMEVAVLTDDPLPWDQQQVLARLQLLEQQWG GEQAFSIKDLKE HKRRKRYADERRKQLVAALQNSDEDSGD VLLLSIVYDSIQEEVRAKS KLLΞKMQRKLRAAEVEIKDLQSEFQLEKIDYLATIRRQERDS LLQQLLEQVQPLIRR DCNYSNLEKILRESC DEDNGF KIPHPVITKTSLPVAVSTGPQNKPARKTSAADNGE P MEEDRYRLMLSRSNSENIASNYFRSK ASQILSTDARKSLTHHNSPPGLSCPLSNTM SAIPPTQAPEMPQPRPFRLESLDIPFTKAKRKKSKSNFGSEPL

Further analysis of the NOV64a protein yielded the following properties shown in Table 64B.

Table 64B. Protein Sequence Properties NOV64a

PSort 0.5834 probability located in mitochondrial matrix space; 0.4900 probability analysis: located in nucleus; 0.3000 probability located in microbody (peroxisome); 0.2942 probability located in mitochondrial inner membrane

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV64a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 64C.

506

In a BLAST search of public sequence databases, the NOV64a protein was found to have homology to the proteins shown in the BLASTP data in Table 64D.

PFam analysis indicates that the NOV64a protein contains the domains shown in the Table 64E.

Table 64E. Domain Analysis of NOV64a

Identities/

Pfam Domain NOV64a Match Region Similarities Expect Value

I for the Matched Region

! kinesin 11-364 192/417 (46%) 1.8e-181 304/417 (73%)

Example 65.

The NOV65 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 65A.

Table 65A. NOV65 Sequence Analysis

SEQ ID NO: 213 957 bp

NOV65a, GCGCCCCGCGCCCCGCCACCGCCGCCGCCGAGCAAAGCCGGGCTGGGCTTGGAGCTGC

CGI 10160-01 DNA TCATGGAGAAAGTGCCAGGCGAGATGGAGATCGAGCGCAGGGAGCGGAGCGAGGAGCT GTCCGAGGCGGAGAGGAAGGCGGTGCAGGCTATGTGGGCCCGGCTCTATGCCAACTGC _: Sequence GAGGACGTGGGGGTGGCCATCCTGGTGAGGTTCTTTGTGAACTTCCCCTCGGCCAAGC AGTACTTCAGCCAGTTCAAGCACATGGAGGATCCCCTGGAGATGGAGCGGAGCCCCCA GCTGCGGAAGCACGCCTGCCGAGTCATGGGGGCCCTCAACACTGTCGTGGAGAACCTG CATGACCCCGACAAGGTGTCCTCTGTGCTCGCCCTTGTGGGGAAAGCCCACGCCCTCA AGCACAAGGTGGAACCGGTGTACTTCAAGATCCTCTCTGGGGTCATTCTGGAGGTGGT CGCCGAGGAATTTGCCAGTGACTTCCCACCTGAGACGCAGAGAGCCTGGGCCAAGCTG CGTGGCCTCATCTACAGCCACGTGACCGCTGCCTACAAGGAAGTGGGCTGGGTGCAGC AGGTCCCCAACGCCACCACCCCACCGGCCACACTGCCCTCTTCGGGGCCGTAGGACCC

CTAACTCCACCCCCCTCCCTGGCAGCACCTCGAGCAGAAGGCCGAGTTCTGAAGACCC

TCCTTGACGCTCCATTTCTGGGTGCCAAGGAAGCTGGAGGAATCCCTGACTCAACTTC

CCCGAAGGAGGCCTCTGTGGCGGCCAGGGTCCCCCCCTGGAGCTGCTGGGAGGCGGCG

CTGGCTGCCTGGATGCTGACCCCAGCGCGGCGGGCAGAGCGGGGCCCACTCTTCTTAG

CTTTTCTACTCACTGTTAGAGAGAGACCTAGCTGAGCGGCTGGCAGGAAGCGGGACAG

GTCTAGGAGTCCCTTAGGGAATAAACCAG

ORF Start: ATG at 61 ORF Stop: TAG at 631

SEQ ID NO: 214 190 aa MW at 21404.4kD

NOV65a, MEKVPGEMEIERRERSEELSEAER AVQAM ARLYA CEDVGVAILVRFFVNFPSAKQ CG110160-01 YFSQFKHMEDPLEMERSPQLRKHACRVMGALNT ENLHDPDKVSSVLALVGKAHALK HKVEPλrϊFKILSGVILEWAΞEFASDFPPETQRAWAKLRGLIYSHVTAAYKEVG VQQ Protein Sequence VPNATTPPATLPSSGP

SEQ ID NO: 215 682 bp

NOV65b, CTTGGAGCTGCTCATGGAGAAAGTGCCAGGCGAGATGGAGATCGAGCGCAGGGAGCGG

CGI 10160-02 DNA AGCGAGGAGCTGTCCGAGGCGGAGAGGAAGGCGGTGCAGGCTATGTGGGCCCGGCTCT ATGCCAACTGCGAGGACGTGGGGGTGGCCATCCTGGTGAGGTTCTTTGTGAACTTCCC

Sequence CTCGGCCAAGCAGTACTTCAGCCAGTTCAAGCACATGGAGGATCCCCTGGAGATGGAG

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 65B.

Table 65B. Comparison of NOVόSa against NOV65b. I

NOV65a Residues/ j Identities/ j Protein Sequence

Match Residues j Similarities for the Matched Region

NOV65b 1..190 172/190 (90%) 1..190 172/190 (90%)

Further analysis of the NOV65a protein yielded the following properties shown in Table 65C.

Table 65C. Protein Sequence Properties NOV65a

PSort 0.4500 probability located in cytoplasm; 0.3071 probability located in microbody analysis: (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0A000 probability located in lysosome (lumen)

SignalP No Known Signal Sequence Indicated j analysis: A search of the NOV65a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 65D.

In a BLAST search of public sequence databases, the NOVόSa protein was found to have homology to the proteins shown in the BLASTP data in Table 65E.

PFam analysis indicates that the NOV65a protein contains the domains shown in the Table 65F.

Table 65F. Domain Analysis of NOV65a

Identities/

Pfam Domain NOV65a Match Region Similarities Expect Value for the Matched Region

Example 66.

The NOV66 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 66A.

Table 66A. NOV66 Sequence Analysis

SEQ ID NO: 217 1820 bp

|NOV66a, AGGTGCTGCCCGGCGGAGGTCACGAGTCCAGGCAGGGGATCAACATGGCCGCTGCACC i CGI 10350-01 DNA CCGGACTGTGTTGATCTCCGGCTGCTCATCAGGAATTGGTCTGGAACTTGCAGTGCAA CTGGCCCATGACCCCAAGAAGCGCTACCAGGTCGTGGCCACCATGAGGGACCTGGGGA

Sequence . AGAAGGAGACACTGGAGGCAGCTGCTGGGGAGGCTCTGGGGCAGACCCTCACCGTGGC CCAGCTGGACGTGTGCAGTGATGAGTCGGTGGCCCAGTGTCTCAGCTGTATCCAGGGA GAAGTGGACGTGCTGGGTGTCATCTTCAACGATGTCTATGCAGCTTCCAAGTTCGCCC TGGAGGGATTCTTCGAAAGCCTCGCTATCCAGCTGCTGCAGTTCAACATCTTCATCTC CCTGGTGGAGCCAGGCCCCGTGGTCACCGAGTTTGAGGGGAAGCTTCTGGCGCAGGTT TCTACGGCTGAGTTCCCAGGCACTGACCCTGAGACCCTGCACTACTTCCGGGACCTCT ATCTCCCAGCCTCCAGGAAGCTGTTTTGCTCCGTGGGACAGAACCCACAGGACGTGGT TCAGGCCATTGTCAACGTCATCAGCTCGACTCGACCACCCCTGCGCCGACAGACCAAC ATCCGCTACTCGCCGCTGACCACGCTCAAAACCGTGGATTCCTCTGGCAGCCTGTATG TGCGAACGACCCACCGCCTCCTCTTCCGCTGTCCACGCCTCCTCAACCTTGGCCTTCA ATGTCTGTCCTGCGGCTGCCTCCCAACGCGGGTGCGGCCAAGATGAGCAGAACAGAGC TTCACGAT

ORF Start: ATG at 45 jORF Stop: TGA at 798

ISEQ ID NO: 218 251 aa MW at 27376.3kD

JNOVόόa, MAAAPRTVLISGCSSGIGLELAVQLAHDPKKRYQWATMRDLGKKETLEAAAGEALGQ jCGl 10350-01 TLTVAQLDVCSDESVAQCLSCIQGΞVDVLGVIFNDVYAAS FALEGFFΞSLAIQLLQF NIFISLVEPGPWTΞFEGKLLAQVSTAEFPGTDPETLHYFRDLYLPASRKLFCSVGQN j Protein Sequence PQDWQAIVNVISSTRPPLRRQTNIRYSPLTTLKTVDSSGSLYVRTTHRLLFRCPRLL NLGLQCLS CGCLPTRVRPR

Further analysis of the NOV66a protein yielded the following properties shown in Table 66B.

Table 66B. Protein Sequence Properties NOVόόa

PSort 0.3600 probability located in mitochondrial matrix space; 0.3000 probability j analysis: located in nucleus; 0.1986 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOVόόa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 66C.

i l l

In a BLAST search of public sequence databases, the NOV66a protein was found to have homology to the proteins shown in the BLASTP data in Table 66D.

PFam analysis indicates that the NOVόόa protein contains the domains shown in the Table 66E.

Table 66E. Domain Analysis of NOVόόa

Identities/

Pfam Domain NOVόόa Match Region Similarities Expect Value for the Matched Region adh short 4-205 50/283 (18%) 8.2e-05 144/283 (51%)

Example 67.

The NOV67 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 67A.

Table 67A. NOV67 Sequence Analysis

SEQ ID NO: 219 1419 bp

NOV67a, GAGTACGGACTGGGCCTGGCCTGGGGCGTCCCCGCGAAGCCTGGGCCTGTCAGGCGGT

CGI 10360-01 DNA TCCGTCCGGGTCTCGGCCACCGTCGAGTTCCGTCGAGTTCCGTCCCGGCCCTGCTCAC

AGCAGCGCCCTCGGAGCGCCCAGCACCTGCGGCCGGCCAGGCAGCGCGATCCTGCGGC

Sequence GTCTGGCCATCCCGAATGCTATGGCCGCCGTCGCCGTCTTGCGGGCCTTCGGGGCAAG

TGGGCCCATGTGTCTCCGGCGCGGCCCCTGGGCCCAGCTCCCCGCCCGCTTCTGCAGC CGGGACCCGGCCGGGGCGGGGCGGCGGGAGTCGGAGCCGCGGCCCACCAGCGCGCGGC AGCTGGACGGCATAAGGAACATCGTCTTGAGCAATCCCAAGAAGAGGAACGCGTTGTC ACTTGCAATGCTGAAGTCTCTCCAAAGTGACATTCTTCATGACGCTGACAGCAACGAT CTGAAAGTCATTATCATCTCGGCTGAGGGGCCTGTGTTTTCTTCTGGGCATGACTTAA AGGAGCTGACAGAGGAGCAAGGCCGTGATTACCATGCCGAAGTATTTCAGACCTGTTC CAAGGTCATGATGCACATCCGGAACCACCCCGTTCCCGTCATTGCCATGGTCAATGGC CTGGCCGCGGCTGCCGGCTGTCAACTGGTTGCCAGCTGCGACATTGCCGTGGCGAGCG ACAAGTCCTCTTTTGCCACTCCTGGGGTGAACGTCGGGCTCTTCTGTTCTACCCCTGG GGTTGCCTTGGCAAGAGCAGTGCCTAGAAAGGTGGCCTTGGAGATGCTCTTTACTGGT GAGCCCATTTCTGCCCAGGAGGCCCTGCTCCACGGGCTGCTTAGCAAGGTGGTGCCAG AGGCGGAGCTGCAGGAGGAGACCATGCGGATCGCTAGGAAGATCGCATCGCTGAGCCG TCCGGTGGTGTCCCTGGGCAAAGCCACCTTCTACAAGCAGCTGCCCCAGGACCTGGGG ACGGCTTACTACCTCACCTCCCAGGCCATGGTGGACAACCTGGCCCTGCGGGACGGGC AGGAGGGCATCACGGCCTTCCTCCAGAAGAGAAAACCTGTCTGGTCACACGAGCCAGT GTGAGTGGAGGCAGAGGAGTGAGGCCCACGGGCAGCGCCCAGGAGCCCACCTTCCCCT CTGGCCCAGCCACCACTGCCTCTCAGCTTAAACAGGTGACAGGCTGCTTTCGTGACTT

Further analysis of the NOV67a protein yielded the following properties shown in Table 67B.

A search of the NOV67a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 67C.

AAU23638 J Novel human enzyme polypeptide 11..199 126/189 (66%) 5e-59 j #724 - Homo sapiens, 206 aa. 17..204 135/189 (70%) ] [WO200155301-A2, 02-AUG-2001]

In a BLAST search of public sequence databases, the NOV67a protein was found to have homology to the proteins shown in the BLASTP data in Table 67D.

PFam analysis indicates that the NOV67a protein contains the domains shown in the Table 67E.

Table 67E. Domain Analysis of NOV67a

Identities/

! Pfam Domain NOV67a Match Region Similarities Expect Value for the Matched Region

ECH 57-225 57/177 (32%) 1.5e-41 135/177 (76%)

Example 68.

The NOV68 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 68A. Table 68A. NO 68 Sequence Analysis iSEQ ID NO: 221 1262 bp

.NOVόSa, CCACGTCTTCTGCGTGTTGAGCCCGTTACCGACCCAGGTATTGGGCCACATGCACCCA

^:CG120509-01 DNA GAATGTGACTTCATCACCCAGCTGAGAGAGGATGAGAGTGCCTGTCTACAAGCAGCAG AGGAGATGCCCAACACCACCCTGGGCTGCCCTGCGACCTGGGATGGGCTGCTGTGCTG l Sequence GCCAACGGCAGGCTCTGGCGAGTGGGTCACCCTCCCCTGCCCGGATTTCTTCTCTCAC TTCAGCTCAGAGTCAGGGGCTGTGAAACGGGATTGTACTATCACTGGCTGGTCTGAGC CCTTTCCACCTTACCCTGTGGCCTGCCCTGTGCCTCTGGAGCTGCTGGCTGAGGAGGA ATCTTACTTCTCCACAGTGAAGATTATCTACACCGTGGGCCATAGCATCTCTATTGTA GCCCTCTTCGTGGCCATCACCATCCTGGTTGCTCTCAGGAGGCTCCACTGCCCCCGGA ACTACGTCCACACCCAGCTGTTCACCACTTTTATCCTCAAGGCGGGAGCTGTGTTCCT GAAGGATGCTGCCCTTTTCCACAGCGACGACACTGACCACTGCAGCTTCTCCACTGTT CTATGCAAGGTCTCTGTGGCCGCCTCCCATTTCGCCACCATGACCAACTTCAGCTGGC TGTTGGCAGAAGCCGTCTACCTGAACTGCCTCCTGGCCTCCACCTCCCCCAGCTCAAG GAGAGCCTTCTGGTGGCTGGTTCTCGCTGACTGGGGGCTGCCCGTGCTCTTCACTGGC ACGTGGGTGAGCTGCAAACTGGCCTTCGAGGACATCGCGTGCTGGGACCTGGACGACA CCTCCCCCTACTGGTGGATCATCAAAGGGCCCATTGTCCTCTCGGTCGGGGTGAACTT TGGGCTTTTTCTCAATATTATCCGCATCCTGGTGAGGAAACTGGAGCCAGCTCAGGGC AGCCTCCATACCCAGTCTCAGTATTGGCGTCTCTCCAAGTCGACACTTTTCCTGATCC CACTCTTTGGAATTCACTACATCATCTTCAACTTCCTGCCAGACAATGCTGGCCTGGG CATCCGCCTCCCCCTGGAGCTGGGACTGGGTTCCTTCCAGGTGAGGACTGAGATCTCA CGGAAGTGGCATGGCCATGACCCTGAGCTTCTGCCAGCCTGGAGGACCCGTGCTAAGT GGACCACGCCTTCCCGCTCGGCGGCAAAGGTGCTGACATCTATGTGCTAGGCTGCCTC ATCACGCCACTGGAGTCCACACTTGAATTTGGGCAGCTACCTAC

ORF Start: at 2 IORF Stop: TAG at 1208

SEQ ID NO: 222 402 aa MW at 44971.5kD

!NOV68a, HVFCVLSPLPTQVLGHMHPΞCDFITQLRΞDESACLQAAEΞMPNTTLGCPATDGLLC 'CG120509-01 PTAGSGEWVTLPCPDFFSHFSSESGAVKRDCTITGWSEPFPPYPVACPVPLELLAEEE SYFSTVKIIYTVGHSISIVALFVAITILVALRRLHCPRNYVHTQLFTTFIL AGAVFL .Protein Sequence JKDAALFHSDDTDHCSFSTVLCKVSVAASHFATMTNFSWLLAEAVYLNCLLASTSPSSR JRAFW LVLAD GLPVLFTGT VSCKLAFEDIAC DLDDTSPY IIKGPIVLSVGVNF IGLFLNIIRILVRKLEPAQGSLHTQSQYRLSKSTLFLIPLFGIHYIIFNFLPDNAGLG LLRLPLELGLGSFQVRTEISRK HGHDPΞLLPA RTRAKWTTPSRSAAKVLTSMC

SEQ ID NO: 223 1633 bp

;NOV68b, CCACGTCTTCTGCGTGTTGAGCCCGTTACCGACCACCAGCAGTGTGGCATCTTTAAAT

;CG120509-02 DNA CTCAGTTCCCACGGCACACATCCTCATGTCACCTCCTCTGATTCTGACTCTCTTGCCT

ACTGCCCATCCTATAAGGAGCCTTGCGATTACATCAGGCCTACTCAGATAATCAGGGA I Sequence TGAGCTTTGCATCTCAAGATCCTGAACTCAATCACATCTGCAAAGTCCTTTTGCCGTT

TAAGGGAGCAGGAGTGGAGAGCAAGGAGAATGACACAGGGAAGGAGGAAAGGCCCTGA

TGAGAATGGAGTTGGCCATCCCTGTGAGATCTTCAGAAGCATATTGTCTAATGTGTCT

CAGAACTTACTTACATGAGACAGAATGGAGAAACATCCATCCAAACCTAGGCAGACCC

AGGTATTGGGCCACATGCACCCAGAATGTGACTTCATCACCCAGCTGAGAGAGGATGA GAGTGCCTGTCTACAAGCAGCAGAGGAGATGCCCAACACCACCCTGGGCTGCCCTGCG ACCTGGGATGGGCTGCTGTGCTGGCCAACGGCAGGCTCTGGCGAGTGGGTCACCCTCC CCTGCCCGGATTTCTTCTCTCACTTCAGCTCAGAGTCAGGGGCTGTGAAACGGGATTG TACTATCACTGGCTGGTCTGAGCCCTTTCCACCTTACCCTGTGGCCTGCCCTGTGCCT CTGGAGCTGCTGGCTGAGGAGGAATCTTACTTCTCCACAGTGAAGATTATCTACACCG TGGGCCATAGCATCTCTATTGTAGCCCTCTTCGTGGCCATCACCATCCTGGTTGCTCT CAGGAGGCTCCACTGCCCCCGGAACTACGTCCACACCCAGCTGTTCACCACTTTTATC CTCAAGGCGGGAGCTGTGTTCCTGAAGGATGCTGCCCTTTTCCACAGCGACGACACTG ACCACTGCAGCTTCTCCACTGTTCTATGCAAGGTCTCTGTGGCCGCCTCCCATTTCGC CACCATGACCAACTTCAGCTGGCTGTTGGCAGAAGCCGTCTACCTGAACTGCCTCCTG GCCTCCACCTCCCCCAGCTCAAGGAGAGCCTTCTGGTGGCTGGTTCTCGCTGACTGGG GGCTGCCCGTGCTCTTCACTGGCACGTGGGTGAGCTGCAAACTGGCCTTCGAGGACAT CGCGTGCTGGGACCTGGACGACACCTCCCCCTACTGGTGGATCATCAAAGGGCCCATT GTCCTCTCGGTGGGGGTGAACTTTGGGCTTTTTCTCAATATTATCCGCATCCTGGTGA GGAAACTGGAGCCAGCTCAGGGCAGCCTCCATACCCAGTCTCAGTATTGGCGTCTCTC , CAAGTCGACACTTTTCCTGATCCCACTCTTTGGAATTCACTACATCATCTTCAACTTC J I CTGCCAGACAATGCTGGCCTGGGCATCCGCCTCCCCCTGGAGCTGGGACTGGGTTCCT J ' CCAGGTGAGGACTGAGATCTCACGGAAGTGGCATGGCCATGACCCTGAGCTTCTGCC J IAGCCTGGAGGACCCGTGCTAAGTGGACCACGCCTTCCCGCTCGGCGGCAAAGGTGCTG !

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 68B.

Table 68B. Comparison of NOV68a against NOV68b.

NOV68a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV68b 8..402 381/395 (96%) 8..402 381/395 (96%)

Further analysis of the NOVόSa protein yielded the following properties shown in Table 68C.

Table 68C. Protein Sequence Properties NOV68a

SignalP Cleavage site between residues 16 and 17 analysis:

A search of the NOV68a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 68D.

In a BLAST search of public sequence databases, the NOV68a protein was found to have homology to the proteins shown in the BLASTP data in Table 68E.

PFam analysis indicates that the NOV68a protein contains the domains shown in the Table 68F.

518 Table 68F. Domain Analysis of NOV68a

Identities/

Pfam Domain NOVόSa Match Region Similarities Expect Value for the Matched Region ]

HRM 45..110 33/81 (41%) 6.5e-23 59/81 (73%)

I 7tm 2 119-366 102/284 (36%) 1.5e-92 206/284 (73%)

Example 69.

The NOV69 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 69A.

j Table 69A. NOV69 Sequence Analysis

SEQ ID NO: 225 1101 bp jNOV69a, CCGAACGCCCGCAGCAGGGTCAGAAGGGAGGTGGCCGGTCTCCGTCGTGACCTCTGAC

:CG12145: -02 DNA GGTTTCTGAGCGTTGGCCTTTGGCACGCGCTACCCCCTTTTGCTTTGGTTCTGCCATG

CCGATGTACCAGGAAGAGTCTAACCTGTCTCTGCAAGCTCTTGAGTCCCGCCAAGATG

'.Sequence ATATTTTAAAACGTCTGTATGAGTTGAAAGCTGCAGTTGATGGCCTCTCCAAGATGAT TCAAACACCAGATGCAGACTTGGATGTAACCAACATAATCCAAGCGGATGAGCCCACG ACTTTAACCACCAATGCGCTGGACTTGAATTCAGTGCTTGGGAAGGATTACGGGGCGC TGAAAGACATCGTGATCAACGCAAACCCGGCCTCCCCTCCCCTCTCCCTGCTTGTGCT GCACAGGCTGCTCTGTGAGCACTTCAGGGTCCTGTCCACGGTGCACACGCACTCCTCG GTCAAGAGCGTGCCTGAAAACCTTCTCAAGTGCTTTGGAGAACAGAATAAAAAACAGC CCCGCCAAGACTATCAGCTGGGATTCACTTTAATTTGGAAGAATGTGCCGAAGACGCA GATGAAATTCAGCATCCAGACGATGTGCCCCATCGAAGGCGAAGGGAACATTGCACGT TTCTTGTTCTCTCTGTTTGGCCAGAAGCATAATGCTGTCAACGCAACCCTTATAGATA GCTGGGTAGATATTGCGATTTTTCAGTTAAAAGAGGGAAGCAGTAAAGAAAAAGCCGC TGTTTTCCGCTCCATGAACTCTGCTCTTGGGAAGAGCCCTTGGCTCGCTGGGAATGAA CTCACCGTAGCAGACGTGGTGCTGTGGTCTGTACTCCAGCAGATCGGAGGCTGCAGTG TGACAGTGCCAGCCAATGTGCAGAGGTGGATGAGGTCTTGTGAAAACCTGGCTCCTTT TTAACACGGCCCTCAAGCTCCTTAAGTGAATTGCCGTAACTGATTTTAAAGGGTTTAG

ATTTTAAGAATGGTGCTCTTTCATGCCTATTATCAGTAAGGGGACTTGTATTAGAGTC

AGAGTCTTTTTATTTAGGCCAGTTGTCAAGTGTCAATAAAAGCGCATCATGTAATTT

ORF Start: ATG at 114 ORF Stop: TAA at 930

SEQ ID NO: 226 272 aa MW at 30243.5kD

NOV69a, PMYQEESNLSLQALESRQDDILKRLYELKAAVDGLSKMIQTPDADLDVTNIIQADEP CG121453-02 TTLTTNALDLNSVLGKDYGALKDIVINA PASPPLSLLVLHRLLCEHFRVLSTVHTHS SVKSVPENLLKCFGEQNKKQPRQDYQLGFTLI K VP TQMKFS IQTMCPIEGEGNIA Protein Sequence RFLFSLFGQIvΗNAVNATLIDSWVDIAIFQLKEGSSKEKAAVFRSMNSALGKSPWLAGN ELTVADWLWSVLQQIGGCSVTVPANVQR MRSCENLAPF

Further analysis of the NOV69a protein yielded the following properties shown in Table 69B.

Table 69B. Protein Sequence Properties NOV69a

PSort 0.6500 probability located in cytoplasm; 0.1000 probability located in analysis: 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV69a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 69C.

In a BLAST search of public sequence databases, the NOV69a protein was found to have homology to the proteins shown in the BLASTP data in Table 69D.

j (Human), 320 aa.

Q96CZ5 j JTV1 GENE - Homo sapiens 5-272 267/268 (99%) e-l 52 I (Human), 320 aa. 45..312 ! 267/268 (99%)

AAH24480 HYPOTHETICAL 31.1 KDA 1..272 241/272 (88%) e-138 PROTEIN - Mus musculus (Mouse), 1..272 253/272 (92%) 280 aa.

AAH26958 j HYPOTHETICAL 35.4 KDA | 5-272 237/268 (88%) e-136

PROTEIN - Mus musculus (Mouse), | 45..312 249/268 (92%) 320 aa. I

AAH24410 j HYPOTHETICAL 35.4 KDA j 5-272 237/268 (88%) e-136

¹ PROTEIN - Mus musculus (Mouse), | 45..312 249/268 (92%) 320 aa. I

PFam analysis indicates that the NOV69a protein contains the domains shown in the Table 69E.

Table 69E. Domain Analysis of NOV69a

Identities/

; Pfam Domain NOV69a Match Region Similarities Expect Value for the Matched Region

GST C 223-270 1 1/55 (20%) 0.097 37/55 (67%)

Example 70.

The NOV70 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 70A.

Table 70A. NOV70 Sequence Analysis iSEQ ID NO: 227 983 bp

NOV70a, ATGGATTCGATATCAGTGTGTGAAGCTGAATGATGGTCACTTCGTGCCTGTCCTGGGA CG59693-02 TTTGGCACCTATGCGCCTGCAGAGGTTACTCCCCCAGGTTCCTAAAAGTAAAGCTTTA GAGGCCACCAAATTGGCAATTGAAGCTGGCTTCCGCCATATTGATTCTGCTCATTTAT DNA ACAATAATGAGGAGCAGGTTGGACTGGCCATCCGAAGCAAGATTGCAGATGGCAGTGT Sequence GAAGAGAGAAGACATATTCTACACTTCAAAGCTTTGGTGCAATTCCCATCGACCAGAG TTGGTCCGACCAGCCTTGGAAAGGTCACTGAAAAATCTTCAATTGGATTATGTTGACC TCTACCTTATTCATTTTCCAGTGTCTGTAAAGCCAGGTGAGGAAGTGATCCCAAAAGA TGAAAGTGGAAAAATACTATTTGACACAGTGGATCTCTGTGCCACGTGGGAGGCCGTG GAGAAGTGTAAAGATGCAGGATTGGCCAAGTCCATCGGGGTGTCCAACTTCAACCGCA GGCAGCTGGAGATGATCCTCAACAAGCCAGGGCTCAAGTACAAGCCTGTCTGCAACCA GGTGGAATGTCATCCTTACTTCAACCAGAGAAAACTGCTGGATTTCTGCAAGTCAAAA GACATTGTTCTGGTTGCCTATAGTGCTCTGGGATCCCACCGAGAAGAACCATGGGTGG ACCCGAACTCCCCGGTGCTCTTGGAGGACCCAGTCCTTTGTGCCTTGGCAAAAAAGCA CAAGCGAACCCCAGCCCTGGTTGCCCTGCGCTACCAGCTACAGCGTGGGGTTGTGGTC CTGGCCAAGAGCTACAATGAGCAGCGCATCAGACAGAACGTGCAGGTGTTTGAATTCC AGTTGACTTCAGAGGAGATGAAAGCCATAGATGGCCTAAACAGAAATGTGCGATATTT GACCCTTGATATTTTTGCTGGCCCCCCTAATTATCCATTTTCTGATGAATATTAA

.21 IORF Start: ATG at 30 iORF Stop: TAA at 981

;SEQ ID NO: 22S 1317 aa MW at 36217.5kD

NOV70a, :MMVTSCLS DLAPMRLQRLLPQVPKSKALEATKLAIEAGFRHIDSAHLYIsTtvTEEQVGLA CG59693-02 SlRSKIADGSVKREDIFYTSKLWCNSHRPELVRPALERSL NLQLDYVDLYLIHFPVSV jKPGΞEVIPKDΞSGKILFDTVDLCATWΞAVEKCKDAGLAKSIGVSNFNRRQLEMILNKP Protein jGLKYKPVCNQVECHPYFNQRKLLDFCKSKDIVLVAYSALGSHREEP λTOPNSPVLLED Sequence jPVLCALAKKHKRTPALVALRYQLQRGVWLAKSYNEQRIRQNVQVFEFQLTSEE KAI DGLNRNVRYLTLDIFAGPPNYPFSDEY

SEQ ID NO: 229 1972 bp

NOV70b, ATGGATTCGAAATATCAGTGTGTGAAGCTGAATGATGGTCACTTCATGCCTGTCCTGG CG59693-03 GATTTGGCACCTATGCGCCTGCAGAGGTTCCTAΆAAGTAAΆGCTTTAGAGGCCACCAA ATTGGCAATTGAAGCTGGCTTCCGCCATATTGATTCTGCTCATTTATACAATAATGAG DNA .GAGCAGGTTGGACTGGCCATCCGAAGCAAGATTGCAGATGGCAGTGTGAAGAGAGAAG Sequence _JACATATTCTACACTTCAAAGCTTTGGTGCAATTCCCATCGACCAGAGTTGGTCCGACC |AGCCTTGGAAAGGTCACTGAAAAATCTTCAATTGGATTATGTTGACCTCTACCTTATT JCATTTTCCAGTGTCTGTAAAGCCAGGTGAGGAAGTGATCCCAAAAGATGAAAATGGAA

JAAATACTATTTGACACAGTGGATCTCTGTGCCACGTGGGAGGCCGTGGAGAAGTGTAA

JAGATGCAGGATTGGCCAAGTCCATCGGGGTGTCCAACTTCAACCGCAGGCAGCTGGAG IATGATCCTCAACAAGCCAGGGCTCAAGTACAAGCCTGTCTGCAACCAGGTGGAATGTC IATCCTTACTTCAACCAGAGAAAACTGCTGGATTTCTGCAAGTCAAAAGACATTGTTCT JGGTTGCCTATAGTGCTCTGGGATCCCACCGAGAAGAACCATGGGTGGACCCGAACTCC ;CCGGTGCTCTTGGAGGACCCAGTCCTTTGTGCCTTGGCAAAAAAGCACAAGCGAACCC ICAGCCCTGATTGCCCTGCGCTACCAGCTACAGCGTGGGGTTGTGGTCCTGGCCAAGAG JATACAATGAGCAGCGCATCAGACAGAACGTGCAGGTGTTTGAATTCCAGTTGACTTCA ^'GAGGAGATGAAAGCCATAGATGGCCTAAACAGAAATGTGCGATATTTGACCCTTGATA ITTTTTGCTGGCCCCCCTAATTATCCATTTTCTGATGAATATTAA

I ORF Start: ATG at 1 JORF Stop: TAA at 970

C ]SEQ ID NO: 230 ^" !323 aa IMW at 36857.0kD

NOV70b, MDSKYQCVKLNDGHFMPVLGFGTYAPAEVPKSKALEATKLAIEAGFRHIDSAHLYNNE CG59693-03 EQVGLAIRSKIADGSVKREDIFYTSKL CNSHRPELVRPALERSLKNLQLDYVDLYLI HFPVSV PGΞEVIPKDENGKILFDTVDLCATVJEAVΞKC DAGLAKSIGVSNFNRRQLE Protein MILNKPGLKYKPVCNQVECHPYFNQRKLLDFCKSKDIVLVAYSALGSHREΞP VDPNS Sequence PVLLEDPVLCALAKKHKRTPALIALRYQLQRGλ/WLAKRYNEQRIRQNVQVFEFQLTS EEMKAIDGLNRNVRYLTLDIFAGPPNYPFSDEY

SEQ ID NO: 231 901 bp

NOV70c, GCCAGATCTCTGAATGATGGTCACTTCATGCCTGTCCTGGGATTTGGCACCTATGCGC 268669100 CTGCAGAGGTTCCTAAAAGTAAAGCTTTAGAGGCCACCAAATTGGCAATTGAAGCTGG CTTCCGCCATATTGATTCTGCTCATTTATACAATAATGAGGAGCAGGTTGGACTGGCC DNA ATCCGAAGCAAGATTGCAGATGGCAGTGTGAAGAGAGAAGACATATTCTACACTTCAA Sequence AGCTTTGGTGCAATTCCCATCGACCAGAGTTGGTCCGACCAGCCTTGGAAAGGTCACT GAAAAATCTTCAATTGGATTATGTTGACCTCTACCTTATTCATTTTCCAGTGTCTGTA AAGCCAGGTGAGGAAGTGATCCCAAAAGATGAAAATGGAAAAATACTATTTGACACAG TGGATCTCTGTGCCACGTGGGAGGCCGTGGAGAAGTGTAAAGATGCAGGATTGGCCAA GTCCATCGGGGTGTCCAACTTCAACCGCAGGCAGCTGGAGATGATCCTCAACAAGCCA GGGCTCAAGTACAAGCCTGTCTGCAACCAGGTGGAATGTCATCCTTACTTCAACCAGA GAAAACTGCTGGATTTCTGCAAGTCAAAAGACATTGTTCTGGTTGCCTATAGTGCTCT GGGATCCCACCGAGAAGAACCATGGGTGGACCCGAACTCCCCGGTGCTCTTGGAGGAC CCAGTCCTTTGTGCCTTGGCAAAAAAGCACAAGCGAACCCCAGCCCTGATTGCCCTGC GCTACCAGCTACAGCGTGGGGTTGTGGTCCTGGCCAAGAGCTACAATGAGCAGCGCAT CAGACAGAACGTGCAGGTGTTTGAATTCCAGTTGACTTCAGAGGAGATGAAAGCCATA GATGGCCTAAACAGAAATGTGCTCGAGGGTG

ORF Start: at 1 ORF Stop: at 901

SEQ ID NO: 232 300 aa MW at 33957.7kD

NOV70c, ARSLNDGHFMPVLGFGTYAPAEVPKSKALEATKLAIEAGFRHIDSAHLYNlsTEEQVGLA 268669100 IRSKIADGSVKREDIFYTSKL CNSHRPELVRPALERSLKNLQLDYVDLYLIHFPVSV

Protein KPGEEVIPKDENGKILFDTλ DLCAT EAVEKCKDAGLAKSIGVSNFNRRQLEMILNKP GLKYKPVCNQVECHPYFNQRKLLDFCKSKDIVLVAYSALGSHREEP VDPNSPVLLED

Sequence PVLCALAKKHKRTPALIALRYQLQRGWVLAKSYNΞQRIRQNVQVFEFQLTSEΞMKAI DGLNRNVLEG

SEQ ID NO: 233 11012 bp

)NOV70d, GCCGGTACCACCATGGGCCACCATCACCACCATCACGATTCGAAATATCAGTGTGTGA J277583389 AGCTGAATGATGGTCACTTCATGCCTGTCCTGGGATTTGGCACCTATGCGCCTGCAGA GGTTCCTAAAAGTAAAGCTTTAGAGGCCACCAAATTGGCAATTGAAGCTGGCTTCCGC [DNA CATATTGATTCTGCTCATTTATACAATAATGAGGAGCAGGTTGGACTGGCCATCCGAA 'Sequence GCAAGATTGCAGATGGCAGTGTGAAGAGAGAAGACATATTCTACACTTCAAAGCTTTG GTGCAATTCCCATCGACCAGAGTTGGTCCGACCAGCCTTGGAAAGGTCACTGAAAAAT CTTCAATTGGATTATGTTGACCTCTACCTTATTCATTTTCCAGTGTCTGTAAAGCCAG GTGAGGAAGTGATCCCAAAAGATGAAAATGGAAAAATACTATTTGACACAGTGGATCT CTGTGCCACGTGGGAGGCCGTGGAGAAGTGTAAAGATGCAGGATTGGCCAAGTCCATC GGGGTGTCCAACTTCAACCGCAGGCAGCTGGAGATGATCCTCAACAAGCCAGGGCTCA AGTACAAGCCTGTCTGCAACCAGGTGGAATGTCATCCTTACTTCAACCAGAGAAAACT GCTGGATTTCTGCAAGTCAAAAGACATTGTTCTGGTTGCCTATAGTGCTCTGGGATCC CACCGAGAAGAACCATGGGTGGACCCGAACTCCCCGGTGCTCTTGGAGGACCCAGTCC TTTGTGCCTTGGCAAAAAAGCACAAGCGAACCCCAGCCCTGATTGCCCTGCGCTACCA GCTACAGCGTGGGGTTGTGGTCCTGGCCAAGAGCTACAATGAGCAGCGCATCAGACAG AACGTGCAGGTGTTTGAATTCCAGTTGACTTCAGAGGAGATGAAAGCCATAGATGGCC TAAACAGAAATGTGCGATATTTGACCCTTGATATTTTTGCTGGCCCCCCTAATTATCC ATTTTCTGATGAATATCTCGAGGGTG

ORF Start: at 1 ORF Stop: at 1012

SEQ ID NO: 234 MW at 38297.5kD

NOV70d, AGTTMGHHHHHHDSKYQCVKLNDGHFMPVLGFGTYAPAEVPKSKALEATKLAIEAGFR 277583389 ΌIDSAHLYNNEEQVGLAIRSKIADGSVKREDIFYTSKL CNSHRPELVRPALERSLKN LQLDYVDLYLIHFPVSVKPGEEVI KDENGKILFDTVDLCATWEAVEKCKDAGLAKS I j Protein IGVSNFNRRQLEMILNKPGLKYKPVCNQVECHPYFNQRKLLDFCKSKDIVLVAYSALGS Sequence IHREEPWVDPNSPVLLEDPVLCALAKKHKRTPALIALRYQLQRGVWLAKSYNEQRIRQ J VQVFEFQLTSEEMKAIDGLNRNVRYLTLDIFAGPPNYPFSDEYLEG

SEQ ID NO: 538 |972 bp

;NOV70e, TGGATTCGAAATATCAGTGTGTGAAGCTGAATGATGGTCACTTCATGCCTGTCCTGGGA ICG59693-01 TTTGGCACCTATGCGCCTGCAGAGGTTCCTAΆAAGTAAAGCTTTAGAGGCCACCAAATTG

!DNA GCAATTGAAGCTGGCTTCCGCCATATTGATTCTGCTCATTTATACAATAATGAGGAGCAG GTTGGACTGGCCATCCGAAGCAAGATTGCAGATGGCAGTGTGAAGAGAGAAGACATATTC

■Sequence TACACTTCAAAGCTTTGGTGCAATTCCCATCGACCAGAGTTGGTCCGACCAGCCTTGGAA AGGTCACTGAAAAATCTTCAATTGGATTATGTTGACCTCTACCTTATTCATTTTCCAGTG TCTGTAAAGCCAGGTGAGGAAGTGATCCCAAAAGATGAAAATGGAAAAATACTATTTGAC ACAGTGGATCTCTGTGCCACGTGGGAGGCCGTGGAGAAGTGTAAAGATGCAGGATTGGCC AAGTCCATCGGGGTGTCCAACTTCAACCGCAGGCAGCTGGAGATGATCCTCAACAAGCCA GGGCTCAAGTACAAGCCTGTCTGCAACCAGGTGGAATGTCATCCTTACTTCAACCAGAGA AAACTGCTGGATTΓCTGCAAGTCAAAAGACATTGTTCTGGTTGCCTATAGTGCTCTGGGA TCCCACCGAGAAGAACCATGGGTGGACCCGAACTCCCCGGTGCTCTTGGAGGACCCAGTC CTTTGTGCCTTGGCAAAAAAGCACAAGCGAACCCCAGCCCTGATTGCCCTGCGCTACCAG CTACAGCGTGGGGTTGTGGTCCTGGCCAAGAGCTACAATGAGCAGCGCATCAGACAGAAC GTGCAGGTGTTTGAATTCCAGTTGACTTCAGAGGAGATGAAAGCCATAGATGGCCTAAAC AGAAATGTGCGATATTTGACCCTTGATATTTTTGCTGGCCCCCCTAATTATCCATTTTCT GATGAATATTAA

ORF Start: at 1 ORF Stop: TAA at 970

SEQ ID NO: 539 323 aa MW at 36857 kD

NOV70e, MDSKYQCV LNDGHFMPVLGFGTYAPAEVPKSKALEATKLAIEAGFRHIDSAHLYNNEEQ

CG59693-01 VGLAIRSKIADGSVKREDIFYTSKLWCNSHRPELVRPALERSLKNLQLDYVDLY IHFPV SVKPGEEVIPKDENGKILFDTVDLCAT EAVEKCKDAGLAKSIGVSNFNRRQLEMILNKP

Protein GLKYKPVCNQVECHPYFNQRKLLDFCKSKDIVLVAYSALGSHREEPWVDPNSPVLLEDPV Sequence |LCALAKKHKRTPALIALRYQLQRG AA/LAKSY ΞQRIRQNVQVFEFQLTSEEMKAIDGLN

1R VRYLTLDIFAGPPNYPFSDEY

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 70B.

Further analysis of the NOV70a protein yielded the following properties shown in Table 70C.

Table 70C. Protein Sequence Properties NOV70a i PSort j 0.7350 probability located in mitochondrial matrix space; 0.4200 probability analysis: | located in nucleus; 0.4157 probability located in mitochondrial inner membrane; 0.4157 probability located in mitochondrial intermembrane space

SignalP No Known Signal Sequence Indicated analysis:

A search of the NOV70a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 70D.

In a BLAST search of public sequence databases, the NOV70a protein was found to have homology to the proteins shown in the BLASTP data in Table 70E-1.

* HYDROXYSTEROID 28-323 I 289/296 (97%)

! DEHYDROGENASE HOMOLOG

I

] Homo sapiens (Human), 323 aa. In a BLAST search of public sequence databases, the NOV70e protein was found to have homology to the proteins shown in the BLASTP data in Table 70E-2.

Table 70E-2. Public BLASTP Results for NOV70e

Identities/

NOV70e

Protein Similarities

Residues/ Expect

Accession Protein/Organism/Length for the

Match Value

Number Matched

Residues

Portion

Q04828 ! Aldo-keto reductase family 1 member Cl 1..323 100% ^; (EC 1.1.1.-) (Trans- 1,2- dihydrobenzene- 1..323 (323 of 323) 1 1 ,2-diol dehydrogenase) (EC 1.3.1.20) ! (High-affinity hepatic bile acid-binding ! protein) (HBAB) (Chlordecone reductase ; homolog HAKRC) (Dihydrodiol , dehydrogenase 2) (DD2) (20 alpha- i hydroxysteroid dehydrogenase) - Homo sapiens (Human), 323 aa.

PFam analysis indicates that the NOV70a protein contains the domains shown in the

Table 70F.

Example 71.

The NOV71 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 71 A.

CAGCCCGTGCGTGGGAGTGTACTAAGGACAGATGTGGGGAAGTCAGAAATGAAGAAAAJ

TGCCTGTCACTGCTCAGAGGACTGCTTGGCCAGGGGAGACTGCTGTACCAATTACCAAI

GTGGTTTGCAAAGGAGAGTCGCATTGGGTTGATGATGACTGTGAGGAAATAAAGGCCG

CAGAATGCCCTGCAGGGTTTGTTCGCCCTCCATTAATCATCTTCTCCGTGGATGGCTT

CCGTGCATCATACATGAAGAAAGGCAGCAAAGTCATGCCTAATATTGAAAAACTAAGG

TCTTGTGGCACACACTCTCCCTACATGAGGCCGGTGTACCCAACTAAAACCTTTCCTA

ACTTATACACTTTGGCCACTGGGCTATATCCAGAATCACATGGAATTGTTGGCAATTC

AATGTATGATCCTGTATTTGATGCCACTTTTCATCTGCGAGGGCGAGAGAAATTTAAT

CATAGATGGTGGGGAGGTCAACCGCTATGGATTACAGCCACCAAGCAAGGGGTGAAAG

CTGGAACATTCTTTTGGTCTGTTGTCATCCCTCACGAGCGGAGAATATTAACCATATT

GCAGTGGCTCACCCTGCCAGATCATGAGAGGCCTTCGGTCTATGCCTTCTATTCTGAG

CAACCTGATTTCTCTGGACACAAATATGGCCCTTTCGGCCCTGAGATGACAAΆTCCTC

TGAGGGAAATCGACAAAATTGTGGGGCAΆTTAATGGATGGACTGAAACAACTAAAACT

GCATCGGTGTGTCAACGTCATCTTTGTCGGAGACCATGGAATGGAAGATGTCACATGT

GATAGAACTGAGTTCTTGAGTAATTACCTAACTAATGTGGATGATATTACTTTAGTGC

CTGGAACTCTAGGAΆGAATTCGATCCAAATTTAGCAACAATGCTAAATATGΆCCCCAA

AGCCATTATTGCCAATCTCACGTGTAAAAAACCAGATCAGCACTTTAAGCCTTACTTG

AAACAGCACCTTCCCAAACGTTTGCACTATGCCAACAACAGAAGAATTGAGGATATCC

ATTTATTGGTGGAACGCAGATGGCATGTTGCAAGGAAACCTTTGGATGTTTATAAGAA CCATCAGGAAAATGCTTTTTCCAGGGAGACCACGGATTTGATAACAAGGTCAACAGC

ATGCAGACTGTTTTTGTAGGTTATGGCCCAACATTTAAGTACAAGACTAAAGTGCCTC

CATTTGAAAACATTGAACTTTACAATGTTATGTGTGATCTCCTGGGATTGAAGCCAGC CCTAATAATGGGACCCATGGAAGTTTGAATCATCTCCTGCGCACTAATACCTTCAGG

CCAACCATGCCAGAGGAAGTTACCAGACCCAATTATCCAGGGATTATGTACCTTCAGT

CTGATTTTGACCTGGGCTGCACTTGTGATGATAAGGTAGAGCCAAAGAACAAGTTGGA

TGAACTCAACAAACGGCTTCATACAAAAGGGTCTACAGAAGAGAGACACCTCCTCTAT

GGGCGACCTGCAGTGCTTTATCGGACTAGATATGATATCTTATATCACACTGACTTTG

AAAGTGGTTATAGTGAAATATTCCTAATGCCACTCTGGACATCATATACTGTTTCCAA

ACAGGCTGAGGTTTCCAGCGTTCCTGACCATCTGACCAGTTGCGTCCGGCCTGATGTC

CGTGTTTCTCCGAGTTTCAGTCAGAACTGTTTGGCCTACAAAAATGATAAGCAGATGT

CCTACGGATTCCTCTTTCCTCCTTATCTGAGCTCTTCACCAGAGGCTAAATATGATGC

ATTCCTTGTAACCAATATGGTTCCAATGTATCCTGCTTTCAAACGGGTCTGGAATTAT

TTCCAAAGGGTATTGGTGAAGAAATATGCTTCGGAAAGAAATGGAGTTAACGTGATAA

GTGGACCAATCTTCGACTATGACTATGATGGCTTACATGACACAGAAGACAAAATAAA

ACAGTACGTGGAAGGCAGTTCCATTCCTGTTCCAACTCACTACTACAGCATCATCACC

AGCTGTCTGGATTTCACTCAGCCTGCCGACAAGTGTGACGGCCCTCTCTCTGTGTCCT

CCTTCATCCTGCCTCACCGGCCTGACAACGAGGAGAGCTGCAATAGCTCAGAGGACGA

ATCAAAATGGGTAGAAGAACTCATGAAGATGCACACAGCTAGGGTGCGTGACATTGAA

CATCTCACCAGCCTGGACTTCTTCCGAAAGACCAGCCGCAGCTACCCAGAAATCCTGA

CACTCAAGACATACCTGCATACATATGAGAGCGAGATTTAACTTTCTGAGCATCTGCA

GTACAGTCTTATCAACTGGTTGTATATTTTTATATTGTTTTTGTATTTATTAATTTGA

AACCAGGACATTAAAAATGTTAGTATTTTAATCCTGTACCAAATCTGACATATTATGC

CTGAATGACTCCACTGTTTTTCTCTAATGCTTGATTTAGGTAGCCTTGTGTTCTGAGT

AGAGCTTGTAATAAATACTGCAGCTTGAGTTTTTAGTGGAAGCTTCTAAATGGTGCTG

CAGATTTGATATTTGCATTGAGGAAATATTAATTTTCCAATGCACAGTTGCCACATTT

AGTCCTGTACTGTATGGAAACACTGATTTTGTAAAGTTGCCTTTATTTGCTGTTAACT

GTTAACTATGACAGATATATTTAAGCCTTATAAACCAATCTTAAACATAATAAATCAC

ACATTCAGTTTTTTCTGGTAAAAAAAAAAAAAAAAA

ORF Start: ATG at 60 ORF Stop: TAA at 2649

SEQ ID NO: 236 863 aa MW at 99016.6kD

NOV71a, IVLARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEGWEEGPPTVLSDSPWTNISGS

CG93541-01 Protein CKGRCFELQΞAGPPDCRCDNLCKSYTSCCHDFDELCLKTARAWECT DRCGEVRNEEN ACHCSEDCLARGDCCT YQWCKGESHKTVDDDCEEIKAAECPAGFVRPPLIIFSλπDGF Sequence RASYMKKGSKV PNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPESHGIVGNS MYDPVFDATFHLRGREKFNHR GGQPL ITATKQGVKAGTFFWSWIPHΞRRILTIL Q LTLPDHERPSVYAFYSEQPDFSGHKYGPFGPEMTNPLREIDKIVGQL DGLKQLKL HRCVFVIFVGDHG EDVTCDRTEFLS YLT VDDITLVPGTLGRIRSKFSNLvJAKYDPK AIIANLTCKKPDQHFKPYLKQHLPKRLHYANNRRIEDIHLLVERRWHVARKPLDVYKK PSG CFFQGDHGFDNIO SMQTVFVGYGPTFKYKTiα/^'PPFENIELYNVMCDLLGLKPA PNNGTHGSLNHLLRTNTFRPTMPEEVTRPNYPGI YLQSDFDLGCTCDDKVEPKNKLD ELNKRLHTKGSTEERHLLYGRPAVLYRTRYDILYHTDFESGYSEIFLMPL TSYTVSK QAEVSSVPDHLTSCVRPDVRVSPSFSQNCLAYKNDKQMSYGFLFPPYLSSSPEAKYDA FL TNMVPMYPAFKRVW YFQ VLVKKYASERNGVNVISGPIFDYDYDG HDTEDKIK QYVEGSSIPVPTHYYSIITSCLDFTQPADKCDGPLSVSSFILPHRPDNEESCNSSEDE SK VEELMKMHTARVRDIEHLTSLDFFRKTSRSYPEILTLKTYLHTYESEI

SEQ ID NO: 237 1080 bp

NOV71b, CGTGAAGGCAAAGAGAACACGCTGCAAAAGGCTTCCAAGAATCCTCGACATGGCAAGA CG93541-02 DNA AGGAGCTCGTTCCAGTCGTGTCAGATAATATCCCTGTTCACTTTTGCCGTTGGAGTCA ATATCTGCTTAGGATTCACTGCACATCGAATTAAGAGAGCAGAAGGATGGGAGGAAGG Sequence TCCTCCTACAGTGCTATCAGACTCCCCCTGGACCAACATCTCCGGATCTTGCAAGGGC AGGTGCTTTGAACTTCAAGAGGCTGGACCTCCTGATTGTCGCTGTGACAACTTGTGTA AGAGCTATACCAGTTGCTGCCATGACTTTGATGAGCTGTGTTTGAAGACAGCCCGTGG CTGGGAGTGTACTAAGGACAGATGTGGAGAAGTCAGAAATGAAGAAAATGCCTGTCAC TGCTCAGAGGACTGCTTGGCCAGGGGAGACTGCTGTACCAATTACCAAGTGGTTTGCA AAGGAGAGTCGCATTGGGTTGATGATGACTGTGAGGAAATAAAGGCCGCAGAATGCCC TGCAGGGTTTGTTCGCCCTCCATTAATCATCTTCTCCGTGGATGGCTTCCGAAAGACC AGCCGCAGCTACCCAGAAATCCTGACACTCAAGACATACCTGCATACATATGAGAGCG AGATTTAACTTTCTGAGCATCTGCAGTACAGTCTTATCAACTGGTTGTATATTTTTAT

ATTGTTTTTGTATTTATTAATTTGAAACCAGGACATTAAAAATGTTAGTATTTTAATC

CTGTACCAAATCTGACATATTATGCCTGAATGACTCCACTGTTTTTCTCTAATGCTTG

ATTTAGGTAGCCTTGTGTTCTGAGTAGAGCTTGTAATAAATACTGCAGCTTGAGAAAA

AGTGGAAGCTTCTAAATGGTGCTGCAGATTTGATATTTGCATTGAGGAAATATTAATT

TTCCAATGCACAGTTGCCACATTTAGTCCTGTACTGTATGGAAACACTGATTTTGTAA

AGTTGCCTTTATTTGCTGTTAACTGTTAACTATGACAGATATATTTAAGCCTTATAAA

CCAATCTTAAACATAATAAATCACACATTCAGTTTT

ORF Start: ATG at 50 ORF Stop: TAA at 644

SEQ ID NO: 238 198 aa MW at 22254.8kD

^'NOV71b, SMARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAΞG EEGPPTVLSDSPWTNISGS

CG93541-02 Protein CKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRCGEVRNEEN ACHCSEDCLARGDCCTNYQWCKGΞSH VDDDCEEIKAAECPAGFVRPPLI IFSVDGF

: Sequence RKTS RS YPE I LTLKTYLHTYE S E I

SEQ ID NO: 239 251 1 bp

^NOV71c, ACCATGGTAAGCGCTATTGTTTTATATGTGCTTTTGGCGGCGGCGGCGCATTCTGCCT |CG93541-03 DNA TTGCGGACTCCCCCTGGACCAACATCTCCGGATCTTGCAAGGGCAGGTGCTTTGAACT TCAAGAGGCTGGACCTCCTGATTGTCGCTGTGACAACTTGTGTAAGAGCTATACCAGT Sequence TGCTGCCATGACTTTGATGAGCTGTGTTTGAAGACAGCCCGTGGCTGGGAGTGTACTA AGGACAGATGTGGAGAAGTCAGAAATGAAGAAAATGCCTGTCACTGCTCAGAGGACTG CTTGGCCAGGGGAGACTGCTGTACCAATTACCAAGTGGTTTGCAAAGGAGAGTCGCAT TGGGTTGATGATGACTGTGAGGAAATAAAGGCCGCAGAATGCCCTGCAGGGTTTGTTC GCCCTCCATTAATCATCTTCTCCGTGGATGGCTTCCGTGCATCATACATGAAGAAAGG CAGCAAAGTCATGCCTAATATTGAAAAACTAAGGTCTTGTGGCACACACTCTCCCTAC ATGAGGCCGGTGTACCCAACTAAAACCTTTCCTAACTTATACACTTTGGCCACTGGGC TATATCCAGAATCACATGGAATTGTTGGCAATTCAATGTATGATCCTGTATTTGATGC CACTTTTCATCTGCGAGGGCGAGAGAAATTTAATCATAGATGGTGGGGAGGTCAACCG CTATGGATTACAGCCACCAAGCAAGGGGTGAAAGCTGGAACATTCTTTTGGTCTGTTG TCATCCCTCACGAGCGGAGAATATTAACCATATTGCAGTGGCTCACCCTGCCAGATCA TGAGAGGCCTTCGGTCTATGCCTTCTATTCTGAGCAACCTGATTTCTCTGGACACAAA TATGGCCCTTTCGGCCCTGAGATGACAAATCCTCTGAGGGAAATCGACAAAATTGTGG GGCAATTAATGGATGGACTGAAACAACTAAAACTGCATCGGTGTGTCAACGTCATCTT TGTCGGAGACCATGGAATGGAAGATGTCACATGTGATAGAACTGAGTTCTTGAGTAAT TACCTAACTAATGTGGATGATATTACTTTAGTGCCTGGAACTCTAGGAAGAATTCGAT CCAAATTTAGCAACAATGCTAAATATGACCCCAAAGCCATTATTGCCAATCTCACGTG TAAAAAACCAGATCAGCACTTTAAGCCTTACTTGAAACAGCACCTTCCCAAACGTTTG! CACTATGCCAACAACAGAAGAATTGAGGATATCCATTTATTGGTGGAACGCAGATGGC ATGTTGCAAGGAAACCTTTGGATGTTTATAAGAAACCATCAGGAAAATGCTTTTTCCA GGGAGACCACGGATTTGATAACAAGGTCAACAGCATGCAGACTGTTTTTGTAGGTTATi

528 IGGCCCAACATTTAAGTACAAGACTAAAGTGCCTCCATTTGAAAACATTGAACTTTACAL SATGTTATGTGTGATCTCCTGGGATTGAAGCCAGCTCCTAATAATGGGACCCACGGAAG!

ITTTGAATCATCTCCTGCGCACTAATACCTTCAGGCCAACCATGCCAGAGGAAGTTACC jAGACCCAATTATCCAGGGATTATGTACCTTCAGTCTGATTTTGACCTGGGCTGCACTT

GTGATGATAAGGTAGAGCCAAAGAACAAGTTGGATGAACTCAACAAACGGCTTCATAC

AAAAGGGTCTACAGAAGAGAGACACCTCCTCTATGGGCGACCTGCAGTGCTTTATCGG

ACTAGATATGATATCTTATATCACACTGACTTTGAAAGTGGTTATAGTGAAATATTCC

TAATGCCACTCTGGACATCATATACTGTTTCCAAACAGGCTGAGGTTTCCAGCGTTCC

TGACCATCTGACCAGTTGCGTCCGGCCTGATGTCCGTGTTTCTCCGAGTTTCAGTCAG

AACTGTTTGGCCTACAAAAATGATAAGCAGATGTCCTACGGATTCCTCTTTCCTCCTT

ATCTGAGCTCTTCACCAGAGGCTAAATATGATGCATTCCTTGTAACCAATATGGTTCC

AATGTATCCTGCTTTCAAACGGGTCTGGAATTATTTCCAAAGGGTATTGGTGAAGAAA

TATGCTTCGGAAAGAAATGGAGTTAACGTGATAAGTGGACCAATCTTCGACTATGACT

ATGATGGCTTACATGACACAGAAGACAAAATAAAACAGTACGTGGAAGGCAGTTCCAT

TCCTGTTCCAACTCACTACTACAGCATCATCACCAGCTGTCTGGATTTTACTCAGCCT

GCCGACAAGTGTGACGGCCCTCTCTCTGTGTCCTCCTTCATCCTGCCTCACCGGCCTG

ACAACGAGGAGAGCTGCAATAGCTCAGAGGACGAATCAAAATGGGTAGAAGAACTCAT

GAAGATGCACACAGCTAGGGTGCGTGACATTGAACATCTCACCAGCCTGGACTTCTTC

CGAAAGACCAGCCGCAGCTACCCAGAAATCCTGACACTCAAGACATACTTGCATACAT

!ATGAGAGCGAGATTTAA

ORF Start: at 1 ORF Stop: at 835

SEQ ID NO: 240 278 aa MW al 31297.3kD

NOV71 c, TMVSAIVLYVLLAAAAHSAFADSPWTNISGSCKGRCFELQEAGPPDCRCDNLCKSYTS

CG93541 -03 Protein CCHDFDELCL TARG ECTKDRCGEVRNEENACHCSEDCLARGDCCT YQWC GESH WDDDCEEIP AAECPAGFVRPPLIIFSVDGFRASYMKKGSKVMPNIEKLRSCGTHSPY Sequence MRPVYPTKTFPNLYTLATGLYPESHGIVGNSMYDPVFDATFHLRGREKFNHR GGQP LWITATKQGVKAGTFFWS IPHERRILTILQWLTLPDHERPSVYA

SEQ ID NO: 241 2596 bp

^■NOV71 d, CCACCATGGCAAGGAGGAGCTCGTTCCAGTCGTGTCAGATAATATCCCTGTTCACTTT

CG93541-04 DNA TGCCGTTGGAGTCAATATCTGCTTAGGATTCACTGCACATCGAATTAAGAGAGCAGAA GGATGGGAGGAAGGTCCTCCTACAGTGCTATCAGACTCCCCCTGGACCAACATCTCCG Sequence GATCTTGCAAGGGCAGGTGCTTTGAACTTCAAGAGGCTGGACCTCCTGATTGTCGCTG TGACAACTTGTGTAAGAGCTATACCAGTTGCTGCCATGACTTTGATGAGCTGTGTTTG AAGACAGCCCGTGGCTGGGAGTGTACTAAGGACAGATGTGGAGAAGTCAGAAATGAAG AAAATGCCTGTCACTGCTCAGAGGACTGCTTGGCCAGGGGAGACTGCTGTACCAATTA CCAAGTGGTTTGCAAAGGAGAGTCGCATTGGGTTGATGATGACTGTGAGGAAATAAAG GCCGCAGAATGCCCTGCAGGGTTTGTTCGCCCTCCATTAATCATCTTCTCCGTGGATG GCTTCCGTGCATCATACATGAAGAAAGGCAGCAAAGTCATGCCTAATATTGAAAAACT AAGGTCTTGTGGCACACACTCTCCCTACATGAGGCCGGTGTACCCAACTAAAACCTTT CCTAACTTATACACTTTGGCCACTGGGCTATATCCAGAATCACATGGAATTGTTGGCA ATTCAATGTATGATCCTGTATTTGATGCCACTTTTCATCTGCGAGGGCGAGAGAAATT TAATCATAGATGGTGGGGAGGTCAACCGCTATGGATTACAGCCACCAAGCAAGGGGTG AAAGCTGGAACATTCTTTTGGTCTGTTGTCATCCCTCACGAGCGGAGAATATTAACCA TATTGCAGTGGCTCACCCTGCCAGATCATGAGAGGCCTTCGGTCTATGCCTTCTATTC TGAGCAACCTGATTTCTCTGGACACAAATATGGCCCTTTCGGCCCTGAGATGACAAAT CCTCTGAGGGAAATCGACAAAATTGTGGGGCAATTAATGGATGGACTGAAACAACTAA AACTGCATCGGTGTGTCAACGTCATCTTTGTCGGAGACCATGGAATGGAAGATGTCAC ATGTGATAGAACTGAGTTCTTGAGTAATTACCTAACTAATGTGGATGATATTACTTTA GTGCCTGGAACTCTAGGAAGAATTCGATCCAAATTTAGCAACAATGCTAAATATGACC CCAAAGCCATTATTGCCAATCTCACGTGTAAAAAACCAGATCAGCACTTTAAGCCTTA CTTGAAACAGCACCTTCCCAAACGTTTGCACTATGCCAACAACAGAAGAATTGAGGAT ATCCATTTATTGGTGGAACGCAGATGGCATGTTGCAAGGAAACCTTTGGATGTTTATA AGAAACCATCAGGAAAATGCTTTTTCCAGGGAGACCACGGATTTGATAACAAGGTCAA CAGCATGCAGACTGTTTTTGTAGGTTATGGCCCAACATTTAAGTACAAGACTAAAGTG CCTCCATTTGAAAACATTGAACTTTACAATGTTATGTGTGATCTCCTGGGATTGAAGC CAGCTCCTAATAATGGGACCCACGGAAGTTTGAATCATCTCCTGCGCACTAATACCTT CAGGCCAACCATGCCAGAGGAAGTTACCAGACCCAATTATCCAGGGATTATGTACCTT CAGTCTGATTTTGACCTGGGCTGCACTTGTGATGATAAGGTAGAGCCAAAGAACAAGT

529 ;TGGATGAACTCAACAAACGGCTTCATACAAAAGGGTCTACAGAAGAGAGACACCTCCT'

¹CTATGGGCGACCTGCAGTGCTTTATCGGACTAGATATGATATCTTATATCACACTGAC ^'■

,TTTGAAAGTGGTTATAGTGAAATATTCCTAATGCCACTCTGGACATCATATACTGTTTj

;CCAAACAGGCTGAGGTTTCCAGCGTTCCTGACCATCTGACCAGTTGCGTCCGGCCTGA_| iTGTCCGTGTTTCTCCGAGTTTCAGTCAGAACTGTTTGGCCTACAAAAATGATAAGCAG;

^''ATGTCCTACGGATTCCTCTTTCCTCCTTATCTGAGCTCTTCACCAGAGGCTAAATATGI

ATGCATTCCTTGTAACCAATATGGTTCCAATGTATCCTGCTTTCAAACGGGTCTGGAA

TTATTTCCAAAGGGTATTGGTGAAGAAATATGCTTCGGAAAGAAATGGAGTTAACGTG

ATAAGTGGACCAATCTTCGACTATGACTATGATGGCTTACATGACACAGAAGACAAAA

TAAAACAGTACGTGGAAGGCAGTTCCATTCCTGTTCCAACTCACTACTACAGCATCAT

CACCAGCTGTCTGGATTTCACTCAGCCTGCCGACAAGTGTGACGGCCCTCTCTCTGTG

TCCTCCTTCATCCTGCCTCACCGGCCTGACAACGAGGAGAGCTGCAATAGCTCAGAGG

ACGAATCAAAATGGGTAGAAGAACTCATGAAGATGCACACAGCTAGGGTGCGTGACAT

TGAACATCTCACCAGCCTGGACTTCTTCCGAAAGACCAGCCGCAGCTACCCAGAAATC

CTGACACTCAAGACATACTTGCATACATATGGAGCGAGATTTAA

ORF Start: at 3 ORF Stop: at 2595

SEQ ID NO: 242 864 aa MW at 99076.7kD

,NOV71d, TMARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEG EEGPPTVLSDSP TNISG JCG93541 -04 Protein SCKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRCGEVRNEΞ

JNACHCSEDCLARGDCCTNYQWC GΞSHWVDDDCEEIKAAECPAGFVRPPLIIFSVDG

'Sequence JFRASYMKKGSKVMPNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPESHGIVGN

ISMYDPVFDATFHLRGREKFNHRWWGGQPLWITATKQGVKAGTFFWSWIPHERRILTI

JLQWLTLPDHERPSVYAFYSEQPDFSGHKYGPFGPEMTNPLREIDKIVGQLMDGLKQLK ILHRC-VIJVIFVGDHGMEDVTCDRTEFLSNYLTNVDDITLVPGTLGRIRSKFSNNAKYDP ; KAIIANLTCK PDQHFKPYLKQHLPKRLHYANNRRIEDIHLLVERR HVARKPLD^"VYK KPSGKCFFQGDHGFDNKVNSMQTVFVGYGPTFKY TKVPPFENIELYNVMCDLLGLKP AP NGTHGSLNHLLRTNTFRPT PEEVTRPNYPGIMYLQSDFDLGCTCDDKVEPKNKL DELNKRLHTKGSTEERHLLYGRPAVLYRTRYDILYHTDFESGYSEIFLMPLWTSYTVS KQAEVSSVPDHLTSCVRPDVRVSPSFSQNCLAYKNDKQMSYGFLFPPYLSSSPEAKYD AFLVTNMVPMYPAFKRV NYFQRVLVKKYASERNGVNVISGPIFDYDYDGLHDTEDKI QYVEGSSIPVPTHYYSIITSCLDFTQPADKCDGPLSVSSFILPHRPDNEESCNSSED ESK VEELMKMHTARVRDIEHLTSLDFFRKTSRSYPEILTLKTYLHTYGARF

ISEQ ID NO: 243 2617 bp _ιNOV71e ,CACCATGGGCCACCATCACCACCATCACGCAAGGAGGAGCTCGTTCCAGTCGTGTCAG

!CC ""541-05 DNA i-A.TAATATCCCTGTTCACTTTTGCCGTTGGAGTCAATATCTGCTTAGGATTCACTGCAC

I ^{J ~} TCGAATTAAGAGAGCAGAAGGATGGGAGGAAGGTCCTCCTACAGTGCTATCAGACTC JSequence J_CCCCTGGACCAACATCTCCGGATCTTGCAAGGGCAGGTGCTTTGAACTTCAAGAGGCT ¹ •GGACCTCCTGATTGTCGCTGTGACAACTTGTGTAAGAGCTATACCAGTTGCTGCCATG

|ACTTTGATGAGCTGTGTTTGAAGACAGCCCGTGGCTGGGAGTGTACTAAGGACAGATG ITGGAGAAGTCAGAAATGAAGAAAATGCCTGTCACTGCTCAGAGGACTGCTTGGCCAGG GGAGACTGCTGTACCAATTACCAAGTGGTTTGCAAAGGAGAGTCGCATTGGGTTGATG ATGACTGTGAGGAAATAAAGGCCGCAGAATGCCCTGCAGGGTTTGTTCGCCCTCCATT AATCATCTTCTCCGTGGATGGCTTCCGTGCATCATACATGAAGAAAGGCAGCAAAGTC ATGCCTAATATTGAAAAACTAAGGTCTTGTGGCACACACTCTCCCTACATGAGGCCGG TGTACCCAACTAAAACCTTTCCTAACTTATACACTTTGGCCACTGGGCTATATCCAGA ATCACATGGAATTGTTGGCAATTCAATGTATGATCCTGTATTTGATGCCACTTTTCAT CTGCGAGGGCGAGAGAAATTTAATCATAGATGGTGGGGAGGTCAACCGCTATGGATTA CAGCCACCAAGCAAGGGGTGAAAGCTGGAACATTCTTTTGGTCTGTTGTCATCCCTCA CGAGCGGAGAATATTAACCATATTGCAGTGGCTCACCCTGCCAGATCATGAGAGGCCT TCGGTCTΆTGCCTTCTATTCTGAGCAACCTGATTTCTCTGGACACAAΆTATGGCCCTT TCGGCCCTGAGATGACAAATCCTCTGAGGGAAATCGACAAAATTGTGGGGCAATTAAT GGATGGACTGAAACAACTAAAACTGCATCGGTGTGTCAACGTCATCTTTGTCGGAGAC CATGGAATGGAAGATGTCACATGTGATAGAACTGAGTTCTTGAGTAATTACCTAACTA ATGTGGATGATATTACTTTAGTGCCTGGAACTCTAGGAAGAATTCGATCCAAATTTAG CAACAATGCTAAATATGACCCCAAAGCCATTATTGCCAATCTCACGTGTAAAAAACCA GATCAGCACTTTAAGCC_TTAC_TTGAAACAGCACCTTCCCAAACGTTTGCACTATGCCA ACAACAGAAGAATTGAGGATATCCATTTATTGGTGGAACGCAGATGGCATGTTGCAAG GAAACCTTTGGATGTTTATAAGAAACCATCAGGAAAATGCTTTTTCCAGGGAGACCAC JGGATTTGATAACAAGGTCAACAGCATGCAGACTGTTTTTGTAGGTTATGGCCCAACAT FTTAAGTACAAGACTAAAGTGCCTCCATTTGAAAACATTGAACTTTACAATGTTATGTG ^'TGATCTCCTGGGATTGAAGCCAGCTCCTAATAATGGGACCCACGGAAGTTTGAATCAT CTCCTGCGCACTAATACCTTCAGGCCAACCATGCCAGAGGAAGTTACCAGACCCAATT ATCCAGGGATTATGTACCTTCAGTCTGATTTTGACCTGGGCTGCACTTGTGATGATAA GGTAGAGCCAAAGAACAAGTTGGATGAΆCTCAACAAACGGCTTCATACAAAAGGGTCT ACAGAAGAGAGACACCTCCTCTATGGGCGACCTGCAGTGCTTTATCGGACTAGATATG ATATCTTATATCACACTGACTTTGAAAGTGGTTATAGTGAAATATTCCTAATGCCACT CTGGACATCATATACTGTTTCCAAACAGGCTGAGGTTTCCAGCGTTCCTGACCATCTG ACCAGTTGCGTCCGGCCTGATGTCCGTGTTTCTCCGAGTTTCAGTCAGAACTGTTTGG CCTACAAAAATGATAAGCAGATGTCCTACGGATTCCTCTTTCCTCCTTATCTGAGCTC TTCACCAGAGGCTAAATATGATGCATTCCTTGTAACCAATATGGTTCCAATGTATCCT GCTTTCAAACGGGTCTGGAATTATTTCCAAAGGGTATTGGTGAAGAAATATGCTTCGG AAAGAAATGGAGTTAACGTGATAAGTGGACCAATCTTCGACTATGACTATGATGGCTT ACATGACACAGAAGACAAAATAAAACAGTACGTGGAAGGCAGTTCCATTCCTGTTCCA ACTCACTACTACAGCATCATCACCAGCTGTCTGGATTTTACTCAGCCTGCCGACAAGT GTGACGGCCCTCTCTCTGTGTCCTCCTTCATCCTGCCTCACCGGCCTGACAACGAGGA GAGCTGCAATAGCTCAGAGGACGAATCAAAATGGGTAGAAGAACTCATGAAGATGCAC ACAGCTAGGGTGCGTGACATTGAACATCTCACCAGCCTGGACTTCTTCCGAAAGACCA GCCGCAGCTACCCAGAAATCCTGACACTCAAGACATACTTGCATACATATGAGAGCGA

GATTTAA

ORF Start: at 2 ORF Stop: TAA at 2615

SEQ ID NO: 244 871 aa iMW at 99983.61.D

NOV71e, TMGHHHHHHARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEGWEEGPPTVLΞDS :CG93541- 05 Protein PWTNISGSCKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRC GEVRNEENACHCSEDCLARGDCCTNYQWC GESHWVDDDCEEIKAAECPAGFVRPPL 'Sequence IIFSVDGFRASY KKGSKWPNIEKLRSCGTHSPYMRPWPTKTFPNLYTLATGLYPE SHGIVGNSMYDPVFDATFHLRGRE FNHRWWGGQPLWITATKQGVKAGTFFWSWIPH ERRILTILQ LTLPDHΞRPSVYAFYSEQPDFSGHKYGPFGPE TNPLREIDKIVGQLM DGLKQL LHRCλπWIFVGDHGMEDVTCDRTEFLSNYLTNVDDITLVPGTLGRIRSKFS ISπvTAKYDPIG.IIANLTCKKPDQHFKPYLKQHLPKRLHYAIsJNRRIEDIHLLVERR HVAR KPLDλYKKPSG CFFQGDHGFDN λ/NSMQTVFVGYGPTFKYKTKVPPFENIELYNλ C DLLGL PAPNNGTHGSLNHLLRTNTFRPTMPEEVTRPNYPGIMYLQSDFDLGCTCDD VEP^'KNKLDELNKRLHTKGSTEERHLLYGRPAVLYRTRYDILYHTDFESGYSEIFLMPL TSYTVSKQAEVSSVPDHLTSCVRPDVRVSPSFSQNCLAYKNDKQMSYGFLFPPYLSS SPEAKYDAFLVTNTWPMYPAFKRV NYFQRVLVKKYASERNGλ VISGPIFDYDYDGL HDTEDKIKQYVEGSSIPVPTHYYS11TSCLDFTQPADKCDGPLSVSSFILPHRPDNEE SCNSSEDESKWVEΞLM MHTARVRDIEHLTSLDFFRKTSRSYPEILTLKTYLHTYESE I

SEQ ID NO: 245 2644 bp

!NOV71f, CCACCATGGCAAGGAGGAGCTCGTTCCAGTCGTGTCAGATAATATCCCTGTTCACTTT CG93541 -06 DNA TGCCGTTGGAGTCAATATCTGCTTAGGATTCACTGCACATCGAATTAAGAGAGCAGAA GGATGGGAGGAAGGTCCTCCTACAGTGCTATCAGACTCCCCCTGGACCAACATCTCCG ; Sequence GATCTTGCAAGGGCAGGTGCTTTGAACTTCAAGAGGCTGGACCTCCTGATTGTCGCTG TGACAACTTGTGTAAGAGCTATACCAGTTGCTGCCATGACTTTGATGAGCTGTGTTTG AAGACAGCCCGTGGCTGGGAGTGTACTAAGGACAGATGTGGAGAAGTCAGAAATGAAG AAAATGCCTGTCACTGCTCAGAGGACTGCTTGGCCAGGGGAGACTGCTGTACCAATTA CCAAGTGGTTTGCAAAGGAGAGTCGCATTGGGTTGATGATGACTGTGAGGAAATAAAG GCCGCAGAATGCCCTGCAGGGTTTGTTCGCCCTCCATTAATCATCTTCTCCGTGGATG GCTTCCGTGCATCATACATGAAGAAAGGCAGCAAAGTCATGCCTAATATTGAAAAACT AAGGTCTTGTGGCACACACTCTCCCTACATGAGGCCGGTGTACCCAACTAAAACCTTT CCTAACTTATACACTTTGGCCACTGGGCTATATCCAGAATCACATGGAATTGTTGGCA ATTCAATGTATGATCCTGTATTTGATGCCACTTTTCATCTGCGAGGGCGAGAGAAATT TAATCATAGATGGTGGGGAGGTCAACCGCTATGGATTACAGCCACCAAGCAAGGGGTG AAAGCTGGAACATTCTTTTGGTCTGTTGTCATCCCTCACGAGCGGAGAATATTAACCA TATTGCAGTGGCTCACCCTGCCAGATCATGAGAGGCCTTCGGTCTATGCCTTCTATTC TGAGCAACCTGATTTCTCTGGACACAAATATGGCCCTTTCGGCCCTGAGATGACAAAT CCTCTGAGGGAAATCGACAAAATTGTGGGGCAATTAATGGATGGACTGAAACAACTAA

531 AACTGCATCGGTGTGTCAACGTCATCTTTGTCGGAGACCATGGAATGGAAGATGTCAC ATGTGATAGAACTGAGTTCTTGAGTAATTACCTAACTAATGTGGATGATATTACTTTA GTGCCTGGAACTCTAGGAAGAATTCGATCCAAATTTAGCAACAATGCTAAATATGACC CCAAAGCCATTATTGCCAATCTCACGTGTAAAAAACCAGATCAGCACTTTAAGCCTTA CTTGAAACAGCACCTTCCCAAACGTTTGCACTATGCCAACAACAGAAGAATTGAGGAT ATCCATTTATTGGTGGAACGCAGATGGCATGTTGCAAGGAAACCTTTGGATGTTTATA AGAAACCATCAGGAAAATGCTTTTTCCAGGGAGACCACGGATTTGATAACAAGGTCAA CAGCATGCAGACTGTTTTTGTAGGTTATGGCCCAACATTTAAGTACAAGACTAAAGTG CCTCCATTTGAAAACATTGAACTTTACAATGTTATGTGTGATCTCCTGGGATTGAAGC CAGCTCCTAATAATGGGACCCACGGAAGTTTGAATCATCTCCTGCGCACTAATACCTT CAGGCCAACCATGCCAGAGGAAGTTACCAGACCCAATTATCCAGGGATTATGTACCTT CAGTCTGATTTTGACCTGGGCTGCACTTGTGATGATAAGGTAGAGCCAAAGAACAAGT TGGATGAACTCAACAAACGGCTTCATACAAAAGGGTCTACAGAAGAGAGACACCTCCT CTATGGGCGACCTGCAGTGCTTTATCGGACTAGATATGATATCTTATATCACACTGAC TTTGAAAGTGGTTATAGTGAAATATTCCTAATGCCACTCTGGACATCATATACTGTTT CCAAACAGGCTGAGGTTTCCAGCGTTCCTGACCATCTGACCAGTTGCGTCCGGCCTGA TGTCCGTGTTTCTCCGAGTTTCAGTCAGAACTGTTTGGCCTACAAAAATGATAAGCAG ATGTCCTACGGATTCCTCTTTCCTCCTTATCTGAGCTCTTCACCAGAGGCTAAATATG ATGCATTCCTTGTAACCAATATGGTTCCAATGTATCCTGCTTTCAAACGGGTCTGGAA TTATTTCCAAAGGGTATTGGTGAAGAAATATGCTTCGGAAAGAAATGGAGTTAACGTG ATAAGTGGACCAATCTTCGACTATGACTATGATGGCTTACATGACACAGAAGACAAAA TAAAACAGTACGTGGAAGGCAGTTCCATTCCTGTTCCAACTCACTACTACAGCATCAT CACCAGCTGTCTGGATTTTACTCAGCCTGCCGACAAGTGTGACGGCCCTCTCTCTGTG TCCTCCTTCATCCTGCCTCACCGGCCTGACAACGAGGAGAGCTGCAATAGCTCAGAGG ACGAATCAAAATGGGTAGAAGAACTCATGAAGATGCACACAGCTAGGGTGCGTGACAT TGAACATCTCACCAGCCTGGACTTCTTCCGAAAGACCAGCCGCAGCTACCCAGAAATC iCTGACACTCAAGACATACTTGCATACATATGAGAGCGAGATTCACCATCACCACCATC ACTAAGCGGCGTCGAGTCTAGAGGGCCGTTTAAC

ORF Start: at 3 ORF Stop: TAA at 2613

SEQ ID NO: 246 870 aa MW at 99926.5kD I

•NOV71f, TMARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEG EEGPPTVLSDSPWTNISG|

;CG93541-06 Protein SCKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRCGEVRNEE!

NACHCSEDCLARGDCCTNYQWCKGESH VDDDCEEIKAAECPAGFVRPPLIIFSVDG Sequence FRASYMKKGSKVMPNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPΞSHGIVGN

SMYDPVFDATFHLRGREKFNHRW GGQPL ITATKQGVKAGTFFWSΛA/IPHERRILTI

LQWLTLPDHERPSVYAFYSEQPDFSGHKYGPFGPEMTNPLREIDKIVGQLMDGLKQLK

LHRCΛTNVIFVGDHGMEDVTCDRTEFLSNYLTNVDDITLVPGTLGRIRSKFSNNAKYDP

KAIIANLTCKKPDQHFKPYLKQHLPKRLHYAN1MRRIEDIHLLVERRWHVARKPLDVYK

KPSGKCFFQGDHGFDNKΛ SMQTVFVGYGPTFKY TKVPPFENIELYNVMCDLLGLKP

APNNGTHGSLNHLLRTNTFRPTMPEEVTRPNYPGIMYLQSDFDLGCTCDDKVEPK KL

DELN RLHTKGSTEERHLLYGRPAV YRT YDILYHTDFESGYSEIFL PL TSYTVS

KQAEVSSVPDHLTSCVRPDVRVSPSFSQNCLAYKNDKQMSYGFLFPPYLSSSPEAKYD

AF VTNMVPMYPAFKRVWNYFQRVLVKKYASERNGV VISGPIFD D DGLHDTΞDKI

KQYVEGSSIPVPTHYYSIITSCLDFTQPADKCDGPLSVSSFILPHRPDNEESCNSSED

ESK VEEL K HTARVRDIEHLTSLDFFRKTSRSYPEILTLKTYLHTYESEIHHHHHH

SEQ ID NO: 247 2719 bp

NOV71g, CCACCATGGCAAGGAGGAGCTCGTTCCAGTCGTGTCAGATAATATCCCTGTTCACTTT 171741 160 DNA TGCCGTTGGAGTCAATATCTGCTTAGGATTCACTGCACATCGAATTAAGAGAGCAGAA GGATGGGAGGAAGGTCCTCCTACAGTACTATCAGACTCCCCCTGGACCAACATCTCCG Sequence GATCTTGCAAGGGCAGGTGCTTTGAACTTCAAGAGGCTGGACCTCCTGATTGTCGCTG TGACAACTTGTGTAAGAGCTATACCAGTTGCTGCCATGACTTTGATGAGCTGTGTTTG AAGACAGCCCGTGGCTGGGAGTGTACTAAGGACAGATGTGGAGAAGTCAGAAATGAAG AAAATGCCTGTCACTGCTCAGAGGACTGCTTGGCCAGGGGAGACTGCTGTACCAATTA CCAAGTGGTTTGCAAAGGAGAGTCGCATTGGGTTGATGATGACTGTGAGGAAATAAAG GCCGCAGAATGCCCTGCAGGGTTTGTTCGCCCTCCATTAATCATCTTCTCCGTGGATG GCTTCCGTGCATCATACATGAAGAAAGGCAGCAAAGTCATGCCTAATATTGAAAAACT AAGGTCTTGTGGCACACACTCTCCCTACATGAGGCCGGTGTACCCAACTAAAACCTTT CCTAACTTATACACTTTGGCCACTGGGCTATATCCAGAATCACATGGAATTGTTGGCA ATTCAATGTATGATCCTGTATTTGATGCCACTTTTCATCTGCGAGGGCGAGAGAAATT TAATCATAGATGGTGGGGAGGTCAACCGCTATGGATTACAGCCACCAAGCAAGGGGTG jAAAGCTGGAACATTCTTTTGGTCTGTTGTCATCCCTCACGAGCGGAGAATATTAACCA TATTGCAGTGGCTCACCCTGCCAGATCATGAGAGGCCTTCGGTCTATGCCTTCTATTC TGAGCAACCTGATTTCTCTGGACACAAATATGGCCCTTTCGGCCCTGAGATGACAAATJ CCTCTGAGGGAAATCGACAAAATTGTGGGGCAATTAATGGATGGACTGAAACAACTAA AACTGCATCGGTGTGTCAACGTCATCTTTGTCGGAGACCATGGAATGGAAGATGTCAC ATGTGATAGAACTGAGTTCTTGAGTAATTACCTAACTAATGTGGATGATATTACTTTA GTGCCTGGAACTCTAGGAAGAATTCGATCCAAATTTAGCAACAATGCTAAATATGACC CCAAAGCCATTATTGCCAATCTCACGTGTAAAAAACCAGATCAGCACTTTAAGCCTTA CTTGAAACAGCACCTTCCCAAACGTTTGCACTATGCCAACAACAGAAGAATTGAGGAT ATCCATTTATTGGTGGAACGCAGATGGCATGTTGCAAGGAAACCTTTGGATGTTTATA AGAAACCATCAGGAAAATGCTTTTTCCAGGGAGACCACGGATTTGATAACAAGGTCAA CAGCATGCAGACTGTTTTTGTAGGTTATGGCCCAACATTTAAGTACAAGACTAAAGTG CCTCCATTTGAAAACATTGAACTTTACAATGTTATGTGTGATCTCCTGGGATTGAAGC CAGCTCCTAATAATGGGACCCATGGAAGTTTGAATCATCTCCTGCGCACTAATACCTT CAGGCCAACCATGCCAGAGGAAGTTACCAGACCCAATTATCCAGGGATTATGTACCTT CAGTCTGATTTTGACCTGGGCTGCACTTGTGATGATAAGGTAGAGCCAAAGAACAAGT TGGATGAGCTCAACAAACGGCTTCATACAAAAGGGTCTACAGAAGCTGAAACCAGGAA ATACAGAGGCACCAGAAATGAAAACAAGGAAAACATTAATGGAAATTTTGAACCTAGA AAAGAGAGACACCTCCTCTATGGGCGACCTGCAGTGCTTTATCGGACTAGATATGATA TCTTATATCACACTGACTTTGAAAGTGGTTATAGTGAAATATTCCTAACGCCACTCTG GACATCATATACTGTTTCCAAACAGGCTGAGGTTTCCAGCGTTCCTGACCATCTGACC AGTTGCGTCCGGCCTGATGTCCGTGTTTCTCCGAGTTTCAGTCAGAACTGTTTGGCCT ACAAAAATGATAAGCAGATGTCCTACGGATTCCTCTTTCCTCCTTATCTGAGCTCTTC GCCAGAGGCTAAATATGATGCATTCCTTGTAACCAATATGGTTCCAATGTATCCTGCT TTCAAACGGGTCTGGAATTATTTCCAAAGGGTATTGGTGAAGAAATATGCTTCGGAAA GAAATGGAGTTAACGTGATAAGTGGACCAATCTTCGACTATGACTATGATGGCTTACA TGACACAGAAGACAAAATAAAACAGTACGTGGAAGTCAGTTCCATTCCTGTTCCAACT CACTACTACAGCATCATCACCAGCTGTCTGGATTTCACTCAGCCTGCCGACAAGTGTG ACGGCCCTCTCTCTGTGTCCTCCTTCATCCTGCCTCACCGGCCTGACAACGAGGAGAG CTGCAATAGCTCAGAGGACGAATCAAAATGGGTAGAAGAACTCATGAAGATGCACACA GCTAGGGTGCGTGACATTGAACATCTCGCCAGCCTGGACTTCTTCCGAAAGACCAGCC GCAGCTACCCAGAAATCCTGACACTCAAGACATACCTGCATACATATGAGAGCGAGAT TCACCATCACCACCATCACTAAGCGGCGCTCGAGTCTAGAGGGCCGTTTAA

ORF Start: at : ORF Stop: TAA at 2688

SEQ ID NO: 248 895 aa IMW at 102912.8kD

NOV71g, TMARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEG EEGPPTVLSDSP TNISG 171741160 Protein SCKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDΞLCLKTARGWECTKDRCGEVRNΞE NACHCSEDCLARGDCCT YQWCKGESHtWDDDCEEI AAECPAGFVRPPLIIFSVDG Sequence FRASYMKKGSKV PNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPESHGIVGN SMYDPVFDATFHLRGREKFNHRWWGGQPLWITATKQGVKAGTFFWSWIPHERRILTI LQWLTLPDHΞRPSWAFYSEQPDFSGHKYGPFGPE TNPLREIDKIVGQLMDGLKQLK LHRC\WVIFVGDHGMEDVTCDRTΞFLSNYLTNVDDITLVPGTLGRIRSKFS NAKYDP KAIIANLTCKKPDQHFKPYLKQHLPKRLHYANNRRIEDIHLLVERR HVARKPLDATYK KPSGKCFFQGDHGFDNKV SMQTVFVGYGPTFKYKTKVPPFENIELY V CDLLGLKP APN GTHGSLNHLLRTNTFRPTMPEEVTRP YPGI YLQSDFDLGCTCDDKVEP KL DELNKRLHTKGSTEAETRKYRGTRNENKENINGNFEPRKERHLLYGRPAVLYRTRYDI LYHTDFESGYSEIFLTPLWTSYTVSKQAΞVSSVPDHLTSCVRPDVRVSPSFSQNCLAY KNDKQMSYGFLFPPYLSSSPEAKYDAFLVTNIWPMYPAFKR NYFQRVLVKKYASER NGλTNVISGPIFDYDYDGLHDTEDKIKQYVEVSSIPVPTHYYSIITSCLDFTQPADKCD GPLSVSSFILPHRPDNEESCNSSEDESK VEELMKMHTARVRDIEHLASLDFFRKTSR SYPEILTLKTYLHTYESEIHHHHHH

SEQ ID NO: 249 2614 bp

NOV71h, CACCATGGCAAGGAGGAGCTCGTTCCAGTCGTGTCAGATAATATCCCTGTTCACTTTT 181518641 DNA GCCGTTGGAGTCAATATCTGCTTAGGATTCACTGCACATCGAATTAAGAGAGCAGAAG GATGGGAGGAAGGTCCTCCTACAGTGCTATCAGACTCCCCCTGGACCAACATCTCCGG Sequence ATCTTGCAAGGGCAGGTGCTTTGAACTTCAAGAGGCTGGACCTCCTGATTGTCGCTGT JGACAACTTGTGTAAGAGCTATACCAGTTGCTGCCATGACTTTGATGAGCTGTGTTTGA AGACAGCCCGTGGCTGGGAGTGTACTAAGGACAGATGTGGAGAAGTCAGAAATGAAGA AAATGCCTGTCACTGCTCAGAGGACTGCTTGGCCAGGGGAGACTGCTGTACCAATTACJ CAAGTGGTTTGCAAAGGAGAGTCGCATTGGGTTGATGATGACTGTGAGGAAATAAAGG CCGCAGAATGCCCTGCAGGGTTTGTTCGCCCTCCATTAATCATCTTCTCCGTGGATGG CTTCCGTGCATCATACATGAAGAAAGGCAGCAAAGTCATGCCTAATATTGAAAAACTA' AGGTCTTGTGGCACACACTCTCCCTACATGAGGCCGGTGTACCCAACTAAAACCTTTC CTAACTTATACACTTTGGCCACTGGGCTATATCCAGAATCACATGGAATTGTTGGCAA TTCAATGTATGATCCTGTATTTGATGCCACTTTTCATCTGCGAGGGCGAGAGAAATTT AATCATAGATGGTGGGGAGGTCAACCGCTATGGATTACAGCCACCAAGCAAGGGGTGA AAGCTGGAACATTCTTTTGGTCTGTTGTCATCCCTCACGAGCGGAGAATATTAACCAT ATTGCAGTGGCTCACCCTGCCAGATCATGAGAGGCCTTCGGTCTATGCCTTCTATTCT GAGCAACCTGATTTCTCTGGACACAAATATGGCCCTTTCGGCCCTGAGATGACAAATC CTCTGAGGGAAATCGACAAAATTGTGGGGCAATTAATGGATGGACTGAAACAACTAAA ACTGCATCGGTGTGTCAACGTCATCTTTGTCGGAGACCATGGAATGGAAGATGTCACA TGTGATAGAACTGAGTTCTTGAGTAATTACCTAACTAATGTGGATGATATTACTTTAG TGCCTGGAACTCTAGGAAGAATTCGATCCAAATTTAGCAACAATGCTAAATATGACCC CAAAGCCATTATTGCCAATCTCACGTGTAAAAAACCAGATCAGCACTTTAAGCCTTAC TTGAAACAGCACCTTCCCAAACGTTTGCACTATGCCAACAACAGAAGAATTGAGGATA TCCATTTATTGGTGGAACGCAGATGGCATGTTGCAAGGAAACCTTTGGATGTTTATAA GAAACCATCAGGAAAATGCTTTTTCCAGGGAGACCACGGATTTGATAACAAGGTCAAC AGCATGCAGACTGTTTTTGTAGGTTATGGCCCAACATTTAAGTACAAGACTAAAGTGC CTCCATTTGAAAACATTGAACTTTACAATGTTATGTGTGATCTCCTGGGATTGAAGCC AGCTCCTAATAATGGGACCCACGGAAGTTTGAATCATCTCCTGCGCACTAATACCTTC AGGCCAACCATGCCAGAGGAAGTTACCAGACCCAATTATCCAGGGATTATGTACCTTC AGTCTGATTTTGACCTGGGCTGCACTTGTGATGATAAGGTAGAGCCAAAGAACAAGTT GGATGAACTCAACAAACGGCTTCATACAAAAGGGTCTACAGAAGAGAGACACCTCCTC TATGGGCGACCTGCAGTGCTTTATCGGACTAGATATGATATCTTATATCACACTGACT TTGAAAGTGGTTATAGTGAAATATTCCTAATGCCACTCTGGACATCATATACTGTTTC CAAACAGGCTGAGGTTTCCAGCGTTCCTGACCATCTGACCAGTTGCGTCCGGCCTGAT GTCCGTGTTTCTCCGAGTTTCAGTCAGAACTGTTTGGCCTACAAAAATGATAAGCAGA TGTCCTACGGATTCCTCTTTCCTCCTTATCTGAGCTCTTCACCAGAGGCTAAATATGA TGCATTCCTTGTAACCAATATGGTTCCAATGTATCCTGCTTTCAAACGGGTCTGGAAT TATTTCCAAAGGGTATTGGTGAAGAAATATGCTTCGGAAAGAAATGGAGTTAACGTGA TAAGTGGACCAATCTTCGACTATGACTATGATGGCTTACATGACΆCAGAΆGACAAAAT AAAACAGTACGTGGAΆGGCAGTTCCATTCCTGTTCCAACTCACTACTACAGCATCATC ACCAGCTGTCTGGATTTTACTCAGCCTGCCGACAAGTGTGACGGCCCTCTCTCTGTGT CCTCCTTCATCCTGCCTCACCGGCCTGACAACGAGGAGAGCTGCAATAGCTCAGAGGA CGAATCAAAATGGGTAGAAGAACTCATGAAGATGCACACAGCTAGGGTGCGTGACATT GAACATCTCACCAGCCTGGACTTCTTCCGAAAGACCAGCCGCAGCTACCCAGAAATCC TGACACTCAAGACATACTTGCATACATATGAGAGCGAGATTCACCATCACCACCATCA

CTAA

ORF Start: at 2 ORF Stop: TAA at 2612

SEQ ID NO: 250 870 aa MW at 99926.5kD

NOV71h, TMARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEG EEGPPTVLSDSP TNISG

181518641 Protein SCKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRCGEVR EE NACHCSEDCLARGDCCT YQWCKGESH VDDDCEEIKAAECPAGFVRPPLIIFSVDG

Sequence FRASYMKKGSKVMPNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPESHGIVGN SMYDPVFDATFHLRGREKFNHR WGGQPL ITATKQGVKAGTFF SλA/IPHERRILTI LQ LTLPDHERPSVYAFYSEQPDFSGHKYGPFGPEMTNPLREIDKIVGQLMDGLKQLK LHRCVNVIFVGDHGMEDVTCDRTEFLSlsr-'LT.TTODITLVPGTLGRIRSKFSNNAKYDP KAIIA LTCKKPDQHFKPYLKQHLPKRLHYANRRIEDIHLLVERR HVARKPLDVYK KPSGKCFFQGDHGFDNKVNSMQTVFVGYGPTFKYKTKVPPFENIELYNVMCDLLGLKP APNNGTHGSLNHLLRTNTFRPTMPEEVTRPNYPGIMYLQSDFDLGCTCDDKVEPKNPL DΞL KRLHTKGSTEERHLLYGRPAVLYRTRYDILYHTDFESGYSEIFL PLWTSYTVS KQAEVSS VPDHLTSCλtRPDVRVSPSFSQNCLAYKNDKQMSYGFLFPPYLSSSPEAKYD AFLVT MVPMYPAFKRVWNYFQRVLVKKYASERNGλTNVISGPIFDYDYDGLHDTEDKI KQYVEGSSIPVPTHYYSIITSCLDFTQPADKCDGPLSVSSFILPHRPDNEESCNSSED ΞSKWVEELMKMHTARVRDIEHLTSLDFFR TSRSYPEILTLKTYLHTYESEIHHHHHH |SEQ ID NO: 251 |2642 bp jNOV71i, JATAATATCCGATATCATACGTCCACATCGGCGCGGATCCCCACCATGGGCCACCATCA 1171741118 DNA ^!CCACCATCACGCAAGGAGGAGCTCGTTCCAGTCGTGTCAGATAATATCCCTGTTCACT TTTGCCGTTGGAGTCAATATCTGCTTAGGATTCACTGCACATCGAATTAAGAGAGCAG Sequence AAGGATGGGAGGAAGGTCCTCCTACAGTGCTATCAGACTCCCCCTGGACCAACATCTC CGGATCTTGCAAGGGCAGGTGCTTTGAACTTCAAGAGGCTGGACCTCCTGATTGTCGC TGTGACAACTTGTGTAAGAGCTATACCAGTTGCTGCCATGACTTTGATGAGCTGTGTT TGAAGACAGCCCGTGGCTGGGAGTGTACTAAGGACAGATGTGGAGAAGTCAGAAATGA AGAAAATGCCTGTCACTGCTCAGAGGACTGCTTGGCCAGGGGAGACTGCTGTACCAAT TACCAAGTGGTTTGCAAAGGAGAGTCGCATTGGGTTGATGATGACTGTGAGGAAATAA AGGCCGCAGAATGCCCTGCAGGGTTTGTTCGCCCTCCATTAATCATCTTCTCCGTGGA TGGCTTCCGTGCATCATACATGAAGAAAGGCAGCAAAGTCATGCCTAATATTGAAAAA CTAAGGTCTTGTGGCACACACTCTCCCTACATGAGGCCGGTGTACCCAACTAAAACCT TTCCTAACTTATACACTTTGGCCACTGGGCTATATCCAGAATCACATGGAATTGTTGG CAATTCAATGTATGATCCTGTATTTGATGCCACTTTTCATCTGCGAGGGCGAGAGAAA TTTAATCATAGATGGTGGGGAGGCCAACCGCTATGGATTACAGCCACCAAGCAAGGGG TGAAAGCTGGAACATTCTTTTGGTCTGTTGTCATCCCTCACGAGCGGAGAATATTAAC CATATTGCAGTGGCTCACCCTGCCAGATCATGAGAGGCCTTCGGTCTATGCCTTCTAT TCTGAGCAACCTGATTTCTCTGGACACAAATATGGCCCTTTCGGCCCTGAGATGACAA ATCCTCTGAGGGAAATCGACAAAATTGTGGGGCAATTAATGGATGGACTGAAACAAAA ACTGCATCGGTGTGTCAACGTCATCTTTGTCGGAGACCATGGAATGGAAGATGTCACA TGTGATAGAACTGAGTTCTTGAGTAATTACCTAACTAATGTGGATGATATTACTTTAG TGCCTGGAACTCTAGGAAGAATTCGATCCAAATTTAGCAACAATGCTAAATATGACCC CAAAGCCATTATTGCCAATCTCACGTGTAAAAAACCAGATCAGCACTTTAAGCCTTAC TTGAAACAGCACCTTCCCAAACGTTTGCACTATGCCAACAACAGAAGAATTGAGGATA TCCATTTATTGGTGGAACGCAGATGGCATGTTGCAAGGAAACCTTTGGATGTTTATAA GAAACCATCAGGAAAATGCTTTTTCCAGGGAGACCACGGATTTGATAACAAGGTCAAC AGCATGCAGACTGTTTTTGTAGGTTATGGCCCAACATTTAAGTACAAGACTAAAGTGC CTCCATTTGAAAACATTGAACTTTACAATGTTATGTGTGATCTCCTGGGATTGAAGCC AGCTCCTAATAATGGGACCCATGGAAGTTTGΆΆTCATCTCCTGCGCACTAATACCTTC AGGCCAACCATGCCAGAGGAAGTTACCAGACCCAATTATCCAGGGATTATGTACCTTC AGTCTGATTTTGACCTGGGCTGCACTTGTGATGATAAGAACAAGTTGGATGAACTCAA CAAACGGCTTCATACAAAAGGGTCTACAGAAGAGAGACACCTCCTCTATGGGCGACCT GCAGTGCTTTATCGGACTAGATATGATATCTTATATCACACTGACTTTGAAAGTGGTT ATAGTGAAATATTCCTAATGCCACTCTGGACATCATATACTGTTTCCAAACAGGCTGA GGTTTCCAGCGTTCCTGACCATCTGACCAGTTGCGTCCGGCCTGATGTCCGTGTTTCT CCGAGTTTCAGTCAGAACTGTTTGGCCTACAAAAATGATAAGCAGATGTCCTACGGAT TCCTCTTTCCTCCTTATCTGAGCTCTTCACCAGAGGCTAAATATGATGCATTCCTTGT AACCAATATGGTTCCAATGTATCCTGCTTTCAAACGGGTCTGGAATTATTTCCAAAGG GTATTGGTGAAGAAATATGCTTCGGAAAGAAATGGAGTTAACGTGATAAGTGGACCAA TCTTCGACTATGACTATGATGGCTTACATGACACAGAAGACAAAATAAAACAGTACGT GGAAGGCAGTTCCATTCCTGTTCCAACTCACTACTACAGCATCATCACCAGCTGTCTG GATTTCACTCAGCCTGCCGACAAGTGTGACGGCCCTCTCTCTGTGTCCTCCTTCATCC TGCCTCACCGGCCTGACAACGAGGAGAGCTGCAATAGCTCAGAGGACGAATCAAAATG GGTAGAAGAACTCATGAAGATGCACACAGCTAGGGTGCGTGACATTGAACATCTCACC AGCCTGGACTTCTTCCGAAAGACCAGCCGCAGCTACCCAGAGATCCTGACACTCAAGA CATACCTGCATACATATGAGAGCGAGATTTAA

ORF Start: at 3 ORF Stop: TAA at 2640

SEQ ID NO: 252 879 aa MW at 100914.6kD

NOV71L NIRYHTSTSARIPTMGHHHHHHARRSSFQSCQIISLFTFAVG\71VTICLGFTAHRIKRAE

171741118 Protein GWEEGPPTVLSDSP TNISGSCKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDΞLCL KTA RGWECTKDRCGEVRNEENACHCSEDCLARGDCCTNYQWCKGΞSHWVDDDCEEIK

Sequence AAECPAGFVRPPLIIFSVDGFRASYMKKGSKVMPNIEKLRSCGTHSPY RPVYPT TF PNLYTLATGLYPESHGIVGNSMYDPVFDATFHLRGREKF HR WGGQPL ITATKQGV KAGTFFWSWIPHERRILTILQWLTLPDHERPSWAFYSEQPDFSGHKYGPFGPEMTN PLRΞIDKIVGQLMDGLKQ LHRCV VIFVGDHGMΞDVTCDRTEFLSNYLTNVDDITLV PGTLGRIRSKFS1SINAKYDPKAIIANLTC KPDQHFKPYLKQHLPKRLHYAN RRIEDI HLLVERR HVARKPLD'VYKKPSGKCFFQGDHGFDNKVNSMQTVFVGYGPTFKYKTKVP PFENIELYN\ CDLLGLKPAPlvTNGTHGSLlvraLLRTNTFRPTMPEEVTRPNYPGI_ _YLQ ; SDFDLGCTCDDKNKLDELNKRLHTKGSTEERHLLYGRPAVLYRTRYDILYHTDFESGY

J SEIFLMPL TSYTVSKQAEVSSVPDHLTSCVRPDVRVSPSFSQNCLAYI NDKQMSYGF

J LFPPYLS S S PEAKYDAFLVTNMVPMYP AFKRVWNYFQRVLVKKYAS ERNGV VI SGP I

FDYDYDGLHDTEDKIKQYVΞGS S I PVPTHYYS 11 TS CLDFTQPADKCDGPLS VS S F I L

PHRPDNEESCNSSEDESKVJVEELMKI .HTARVRDIEHLTSLDFFRKTSRSYPEILTLKT

YLHTYESEI

ISEQ ID NO: 253 2719 bp

JNOV71J, CCACCATGGCA.AGGAGGAGCTCGTTCCAGTCGTGTCAGATAATATCCCTGTTCACTTT 171741160 DNA TGCCGTTGGAGTCAATATCTGCTTAGGATTCACTGCACATCGAATTAAGAGAGCAGAA: GGATGGGAGGAAGGTCCTCCTACAGTACTATCAGACTCCCCCTGGACCAACATCTCCG Sequence GATCTTGCAAGGGCAGGTGCTTTGAACTTCAAGAGGCTGGACCTCCTGATTGTCGCTG TGACAACTTGTGTAAGAGCTATACCAGTTGCTGCCATGACTTTGATGAGCTGTGTTTG AAGACAGCCCGTGGCTGGGAGTGTACTAAGGACAGATGTGGAGAAGTCAGAAATGAAG AAAATGCCTGTCACTGCTCAGAGGACTGCTTGGCCAGGGGAGACTGCTGTACCAATTA JCCAAGTGGTTTGCAAAGGAGAGTCGCATTGGGTTGATGATGACTGTGAGGAAATAAAG JGCCGCAGAATGCCCTGCAGGGTTTGTTCGCCCTCCATTAATCATCTTCTCCGTGGATG JGCTTCCGTGCATCATACATGAAGAAAGGCAGCAAAGTCATGCCTAATATTGAAAAACT JAAGGTCTTGTGGCACACACTCTCCCTACATGAGGCCGGTGTACCCAACTAAAACCTTT ICCTAACTTATACACTTTGGCCACTGGGCTATATCCAGAATCACATGGAATTGTTGGCA ^'ATTCAATGTATGATCCTGTATTTGATGCCACTTTTCATCTGCGAGGGCGAGAGAAATT TAATCATAGATGGTGGGGAGGTCAACCGCTATGGATTACAGCCACCAAGCAAGGGGTG AAGCTGGAACATTCTTTTGGTCTGTTGTCATCCCTCACGAGCGGAGAATATTAACCA TATTGCAGTGGCTCACCCTGCCAGATCATGAGAGGCCTTCGGTCTATGCCTTCTATTC TGAGCAACCTGATTTCTCTGGACACAAATATGGCCCTTTCGGCCCTGAGATGACAAAT CCTCTGAGGGAAATCGACAAAATTGTGGGGCAATTAATGGATGGACTGAAACAACTAA AΆCTGCATCGGTGTGTCAACGTCATCTTTGTCGGAGACCATGGAATGGAAGATGTCAC ATGTGATAGAACTGAGTTCTTGAGTAATTACCTAACTAATGTGGATGATATTACTTTA GTGCCTGGAACTCTAGGAAGAATTCGATCCAAATTTAGCAACAATGCTAAATATGACC CCAAAGCCATTATTGCCAATCTCACGTGTAΆAAAACCAGATCAGCACTTTAAGCCTTA CTTGAAACAGCACCTTCCCAAACGTTTGCACTATGCCAACAACAGAAGAATTGAGGAT ATCCATTTATTGGTGGAACGCAGATGGCATGTTGCAAGGAAACCTTTGGATGTTTATA AGAAACCATCAGGAAAATGCTTTTTCCAGGGAGACCACGGATTTGATAACAAGGTCAA CAGCATGCAGACTGTTTTTGTAGGTTATGGCCCAACATTTAAGTACAAGACTAAAGTG CCTCCATTTGAAAACATTGAACTTTACAATGTTATGTGTGATCTCCTGGGATTGAAGC CAGCTCCTAATAATGGGACCCATGGAAGTTTGAATCATCTCCTGCGCACTAATACCTT CAGGCCAACCATGCCAGAGGAAGTTACCAGACCCAATTATCCAGGGATTATGTACCTT ICAGTCTGATTTTGACCTGGGCTGCACTTGTGATGATAAGGTAGAGCCAAAGAACAAGT ITGGATGAGCTCAACAAACGGCTTCATACAAAAGGGTCTACAGAAGCTGAAACCAGGAA JATACAGAGGCACCAGAAATGAAAACAAGGAAAACATTAATGGAAATTTTGAACCTAGA AAAGAGAGACACCTCCTCTATGGGCGACCTGCAGTGCTTTATCGGACTAGATATGATA TCTTATATCACACTGACTTTGAAAGTGGTTATAGTGAAATATTCCTAACGCCACTCTG GACATCATATACTGTTTCCAAACAGGCTGAGGTTTCCAGCGTTCCTGACCATCTGACC AGTTGCGTCCGGCCTGATGTCCGTGTTTCTCCGAGTTTCAGTCAGAACTGTTTGGCCT ACAAAAATGATAAGCAGATGTCCTACGGATTCCTCTTTCCTCCTTATCTGAGCTCTTC GCCAGAGGCTAAATATGATGCATTCCTTGTAACCAATATGGTTCCAATGTATCCTGCT TTCAAACGGGTCTGGAATTATTTCCAAAGGGTATTGGTGAAGAAATATGCTTCGGAAA GAAATGGAGTTAACGTGATAAGTGGACCAATCTTCGACTATGACTATGATGGCTTACA TGACACAGAAGACAAAATAAAACAGTACGTGGAAGTCAGTTCCATTCCTGTTCCAACT CACTACTACAGCATCATCACCAGCTGTCTGGATTTCACTCAGCCTGCCGACAAGTGTG ACGGCCCTCTCTCTGTGTCCTCCTTCATCCTGCCTCACCGGCCTGACAACGAGGAGAG CTGCAATAGCTCAGAGGACGAATCAAAATGGGTAGAAGAACTCATGAAGATGCACACA GCTAGGGTGCGTGACATTGAACATCTCGCCAGCCTGGACTTCTTCCGAAAGACCAGCC GCAGCTACCCAGAAATCCTGACACTCAAGACATACCTGCATACATATGAGAGCGAGATI TCACCATCACCACCATCACTAAGCGGCGCTCGAGTCTAGAGGGCCGTTTAA

ORF Start: at 3 ORF Stop: TAA at 2688

SEQ ID NO: 254 895 aa MW at 102912.8kD

NOV71J, TMARRSSFQSCQIISLFTFAVGVNICLGFTAHRI RAEGWEEGPPTVLSDSPWTNISG 171741160 Protein SCKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRCGEVRNEE

536 j Sequence INACHCSEDCLARGDCCTNYQWCKGESHWVDDDCEEIKAAECPAGFVRPPLI IFSVDG l FRASYMKKGSK^"V PNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPESHGIVGN j SMYDPVFDATFHLRGREKFNHRWWGGQPLWITATKQGVKAGTFFWS IPHERRILTI

| L LTLPDHERPSVYAFYSEQPDFSGH YGPFGPEMTNPLREIDKIVGQLMDGL QLK

LH CVNVIFVGDHGMEDVTCDRTEFLSlsr_^"LT VDDITLVPGTLGRIRSKFS NAKYDP

I_AIIANLTC KPDQHFKPYLKQHLPKRLHYA ^]vTRRIEDIHLLVERR HVARKPLD\ry-K

KPSGKCFFQGDHGFDNKV SMQTVFVGYGPTFKYKTKVPPFENIELYNVMCDLLGLKP

AP lsTGTHGSLlvraLLRTNTFRPTMPΞEVTRP_^PGIMYLQSDFDLGCTCDDKVEPK_IKL

DELNKRLHTKGSTΞAΞTRKYRGTRNE KENINGNFΞPRKERHLLYGRPAVLYRTRYDI

LYHTDFESGYSEIFLTPL TSYTVSKQAEVSSVPDHLTSCVRPDVRVSPSFSQNCLAY

I_vTDKQ SYGFLFPPYLSSSPEAKYDAFLVTNMVPMYPAFKRVJNYFQRVLVKKYASER

NGVNVISGPIFDYDYDGLHDTED IKQYVEVSSIPVPTHYYSIITSCLDFTQPADKCD

GPLSVSSFILPHRPDNEESCNSSEDESK VEΞLMKMHTARVRDIEHLASLDFFRKTSR

SYPEILTLKTYLHTYESEIHHHHHH

SEQ ID NO: 255 2614 bp

|NOV71k, CACCATGGCAAGGAGGAGCTCGTTCCAGTCGTGTCAGATAATATCCCTGTTCACTTTT ^• 181518641 DNA GCCGTTGGAGTCAATATCTGCTTAGGATTCACTGCACATCGAATTAAGAGAGCAGAAG GATGGGAGGAAGGTCCTCCTACAGTGCTATCAGACTCCCCCTGGACCAACATCTCCGG

■Sequence ATCTTGCAAGGGCAGGTGCTTTGAACTTCAAGAGGCTGGACCTCCTGATTGTCGCTGT GACAACTTGTGTAAGAGCTATACCAGTTGCTGCCATGACTTTGATGAGCTGTGTTTGA AGACAGCCCGTGGCTGGGAGTGTACTAAGGACAGATGTGGAGAAGTCAGAAATGAAGA AAATGCCTGTCACTGCTCAGAGGACTGCTTGGCCAGGGGAGACTGCTGTACCAATTAC CAAGTGGTTTGCAAAGGAGAGTCGCATTGGGTTGATGATGACTGTGAGGAAATAAAGG CCGCAGAATGCCCTGCAGGGTTTGTTCGCCCTCCATTAATCATCTTCTCCGTGGATGG CTTCCGTGCATCATACATGAAGAAAGGCAGCAAAGTCATGCCTAATATTGAAAAACTA AGGTCTTGTGGCACACACTCTCCCTACATGAGGCCGGTGTACCCAACTAAAACCTTTC CTAACTTATACACTTTGGCCACTGGGCTATATCCAGAATCACATGGAATTGTTGGCAA TTCAATGTATGATCCTGTATTTGATGCCACTTTTCATCTGCGAGGGCGAGAGAAATTT AATCATAGATGGTGGGGAGGTCAACCGCTATGGATTACAGCCACCAAGCAAGGGGTGA AAGCTGGAACATTCTTTTGGTCTGTTGTCATCCCTCACGAGCGGAGAATATTAACCAT ATTGCAGTGGCTCACCCTGCCAGATCATGAGAGGCCTTCGGTCTATGCCTTCTATTCT GAGCAACCTGATTTCTCTGGACACAAATATGGCCCTTTCGGCCCTGAGATGACAAATC CTCTGAGGGAAATCGACAAAATTGTGGGGCAATTAATGGATGGACTGAAACAACTAAA ACTGCATCGGTGTGTCAACGTCATCTTTGTCGGAGACCATGGAATGGAAGATGTCACA TGTGATAGAACTGAGTTCTTGAGTAATTACCTAACTAATGTGGATGATATTACTTTAG TGCCTGGAACTCTAGGAAGAATTCGATCCAAATTTAGCAACAATGCTAAATATGACCC CAAAGCCATTATTGCCAATCTCACGTGTAAAAAACCAGATCAGCACTTTAAGCCTTAC TTGAAACAGCACCTTCCCAAACGTTTGCACTATGCCAACAACAGAAGAATTGAGGATA TCCATTTATTGGTGGAACGCAGATGGCATGTTGCAAGGAAACCTTTGGATGTTTATAA GAAACCATCAGGAAAATGCTTTTTCCAGGGAGACCACGGATTTGATAACAAGGTCAAC AGCATGCAGACTGTTTTTGTAGGTTATGGCCCAACATTTAAGTACAAGACTAAAGTGC CTCCATTTGAAAACATTGAACTTTACAATGTTATGTGTGATCTCCTGGGATTGAAGCC AGCTCCTAATAATGGGACCCACGGAAGTTTGAATCATCTCCTGCGCACTAATACCTTC AGGCCAACCATGCCAGAGGAAGTTACCAGACCCAATTATCCAGGGATTATGTACCTTC AGTCTGATTTTGACCTGGGCTGCACTTGTGATGATAAGGTAGAGCCAAAGAACAAGTT GGATGAACTCAACAAACGGCTTCATACAAAAGGGTCTACAGAAGAGAGACACCTCCTC TATGGGCGACCTGCAGTGCTTTATCGGACTAGATATGATATCTTATATCAGACTGACT TTGAAAGTGGTTATAGTGAAATATTCCTAATGCCACTCTGGACATCATATACTGTTTC CAAACAGGCTGAGGTTTCCAGCGTTCCTGACCATCTGACCAGTTGCGTCCGGCCTGAT GTCCGTGTTTCTCCGAGTTTCAGTCAGAACTGTTTGGCCTACAAAAATGATAAGCAGA TGTCCTACGGATTCCTCTTTCCTCCTTATCTGAGCTCTTCACCAGAGGCTAAATATGA TGCATTCCTTGTAACCAATATGGTTCCAATGTATCCTGCTTTCAAACGGGTCTGGAAT TATTTCCAAAGGGTATTGGTGAAGAAATATGCTTCGGAAAGAAATGGAGTTAACGTGA TAAGTGGACCAATCTTCGACTATGACTATGATGGCTTACATGACACAGAAGACAAAAT AAAACAGTACGTGGAAGGCAGTTCCATTCCTGTTCCAACTCACTACTACAGCATCATC ACCAGCTGTCTGGATTTTACTCAGCCTGCCGACAAGTGTGACGGCCCTCTCTCTGTGT CCTCCTTCATCCTGCCTCACCGGCCTGACAACGAGGAGAGCTGCAATAGCTCAGAGGA CGAATCAAAATGGGTAGAAGAACTCATGAAGATGCACACAGCTAGGGTGCGTGACATT GAACATCTCACCAGCCTGGACTTCTTCCGAAAGACCAGCCGCAGCTACCCAGAAATCC TGACACTCAAGACATACTTGCATACATATGAGAGCGAGATTCACCATCACCACCATCA I CTAA ]

J0RF Start: at 2 ORF Stop: TAA at 2612 j

;SEQ ID NO: 256 870 aa JMW at 99926.51.D !

|NOV71k, T.-JARRSSFQSCQI ISLFTFAVGWICLGFTAHRIKRAEGWEEGPPTVLSDSPWTNISG J 181518641 Protein SCKGRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARG ECTKDRCGEVRNEE ; Sequence NACHCSEDCLARGDCCTNYQVVCKGESHWVΌDDCEEIKAAECPAGFVRPPLIIFSVDG FPJ_SYMKKGSKVMPNIEKLRSCGTHSPYMRPΛTYPT TFPNLYTLATGLYPESHGIVGN SMYDPVFDATFHLRGREKF HRWWGGQPLWITATKQGVKAGTFFWS IPHERRILTI LQWLTLPDHERPSVYAFYSEQPDFSGHKYGPFGPEMTNPLREIDKIVGQLMDGLKQLK LHRCVNVIFVGDHGMEDVTCDRTEFLSNYLT_TVDDITLVPGTLGRIRSKFS NAKYDP KAIIA LTCKKPDQHFKPYLKQHLPKRLHYANNRRIEDIHLLVERR HVARKPLDVYK KPSGKCFFQGDHGFDNKV SMQTVFVGYGPTFKYKT VPPFΞNIELY VMCDLLGLKP AP_S GTHGSLNHLLRTNTFRPTMPEEVTRPNYPGIMYLQSDFDLGCTCDDKVEPKNKL DELNKRLHTKGSTEERHLLYGRPAVLYRTRYDILYHTDFESGYSEIFLMPL TSYTVS KQAEVSSVPDHLTSCVRPDVRVSPSFSQNCLAYKNDKQMSYGFLFPPYLSSSPEAKYD AFLVTNLVRVPMYPAFKRΛ NYFQRVLVKKYASERNGVNVISGPIFDYDYDGLHDTEDKI KQYVEGSS IPVPTHYYSIITSCLDFTQPAD CDGPLSVSSFILPHRPDNEESCNSSΞD ESKWVEELMKMHTARVRDIEHLTSLDFFRKTSRSYPEILTLKTYLHTYESEIHHHHHH

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 7 IB.

Further analysis of the NOV7 la protein yielded the following properties shown in Table 7 IC.

Table 71C. Protein Sequence Properties NOV71a

PSort 0.6850 probability located in plasma membrane; 0.6400 probability located in analysis: endoplasmic reticulum (membrane); 0.3700 probability located in Golgi body; 0.1236 probability located in microbody (peroxisome) j SignalP Cleavage site between residues 28 and 29 t analysis:

A search of the NOV71 a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7 ID.

In a BLAST search of public sequence databases, the NOV7 la protein was found to have homology to the proteins shown in the BLASTP data in Table 7 IE.

Table 71E. Public BLASTP Results for NOV71a

Protein NOV71a Identities/ Expect

Protein/Organism/Length Value

PFam analysis indicates that the NOV71a protein contains the domains shown in the Table 7 IF.

Table 71F. Domain Analysis of NOV71a

Example 72.

The NOV72 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 72A.

540 ATGCCTTTGGCCTGAGGCCTCCTCTGTCTCTTCCCCCAGCCATCCCAACATCCTGCGT CTCTACAACTATTTTTATGACCGGAGGAGGATCTACTTGATTCTAGAGTATGCCCCCC GCGGGGAGCTCTACAAGGAGCTGCAGAAGAGCTGCACATTTGACGAGCAGCGAACAGC CACGATCATGGAGGAGTTGGCAGATGCTCTAATGTACTGCCATGGGAAGAAGGTGATT CACAGAGACATAAAGCCAGAAAATCTGCTCTTAGGGCTCAAGGGAGAGCTGAAGATTG CTGACTTCGGCTGGTCTGTGCATGCGCCCTCCCTGAGGAGGAAGACGATGTGTGGCAC CCTGGACTACCTGCCCCCAGAGATGATTGAGGGGCGCATGCACAATGAGAAGGTGGAT CTGTGGTGCATTGGAGTGCTTTGCTATGAGCTGCTGGTGGGGAACCCACCCTTTGAGA GTGCATCACACAACGAGACCTATCGCCGCATCGTCAAGGTGGACCTAAAGTTCCCCGC TTCCGTGCCCACGGGAGCCCAGGACCTCATCTCCAAACTGCTCAGGCATAACCCCTCG GAACGGCTGCCCCTGGCCCAGGTCTCAGCCCACCCTTGGGTCCGGGCCAACTCTCGGA GGGTGCTGCCTCCCTCTGCCCTTCAATCTGTCGCCTGATGGTCCCTGTCATTCACTCG GGTGCGTGTGTTTGTATGTCTGTGTATGTA

ORF Start: ATG at 28 ORF Stop: TGA at 964

SEQ ID NO: 258 1312 aa MW at 35241.2kD

^■NOV72a, MAQKENSYPWPYGRQTAPSGLSTLPQRVLRKEPVTPSALVLTSRSlμ/QPTAAPGQKVM

CG95872-02 Protein ENSSGTPDILTRHFTIDDFEIGRPLGKALLCLWPEASSVSSPSHPNILRLYNYFYDRR RIYLILEYAPRGELYKELQKSCTFDEQRTATIMEELADALMYCHGKKVIHRDIKPENL

Sequence LLGLKGELKIADFGWSVHAPSLRRKT CGTLDYLPPEMIEGRMHNEKVDLWCIGVLCY ELLVGNPPFESASHNETYRRIVKVDLKFPASVPTGAQDLISKLLRHNPSERLPLAQVS AHPWVRA SRRVLPPSALQSVA

Further analysis of the NOV72a protein yielded the following properties shown in Table 72B.

Table 72B. Protein Sequence Properties NOV72a

¹ PSort j 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody analysis: | (peroxisome); 0.1546 probability located in lysosome (lumen); 0.1000 I probability located in mitochondrial matrix space

SignalP J No Known Signal Sequence Indicated analysis:

A search of the NOV72a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 72C.

In a BLAST search of public sequence databases, the NOV72a protein was found to have homology to the proteins shown in the BLASTP data in Table 72D.

PFam analysis indicates that the NOV72a protein contains the domains shown in the Table 72E.

Table 72E. Domain Analysis of NOV72a

Identities/

I Pfam Domain NOV72a Match Region Similarities Expect Value for the Matched Region pkinase 101-295 72/234 (31%) 1.2e-58 146/234 (62%) Example B: Sequencing Methodology and Identification of NOVX Clones

The following technologies were used in the examples of the invention.

1. GeneCalling ^' Technology: This is a proprietary method of performing differential gene expression profiling between two or more samples developed at CuraGen and described by Shimkets, et al., "Gene expression analysis by transcript profiling coupled to a gene database query" Nature Biotechnology 17:198-803 (1999). cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then digested with up to as many as 120 pairs of restriction enzymes and pairs of linker-adaptors specific for each pair of restriction enzymes were ligated to the appropriate end. The restriction digestion generates a mixture of unique cDNA gene fragments. Limited PCR amplification is performed with primers homologous to the linker adapter sequence where one primer is biotinylated and the other is fluorescently labeled. The doubly labeled material is isolated and the fluorescently labeled single strand is resolved by capillary gel electrophoresis. A computer algorithm compares the electropherograms from an experimental and control group for each of the restriction digestions. This and additional sequence-derived information is used to predict the identity of each differentially expressed gene fragment using a variety of genetic databases. The identity of the gene fragment is confirmed by additional, gene-specific competitive PCR or by isolation and sequencing of the gene fragment.

2. SeqCalling ^' Technology: cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then sequenced using CuraGen's proprietary SeqCalling technology. Sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95%_> over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations. 3. PathCalling™ Technology:

The NOVX nucleic acid sequences are derived by laboratory screening of cDNA library by the two-hybrid approach. cDNA fragments covering either the full length of the DNA sequence, or part of the sequence, or both, are sequenced. In silico prediction was based on sequences available in CuraGen Corporation's proprietary sequence databases or in the public human sequence databases, and provided either the full length DNA sequence, or some portion thereof. The laboratory screening was performed using the methods summarized below: cDNA libraries were derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then directionally cloned into the appropriate two- hybrid vector (Gal4-activation domain (Gal4-AD) fusion). Such cDNA libraries as well as commercially available cDNA libraries from Clontech (Palo Alto, CA) were then transferred from E.coli into a CuraGen Corporation proprietary yeast strain (disclosed in U. S. Patents 6,057,101 and 6,083,693, incorporated herein by reference in their entireties).

Gal4-binding domain (Gal4-BD) fusions of a CuraGen Corportion proprietary library of human sequences was used to screen multiple Gal4-AD fusion cDNA libraries resulting in the selection of yeast hybrid diploids in each of which the Gal4-AD fusion contains an individual cDNA. Each sample was amplified using the polymerase chain reaction (PCR) using non-specific primers at the cDNA insert boundaries. Such PCR product was sequenced; sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least

95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations. Physical clone: the cDNA fragment derived by the screening procedure, covering the entire open reading frame is, as a recombinant DNA, cloned into pACT2 plasmid (Clontech) used to make the cDNA library. The recombinant plasmid is inserted into the host and selected by the yeast hybrid diploid generated during the screening procedure by the mating of both CuraGen Corporation proprietary yeast strains N106' and YULH (U. S. Patents 6,057,101 and 6,083,693).

4. RACE: Techniques based on the polymerase chain reaction such as rapid amplification of cDNA ends (RACE), were used to isolate or complete the predicted sequence of the cDNA of the invention. Usually multiple clones were sequenced from one or more human samples to derive the sequences for fragments. Various human tissue samples from different donors were used for the RACE reaction. The sequences derived from these procedures were included in the SeqCalling Assembly process described in preceding paragraphs.

5. Exon Linking: The NOVX target sequences identified in the present invention were subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or protein sequence of the target sequence, or by translated homology of the predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component of the assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein. 6. Physical Clone: Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein.

The PCR product derived by exon linking, covering the entire open reading frame, was cloned into the pCR2.1 vector from Invitrogen to provide clones used for expression and screening purposes.

Example C: Quantitative expression analysis of clones in various cells and tissues

The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel 5D/5I (containing human tissues and cell lines with an emphasis on metabolic diseases), AI_comprehensive_panel (containing normal tissue and samples from autoimmune diseases), Panel CNSD.01 (containing central nervous system samples from normal and diseased brains) and CNSjt_eurodegeneration_panel (containing samples from normal and Alzheimer's diseased brains). RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s:l 8s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon.

First, the RNA samples were normalized to reference nucleic acids such as constitutively expressed genes (for example, β-actin and GAPDH). Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions.

In other cases, non-normalized RNA samples were converted to single strand cDNA (sscDNA) using Superscript II (Invitrogen Corporation; Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 μg of total RNA were performed in a volume of 20 μl and incubated for 60 minutes at 42°C. This reaction can be scaled up to 50 μg of total RNA in a final volume of 100 μl. sscDNA samples are then normalized to reference nucleic acids as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions.

Probes and primers were designed for each assay according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for reaction conditions and the following parameters were set before selecting primers: primer concentration = 250 nM, primer melting temperature (Tm) range = 58°-60°C, primer optimal Tm = 59°C, maximum primer difference = 2°C, probe does not have 5'G, probe Tm must be 10°C greater than primer Tm, amplicon size 75bp to lOObp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, TX, USA). Probes were double purified by HPLC to remove uncoupled dye and evaluated by mass speetroscopy to verify coupling of reporter and quencher dyes to the 5' and 3' ends of the probe, respectively. Their final concentrations were: forward and reverse primers, 900nM each, and probe, 200nM.

PCR conditions: When working with RNA samples, normalized RNA from each tissue and each cell line was spotted in each well of either a 96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 48°C for 30 minutes followed by amplification/PCR cycles as follows: 95°C 10 min, then 40 cycles of 95°C for 15 seconds, 60°C for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100.

When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95°C 10 min, then 40 cycles of 95°C for 15 seconds, 60°C for 1 minute. Results were analyzed and processed as described previously. Panels 1, 1.1, 1.2, and 1.3D

The plates for Panels 1 , 1.1 , 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose.

In the results for Panels 1 , 1.1, 1.2 and 1.3D, the following abbreviations are used: ca. = carcinoma,

* = established from metastasis, met = metastasis, s cell var = small cell variant, non-s = non-sm = non-small, squam = squamous, pi. eff = pi effusion = pleural effusion, glio = glioma, astro = astrocytoma. and neuro = neuroblastoma. General_screening_panel_\T.4 and General_screening_panel_vl.5

The plates for Panels 1.4 and 1.5 include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in Panels 1.4 and 1.5 are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panel 1.4 are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panels 1.4 and 1.5 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D. Panels 2D and 2.2

The plates for Panels 2D and 2.2 generally include 2 control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI). The tissues are derived from human malignancies and in cases where indicated many malignant tissues have "matched margins" obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted "NAT" in the results below. The tumor tissue and the "matched margins" are evaluated by two independent pathologists (the surgical pathologists and again by a pathologist at NDRI or CHTN). This analysis provides a gross l istopatho logical assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated "NAT", for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, CA), Research Genetics, and Invitrogen. Panel 3D

The plates of Panel 3D are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D and 1.3D are of the most common cell lines used in the scientific literature. Panels 4D, 4R, and 4.1D

Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D/4.1D) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, CA) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, CA). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, PA).

Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, MD) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12-14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately l-5ng/ml, TNF alpha at approximately 5-10ng/ml, IFN gamma at approximately 20-50ng/mI, IL-4 at approximately 5-10ng/ml, IL-9 at approximately 5-10ng/ml, IL-13 at approximately 5- 10ng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1 % serum.

Mononuclear cells were prepared from blood of employees at CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5%> FCS (Hyclone), 1 OOμM non essential amino acids (Gibco/Life Technologies, RockviUe, MD), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO°M (Gibco), and lOmM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20ng/ml PMA and 1-2 μg/ml ionomycin, IL-12 at 5-10ng/ml, IFN gamma at 20-50ng/ml and IL-18 at 5- lOng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10°M (Gibco), and lOmM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5μg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1 :1 at a final concentration of approximately xlO s6 cells/ml in DMEM 5%> FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol (5.5xl0^"?M) (Gibco), and lOmM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1- 7 days for RNA preparation. Monocytes were isolated from mononuclear cells using CD 14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, UT), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0°M (Gibco), and lOmM Hepes (Gibco), 50ng/ml GMCSF and 5ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^_:>M (Gibco), lOmM Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50ng/ml. Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at lOOng/ml. Dendritic cells were also stimulated with anti-CD40 monoclonal antibody (Pharmingen) at lOμg/ml for 6 and 12-14 hours.

CD4 lymphocytes, CD 8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CDS, CD56. CD 14 and CD 19 cells using CDS, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0°M (Gibco), and lOmM Hepes (Gibco) and plated at 10⁶cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5μg/ml anti-CD28 (Pharmingen) and 3ug/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CDS lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0°M (Gibco), and lOmM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. The isolated NK cells were cultured in DMEM 5%> FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"?M (Gibco), and lOmM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared. To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed- through a sieve. Tonsil cells were then spun down and resupended at 10⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0°M (Gibco), and lOmM Hepes (Gibco). To activate the cells, we used PWM at 5 μg/ml or anti-CD40 (Pharmingen) at approximately 10 μg/ml and IL-4 at 5-10ng/ml. Cells were harvested for RNA preparation at 24,48 and 72 hours.

To prepare the primary and secondary Thl/Th2 and Tri cells, six- well Falcon plates were coated overnight with lOμg/ml anti-CD28 (Pharmingen) and 2μg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, MD) were cultured at 10⁵-10⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^" ⁵M (Gibco), lOmM Hepes (Gibco) and IL-2 (4ng/ml). IL-12 (5ng/ml) and anti-IL4 (1 μg/ml) were used to direct to Thl, while IL-4 (5ng/ml) and anti-IFN gamma (1 μg/ml) were used to direct to Th2 and IL-10 at 5ng/ml was used to direct to Tri. After 4-5 days, the activated Thl, Th2 and Tri lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5%o FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), lOmM Hepes (Gibco) and IL-2 (1 ng/ml). Following this, the activated Thl, Th2 and Tri lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (1 μg/ml) to prevent apoptosis. After 4-5 days, the Thl, Th2 and Tri lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Thl and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Thl, Th2 and Tri after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2.

The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1 , KU-812. EOL cells were further differentiated by culture in O.lmM dbcAMP at 5xl 0⁵cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to SxlO^cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), 1 OOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), lOmM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at lOng/ml and ionomycin at 1 μg/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^_:,M (Gibco), and lOmM Hepes (Gibco). CCD1 106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and 1 ng/ml IL- 1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5ng/ml IL-4, 5ng/ml IL-9, 5ng/ml IL-13 and 25ng/ml IFN gamma.

For these cell lines and blood cells, RNA was prepared by lysing approximately 10⁷cells/ml using Trizol (Gibco BRL). Briefly, 1/10 volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was removed and placed in a 15ml Falcon Tube. An equal volume of isopropanol was added and left at -20°C overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70%> ethanol. The pellet was redissolved in 300μl of RNAse-free water and 35μl buffer (Promega) 5μl DTT, 7μl RNAsin and 8μl DNAse were added. The tube was incubated at 37°C for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re-precipitated with ^Q 1/10 volume of 3M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in RNAse free water. RNA was stored at -80°C. AI_comprehensive panel vl.O The plates for AI_comprehensive panel vl .0 include two control wells and 89 test samples comprised of cDNA isolated from surgical and postmortem human tissues obtained from the Backus Hospital and Clinomics (Frederick, MD). Total RNA was extracted from tissue samples from the Backus Hospital in the Facility at CuraGen. Total RNA from other tissues was obtained from Clinomics. Joint tissues including synovial fluid, synovium, bone and cartilage were obtained from patients undergoing total knee or hip replacement surgery at the Backus Hospital. Tissue samples were immediately snap frozen in liquid nitrogen to ensure that isolated RNA was of optimal quality and not degraded. Additional samples of osteoartliritis and rheumatoid arthritis joint tissues were obtained from Clinomics. Normal control tissues were supplied by Clinomics and were obtained during autopsy of trauma victims.

Surgical specimens of psoriatic tissues and adjacent matched tissues were provided as total RNA by Clinomics. Two male and two female patients were selected between the ages of 25 and 47. None of the patients were taking prescription drugs at the time samples were isolated. Surgical specimens of diseased colon from patients with ulcerative colitis and Crohns disease and adjacent matched tissues were obtained from Clinomics. Bowel tissue from three female and three male Crohn's patients between the ages of 41-69 were used. Two patients were not on prescription medication while the others were taking dexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue was from three male and four female patients. Four of the patients were taking lebvid and two were on phenobarbital.

Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha- 1 anti-trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35-80 and included both smokers and non-smokers. Most patients were taking corticosteroids, and bronchodilators.

In the labels employed to identify tissues in the AI_comprehensive panel vl.O panel, the following abbreviations are used: Al = Autoimmunity Syn = Synovial Normal = No apparent disease Rep22 /Rep20 = individual patients RA = Rheumatoid arthritis

Backus = From Backus Hospital OA = Osteoarthritis (SS) (BA) (MF) = Individual patients Adj = Adjacent tissue Match control = adjacent tissues

-M = Male -F = Female COPD = Chronic obstructive pulmonary disease Panels 5D and 51

The plates for Panel 5D and 51 include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained.

In the Gestational Diabetes study subjects are young (18 - 40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (<1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile saline, blotted and fast frozen within 5 minutes from the time of removal. The tissue was then flash frozen in liquid nitrogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus) and subcutaneous adipose. Patient descriptions are as follows:

Patient 2: Diabetic Hispanic, overweight, not on insulin Patient 7-9: Nondiabetic Caucasian and obese (BMI>30) Patient 10: Diabetic Hispanic, overweight, on insulin Patient 11 : Nondiabetic African American and overweight Patient 12: Diabetic Hispanic on insulin

Adipocyte differentiation was induced in donor progenitor cells obtained from Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stem cells (HuMSCs) for CuraGen based on the published protocol found in Mark F. Pittenger, et al.. Multilineage Potential of Adult Human Mesenchymal Stem Cells Science Apr 2 1999:

143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDNA production. A general description of each donor is as follows:

Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated

Donor 2 and 3 AD: Adipose, Adipose Differentiated Human cell lines were generally obtained from ATCC (American Type Culture

Collection), NCI or the German tumor cell bank and fall into the following tissue groups: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA. Panel 51 contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 51.

In the labels employed to identify tissues in the 5D and 51 panels, the following abbreviations are used:

GO Adipose = Greater Omentum Adipose SK = Skeletal Muscle

UT = Uterus

PL = Placenta

AD = Adipose Differentiated

AM = Adipose Midway Differentiated U = Undifferentiated Stem Cells

Panel CNSD.01

The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

Disease diagnoses are taken from patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supernuclear Palsy, Depression, and "Normal controls". Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.

In the labels employed to identify tissues in the CNS panel, the following abbreviations are used:

PSP = Progressive supranuclear palsy Sub Nigra = Substantia nigra Glob Palladus= Globus palladus Temp Pole = Temporal pole Cing Gyr = Cingulate gyrus

BA 4 = Brodman Area 4

Panel CNS_Neurodegeneration_V1.0

The plates for Panel CNS_Neurodegeneration_V1.0 include two control wells and 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology. Disease diagnoses are taken from patient records. The panel contains six brains from Alzheimer's disease (AD) patients, and eight brains from "Normal controls" who showed no evidence of dementia prior to death. The eight normal control brains are divided into two categories: Controls with no dementia and no Alzheimer's like pathology (Controls) and controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0 = no evidence of plaques, 3 = severe AD senile plaque load). Within each of these brains, the following regions are represented: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), and occipital cortex (Brodman area 17). These regions were chosen to encompass all levels of neurodegeneration in AD. The hippocampus is a region of early and severe neuronal loss in AD; the temporal cortex is known to show neurodegeneration in AD after the hippocampus; the parietal cortex shows moderate neuronal death in the late stages of the disease; the occipital cortex is spared in AD and therefore acts as a "control" region within AD patients.

Not all brain regions are represented in all cases.

In the labels employed to identify tissues in the CNS_Neurodegeneration_Vl .0 panel, the following abbreviations are used:

AD = Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy

Control = Control brains; patient not demented, showing no neuropathology

Control (Path) = Control brains; patient not demented but showing sever AD-like pathology

SupTemporal Ctx = Superior Temporal Cortex

Inf Temporal Ctx = Inferior Temporal Cortex

A. CG100446-01: Allantoicase

Expression of gene CG100446-01 was assessed using the primer-probe set Ag4178, described in Table AA. Results of the RTQ-PCR runs are shown in Table AB.

Table AA. Probe Name Ag4178

. _, ! Start SEQ ID

Primers i Sequences Length „ . . ^& ' Position No

Forward '5 ' -tcttacttcacgggagattacg- 3 ' 22 415 ^~ 259 ^{" "}

'TET- 5 ' -tcgagtgtccattcaagcagcaaacτ_-3

Probe ■TAMRA 26 441 260

Reverse !5 ' -gttcctctttctgggatttctg-3 ' ?? ^"485 ^" 261

Table AB. General_screening_panel_vl .4

_ _ iPool _._

Lung ca. HOP-62 ^"ό.ό^" '.Cerebral Cortex Pool

Brain (Substantia nigra) Lung ca. NCI-H522 0.0 0.8 Tool jLiver 0.6 JBrain (Thalamus) Pool 1.0

Fetal Liver 0.7 JBrain (whole) 1.2 JLiver ca. HepG2 0.0 jSpinal Cord Pool 0.6^{" " ""}

Kidney Pool 0 _.0__ iAdrenal Gland 1.3

Fetal Kidney jPituitary gland Pool 0.9

JRenal ca. 786-0 0.0 ₍Salivary Gland 0.0 Renal ca. A498 oTo ^{" ■}Thyroid (female) ^~~ όTό

1 •Pancreatic ca.

.Renal ca. ACHN 0.0 JCAPAN2 0.0

'Renal ca. UO-31 0.0 .Pancreas Pool 0.0

CNS_neurodegeneration_vl.0 Sumraarj': Ag4178 Expression of the CGI 00446-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

General_screening_panel_vl.4 Summary: Ag4178 Highest expression of the CGI 00446-01 gene is detected in a CNS cancer SK-N-AS cell line (CT=31.8). In addition, low expression of this gene is also seen in a lung cancer cell line. Therefore, expression of this gene can be used as diagnostic marker to detect lung and CNS cancer. Furthermore, therapeutic modulation of this gene may be beneficial in the treatment of lung and brain cancer.

Moderate expression of this gene is also seen in testis. Therefore, therapeutic modulation of this gene product may be useful in the treatment of testis related diseases such as fertility and hypogonadism.

Panel 4.1D Summary: Ag4178 Expression of the CG100446-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel. general oncology screening panel_v_2.4 Summary: Ag4178 Expression of the CGI 00446-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

B. CG101025-01 and CG101025-04: CALCIUM/CALMODULIN- DEPENDENT PROTEIN KINASE TYPE II BETA CHAIN

Expression of genes CG101025-01 and CG101025-04 was assessed using the primer- probe set Ag4967, described in Table BA. Results of the RTQ-PCR runs are shown in Tables BB, BC and BD. Table BA. Probe Name Ag4967

Primers] Sequences (Length jStart PositionjSEQ ID No

'Forward 's ' -aaagttcaatgccaggagaaag-3 ' r 22 900 ! 262

_:Probe JTET-5 ' -aagggagccatcctcaccaccat-3 ' -TAMRAJ 23 925 | 263

(Reverse Is ' -aaactcttggctgagaaattcc-3 ' 22 959 ] 264

Table BB. General_screening_panel_vl .5

Fetal Lung i „ , GNS cancer (neuro.met) SK- ]

0.2 ^:N-AS i

I_ung ca. NCΪ-N417 0.0 jCNS cancer (astro) SF-539 1 0.0 |

Lung ca. LX-1 : 0.0 j( rNS cancer (astro) SNB-75 ; 0.1

Tung ca. NCI-H 146 i ^~ 3.0 ;< 3NS cancer (glio) SNB- 19 0.1

'_jLung ca. SHP-77 0.6 j( NS cancer (glio) SF-295 1 0.0

Tung ca. A549 J 0.0 !13rain (Amygdala) Pool j 6.1

^■Lung ca. NCI-H526 0.5 11 Brain (cerebellum) | 48.6

Lung ca. NCI-H23 ! 0.2 jl 3rain (fetal) | loo.o !

Lung ca. NCI-H460 | 0.1 il 3rain (Hippocampus) Pool [ 7.2 ΪLung ca. HOP-62 \ ^{~ ~} o.o ^{" "}T< Cerebral Cortex Pool ] 10.1

[Lung ca. NCΪ-H522 ! 0.4 jl 3rain (Substantia nigra) Pool 6.4

Liver ι ^"Ti ^" lι 3rain (Thalamus) Pool j 12.8 ^"

'Fetal Liver ; 0.0 _t j] 3rain (whole) j 21.8

'Liver ca. HepG2 j 0.0 [Spinal Cord Pool j 2.9

'Kidney Pool ! 0.0 ] Adrenal Gland j 2.0

,Fetal Kidney I 0.6 {Pituitary gland Pool j 4.6

'Renal ca. 786-0 \ 0.0 [Salivary Gland I 0.0

Renal ca. A498 j 0.0 [Thyroid (female) | 0.4

[Renal ca. ACHN i 0.8 [l ³ancreatic ca. CAPAN2 J 0.0

Renafca. UO-31 ! ^"θ.^~4 ii ³ancreas Pool j ^"o.

Table BC. Oncology cell line screenin«_panel v3.1

1 Rel. Exp.(%) Reϊ. Exp.^"(%)

\ Tissue Name Ag4967, Run Tissue Name Ag4967, Run

J 225060931 225060931

'Daoy Ca Ski_Cervical epidermoid

0.0 0.0 _^Medulloblastoma/Cerebellum carcinoma (metastasis)

|TE671 ES-2_Ovarian clear cell

3.8 'Mediilloblastom/Cerebellum 0.5 carcinoma

D283 Med Ramos/όh stim_ Stimulated with

4.0 0.0 iMedulloblastoma/Cerebellum PMA/ionomycin 6h

PFSK-1 Primitive Ramos/14h stim_ Stimulated Neuroectodermal/Cerebellum 1.7 0.0 with PMA/ionomycin 14h

XF-498_CNS MEG-01_Chronic myelogenous

0.0 0.1 leukemia (megokaryoblast)

SNB-78_CNS/glioma 0.1 Raji_Burkitt's lymphoma 0.1

[SF-268_CNS/glioblastoma 0.0 Daudi_Burkitt's lymphoma 0.0

T98G_Glioblastoma U266_B-cell

0.0 0.2 plasmacytoma/myeloma

;SK-N-SH_Neuroblastoma ^■ ~ J (metastasis) 0.4 CA46_Burkitt's lymphoma 0.0

adenocarcinoma

SW-4801Coϊon^{" "}

0.0 ΗT-1080 Fibrosarcoma adenocarcinoma 0.0

'NCI-SNU-5_Gastric ca. 0.5 MG-63_Osteosarcoma (bone) 1.7

SK-LMS-l_Leiomyosarcoma 1

!KATO III_Stomach 0.0 (vulva) j

» S JRH30_Rliabdomyosarcoma

NCI-SNU-16 Gastric ca. 0.0 i (met to bone marrow) 0.0

,NCI-SNU-l_Gastric ca. 0.1 A43 lJEpidermoid ca. 0.0

,RF-l__Gastric adenocarcinoma 0.1 WM266-4_Melanoma _r _ 0._1

RF-48_Gastric adenocarcinoma 0.0 DU 145_Prostate

1 MDA-MB-468_Breast

[MKN-45_Gastric ca. 1.3 0.1 adenocarcinoma

NCI-N87 Gastric ca. 0.0 SSC-4_Tongue 0.0

:OVCAR-5_Ovarian ca. 0.0 SSC-9_Tongue 0.0

RL95-2_Uterine carcinoma 0.0 SSC-15_Tongue 0.0

;HelaS3_Cervical CAL 27_Squamous cell ca. of

0.0 .adenocarcinoma tongue 0.0

Table BD. Panel 5 Islet

Rel. Exp.(%) Rel. Exp.(%)

Tissue Name Ag4967, Run Tissue Name Ag4967, Run

240188656 240188656

^'97457_Patient-

0.0 02go_adipose 94709JDonor 2 AM - A_adipose ] 0.0 i97476_Patient-

5.6 94710_Donor 2 AM - B_adipose 07sk_skeletal muscle 0.0 l97477_Patient- 0.0 07ut uterus 9471 l_Donor 2 AM - C_adipose 0.0

|97478_Patient- 0.0 |07pl_placenta 94712_Donor 2 AD - A_adipose 0.0

,99167_Bayer Patient 1 32.1 94713_Donor 2 AD - B_adipose 0.0

<97482_Patient-

0.0 ;08ut uterus 94714_Donor 2 AD - C_adipose 0.0 l97483_Patient- 94742_Donor 3 U -

0.0 0.0 |08pl_placenta AJVlesenchymal Stem Cells

J97486lPatϊent-^{" "} 6.7 94743^~DOnor^"3^"u - ^"

O9sk skeletal muscle 0.0

B_Mesenchymal Stem Cells

,97487_Patient- 09ut uterus 0.0 94730_Donor 3 AM - A_adipose 0.0

97488_Patient- 09pl_placenta 0.0 94731_Donor 3 AM - B_adipose 0.0

97492_Patient- lOut uterus 0.0 ^' 94732_Donor 3 AM - C_adipose 0.0

564

eneral_screening_panel_vl.5 Summary: Ag 967 H g est expression o t e CGI 01025-01 gene is detected in fetal brain (Ct=27). High to moderate expression of this gene is seen in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. This gene codes for a splice variant of calcium/calmodulin-dependent-dependent kinase II. Calmodulin (CaM) is a major Ca2+-binding protein in the brain, where it plays an important role in the neuronal response to changes in the intracellular Ca2+ concentration. Calmodulin modulates numerous Ca2+-dependent enzymes and participates in relevant cellular functions. Among the different CaM-binding proteins, the Ca2+/CaM dependent protein kinase II and the phosphatase calcineurin are especially important in the brain because of their abundance and their participation in numerous neuronal functions (Sola et al., 2001, Int J Biochem Cell Biol 33(5):439-55, PMID: 11331200). Therefore, therapeutic modulation of this gene product may be useful in the treatment of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. In addition, moderate expression of this gene is also seen in heart and skeletal muscle. Therefore, expression of this gene may be used to distinguish brain, heart and skeletal muscle samples from other samples used in this panel. Furthermore, therapeutic modulation of this gene may be beneficial in the treatment of heart and muscle related diseases. OncoIogy_ceIl_Iine_screening_panel_v3.1 Summary: Ag4967 Expression of this gene is highest in cerebellum (CT = 28.6), consistent with what is observed in Panel 1.5. Please see Panel 1.5 for a description of the potential utility of this gene in the treatment of central nervous system disorders.

In addition, this gene is also expressed at moderate levels in 5 out of 13 lung cancer cell lines. Therefore, expression of this gene may be used to distinguish lung cancer cell lines from the other cell lines on this panel. Furthermore, therapeutic modulation of the activity of this gene or its protein product may be beneficial in the treatment of lung cancer.

Panel 5 Islet Summary: Ag4967 Highest expression of the CG101025-01 gene is detected in skeletal muscle (CT = 29.7). Moderate expression of this gene is also seen in pancreatic islet cells (Bayer patient 1). Therefore, expression of this gene can be used to distinguish muscle and islet cell samples from the other samples used in this panel.

This gene codes for a splice variant of calcium/calmodulin-dependent-dependent kinase II (CaM kinase II). CaM kinase II plays an important role in insulin exocytosis in the beta-cell (Bhatt et al., 2000, Biochem Pharmacol 60(11): 1655-63, PMID: 11077048). Inhibition of this enzyme suppresses calcium-dependent insulin secretion (Easom, 1999,

Diabetes 48(4):675-84, PMID: 10102681). Thus, activation of the CG101025-01 gene may be used as a treatment to increase insulin secretion in Type 2 diabetes. In addition, therapeutic modulation of this gene may be useful in the treatment of muscle related diseases and other endocrine/metabolically related diseases, such as obesity.

C. CG101149-01: CALCIUM-BINDING TRANSPORTER

Expression of gene CG101149-01 was assessed using the primer-probe set Ag4204, described in Table CA. Results of the RTQ-PCR runs are shown in Table CB.

Table CA. Probe Name Ag4204

566 — -₂"₅- .-~~-

Reverse ,5 ' -actgtcattgtcccatcaacat-3 2?

gene is low/undetectable (CTs > 35) across all of the samples on this panel.

General_screening_panel_vl.4 Summary: Ag4204 Expression of the CGI 01 149-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Panel 4.1D Summary: Ag4204 Highest expression of the CG101149-01 gene is detected in dendritic cells (CT=28). In addition, moderate to low levels of expression of this gene is also seen in activated dendritic cells, resting monocytes and macrophages, resting and

568 PMA/ionomycin treated LAK cells, IFN gamma and IL-1 1 treated HUVEC cells. HPAEC cells, two Way MLR. PBMC, eosinophils and normal tissues represented by colon, lung and thymus. Therefore, therapeutic modulation of this gene product through the use of small molecule drug or antibodies may be beneficial in the treatment of Therapeutics designed with the protein encoded by this transcript could therefore be important for the treatment of asthma, emphysema, inflammatory bowel disease, arthritis and psoriasis.

In addition, low levels of expression of this gene is also seen in liver ciιτhosis(CT=34.2), but not in normal liver (no expression in normal liver is detected on Panel 1.4D). Therefore, therapies designed with the protein encoded for by this gene may potentially modulate liver function and play a role in the identification and treatment of inflammatory or autoimmune diseases which effect the liver including liver cirrhosis and fibrosis. general oncology screening panel_v_2.4 Summary: Ag4204 Expression of the CG101 149-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

D. CG101169-01: Lipid-binding serum glycoprotein Expression of gene CGI 01169-01 was assessed using the primer-probe set Ag4205, described in Table DA. Results of the RTQ-PCR runs are shown in Table DB.

Table DA. Probe Name Ag4205

Table DB. Panel 4. ID

gene is low/undetectable (CTs > 35) across all of the samples on this panel.

General_screening_panel_vl.4 Summary: Ag4205 Expression of the CG101 169-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Panel 4. ID Summary: Ag4205 Highest expression of the CG101169-01 gene is detected in kidney (CT=30.2). Moderate level of expression of this gene is also detected in thymus. Therefore, expression of this gene can be used to distinguish the kidney and thymus samples from other samples used in this panel. In addition, therapeutic modulation of this gene product may be useful in the treatment of autoimmune and inflammatory diseases that affect kidney. general oncology screening panel_v_2.4 Summary: Ag4205 Expression of the CG101169-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

E. CG101221-01: Novel OXIDOREDUCTASE UCPA

Expression of gene CGI 01221-01 was assessed using the primer-probe set Ag4219, described in Table EA. Table EA. Probe Name Ag4219

Start SEQ ID

Primers! Sequences [Length]

I 1 Position No

.Forward i 5 ' -attgatcagttcgccaatga- 3 ' ! 20 j 202 271 , _ι -TET- 5 ' -tgttctctttaatgttgctggttttgtcca-3 ' -

|P^robe [T_AMRA 1 30 1 237 272

[Reverse [5 ' -caatccaggacagttccatg-3 ' i ²⁰ ! 26S 273

CNS_neurodegeneration_vl.0 Summary: Ag4219 Expression of the CG101221-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

General_screening_panel_vl.4 Summary: Ag4219 Expression of the CGI 01221 -01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Panel 4. ID Summary: Ag4219 Expression of the CG101221-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Panel 5 Islet Summary: Ag4219 Expression of the CG101221-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel. general oncology screening panel_v_2.4 Summary: Ag4219 Expression of the CGI 01221 -01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

F. CG101330-01: METHIONYL-TRNA FORMYLTRANSFERASE

Expression of gene CGI 01330-01 was assessed using the primer-probe set Ag4209, described in Table FA. Results of the RTQ-PCR runs are shown in Tables FB, FC, FD and FE.

Table FA. Probe Name Ag4209

Table FB. CNS_neurodegeneration_vl.O

Table FC. General screening jpanel v 1.4

Table FD. Panel 4. ID

Rel. Exp.(%) Rel. Exp.(%)

Tissue Name Ag4209, Run Tissue Name Ag4209, Run

174926555 iSecondary Thl act 83.5 [HUVEC IL-1 beta 49.0

Table FE. general oncology screening panel_v_2.4

CNS_neurodegeneration_\T.0 Summary: Ag4209 This panel confirms the expression of the CG101330-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between

Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

Gcneral_screening_panel_vl.4 Summary: Ag4209 Highest expression of the

CG101330-01 gene is detected in colon cancer HCT-1 16 cell line (28.4). Moderate levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Panel 4. ID Summary: Ag4209 Highest expression of the CG101330-01 gene is detected in IFN gamma treated NCI-H292 cell line (CT=32.2). This gene is expressed at moderate to low levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. general oncology screening panel_v_2.4 Summary: Ag4209 Highest expression of the CG101330-01 gene is detected in malignant colon cancer sample (CT=33.9). Significant expression of this gene is also seen in number of cancer samples derived from kidney, colon, metastatic melanoma and kidney. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of these cancers.

G. CG101386-01: ABC_2 transporter

Expression of gene CGI 01386-01 was assessed using the primer-probe set Ag4210, described in Table GA. Results of the RTQ-PCR runs are shown in Tables GB, GC, GD and GE.

Table GA. Probe Name Ag4210

Table GB. CNS_neurodegeneration_vl.O

Tissue Name Rel. Exp.(%) Tissue Name Rel. Exp.(%)

Table GC. General_screeningjpanel_vl .4

[Melanoma* M14 0.0 Gastric ca. KATO III 0.0

[Melanoma* LOXIMVI o^" [Colon ca. SW-948 0.0

Table GD. Panel 4. ID

382 Table GE. general oncology screening I panel_v_2.4

-

Rel. Exp.(%) Rel. Exp.(%)

1 Tissue Name Ag4210, Run Tissue Name Ag4210, Run

268624929 268624929

[Colon cancer 1 0.0 Bladder cancer NAT 2 0.0

[Colon cancer NAT 1 0.0 Bladder cancer NAT 3 0.0

.Colon cancer 2 Bladder cancer NAT 4 o.T ^"

Colon cancer NAT 2 0.0 Adenocarcinoma of the prostate 1 1.2

Colon cancer 3 0.0 Adenocarcinoma of the prostate 2 0.0

'Colon cancer NAT 3 2.0 Adenocarcinoma of the prostate 3 1.1

Colon malignant cancer 4 0.0 Adenocarcinoma of the prostate 4

[Colon normal adjacent

0.0 Prostate cancer NAT 5 0.0 'tissue 4

Lung cancer 1 0.0 Adenocarcinoma of the prostate 6 0.0

Lung NAT 1 0.0 Adenocarcinoma of the prostate 7 0.0

^'Lung cancer 2 0.0 Adenocarcinoma of the prostate 8 0.0

Lung NAT 2 0.0 Adenocarcinoma of the prostate 9 0.0

Squamous cell carcinoma

0.0 Prostate cancer NAT 10 0.0

'j

Lung NAT 3 ^' OΌ Kidney cancer 1 0.0

'metastatic melanoma 1 0.0 KidneyNAT 1 0.0

Melanoma 2 0.0 Kidney cancer 2 100.0

Melanoma 3 0.0 Kidney NAT 2 0.0 metastatic melanoma 4 0.0 Kidney cancer 3 0.0

.metastatic melanoma 5 0.0 Kidney NAT 3 0.0

Bladder cancer 1 0.0 Kidney cancer 4 OΌ .Bladder cancer NAT 1 o.o Kidney NAT 4 ^{" "}o.o Bladder cancer 2 0.0

CNS_neurodegeneration_vl.0 Summary: Ag4210 This panel confirms the expression of the CG101386-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_ l.4 Summary: Ag4210 Highest expression of the CG101386-01 gene is detected in cerebellum (CT=28.2). Moderate expression of this gene is mainly seen in all the regions of the central nervous system, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, expression of this gene may be used to distinguish brain samples from other samples used in this panel. Furthermore, therapeutic modulation of this gene may be useful in the treatment of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

In addition, moderate to low expression of this gene is seen in number of cancer cell lines derived from brain, lung, breast, ovarian cancers and melanoma. Therefore, expression of this gene may be used as diagnostic marker for detection of these cancers and also therapeutic modulation of this gene may be beneficial in the treatment of these cancers.

Panel 4. ID Summary: Ag4210 Highest expression of the CG101386-01 gene is detected in anti-CD40 treated dendritic cells (CT = 29.6)and to a lesser extent in non-activated dendritic cells. This gene is also expressed at a moderate level in LPS activated monocytes, whereas it is not expressed in resting monocytes. The higher expression of this transcript in dendritic cells and in activated monocytes, cells that play a crucial role in linking innate immunity to adaptive immunity, suggests that this gene may play a role in immune-mediated diseases such as autoimmune diseases and other T cell mediated diseases including psoriasis, inflammatory bowel diseases and/or bacterial or viral infections. Therefore, modulation of the activity of the protein encoded by CGI 01386-01 by small molecule drugs, may be beneficial for the prevention or the treatment of these diseases. In addition, this gene is expressed at moderate to low levels in LAK cells, lung fibroblasts, Ramos B cells, macrophages, and normal tissues represent by colon, lung and kidney. Therefore, expression of this gene may be used to distinguish these samples from other samples used in this panel. general oncology screening panel_v_2.4 Summary: Ag4210 Moderate levels of expression of the CG101386-01 gene is detected only in kidney cancer sample (CT=32.8). This expression is higher in cancer sample as compared to the sample derived from adjacent normal control tissue (CT-40). Therefore, expression of this gene may be used to distinguish the cancer sample from the control kidney tissue and other samples used in this panel and also as a marker for detection of kidney cancer. In addtion, therapeutic modulation of this gene may be useful in the treatment of kidney cancer.

H. CG101396-01: GLUTAMATE RECEPTOR DELTA-1

Expression of gene CGI 01396-01 was assessed using the primer-probe set Ag421 1, described in Table HA. Results of the RTQ-PCR runs are shown in Tables HB, HC, HD, HE and HF. Table HA. Probe Name Ag4211

Start SEQ ID

Primers! Sequences [Length [ Position No

•'Forward _'5 ' -aggacagttcgaatccctatgt- 3 ' ^"] T 280 ^{" ~} j_p , '.TET-5 ' -ccagtttgaaatccttggcactacct-3 ' - iPro e j_TAMRA i 26 ! 1261 281 i 1

[Reverse J5 ' -gcatgtctttgccaaaagtct-3 ' PTΓT 1293 282

Table HB. CNS neurodegeneration vl .O

Table HC. General_screening_panel_vl.4

Liver ^[ 0.1 Brain (Thalamus) Pool ! 90.8

Fetal Liver Brain (whole) ! 77.9

Liver ca. HepG2 ; o.o Spinal Cord Pool [ 64.6

Kidney Pool [ 21.5 Adrenal Gland [ 13.7

■Fetal Kidney 1 4.3 Pituitary gland Pool i 1 -5 ¹

{Renal ca. 786-0 j 0.0 Salivary Gland ! LO

ΪRenai ca. A498 1 14.7 Thyroid (female) I 26.ι

Renal ca. ACI N [ 0.1 Pancreatic ca. CAPAN2 i 26.1

[Renal ca. UO-31 | 0.0 ^] Pancreas Pool [ 9.9

Table HD. Panel 4. ID

Table HE. Panel CNS 1

BA17 Parkinson' s2 ₁ 73.7 ^'Cing Gyr Huntington's2 1 3θ^".4 ^" j BA17 Huntington's ! 33.4 [Cing Gyr PSP [ 27.7 j

'BA17 Huntington's2 j 27.4 Cing Gyr PSP2 ! 12.1 | BA17 Depression j^" 17.3 ^{" '} [Cing Gyr Depression ] 14.0 1 ,BA17 Depression ^"| ^{" " "} 40.1 [Cing Gyr Depression2 T ^"~π.i 1

Table HF. general oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4211 This panel does not show differential expression of the CGI 01396-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. General_screening_panel_vl.4 Summary: Ag4211 Highest expression of the

CG101396-01 gene is seen in the fetal brain (CT=29). In addition, this gene is expressed at moderate levels in all regions of the CNS examined. This gene encodes a protein that is homologous to the delta2 glutamate receptor, which is expressed in the cerebellum. This receptor is involved in motor learning and coordination, and synapse plasticity. Based on the prominent expression of this gene product in the CNS, therapeutic modulation of the expression or function of this gene product may be useful for CNS disorders involving memory deficits, including Alzheimer's disease and aging as well as for motor impairments and learning following stroke-related brain damage.

Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle and heart. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. In addition, moderate levels of expression are seen in a cluster of samples derived from ovarian, colon, melanoma and lung cancer cell lines. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of ovarian, colon, melanoma and lung cancers. This gene is also expressed at much higher levels in fetal lung tissue (CT=30) when compared to expression in the adult counterpart (CT=35.5). Thus, expression of this gene may be used to differentiate between the fetal and adult source of this tissue.

Panel 4. ID Summary: Ag4211 Highest expression of this gene is seen in the kidney (CT=30.8). Moderate levels of expression are also seen in the lung and untreated lung microvascular endothelial cells. Low but significant levels of expression are seen in untreated and treated astrocytes and Ramos B cells and activated lung microvascular endothelial cells. Expression in astrocytes is in agreement with the prominent CNS expression seen in Panel 1.4. This expression suggests that this gene product may be involved in the homeostasis of the lung and kidney. Therapeutic modulation of the expression of this protein may be restore or maintain function in these organs during inflammation.

Panel CNS_1 Summary: Ag4211 This panel confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. general oncology screening panel_v_2.4 Summary: Ag4211 Expression of the CGI 01396-01 gene is seen in a kidney cancer sample (CT=31). In addition, moderate to low expression of this gene is detected in melanoma and prostate cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be effective in the treatment of melanoma, kidney and lung cancers.

I. CG101543-01: scop

Expression of gene CG101543-01 was assessed using the primer-probe set Ag4216, described in Table IA. Results of the RTQ-PCR runs are shown in Tables IB, IC, ID. IE and IF.

Table IA. Probe Name Ag4216

Start SEQ ID

Primers , Sequences [Length Position No Forward 5 ' -ccgaaagctagaagttttggat-3 ' 22 2757

'TET-5 ' -caaatatgtgaacttcctgcccgctt-3 Probe [TAMRA 26 2791 284

Reverse '5 ' -ttccggagactgctattacaaa-3 ' 22 2819 285

Table IB. CNS_neurodegeneration_vl .0

Table IC. General_screening_panel_vl .4

tune ca. NCI-H526 18.6 [Brain (cerebellum) 88.9

Table ID. Panel 4. ID

Table IE. Panel CNS 1

Rel. Exp.(%) Ag4216, Rel. Exp.(%) Ag4216,

Tissue Name Tissue Name Run 181012237 Run 181012237

BA4 Control 13.9 :BAI7 PSP 14.4

BA4 Control _ 27.0 jBA17 PSP2__ T⁶

!BA4 ^{_ " "} J .D ^■Sub Nigra Control 82.9 .^'Alzheimer's2

,BA4 Parkinson's 39.0 _;Sub Nigra Control2 43^".5

IBA4 [Sub Nigra 39.2 22.7

Tarkinson's2 ιAlzheimer's2

Table IF. gei leral oncology screenin & σ panel_v_2.4

CNS_neurodegeneration_vl.0 Summary: Ag4216 This panel confirms the expression of the CG101543-01 gene at low levels in the brain in an independent group of individuals. This gene is found to be slightly upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation of the expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease. General_screening_panel_vl.4 Summary: Ag4216 Highest expression of the CG101543-01 gene is detected in thalamus and whole brain (CTs=28). High expression this gene is seen in all the region of the central nervous system examined including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. The CGI 01543-01 gene codes for a homolog of rat SCN circadian oscillatory protein (SCOP). In rat, SCOP was shown to be predominantly expressed in brain and has been implicated in in the intracellular signaling in the SCN (Shimizu et al, 1999, FEBS Lett 458(3):363-9, PMID: 10570941). Therefore, therapeutic modulation of the SCOP encoded by this gene may be useful in the treatment of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Moderate levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Panel 4. ID Summary: Ag4216 Highest expression of the CG101543-01 gene is detected in activated secondary Th2 cells (CT=28.8). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Panel CNS_1 Summary: Ag4216 This panel confirms the expression of the the CGI 01543-01 gene at low levels in the brains of an independent group of individuals. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders. general oncology screening panel_v_2.4 Summary: Ag4216 Highest expression of the CG101543-01 gene is detected in squamous cell carcinoma (CT=28.9). Interestingly, this expression is higher in the cancer sample as compared to adjacent control lung tissue (CT=34.4). Therefore, expression of this gene may be used to distinguish between these two samples and as a marker to detect lung cancer.

Moderate expression of this gene is detected in number of normal and cancer samples examined including lung, kidney, colon, prostate and melanoma. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of these cancers.

J. CG101574-01: Phosphoglycerate mutase

Expression of gene CGI 01574-01 was assessed using the primer-probe set Ag4217, described in Table JA. Results of the RTQ-PCR runs are shown in Tables JB, JC and JD.

Table JA. Probe Name Ag4217

Table JB. General_screening_panel_vl .4

Table JC. Pan el4.1D

Dendritic cells LPS OΌ [Dermal Fibroblasts rest [ 0.0 _ _ ..

Dendritic cells anti-

0.0 [Neutrophils TNFa+LPS _j 0.0 CD40 ^*

Monocytes rest 0.0 [Neutrophils rest i 0.0

Monocytes LPS 1 o.o [Colon i 0.3

(Macrophages rest ] 0.0 [Lung j 0.0

[Macrophages LPS J 0.0 'Thymus [ 4.8

,HUVEC none ^"T o.o [Kidney [ 100.0

HUVEC starved | o.o J [

Table JD. Panel 5 Islet - -

^" Reϊ. xp.(%) ^~ Rel. Exp.(%)

Tissue Name Ag4217, Run Tissue Name Ag4217, Run

258292595 258292595

97457JPatient-

0.0 94709 Donor 2 AM - A adipose 0.0 02go_adipose

97476JPaιient-

0.0 94710_Donor 2 AM - B_adipose 0.0 ,07sk_skeletal muscle

97477_Patient-

0.0 9471 l_Donor 2 AM - C_adipose 0.0 07ut_uterus

[97478_Patient-

0.0 94712_Donor 2 AD - A_adipose 0.0 07pl_placenta

99167 JBayer Patient 1 0.0 94713_Donor 2 AD - B_adipose 0.0

97482_Patient-

0.0 94714_Donor 2 AD - C_adipose 0.0 08ut_uterus

,97483_Patient- 94742_Donor 3 U -

100.0 0.0 08pl_placenta A_Mesenchymal Stem Cells

[97486_Patient- 94743_Donor 3 U -

0.0 0.0 09sk_skeletal muscle B_Mesenchymal Stem Cells

^*97487_Patient-

0.0 94730JDonor 3 AM - A_adipose 0.0 09ut uterus

'97488_Patient-

19.3 94731_Donor 3 AM - B_adipose 0.0 09pl_placenta

•97492_Patient-

0.0 94732_Donor 3 AM - C_adipose 0.0 lOut uterus

[97493_Patient-

0.0 94733_Donor 3 AD - A_adipose 0.0 .lOpljplacenta

[97495_Patient- [l lgo_adipose 0.0 94734_Donor 3 AD - B_adipose 0.0

|97496_Patient-

0.0 94735_Donor 3 AD - C_adipose 0.0 j 11 sk_skeletal muscle

[97497__Patient- j 7138_Liver_HepG2untreated 0.0 jl lut_uterus 0.0 7

Ϊ97498 Patient- 0.0 73556 Heart Cardiac stromal 0.0 11 pl_placenta ^■cells (primary)

97500_Patient- 0.0 '81735 Small Intestine 0.0 12go_adipose

97501 JPatient- 0.0 72409_Kidney_Proximal

0.0 il2sk skeletal muscle Convoluted Tubule j97502_Patient-

0.0 82685 Small intestine Duodenum _. 0.0 •12ut uterus

[97503JPa.ient- 90650_Adrenal_Adrenocortical

0.0 0.0 ]12pl_placenta adenoma

19472 ϊ^{" "} Donor 2 ϋ^""

[A_Mesenchymal Stem 0.0 72410_Kidney_HRCE 0.0 [Cells i94722_Donor 2 U - I 'BJVIesenchymal Stem \ 0.0 72411_Kidney_HRE 0.0 'Cells I

.94723 Donor 2 U - ^{" ■ "}

73139_Uterus_Uterine smooth

,C_Mesenchymal Stem ^! 0.0 0.0 muscle cells

.Cells _ ___ __ j , __ . _ __ _. __

CNS_neurodegeneration_vl.0 Summary: Ag4217 Expression of the CG101574-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

General_screening_panel_vl.4 Summary: Ag4217 Highest expression of the CG101574-01 gene is detected in gastric cancer NCI-N87 cell line (CT=29.7). Moderate to low levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, renal, breast, ovarian, melanoma and brain cancers. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. General_screening_panel_vl.5 Summary: Ag4217 Expression of the CG101574-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Panel 4. ID Summary: Ag4217 Moderate level of expression of the CG101574-01 gene is detected only in kidney (CT=31.3). Therefore, expression of this gene may be used to distinguish kidney sample from other samples used in this panel. In addition, therapeutic modulation of this gene product may tbe beneficial in the treatment of autoimmune and inflammatory diseases that affect kidney, including lupus and glomerulonephritis.

Panel 5 Islet Summary: Ag4217 Expression of the CGI 01574-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel. general oncology screening panel_v_2.4 Summary: Ag4217 Expression of the CG101574-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

K. CG101596-01: LYSOPHOSPHATIDIC ACID ACYLTRANSFERASE- 1

Expression of gene CG101596-01 was assessed using the primer-probe set Ag6753, described in Table KA.

Table KA. Probe Name Ag6753

I „ |, . Start [ SEQ ID Pπmers ! Sequences iLengthi _ ._ . -r ] i 1 [ Position No

Forward i5 ' -gtccccgtggtgtactcttc- 3 ' j 20 j 537 ; 289

[_p i [TET- 5 ' - ctcctccttctacaacaccaagaaga- 3 ' - ∞oe |_TAMRA 27 | 559 | 290

.Reverse [5 ¹ -cctgcactgtgactgttcct- 3 ' 20 j 599 ^• 291

CNS_neurodegeneration_vl.0 Summary: Ag6753 Results from one experiment with the CGI 01596-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screeningjpanel_vl.ό Summary: Ag6753 Results from one experiment with the CG101596-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

L. CG101673-01: DUAL SPECIFICITY PROTEIN PHOSPHATASE

Expression of gene CGI 01673-01 was assessed using the primer-probe set Ag4222, described in Table LA. Results of the RTQ-PCR runs are shown in Tables LB and LC. Table LA. Probe Name Ag4222

Start SEQ ID I

Primers Sequences Length [ Position No I

Forward '5 ' -agtctggaaaaccagtgctgta-3 ' 22 409 292 j p , [TET-5 ' -atcagctatgggccagcttatgacca-3 ' - ^'o [ AMRA 26 432 293 i

Reverse ,5 ' -tagagggagggaaaatctcaac-3 ' 22 ϊ 468 j 294

Table LB. General .creening_panel_vl .4

CNS_neurodegeneration_\T.0 Summary: Ag4222 Expression of the CG101673-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

General_screening_panel_vl.4 Summary: Ag4222 Low expression of the CG101673-01 gene is seen only in the gastric cancer NCI-N87 cell line (CT=34.7). Therefore, expression of this gene may be used to distinguish this sample from other samples used in this panel and also as marker to detect gastric cancer. In addition, therapeutic modulation of this gene may be useful in the treatment of gastric cancer.

Panel 4.1D Summary: Ag4222 Low expression of the CG101673-01 gene is seen only in kidney (CT=30.7). Therefore, expression of this gene may be used to distinguish this sample from other samples used in this panel. In addition, therapeutic modulation of this gene product may be useful in the treatment of autoimmune and inflammatory diseases that affect kidney including lupus and glomerulonephritis. general oncology screening panel_v_2.4 Summary: Ag4222 Expression of the CGI 01673-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

M. CG101826-01: Adenylate Kinase Isoenzyme

Expression of gene CGI 01826-01 was assessed using the primer-probe set Ag4226, described in Table MA. Results of the RTQ-PCR runs are shown in Tables MB, MC, MD, ME and MF.

Table MA. Probe Name Ag4226

Table MB. CNS neurodegeneration vl.O

Table ME. Panel 5 Islet

97457_Patient- 0.2 !94709__Donor 2 AM - A_adipose 9.2 02go_adipose

97476_Patient-

1.7 ;94710_Donor 2 AM - B_adipose 4.2 07sk_skeletal muscle ^r9141l ΥaύeϊΛ- ^"

1.1 9471 lJDonor 2 AM - C_adipose 5.9 [07ut uterus

97478_Patient-

0.0 94712_ Donor 2 AD - A_adipose 6.9 ι07pl_placenta

99167_Bayer Patient 1 ^"θ.ό^" J94713 _Donor 2 AD - B_adipose ^"6.3

97482_Patient- 0.0 94714_Donor 2 AD - C_adipose 8.1 '08ut_uterus

'97483_Patient- 94742__Donor 3 U -

0.0 2.8 08pl__placenta A_Mesenchymal Stem Cells

97486_Patient- [94743_Donor 3 U -

0.2 4.7

09sk_skeletal muscle [B_Mesenchymal Stem Cells

^'97487_Patient-

0.6 94730JDonor 3 AM - A_adipose 5.8 ^'09ut_uterus

^'97488 JPatient-^{" "} 0.0 94731_Donor 3 AM - B_adipose 3.0 09pljplacenta 0.4 94732_Donor 3 AM - C_adipose 4.7

0.0 94733_Donor 3 AD - A_adipose 10.1 lOpRplacenta

97495 JPatient- 0.4 94734JDonor 3 AD - B_adipose [ 3.5 1 1 go_adipose r

97496_Patient- 0.9 94735_Donor 3 AD - C_adipose 12.4

1 1 sk_skeletal muscle

97497_Patient- 77138_Liver__HepG2untreated 5.8 1 lut uterus

97498_Patient- 73556_Heart_Cardiac stromal

0.2 7.3 l lpljplacenta cells (primary)

97500_Patient- 0.6 81735_Small Intestine 2.2

12go_adipose

^■97501 _Patient- 72409^~_Kidney_Proximaf 1.2 65.1

,12sk_skeletal muscle Convoluted Tubule

^;97502_Patieιϊt- 0.6 82685 Small intestine Duodenum 0.0 ;12ut uterus

[97503_Patient- 90650_Adrenal_Adrenocortical

0.0 0.0 ' 12pl jplacenta adenoma

[94721_Donor 2 U - [A_Mesenchymal Stem [ J .D 72410_Kidney_HRCE 100.0 [Cells _j94722_Donor 2 U - B_Mesenchymal Stem 6.9 72411_Kidney_HRE 25.9 Cells 94723_Donor 2 U - 73139_Uterus_Uterine smooth C_Mesenchymal Stem 14.4 59.0 muscle cells Cells

Table MF. general oncology screening panel_v_2.4

CNS_neurodegeneration_\T.0 Summary: Ag4226 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. General_screening_panel_yl.4 Summary: Ag4226 Highest expression of this gene is seen in the thalamus (CT=25.1), with high to moderate levels of expression in all regions of the CNS examined. This gene encodes a putative adenylate kinase 5, a brain specific enzyme involved in the synthesis of adenine nucleotides necessary for the homeostasis of engergy metabolism in cells. (Van Rompay AR, Eur J Biochem 1999 Apr;261(2):509-17) Inouye S et. al (J Neurochem 1998 Jul;71(l):125-33) suggest that this enzyme plays an important role in neuronal function and may be involved in neuronal maturation and regeneration (Inouye S. Biochem Biophys Res Commun 1999 Jan 27;254(3):618-22). Based on the prominent expression in the CNS and homology to adenylate kinase 5, expression of this gene could be used to differentiate between neural and non-neural tissue. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Among tissues with metabolic function, this gene is expressed at low but significant levels in pituitary, adipose, adrenal gland, pancreas, fetal liver and adult and fetal skeletal muscle and heart. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

In addition, high levels of expression are seen in a cluster of samples derived from brain, renal and melanoma cancer cell lines. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of brain, renal and melanoma cancers.

Panel 4.1D Summary: Ag4226 Expression of this gene is essentially restricted ot lung and dermal fibroblasts, with highest expression in IL-4 treated dermal fibroblasts (CT=27.4). Expression in these cells suggests that this gene product may be involved in inflammatory conditions of the lung and skin. Thus, expression of this gene could be used as a marker of fibroblasts. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in reducing or eliminating symptoms in patients with asthma, allergy, emphysema and psoriasis.

Panel 5 Islet Summary: Ag4226 Highest expression of this gene is seen in kidney (CT=27.4). Low but signifificant levels of expression are also seen in adipose. Thus, expression of this gene may be used to distinguish the kidney sample from other samples on this panel.

General oncology screening panel_v_2.4 Summary: Ag4226 Highest expression of this gene is seen in a sample of normal colon tissue adjacent to a colon cancer (CT=33.1). In addition, low but significant expression is seen in normal kidney, and prostate, lung, and melanoma cancer.

N. CG101826-02: adenylate kinase

Expression of gene CGI 01826-02 was assessed using the primer-probe set Ag5337, described in Table NA. Results of the RTQ-PCR runs are shown in Tables NB, NC and ND.

Table NA. Probe Name Ag5337

Start SEQ ID

Primers. Sequences len th i Position No

'Forward [5 ' -tccatacagatcaccaactgtg-3 22 1556 298_

Probe •TET-5 ' -cgtccgaactcttccccttgcttca-3 '

TAMRA 25 1592 299 [Reverse [5 ' -agacattatggaacgtggaga-3 2\ Ϊ7Ϊ8 ^"3OO

Table NB. CNS neurodegeneration vl.O

Table NC. General_screening_panel_vl .5

Table ND. Panel 4. ID

Monocytes LPS ^"1 OΌ^{"" """} 'Colon ^~ ι ^{" "}o.ό^{""~ "}" Macrophages rest ._. 1. 0.0 [Lung , 0.0 Macrophages LPS 0.0 [Thymus [ 0.0

HUVEC none t L6 [Kidney i ^" 0 7 'HUVEC starved ^""1 ^~~ ^"" L7 i I

I

CNS_neurodegeneration_vl.O Summary: Ag5337 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. General_screening_panel_vl.5 Summary: Ag5337 CG101862-02 appears to be mainly expressed in brain derived tissue, with highest expression in the cerebral cortex (CT=25.7). In addition, high levels of expression are seen in thalamus, substantia nigra, thalamus and amygdala. Moderate levels of expression are seen in hippocampus, spinal cord, fetal brain, and a brain cancer cell line. This gene encodes a putative adenylate kinase 5, a brain specific enzyme involved in the synthesis of adenine nucleotides necessary for the homeostasis of engergy metabolism in cells. (V n Rompay AR, Eur J Biochem 1999 Apr;261 (2):509-17) Inouye S et. al (J Neurochem 1998 Jul;71(l): 125-33) suggest that this enzyme plays an important role in neuronal function and may be involved in neuronal maturation and regeneration (Inouye S. Biochem Biophys Res Commun 1999 Jan 27;254(3):618-22). Based on the prominent expression in the CNS and homology to adenylate kinase 5, expression of this gene could be used to differentiate between neural and non-neural tissue. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy. Among tissues with metabolic function, this gene is expressed at low but significant levels in pituitary, adipose, adrenal gland, and adult and fetal skeletal muscle and heart. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

In addition, high to moderate levels of expression are seen in a cluster of samples derived from brain, renal and melanoma cancer cell lines. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of brain, renal and melanoma cancers. Panel 4. ID Summary: Ag5337 Moderate expression of this gene is essentially restricted ot lung and dermal fibroblasts, with highest expression in IL-4 treated dermal fibroblasts (CT=28.3). Moderate to low levels of expression are also seen other cells derived from the lung including treated and untreated HPAECs, and lung and dermal microvascular endothelial cells. Expression in these cells suggests that this gene product may be involved in inflammatory conditions of the lung and skin. Thus, expression of this gene could be used as a marker of fibroblasts. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in reducing or eliminating symptoms in patients with asthma, allergy, emphysema and psoriasis.

O. CG102061-01: Glucose-6-phosphate dehydrogenase

Expression of gene CGI 02061-01 was assessed using the primer-probe set Ag4230, described in Table OA. Results of the RTQ-PCR runs are shown in Tables OB, OC, OD and OE.

Table OA. Probe Name Ag4230

Table OC. General_screening_panel_vl.4

Table OD. Panel 4. ID

.... ... .. _ ___

Macrophages LPS Thymus ^"": ^' 24O

HUVEC none ! 28.5 IKidney ^■ 46.3

HUVEC starved j 68.3 ϊ

Table OE. general oncology screenin g panel_v_2.4

CNS_neurodegeneration_vl.0 Summary: Ag4230 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. General_screening_panel_vl.4 Summary: Ag4230 Highest expression of this gene is seen in skeletal muscle (CT=26.8). In addition this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, fetal liver and adult and fetal skeletal muscle and heart. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

This gene is also expressed at moderate levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Significant levels of expression are also seen in a cluster of samples derived from brain, prostate, melanoma, ovarian, breast and lung cancer cell lines. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of ovarian, breast and lung cancers.

Panel 4.1D Summary: Ag4230 Highest expression of this gene is seen in IFN gamma treated HUVECs (CT=31.2). Low but significant levels of expression are also seen other samples on this panel including clusters of treated and untreated samples of dermal fibroblasts, lung fibroblasts, and HUVECs. Thus, this gene may be involved in inflammatory processes of the lung and skin.

General oncology screening panel_v_2.4 Summary: Ag4230 Highest expression of this gene is seen in melanoma (CT=30.3), with moderate expression also detected in prostate cancer. In addition, expression of this gene is overexpressed in lung cancer compared to expression in the normal adjacent tissue. Thus, expression of this gene could be used as a marker of lung cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of lung, prostate, and melanoma cancers.

P. CG102102-01, CG102102-02 and CG102102-04: PEROXISOMAL SHORT-CHAIN ALCOHOL DEHYDROGENASE Expression of gene CGI 02102-01. CGI 02102-02 and CGI 02102-04 was assessed using the primer-probe sets Ag4428 and Ag5930, described in Tables PA and PB. Please note that CGI 02102-02 is a splice variant of CGI 02102-01 and is only recognized by probe Ag4428. Also, please note that CG102102-04 represents a full-length physical clone of the CGI 02102-01 gene, validating the prediction of the gene sequence. Results of the RTQ-PCR runs are shown in Tables PC, PD, PE and PF.

Table PA. Probe Name Ag4428

Primers; Sequences

■Forward [5 ' -atcactggggaaacagtggt-3 '

Probe [TET-5 ' -ctctgaggaccgggagacagccc- 3 ' -

Reverse 5 ' -gagctagagcccaactctgg-3 '

Table PB. Probe Name Ag5930

Primers ! Sequences Length-Start PositionJSEQ ID Noj

Forward [5 ' -agctctggatggacaaggaa-3 ' 20 432 507

'Probe [TET-5 ' -tgcggataagaaggttaggcga-3 ' -TAMRA 22 477 508

Reverse [5 ' -agtgatgtagctggcatcttca-3 ' 22 538 309

Liver ca. HepG2 [ 7.b i Spinal Cord Pool j ^{~ ~} 78 j

Kidney Pool ^; 19.6 1 Adrenal Gland j 15.9 J

Fetal Kidney [ 10.7 Pituitary gland Pool j 2.4 !

Renal ca. 786-0 [ 14.0 : Salivary Gland [ 6.7

[Renafca. A498 J ^" 9.4 j Thyroid (female) [ ^" 7.9

^" i N ^! li.i 1 Pancreatic ca. [

Renal ca. ACH 15.8 CAPAN2 i i

Renal ca. UO-31 1 15.8 ! Pancreas Pool 13.8 I

Table PD. General screening panel v 1.5

Table PE. Panel 5 Islet Rel. Rel. Rel.

Tissue Name Rel. [

Tissue Name

Exp.(%) ! Exp.(%) Exp.(%) E p.(%)

Table PF. general oncology screening panel_v_2.4

General_screening_panel_vl.4 Summary: Ag4428 Highest expression of the CGI 02102-01 gene is detected in breast cancer T47D cell line (CTs=24.5). High levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

General_screening_panel_vl.5 Summary: Ag5930 Highest expression of the CGI 02102-01 gene is detected in gastric cancer KATO III cell line (CT=29.5). High levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at moderate to low levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 5 Islet Summary: Ag4428/Ag5930 Two experiment with two different probe and primer sets are in excellent agreement with highest expression of this gene in human islet cells (Bayer patient 1) and skeletal muscle (CTs=29.8-33). This gene codes for peroxisomal short-cahin alcohol dehydrogenase. Thus, the expression of this gene in human islet cells suggests that peroxisomal oxidation pathways may be important in beta cell physiology. Therefore, therapeutic modulation of this enzyme, or other enzymes in the same pathway, may be useful for enhancing insulin secretion in Type 2 diabetes.

In addition, moderate levels of expression of this gene is also seen in most of the tissues with metabolic/endocrine function examined including adipose, placenta, uterus, skeletal muscle and small intestine. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. general oncology screening panel_v_2.4 Summary: Ag5930 Highest expression of the CG102102-01 gene is detected in kidney sample (CT=30). Significant levels of expression of this gene is also seen in both normal and cancer samples derived from colon, lung, melanoma, prostate, and kidney. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of lung, prostate, melanoma and some kidney and colon cancers.

Q. CG102102-03: PEROXISOMAL SHORT-CHAIN ALCOHOL

DEHYDROGENASE

Expression of gene CGI 02102-03 was assessed using the primer-probe sets Ag4441 and Ag4428, described in Tables QA and'QB. Results of the RTQ-PCR runs are shown in Tables QC, QD and QE. The CGI 02102-03 gene is a splice variant of the CGI 02102-01 gene and the probe Ag4441 is specific to this splice variant.

Table OA. Probe Name Ag4441

Table QB. Probe Name Ag4428

Primers [ Sequences Length .Start Position SEQ ID No

Forward _j5 ' -atcactggggaaacagtggt-3 ' J 20 128 ^{" " "} ] ^"313

Probe [TET-5 ' -ctctgaggaccgggagacagccc- 3 ' -TAMRA 23 8θ^{" " '}. ^" 3Ϊ4^{_ " "'}

Reverse '5 ' -gagctagagcccaactctgg-3 ' 20 55 115

Table QC. General_screening_panel_y 1.4

Table QD. Panel 5 Islet

Table OE. general oncology screenin I panel_v_2.4

General_screening_panel_vl.4 Summary: Ag4428/Ag4441 Two experiments with different probe and primer sets are in excellent agreement with highest expression of the CGI 02102-03 gene in breast cancer T47D cell line (CTs=24.5-26). High levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Panel 5 Islet Summary: Ag4428 Highest expression of this gene in human islet cells (Bayer patient 1) (CT=29.8). This gene codes for peroxisomal short-cahin alcohol dehydrogenase. Thus, the expression of this gene in human islet cells suggests that peroxisomal oxidation pathways may be important in beta cell physiology. Therefore, pharmacologic modulation of this enzyme, or other enzymes in the same pathway, may be useful for enhancing insulin secretion in Type 2 diabetes.

In addition, moderate levels of expression of this gene is also seen in most of the tissues with metabolic/endocrine function examined including adipose, placenta, uterus, skeletal muscle and small intestine. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. general oncology screening panel_v_2.4 Summary: Ag4441 Highest expression of the CGI 02102-03 gene is detected in kidney sample (CT=27). Significant levels of expression of this gene is also seen in both normal and cancer samples derived from colon, lung, melanoma, prostate, and kidney. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of colon, lung, prostate, melanoma and kidney cancers.

R. CG102554-01: Novel ATPase associated with various cellular activities

Expression of gene CG102554-01 was assessed using the primer-probe set Ag4237, described in Table RA. Results of the RTQ-PCR runs are shown in Tables RB, RC, RD and RE. Table RA. Probe Name Ag4237

Primers [ Sequences 'Length Start ! SEQID ' Position j No

Forward [5 ' -gatatgtctgtccctgcagttg-3 ' J ! 22 484 ] 316 j„ , [TET-5'-tc ttccaagggaagctttaccags ica-3 ' - f ₍ ^Probe 'TAMRA 531 j 317

[Reverse [5 ' -tgcttgttcggataattgatgt-3 ' i 22 562 j 318

Table RB. CNS neurodegeneration vl.O

Table RC. General_screening_panel_vl .4

Table RE. general oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4237 This panel confirms the expression of the CG102554-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4237 Highest expression of the CG101330-01 gene is detected in breast cancer T47D cell line (CT=26.6). Moderate to high levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to high levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Panel 4. ID Summary: Ag4237 Two experiment with same probe and primer set are in good agreement with highest expression of this gene in activated secondary Th2 and IL-9 treated NCI-H292 (CTs=27-27.9). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Results from one experiment with this gene (run 175226756) are not included. The amp plot indicates that there were experimental difficulties with this run. general oncology screening panel_v_2.4 Summary: Ag4237 Highest expression of the CG101330-01 gene is detected in metastatic melanoma (CT=26.3). Moderate to high levels of expression of this gene is also seen in cancer samples derived from colon, bladder, lung, melanoma, prostate, and kidney. Expression of this gene is higher in cancer samples as compared to the adjacent normal control tissue. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of colon, lung, prostate,bladder, melanoma and kidney cancers.

S. CG102605-01: Novel ATPase associated with various cellular activities Expression of gene CGI 02605-01 was assessed using the primer-probe set Ag4240, described in Table SA. Results of the RTQ-PCR runs are shown in Tables SB, SC and SD.

Table SA. Probe Name Ag4240

Table SB. CNS_neurodegeneration_vl .0

Table SC. General_screeningjpanel_vl .4

Table SD. Panel 4. ID

CNS_neurodegeneration_vl.0 Summary: Ag4240 Two experiment with same probe and primer sets are in good agreement. These panels confirm the expression of the CG102605-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non- demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4240 Highest expression of the CG102605-01 gene is detected in colon cancer HCT-116 cell line (CT=30.4). Moderate levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Expression of this gene appears to be higher in cancer cell lines as compared to normal tissues. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adipose, skeletal muscle, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=33.7) when compared to adult liver (CT=39.7). This observation suggests that expression of this gene can be used to distinguish fetal from adult skeletal muscle. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases. In addition, this gene is expressed at low levels in fetal brain and cerebellum. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as ataxia and autism.

Panel 4.1D Summary: Ag4240 Highest expression of the CGI 02605-01 gene is detected in kidney (CT=31). This gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage, and peripheral blood mononuclear cell family, as well as dermal fibroblast and normal tissues represented by lung, thymus and kidney. Furthermore, expression of this gene is stimulated in activated primary and secondary Thl , Th2 and Tri cells. This pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus. psoriasis, rheumatoid arthritis, and osteoarthritis. general oncology screening panel_v_2.4 Summary: Ag4240 Results from one experiment with the CGI 02605-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

T. CG102909-02: CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE TYPE II DELTA CHAIN

Expression of gene CGI 02909-02 was assessed using the primer-probe set Ag4392, described in Table TA. Results of the RTQ-PCR runs are shown in Table TB.

Table TA. Probe Name Ag4392

Table TB. General_screening_panel_vl .4 el. Exp.(%) Ag4392,

Tissue Name Rel. Exp.(%) Ag4392, R

Tissue Name Run 222641443 Run 222641443 Adipose 0.0 |Renal_ca. TK-10 0.0

Melanoma*

2.5 ■Bladder 0.0 [Hs688(A).T

General_screening_panel_vl.4 Summary: Ag4392 Highest expression of the CG102909-02 gene is detected in cerebellum (CT=30.4). Moderate expression of this gene is seen in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. This gene codes for a splice variant of calciiim/calmodulin-dependent-dependent kinase II. Calmodulin (CaM) is a major Ca2+-binding protein in the brain, where it plays an important role in the neuronal response to changes in the intracellular Ca2+ concentration. Calmodulin modulates numerous Ca2+-dependent enzymes and participates in relevant cellular functions. Among the different CaM-binding proteins, the Ca2+/CaM dependent protein kinase II and the phosphatase calcineurin are especially important in the brain because of their abundance and their participation in numerous neuronal functions (Sola et al, 2001, Int J Biochem Cell Biol 33(5):439-55, PMID: 11331200). Therefore, therapeutic modulation of this gene product may be useful in the treatment of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. U. CG102920-01: SHORT CHAIN 3-HYDROXYACYL-COA DEHYDROGENASE PRECURSOR

Expression of gene CG102920-01 was assessed using the primer-probe set Ag5918. described in Table UA. Results of the RTQ-PCR runs are shown in Tables UB, UC, UD and UE.

Table UA. Probe Name Ag5918

.Primers] Sequences LengthjStart PositionjSEQ ID No!

,Forwardl5 ' -catacctcatggaagcaatca-3 21 881 525

Probe ιTET-5 ' -tatgaacgaggtgacgcatccaa-3 ' -TAMR 23 907 326

Reverse 15 ' -cggctcctaatttcatagca-3 ' 20 945 327

Table UB. CNS_neurodegeneration_vl .0

Table UC. General_screening_panel_vl .5

[Rel. Exp.(%) Ag5918, Rel. Exp.(%) Ag5918,

Tissue Name Tissue Name i Run 247834854 Run 247834854

.Adipose 23.0 Renal ca. TK- 10 13.8

[Melanoma*

8.8 Bladder 16.2 [Hs688(A).T

Melanoma* 'Gastric ca. (liver met.)

11.0 15.1 iHs688(B).T 'NCI-N87

Table UE. Panel 5 Islet

CNS__neurodegeneration_vl.O Summary: Ag5918 This panel confirms the expression of the CGI 02920-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.5 Summary: Ag5918 Highest expression of the CGI 02920-01 gene is detected in skeletal muscle pool. In addition, this gene is expressed at high to moderate levels in other tissues with metabolic or endocrine function including pancreas, adipose, adrenal gland, thyroid, pituitary gland, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

The CGI 02920-01 gene codes for a splice variant of short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD). Deficiency in this gene have been associated with fatty acid oxidation (FAO) disorders such as Reye-like illness (hypoketotic-hypoglycemia, hyperammonemia and fatty liver) and cardiomyopathy (Schuler AM, Wood PA, 2002, ILAR J 43(2):57-65, PMID: 11917157). Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of FAO defects.

Moderate levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Brain (SCHAD) is shown to catalyze the oxidation of 17beta-estradiol and dihydroandrosterone as well as alcohols. It inactivates the sex steroid hormones and could weaken the protective effects of estrogen and generate aldehydes in neurons. Hence, it has been proposed that a high concentration of this enzyme in brain could be a potential risk factor for Alzheimer's disease (He et al., 1999, J Biol Chem 274(21): 15014-9, PMID: 10329704). Panel 4.1D Summary: Ag5918 Highest expression of the CG102920-01 gene is detected in kidney (CT=29.9). This gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screeningjpanel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. In addition, expression of this gene is stimulated in activated primary and secondary Thl, Th2 and Tri cells, PWM/PHA-L treated PBMC cells, and PMA/ionomycin treated eosinophils. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Panel 5 Islet Summary: Ag5918 Highest expression of the CG102920-01 gene is detected in islet cells (Bayer patient 1) (CT=28.4). In addition, moderate to low levels of expression of this gene is also seen in samples derived from skeletal muscle, adipose, uterus, placenta, liver, heart, and small intestine. Short chain hydroxyacyl CoA dehydrogenase deficiency in man has been associated with hyperinsulinism. (Clayton PT. J Clin Invest. 2001 Aug;108(3):457-65). Therefore, therapeutic enhancement of the activity of this gene product may be a treatment for hyperinsulinemia, including that associated with insulin resistance syndromes and Type 2 diabetes. Please see panel 1.4 for further discussion on utility of this gene.

V. CG103051-01: human ortholog of a rat potasium channel

Expression of gene CG103051-01 was assessed using the primer-probe set Ag4255, described in Table VA. Results of the RTQ-PCR runs are shown in Tables VB, VC and VD.

T able VA. Probe Name Ag4255

Start SEQ ID

Primers Sequences Length Position No

[Forward 5 ' -ctagaaaagagggagcgagaga-3 ' 22 2774 328 ,TET-5 ' -atggctccaacctggccttcatgtt-3 '

Probe TAMRA 25 2796 329

Reverse '5 ' -caacatgctgatgctgaagac-3 21 2846 330

Table VB. CNS neurodegeneration vl.O

'Control (Path) 1 57.4 'Control (Path) 3 2.3 Temporal Ctx Parietal Ctx _jControl (Path) 2 T.4 Control (Path) 4 46.0 'Temporal Ctx Parietal Ctx

Table VC. General_screening_panel_vl.4

Table VD. Panel 4. ID

Secondary Thl rest 0O_ [HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 lϊ-TU VEC ΪL-ΪT ^" OΌ^"

Bronchial epithelium

'Primary Thl rest 0.0 0.0 [TNFalpha + IL1 beta

[Small airway epithelium

Primary Th2 rest 0.0 0.0 'none

[Small airway epithelium

[Primary Tri rest 0.0 0.0 |TNFalpha + IL-1 beta

CD45RA CD4

0.0 Coronery artery SMC rest ■ 0.0 [lymphocyte act

CD45RO CD4^" [Coronery artery SMC

0.0 0.0 lymphocyte act TNFalpha + IL-1 beta

,008 lymphocyte act o.cT [Astrocytes rest ^"o.o^"

^'[Secondary CD8 [Astrocytes TNFalpha +

0.0 0.0 lymphocyte rest ^!IL-lbeta

CNS_neurodegeneration_vl.0 Summary: Ag4255 This panel confirms the expression of the CG103051-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4255 Highest expression of the CGI 03051-01 gene is detected in cerebellum (CT=27.3). In addition, this gene is expressed at moderate to high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. The CG103051-01 gene codes for a homolog of rat potassium channel subunit. Mutations in the potassium channel subunit, KCNQ2, a protein belonging to potassium chaimel family, have been implicated in benign familial neonatal convulsions, a dominantly inherited form of generalized epilepsy. Therefore, in analogy the potassium channel subunit encoded by this gene may play a role in pathology of neonatal convulsions and therapeutic modulation of this gene product may be beneficial in the treatment of this disorder.

In addition, moderate to low expression of this gene is also seen in tissues with metabolic or endocrine function including adipose, pituitary gland, skeletal muscle, and heart. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Significant expression of this gene is also detected in number of cancer cell lines including a colon cancer, lung cancer and a ovarian cancer cell lines. Therefore, therapeutic modulation of this gene may be useful in the treatment of these cancers.

Panel 4.1D Summary: Ag4255 Moderate level of expression of the CG103051-01 gene is detected only in kidney (CT=30.7). Therefore, expression of this gene may be used to distinguish kidney from other samples used in this panel. Furthermore, therapeutic modulation of this gene may be beneficial in the treatment of autoimmune and inflammatory diseases that affect kidney including lupus and glomerulonephritis.

Panel 5 Islet Summary: Ag4255 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

W. CG103061-01: Potasium channel Expression of gene CG103061-01 was assessed using the primer-probe set Ag4256, described in Table WA.

Table WA. Probe Name A.g4256

Start SEQ ID

Primers i Sequences Length Position No

Forward [5 ' -catctgggaacagattttacga-3 22 481 DD I probe TET- 5 ' -tggaaataattaatgcagttcccttca- 3 ' TAMRA 27 516 DD2

Reverse J5 ' -tccttaaggaaggccagaatac-3 22 551 DJJ

CNS neurodegeneration vl.O Summary: Ag4256 Expression of the CG103061-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Generalj_creening_panel_vl.4 Summary: Ag4256 Expression of the CG103061-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel. Panel 4.1D Summary: Ag4256 Expression of the CG103061-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Panel CNS_1 Summary: Ag4256 Expression of the CG103061-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel. general oncology screening panel_v_2.4 Summary: Ag4256 Expression of the CG103061-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

X. CG103061-03: POTASSIUM CHANNEL SUBUNIT PROTEIN

Expression of gene CG103061-03 was assessed using the primer-probe set Ag5852, described in Tables XA.

Table XA. Probe Name Ag5852

Start . SEQ ID

Primers Sequences Length Position ; No

'Forward 5 ' -aacctctacagggatgaaatgaat-3 24 ^" 3178 ^'"" ! 334^{" "} i _,TET-5 ' -tcatcaaagtaccctctcctacatcctga-3 ' -

Probe ,TAMRA 29 204

'Reverse |5 ' -agctctattctggtatctggagatg-3 ' 25 3239 _> _H

CNS_neurodegeneration_vl.O Summarj': Ag5852 Expression of the CGI 03061-03 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

General_screening_panel_vl.5 Summary: Ag5852 Expression of the CG103061-03 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Panel 4.1D Summary: Ag5852 Expression of the CG103061-03 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Y. CG103061-05: POTASSIUM CHANNEL SUBUNIT PROTEIN

Expression of gene CG103061-05 was assessed using the primer-probe set Ag5854, described in Tables YA.

Table YA. Probe Name Ag5854

CNS_neurodegeneration_vl.O Summary: Ag5854 Expression ofthe CG103061-05 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

General_screening_panel_vl.5 Summary: Ag5854 Expression ofthe CG103061-05 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel. Panel 4.1D Summary: Ag5854 Expression ofthe CG103061-05 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Z. CG103215-01: NATRIUM-PHOSPHATE COTRANSPORTER IIA C- TERMINAL-ASSOCIATED PROTEIN 2

Expression of gene CG103215-01 was assessed using the primer-probe set Ag4257, described in Table ZA.

Table ZA. Probe Name Ag4257

Start [ SEQ ID

Primers) Sequences Length I

Position ! No

Forward 5' -agtgaaagatgagggtggtttt-3' < ^' 22 I 544 '■ 340

_T, , _ιTET-5 ' -cttcagtgtcacccatggcaatcag- ' - '• -_ I _{c o} • , , . P Prroobbee _._ „„_, „ ; 2_> i 568 i 341

I jTAMRA

Reverse ,5 ' -tcagctgctcctccagtactta-3 ' _; 22 [ 612 j 342

CNS_neurodegeneration_vl.O Summary: Ag4257 Expression ofthe CG103215-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel. General_screening_panel_\T.4 Summary: Ag4257 Expression of the CG103215-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Panel 4.1D Summary: Ag4257 Expression ofthe CG103215-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel. general oncology screening panel_v_2.4 Summary: Ag4257 Expression ofthe CGI 03215-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

AA. CG103229-01, CG103229-02, and CG103229-06: Splice variant of CG103229-01, missing exons 12-15, submitted to study DDSMT on 10/03/01 by cpena; clone status=FIS; noveIty=Update- Variants; ORF start=12, ORF stop=1059, frame=3; 1083 bp. Expression of gene CG103229-01, CG103229-02, and CG103229-06 was assessed using the primer-probe sets Ag4258, Ag5424 and Ag5429, described in Tables AAA, AAB and AAC. Please note that probe Ag5429 is specific for CGI 03229-02 and CGI 03229-06 variants, while probe Ag5424 is specific only to variant CG103229-06. Results ofthe RTQ- PCR runs are shown in Tables AAD and AAE. Table AAA. Probe Name Ag4258

Table AAB. Probe Name Ag5424

Table AAC. Probe Name A∑.5429

Table AAD. CNS neurodegeneration vl .O

Table AAE. General_screening_panel_vl .5

CNS_neurodegeneration_vl.O Summary: Ag5429 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. This gene encodes a homolog of adenylate kinase, which has been implicated in neuronal function, differentiation, and regeneration (Inouye S, Biochem Biophys Res Commun 1999 Jan 27;254(3):618-22). Thus, therapeutic modulation ofthe expression or function of this gene product may be effective in the treatment of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease.

Ag4258/Ag5425 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

General_screening_panel_vl.4 Summary: Ag4258 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

General_screening_panel_vl.5 Summary: Ag5429 Expression of this gene is highest in a breast cancer cell line (CT=31.6). Moderate levels of expression are also seen in cell lines derived from ovarian and lung cancers. Thus, modulation ofthe expression or function of this gene product may be effective in the treatment of these cancers.

Ag5424 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4.1D Summary: Ag4258 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Ag5424 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). Ag5429 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

AB. CG103229_:03: Splice variant of CG103229-01

Expression of gene CGI 03229-03 was assessed using the primer-probe set Ag5427, described in Table ABA.

Table ABA. Probe Name Ag5427

CNS_neurodegeneration_vl.O Summary: Ag5427 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). General_screcning_panel_vl.5 Summary: Ag5427 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4. ID Summary: Ag5427 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

AC. CG103229-04: Splice variant of CG103229-01. Expression of gene CGI 03229-04 was assessed using the primer-probe sets Ag4258 and Ag5426, described in Tables ACA and ACB.

Table ACA. Probe Name Ag4258

Table ACB. Probe Name Ag5426

Reverse [5 ' -tcatcgtcgatattttccaca-3 21 360

CNS_neurodegeneration_vl.O Summary: Ag5423/Ag5426 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

General_screening_panel_vl.5 Summary: Ag5423/Ag5426 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4. ID Summary: Ag5423/Ag5426 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). general oncology screening panel_v_2.4 Summary: Ag4258 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

AD. CG103229-05: Splice variant of CG103229-01

Expression of gene CGI 03229-05 was assessed using the primer-probe sets Ag5423 and Ag5426, described in Tables ADA and ADB.

Table ADA. Probe Name Ag5423

.Primers j Sequences [Length ^!Start Position[SEQ ID No

'Forward ;5 ' -gaggctgctgaggaagca-3 ' V 18^{" "}: ^{"" ""}967 ^" I ^{" "}361 [Probe |TET-5 ' -aacgcgagcaccaggaggcc- 3 -TAMRA: 20 I ^' 986 ^" 362 Reverse 15 ' -agagatattctgcccactcctc-3 ' i ^{' "}22 ^" } ^{" "}Ϊ036 ^" 1 ^{" "}363

Table ADB. Probe Name Ag5426

[Primers] Sequences [Length Start Position^'jSEQ ID No

.Forward [5 ' -cgctctttgtgaaggagaatt-3 ' 21 701 ; 364

[Probe ;TET- 5 ' -attcgatgggctgcccaaaca-3 -TAMRA 21 727 [ 365

Reverse Is ' -tcatcgtcgatattttccaca-3 ' .... Xx.. 753 [ 366

CNS_neurodegeneration_vl.O Summary: Ag5423/Ag5426 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). General_screening_panel_vl.5 Summary: Ag5423/Ag5426 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4.1D Summary: Ag5423/Ag5426 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). AE. CG103229-07: Splice variant of CG103229-01

Expression of gene CGI 03229-07 was assessed using the primer-probe sets Ag4258, Ag5428 and Ag5429, described in Tables AEA, AEB and AEC. Results ofthe RTQ-PCR runs are shown in Tables AED and AEE.

Table AEA. Probe Name Ag4258

Table AEB. Probe Name Ag5428

Table AEC. Probe Name Ag5429

.Primers! Sequences T . i ^start SEQ ID

Length _ ... ^& Position No

Forward -5 ' -gaagtcgaagaggaagtgaaaag-3 23 195 D ID

;TET-5 ' -aggctcagtcaattcccctgagaaact-3 ' -

'Probe i TAMRA 27 148 374 [Reverse J5 ' -gagttggcatcacataggtca-3 ^"21 ^" Ϊ2Ϊ 375

Table AED. CNS_neurodegeneration_vl .0

Table AEE. General_screening_jpanel_vl.5

CNS_neurodegeneration_vl.O Summary: Ag5429 This panel oes not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. This gene encodes a homolog of adenylate kinase, which has been implicated in neuronal function, differentiation, and regeneration (Inouye S, Biochem Biophys Res Commun 1999 Jan 27;254(3):618-22). Thus, therapeutic modulation ofthe expression or function of this gene product may be effective in the treatment of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease.

Ag4258/Ag5428 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Ag5428 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4.1D Summary: Ag4258 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). Ag5428 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Ag5429 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). general oncology screening panel_v_2.4 Summary: Ag4258 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

AF. CG103229-08: Splice variant of CG103229-01

Expression of gene CGI 03229-08 was assessed using the primer-probe sets Ag4258 and Ag5425, described in Tables AFA and AFB. Results ofthe RTQ-PCR runs are shown in Tables AFC and AFD.

Table AFA. Probe Name Ag4258

Table AFB. Probe Name Ag5425

Primers Sequences

'Forward |5 ' -ctcatgtcatcttcaagagtctca-3

[TET- 5 ' - caattcccagaattctgtgaggcca-3

[Probe [TAMRA

[Reverse [5 ' -cagcaactacgtatgctgca-3 '

Table AFC. CNS_neurodegeneration_vl.O

Table AFP. General_screening_panel_vl .5

differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. This gene encodes a homolog of adenylate kinase, which has been implicated in neuronal function, differentiation, and regeneration (Inouye S, Biochem Biophys Res Commun 1999 Jan 27;254(3):618-22). Thus, therapeutic modulation ofthe expression or function of this gene product may be effective in the treatment of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease.

General_screening_panel_vl.5 Summary: Ag5425 Highest expression ofthe CG103229- 08 is detected in lung cancer LX-1 cell line (CT=34.2). Low but significant levels of expression of this gene is also seen in fetal lung, trachea and some ofthe cancer cell lines derived from pancreatic, lung, and ovarian cancer. Therefore, therapeutic modulation of this gene may be useful in the treatment of pancreatic, lung and ovarian cancer.

Interestingly, this gene is expressed at much higher levels in fetal (CT=34.6) when compared to adult lung (CT=40). This observation suggests that expression of this gene can be used to distinguish fetal from adult lung. In addition, the relative overexpression of this gene in fetal lung suggests that the protein product may enhance lung growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation ofthe protein encoded by this gene could be useful in treatment of lung related diseases.

Panel 4. ID Summary: Ag4258 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Ag5425 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

AG. CG103229-09: Splice variant of CG103229-01 Expression of gene CG103229-09 was assessed using the primer-probe set Ag6120, described in Table AGA. Results ofthe RTQ-PCR runs are shown in Tables AGB and AGC.

Table AGA. Probe Name Ago 120

_|Primers[ Sequences [Length [Start Position [SEQ ID No

[Forward 5 ' -tctattgaatgatggggttttg-3 ' [ 22 | 14 [ 382

'Probe TET-5 ' -caaagcctgctgggttcgctttt-3 ' -TAMRA 23 1 49 | 383 _jReverse [5 ' -agattcagtctgagagccatca-3 ' 22 ^J 77 [ 384

Table AGB. CNS neurodegeneration vl ,0

Table AGC. General_screening_panel_vl.5

Renal ca. A498 0.0 [Thyroid (female) 0.0 [Renafca. ACHN 49.7 [Pancreatic ca. CAPAN2 49.0 Renal caTU6-3 Ϊ 10.7 iPancreas Pool 13.9

CNS_neurodegeneration_vl.0 Summary: Ag6120 This panel confirms the presence ofthe CGI 03229-09 variant at low but significant levels in the brain. Please see CGI 03229- 06 for discussion of utility of this putative adenylate kinase in the central nervous system.

General_screening_panel_vl.5 Summary: Ago 120 Highest expression ofthe CG103229-09 gene is seen in fetal kidney (CT=32). Thus, expression of this gene could be used to differentiate between adult kidney (CT=35.4) and fetal kidney. Tow but significant levels of expression are also seen in other samples including pancreas, adrenal, fetal and adult lung and pancreatic, renal, lung and ovarian cancer cell lines. Expression in multiple cancer cell lines suggests that this gene product may also be involved in cell growth and/or proliferation.

Panel 4. ID Summary: Ag6120 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

AH. CG103285-01, CG103285-02 and CG103285-03: Ubiquitin carboxyl- terminal hydrolase Expression of gene CG103285-01, CG103285-02 and CG103285-03 was assessed using the primer-probe sets Agl472 and Ag963, described in Tables AHA and AHB. Results of the RTQ-PCR runs are shown in Tables AHC, AHD, AHE and AHF.

Table AHA. Probe Name Agl472

Table AHB. Probe Name Ag963

Table AHC. CNS_neurodegeneration_ vl.O

Table AHD. General_screening_panel_vl .4

Table AHE. Oncology_cell_line_screening_panel_v3.1

Table AHF. general oncology screening panel_v_2.4

CNS_neurodegeneration_vl.0 Summary: Agl472 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Agl472 This gene is expressed at high to moderate levels in all the samples in this panel. Highest expression is detected in an gastric cancer cell line (CT=24). This gene is also highly expressed in all the cell lines on this panel, with higher expression seen in the cancer cell lines than in the normal tissue samples. This ubiquitous pattern of expression suggests a role for this protein product in cell survival and growth, therapeutic modulation of this gene or its protein product, may be useful in the treatment of cancer.

Among tissues with metabolic function, this gene is expressed at high to moderate levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

This gene is also highly expressed in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

In addition, this gene is expressed at much higher levels in fetal lung (CT=25.8) when compared to expression in the adult counterpart (CT=28.8). Thus, expression of this gene may be used to differentiate between the fetal and adult source of this tissue.

Oncology_cell_line_screening_panel_v3.1 Summary: Agl472 Highest expression is seen in a medulloblastoma cell line (CT=24.7). Overall, expression in this panel is ubiquitous, consistent with expression in Panel 1.4. Please see that panel for discussion of utility of this gene in cancer. general oncology screening panel_v_2.4 Summary: Agl472 Highest expression of this gene is seen in lung cancer (CT=25.3). In addition, this gene is overexpressed in lung cancer and kidney cancer when compared to expression in normal adjacent tissue. This gene is also highly expressed in melanoma and prostate cancer. Therefore, expression of this gene could be used as a marker of these cancers. Therapeutic modulation of the expression or function of this gene product may also be effective in the treatment of lung, kidney, prostate, and melanoma cancers.

AL CG103374-01: Kinesin Light Chain 3 (KLC 3)

Expression of gene CG103374-01 was assessed using the primer-probe set Ag4259, described in Table AIA.

Table AIA. Probe Name Ag4259

CNS_neurodegeneration_vl.0 Summary: Ag4259 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). General_screening_panel_vl.4 Summary: Ag4259 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4. ID Summary: Ag4259 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). general oncology screening panel_v_2.4 Summary: Ag4259 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

AJ. CG103415-01 and CG103415-02: Novel Ion Transporter Protein

Expression of gene CG103415-01 and CG103415-02 was assessed using the primer- probe set Ag4260, described in Table AJ A. Results ofthe RTQ-PCR runs are shown in Table AJB. Please note that CG103415-02 represents a full-length physical clone ofthe CG103415- 01 gene, validating the prediction ofthe gene sequence.

Table AJA. Probe Name Ag4260

Table AJB. Panel 4. ID

CNS_neurodegeneration_vl.O Summary: Ag4260 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

General_screening_panel_vl.4 Summary: Ag4260 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4.1D Summary: Ag4260 Expression of this gene is restricted to memory T cells (CT=32.9) and IFN gamma stimulated dermal fibroblasts (CT=39.4). Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel. In addition, therapeutic modulation of this gene may be useful in the treatment of treatment of asthma, emphysema, IBD, lupus or arthritis, psoriasis and in other diseases in which T cells are activated. general oncology screening panel_v_2.4 Summary: Ag4260 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

AK. CG103481-01 and CG103481-02: novel Meis3-lipocaIin

Expression of gene CG103481-01 and CG103481-01 was assessed using the primer- probe set Ag4263, described in Table AKA. Please note that CG103481-02 represents a full- length physical clone ofthe CGI 03481-01 gene, validating the prediction ofthe gene sequence.

Table AKA. Probe Name Ag4263

Primers] Sequences Length Start Position.SEQ ID No

[Forward 5 ' -cacggcgaaacaagaagag-3 ' 19 713 397

[Probe TET- 5 ' - ccaaggtggccaccaacatcatg- 3 ' -TAMRA] 23 743 398 Reverse J5 ' -agaggtgctggaacaacca-3 19 772 399

CNS_neurodegeneration_vl.0 Summary: Ag4263 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). The amp plot indicates that there is a high probability of a probe failure.

General_screening_panel_vl.4 Summary: Ag4263 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). The amp plot indicates that there is a high probability of a probe failure.

Panel 4. ID Summary: Ag4263 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). The amp plot indicates that there is a high probability of a probe failure.

Panel CNS_1 Summary: Ag4263 Expression of this gene is low/undetectable in all samples on this panel (CTs>35). The amp plot indicates that there is a high probability of a probe failure.

AL. CG103900-01: FYVE FINGER-CONTAINING PHOSPHOINOSITIDE KINASE Expression of gene CG 103900-01 was assessed using the primer-probe set Ag4265, described in Table ALA. Results of the RTQ-PCR runs are shown in Tables ALB, ALC and ALD.

Table ALA. Probe Name Ag4265

Table ALB. CNS_neurodegeneration_vl.O

Table ALC. General_screeningjpanel_vl.4

Table ALD. Panel 4. ID

CNS_neurodegenεration_vl.G Summary: Ag4265 This panel confirms the expression ofthe CGI 03900-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4265 Highest expression ofthe CG103900-01 gene is detected in CNS cancer (glio) SF-295 and melanoma SK-MEL-5 cell lines (CTs=26.3). High levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Among tissues with metabolic or endocrine function, this gene is expressed at high levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. The CGI 03900-01 gene codes for homolog of mouse FYVE finger-containing phosphoinositide kinase (PIKfyve). The mouse PIKfyve was first isolated from a mouse adipocyte cDNA library. It is found to be enriched in insulin-sensitive cells and tissues and is implicated in the insulin-signal transduction pathway (Shisheva et al., 1999, Mol Cell Biol 19(l):623-34, PMID: 9858586; Sbrissa et al, 2001, Mol Cell Endocrinol 181(l-2):35-46, PMID: 11476939). Therefore, analogous to mouse protein, the PIKfyve protein encoded by this gene may also play a role in insulin-signal transduction pathway. Interestingly, this gene is expressed at much higher levels in fetal (CTs=27-28.6) when compared to adult lung and liver(CTs=30-33). This observation suggests that expression of this gene can be used to distinguish fetal from adult lung and liver. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance growth or development of lung and liver in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation ofthe protein encoded by this gene could be useful in treatment of liver and lung related diseases.

In addition, this gene is expressed at high levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4. ID Summary: Ag4265 Highest expression ofthe CG103900-01 gene is detected in PMA/ionomycin treated basophils (CT=27.8). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screeningjpanel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

AM. CG104220-01: EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 3

Expression of gene CG104220-01 was assessed using the primer-probe set Ag5919, described in Table AMA. Results ofthe RTQ-PCR runs are shown in Tables AMB and AMC.

Table AMA. Probe Name Ag5919

Table AMC. Panel 5 Islet

widely expressed in this panel, with highest expression in a liver cancer cell line (CT=28.8). Moderate levels of expression are seen in all the cancer cell lines on this panel. This gene encodes a putative equilibrative nucleoside transporter which mediates the uptake of anticancer nucleoside analogues into cells. Since this gene is expressed in cancer cell lines, therapeutic modulation ofthe function of this gene product may be useful in the treatment of these cancers.

Among tissues with metabolic function, this gene is expressed at low but significant levels in adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function. Parodi et. al demonstrated that inhibition of this transporter may contribute to the vasodilation seen in diabetes mellitus. (Circ Res 2002 Mar 22;90(5):570-7). Furthermore, this transporter may be downregulated in some diabetic tissues (Osses N. Reprod Fertil Dev 1995;7(6):1499-503). Therefore, therapeutic modulation ofthe expression or function of this protein may be effective in the treatment of neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. This gene is also expressed at moderate to low levels in the CNS. including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of he expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy. Panel 5 Islet Summary: Ag5919 Highest expression of this gene is seen in a liver cell line (CT=29.8). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. In addition, low but significant levels of expression are seen in adipose. Please see Panel 1.5 for discussion of utility of this gene in metabolic disease.

AN. CG104220-02: EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 3

Expression of gene CGI 04220-02 was assessed using the primer-probe set Ag5931, described in Table ANA. Results ofthe RTQ-PCR runs are shown in Tables ANB, ANC, AND and ANE.

Table ANA. Probe Name Ag5931

TET-5 ' -atgttcaaactccgcaactcctccag-3 ' -

Probe TAMRA 26 258 407

Reverse ,5 ' -ggactgcaaccaggatgtc-3 ^] 19 115 408

Table ANB. CNS neurodegeneration vl.O

Table AND. Panel 4. ID

Table ANE. Panel 5 Islet

CNS_neurodegeneration_vl.O Summary: Ag5931 This panel does not show differential expression of this gene in Alzheimer's disease. However, this panel does show expression of this gene in the brain at low levels. Thus, this gene would be useful for distinguishing brain tissue from non-neural tissue, and may be beneficial as a drug target in neurodegenerative disease.

Generaι_screening_panel_vl.5 Summary: Ag5931 Expression ofthe CG104220-02 gene is much higher in a brain cancer cell line (CT=26) than in the other samples on this panel. Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. Furthemore, therapeutic modulation ofthe expression or function of this gene could be used as a treatment for brain cancer.

Panel 4. ID Summary: Ag5931 Highest expression of this variant is seen in untreated dendritic cells (CT=33). Low but significant levels of expression are also seen in resting macrophages, LAK cells, and treated and untreated NCI-H292 cells. The expression of this gene in resting cells of these lineages suggests that the protein encoded by this transcript may be involved in normal immunological processes associated with immune homeostasis. This gene encodes a putative equilibrative nucleotide transporter, a protein that is involved in macrophage activation and proliferation (Soler C. FASEB J 2001 Sep;15(l l):1979-88). Therefore, agonistic (ligand-like) therapeutics designed with this protein product may also stimulate/provoke the immune response and improve the efficacy of vaccines and antiviral or antibacterial treatments. In addition, expression in dendritic cells suggests that therapeutic utilization ofthe protein encoded by this transcript may be important in immune modulation, organ/bone marrow transplantation, and the treatment of diseases where antigen presentation, a function of mature dendritic cells, plays an important role such as asthma, rheumatoid arthritis, IBD, allergy, and psoriasis.

Panel 5 Islet Summary: Ag5931 The CGI 04220-02 variant is detected only in a liver cell line (CT=32.8). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. In addition, therapeutic modulation of this gene product may be useful in the treatement of liver related diseases.

AO. CG104693-01 and CG104693-02: Adenylate kinase

Expression of gene CG104693-01 and CG104693-02 was assessed using the primer- probe sets Ag4271 and Ag5975, described in Tables AOA and AOB. Please note that probe Ag5975 is specific for the variant CGI 04693-02. Results ofthe RTQ-PCR runs are shown in Tables AOC, AOD, AOE and AOF.

Table AQA. Probe Name Ag4271

Table AOB. Probe Name Ag5975

Table AOC. AI_comprehensive panel_vl.O

[Normal

Table AQD. CNS neurodegeneration vl.O

Table AOF. Panel 4. ID

AI_comprehensive panel_vl.O Summary: Ag5975 Expression ofthe CGI 04693-02 gene is restricted to a few samples of normal tissue adjacent to either psoriasis or Crohn's (CT=34.6). Expression in other samples was low/undetectable. Please see Panel 4. ID for discussion of utility of this gene in inflammation.

CNS_neurodegeneration_vl.0 Summary: Ag4271 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene at low levels in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag4271 Highest expression of this gene is seen in a breast cancer cell line (CT=28), with prominent expression also detected in ovarian cancer cell lines. Thus, expression of this gene could be used to differentiate between the breast cancer cell line and other samples on this panel and as a marker of breast cancer. Therapeutic modulation of the expression or function of this gene may be effective in the treatment of breast and ovarian cancer.

This gene is also expressed at moderate to low levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. This gene is encodes a putative adenylate kinase, which may be involved in neuronal maturation and regeneration. (Inouye S, Biochem Biophys Res Commun 1999 Jan 27;254(3):618-22). Therefore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, fetal skeletal muscle, and adult and fetal heart. This expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

Panel 4.1D Summary: Ag4271 Highest expression of this gene is seen in the KU-812 basophil cell line (CTs=31.2). In addition, low to moderate levels of expression are seen in kidney and thymus. Thus, expression of this gene could be used to differentiate the basophil samples from other samples on this panel and as a potential marker of these cells.

Ag5975 Expression of CGI 04693-02 is detected exclusively in the kidney (CT=34.5). Thus, this gene may be involved in the homeostasis of this organ.

AP. CG104790-01: VACUOLAR ATP SYNTHASE-like protein

Expression of gene CGI 04790-01 was assessed using the primer-probe set Ag4272, described in Table APA. Results ofthe RTQ-PCR runs are shown in Table APB.

Table APA. Probe Name Ag4272

Primers] Sequences JLength] Start | SEQ ID

CNS_neurodegeneration_vl.0 Summary: Ag4272 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

General_screening_panel_vl.4 Summary: Ag4272 Expression of this gene is restricted to fetal kidney, and colon and liver cancer cell lines (CTs=30-33). Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel to differentiate between fetal and adult kidney tissue. Panel 4. ID Summary : Ag4272 Results from one experiment with this gene are not included. The amp plot indicates that there were experimental difficulties with this run.

AQ. CG104800-01 and CG104800-02: POLYPEPTIDE N- ACETYLGALACTOSAMINYLTRANSFERASE

Expression of gene CGI 04800-01 and CGI 04800-02 was assessed using the primer- probe sets Ag3484, Ag4911 and Ag4910, described in Tables AQA, AQB and AQC. Results ofthe RTQ-PCR runs are shown in Tables AQD, AQE, AQF, AQG and AQH. Please note that CG104800-02 represents a full-length physical clone ofthe CG104800-01 gene, validating the prediction ofthe gene sequence.

Table AQA. Probe Name Ag3484

Table AQB. Probe Name Ag4911

Table AQC. Probe Name Ag4910

Table AOD. CNS neurodegeneration vl.O j Rel. Exp.(%) Rel. Exp.(%) Rel. Exp.(%) Rel. Exp.(%) Tissue Name Ag3484, Run Ag4911, Run Tissue Name Ag3484, Run Ag4911, Run 210498247 249286293 ; 210498247 249286293

AD 1 Hippo 5.4 Control (Path) [

10:6 2.9 5.9 3 Temporal

Lung ca. A549 19.: jBrain (Amygdala) Pool 15.:

Tung ca. NCI-H526 0.0 jBrain (cerebellum) 45.1

Lung ca. NCI-H23 0.6 [Brain (fetal) 11.6 iLUng a^"NCμH46θ^" DD . [Brain (Hippocampus) Pool Ϊ5.6^" jLung caTΪTOP-62 ^'"__ 4.0 [Cerebral Cortex Pool 28.1 [Lung ca7NC^"f-H5^"_.2 ^" 0.0 jBrain (Substantia nigra) Pool 16.8 JLiver ^"o.o^" [Brain (Thalamus) Pool [Fetal Liver [Brain (whole) 10.2^" jLiver ca. HepG2 ^"o.o^" Spinal Cord Pool 23-0 [Kidney Pool ^"l.8 Adrenal Gland [Fetal Kidney 3.Ϊ Pituitary gland Pool 2.6 JRenal ca. 786-0 ^"o.^'i Salivary Gland ^" 5.8^" .Renal ca. A498 ^"OΌ Thyroid (female) ^'"""o.o^" ;Renai ca7AC_TN O.O^" Pancreatic ca. CAPAN2 ^" o.i ^" [Renal ca. UO-31 ^' 0.5 Pancreas Pool ^' 8.0

Table AQF. General _creening_panel__v 1.5

Table AQH. Panel 4D

Dendritic cells LPS 0.0 [Dermal fibroblast IL-4 2.4 Dendritic cells anti- 0.0 i 1.6 CD40 __ 1lBD Colitis 2

Monocytes rest jIBD Crohn's 5.7

Monocytes LPS 0.0 IColon 53.2

^"Macrophages rest 0.0 [Lung 7.3

Macrophages LPS 0.0 (Thymus

HUVEC none 0.0 [Kidney 0.9

.HUVEC starved 1.5 | [

CNS_neurodegeneration_vl.0 Summary: Ag3484/Ag4911 Two experiments with two different probe and primer sets produce results that are in excellent agreement. This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag3484 Highest expression ofthe CG104800-01 gene is seen in a brain cancer cell line (CT=28.4). Moderate levels of expression are also seen in cell lines derived from lung cancer, breast cancer and melanoma. Thus, expression of this gene could be used to differentiate the brain cancer sample from other samples on this panel and as a marker of brain cancer. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of these cancers. Low but significant levels of expression are detected in pancreas, adipose, adrenal and pituitary. This expression suggests that this gene product may be involved in the pathogenesis and/or treatment of metabolic disorders, including obesity and diabetes. This gene is also expressed at moderate levels in all regions ofthe CNS examined.

This gene encodes a putative N-acetylgalactosaminyltransferase that may catalyze O- glycosylation in the brain. Therefore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy. General_screeningjpanel_vl.5 Summary: Ag4910/Ag4911 Two experiments produce results that are in excellent agreement. Highest expression is seen in brain derived tissue, with expression highest in cerebellum in one experiment (CT=27.4) and in a brain cancer cell line (CT=26) in the second run. Expression is in agreement with expression in Panel 1.4. Please see 1.4 for discussion of utility of this gene in cancer, metabolic disease and the central nervous system.

Oncology_cell_line_screening_panel_v3.1 Summary: Ag4910/Ag4911 Two experiments with the same probe and primer produce results that are in excellent agreement. Highest expression of this gene is seen in a sample derived from the cerebellum (CTs=27). In addition, prominent levels of expression are seen in a cluster of cell lines derived from lung cancers. Please see Panel 1.4 for discussion of utility of this gene in cancer.

Panel 4D Summary: Ag3484 Highest expression of this gene is seen in TNF-alpha and IL-1 beta stimulated astrocytes (CT=30.7). Moderate levels of expression are also seen in colon. Low but significant levels of expression are seen in keratinocytes, NCI-H292 cells, lung, and Crohn's. Expression of this gene appears to be upregulated in TNF-a/IL-lb treated astrocytes when compared to expression in resting astrocytes. Thus, this transcript may function in astrocyte differentiation and activation. Therefore, therapeutic regulation of this transcript or the design of therapeutics with the encoded protein could be important in the treatment of multiple sclerosis or other inflammatory diseases ofthe CNS. general oncology screening panel__v_2.4 Summary: Ag3484 Results from one experiment with this gene are not included. The amp plot indicates that there were experimental difficulties with this run.

AR. CG104813-01: Phosphatidylethanolamine-binding protein-like protein

Expression of gene CGI 04813-01 was assessed using the primer-probe set Ag4277, described in Table ARA. Results ofthe RTQ-PCR runs are shown in Tables ARB, ARC and ARD.

Table ARA. Probe Name Ag4277

Table ARB. CNS_neurodegeneration_vl.O

AD 3 Hippo 0.0 [AD 1 Occipital Ctx 1 9.5 ιAD 2 Occipital Ctx

^■AD 4 Hippo 17.1 0.0 [(Missing)

;AD 5 hippo 15.3 IAD^" 3 Occipital Ctx i 3.5

AD 6 Hippo 100.0 AD 4 Occipital Ctx 21.6

, Control 2 Hippo 29.5 [AD 5 Occipital Ctx ^"71 24.8

Table ARC. General_screening_panel_y 1.4

Table ARD. general oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4277 This panel confirms the expression ofthe CG104813-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4277 Highest expression ofthe CG104813-01 gene is detected in thymus (CT=29.5). In addition, high expression of this gene is also seen in spleen (CT=29.7). Thus, expression of this gene may be used to distinguish this samples from other samples in the panel. In addition, expression of this gene in thymus and spleen suggests that it may a play an important role in T and B cell development. Therefore, therapeutic modulation of this gene may be useful in the treatment of allergies, autoimmune diseases, and inflammatory diseases.

Moderate level of expression of this gene is also detected in a colon cancer, a CNS cancer and a colon cancer cell lines. Therefore, therapeutic modulation of this gene through the use of small molecule drug may be beneficial in the treatment of colon and brain cancer.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at moderate to low levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. The CGI 04813-01 gene codes for a homolog of phosphatidylethanolamine-binding protein (PEBP)(Hippocampal cholinergic neuro stimulating peptide) (HCNP) (RAF kinase inhibitor protein) (RKIP). PEBP is involved in the phenotype development ofthe septo-hippocampal system and down-regulation of PEBP mRNA is implicated in the pathogenic processes underlying Alzheimer's disease (AD) (Maki et al., 2002, J Neuropathol Exp Neurol 61(2): 176- 85, PMID: 11853019). Therefore, based on homology PEBP-like protein encoded by this gene may also play a role septo-hippocampal system development and therapeutic modulation to increase its expression and function may be useful in the treatment of AD. general oncology screening panel_v_2.4 Summary: Ag4277 Highest expression of the CG104813-01 gene is detected in kidney cancer (CT=30.8). In addition, significant expression of this gene is also seen in kidney, lung, colon, melanoma and prostate cancers. Expression of this gene is higher in cancer as compared to adjacent normal tissue sample. Therefore, expression of this gene may be used as diagnostic marker to detect these cancers and therapeutic modulation of this gene may be beneficial in the treatment kidney, lung, colon, melanoma and prostate cancers.

AS. CG104892-01 and CG104892-02: haloacid dehalogenase

Expression of gene CG104892-01 and CG104892-02 was assessed using the primer- probe set Ag4273, described in Table ASA. Results ofthe RTQ-PCR runs are shown in Tables ASB, ASC and ASD. Please note that CGI 04892-02 represents a full-length physical clone ofthe CG104892-01 gene, validating the prediction ofthe gene sequence. Table ASA. Probe Name Ag4273

Table ASB. CNSjreurodegeneration_ vl .O

Rel. Exp.(%) Rel. Exp.(%)

Tissue Name Ag4273, Run Tissue Name Ag4273, Run

224075731 224075731

Table ASC. General_screening_panel_vl.4

Table ASD. Panel 4. ID

CNS_neurodegeneration__vl.0 Summary: Ag4273 This panel confirms the expression ofthe CGI 04892-01 gene at low levels in the brain in an independent group of individuals. This gene is found to be slightly upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation ofthe expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease. General_screening_panel_vl.4 Summary: Ag4273 Highest expression ofthe CG104892-01 gene is detected in CNS cancer SNB-75 cell line (CT=27.7). High to moderate expression of this gene is seen also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=30) when compared to adult liver (CT=34.7). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation ofthe protein encoded by this gene could be useful in treatment of liver related diseases. In addition, this gene is expressed at moderate to low levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4. ID Summary: Ag4273 Highest expression ofthe CG104892-01 gene is detected in activated CD45RO CD4 lymphocyte (CT=31.3). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

AT. CG104955-01: 10-FORMYLTETRAHYDROFOLATE DEHYDROGENASE

Expression of gene CG104955-01 was assessed using the primer-probe set Ag4303, described in Table ATA. Results ofthe RTQ-PCR runs are shown in Tables ATB, ATC and ATD.

Table ATA. Probe Name Ag4303

Table ATC. Panel 5 Islet

Table ATD. general oncology screening panel_v_2.4

General_screening_panel_vl.4 Summary: Ag4303 Highest expression of this gene is detected in CNS cancer SF-295 cell line (CT=25). In addition, moderate to high expression of this gene is seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=34) when compared to adult liver (CT=40). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation ofthe protein encoded by this gene could be useful in treatment of liver related diseases. In addition, this gene is expressed at moderate levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 5 Islet Summary: Ag4303 Highest expression of this gene is detected in adipose (CT=28.4). High to moderate expression of this gene is seen in skeletal muscle, islet cells, adipose, small intestine and mesenchymal stem cells. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. general oncology screening panel__v_2.4 Summary: Ag4303 Highest expression of this gene is detected in prostate adenocarcinoma (CT=29.3). High expression of this gene in seen in some cancer samples from patients with kidney, lung, melanoma, bladder and prostate cancer compared to the normal adjacent tissue from these patients. Hence the expression of this gene can be used as a diagnostic marker for cancer.

Furthermore, therapeutic modulation of this gene using small molecules, alone or in combination may be beneficial in the treatment of these cancers. AU. CG105056-01: 17 BETA-HYDROXYSTEROID DEHYDROGENASE TYPE VII

Expression of gene CG105056-01 was assessed using the primer-probe set Ag5926, described in Table AUA. Results ofthe RTQ-PCR runs are shown in Tables AUB, AUC, AUD and AUE.

Table AUA. Probe Name Ag5926 j 1 Start j SEQ ID

Trimers⁾ Sequences Length

_! j Position [ No

[Forward [5 ' -tctaatctctgaaacctgcaact-3 ' r^~2_r ^{~ '} 288 i 436

'_p i JTET-5 ' -taagttccttggaggcccggaaga- 3 ' -

[* ^e [TAMRA 24 316 j 437

Reverse '5 ' -ctgaggtcaccattgtcca-3 ' 366 [ 438

Os

[Temporal [Parietal Ctx ^!Ctx

[Control

Control '(Path) 2 28.: 25.2 (Path) 4 _>_.._) 27.5 [Temporal Parietal Ctx Ctx

Table AUC. General_screeningjpanel_vl .5

Table AUD. Panel 4. ID

Table AUE. Panel 5 Islet

CNS_neurodegeneration_vl.0 Summary: Ag5926 Two experiments with the same probe and primer set produce results that are in excellent agreement. This gene appears to be upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation ofthe expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease.

General_screening_panel_vl.5 Summary: Ag5926 This gene is widely expressed at low but significant levels in this panel, with highest expression in a liver cancer cell line (CT=32). Prominent levels of expression are also seen in breast and colon cancer cell lines. This gene encodes a putative 17 betahydroxysteroid dehydrogenase, an enzyme that is involved in the metabolism of estrogen. Gunnarsson et al. suggest that altered expression of this enzyme may play a role in the progression of breast cancer. (Cancer Res 2001 Dec 1 ;61(23):8448-51) Therefore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of these cancers.

Among tissues with metabolic function, this gene is expressed at low but significant levels in pituitary, adrenal gland, pancreas, thyroid, skeletal muscle, and fetal heart and liver. This expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. In addition, this gene is expressed at low levels in all regions ofthe CNS examined. Steroid treatment is used in a number of clinical conditions including Alzheimer's disease (estrogen), menopause associated symptoms (estrogen), multiple sclerosis (glucocorticoids), and spinal cord injury (methylprednisolone). Treatment with an antagonist of this gene product, or reduction ofthe levels of this gene product could slow steroid degredation and lower the necessary amount given for therapeutic effect, thus reducing peripheral side effects. (Holinka CF. Ann N Y Acad Sci 2001 Sep;943:89-108; Matsumoto T. Spine 2001 Feb 15;26(4):426-30; Gaillard PJ. Neuroreport 2001 Jul 20;12(10):2189-93) Panel 4. ID Summary: Ag5926 Highest expression ofthe CGI 05056-01 gene is seen in chronically activated Thl cells (CT=34.1). Therefore, therapeutics designed with the transcript could reduce or inhibit antigen presentation and be important in the treatment of diseases such as asthma, IBD, psoriasis and arthritis in which T cells are chronically stimulated. Panel 5 Islet Summary: Ag5926 The expression of this novel steroid dehydrogenase- like gene is seen exclusively in the liver HepG2 cell line, (CT=33.1). Expression in liver cells suggests that the role of this novel steroid dehydrogenase may be similar to the role of other steroid dehydrogenases which are involved in steroid and bile acid metabolism. Therefore, small molecule therapeutics against this gene product may be effective in disorders in which expression of this gene is dysregulated.

AV. CG105201-01: Hexokinase III splice variant Expression of gene CG105201-01 was assessed using the primer-probe set Ag4282, described in Table AVA. Results ofthe RTQ-PCR runs are shown in Tables AVB, AVC, AVD. AVE and AVF.

Table AVA. Probe Name Aj_.4282

[113665 Syn Fluid

,112382 Ulcer Col-M 0.7 0.0 [Cells3 Normal il 12394 Match [1 17107 Normal

0.7 0.2 Control Ulcer Col-M Cartilage Rep22

1112383 Ulcer Col-M 1.5 113667 Bone4 Normal 0.5

112736 Match 0.3 jl 13668 Synovium4 0.4 Control Ulcer Col-M [Normal

1 13669 Syn Fluid ιl l2423 Psoriasis-F 1.6 0.0 Cells4 Normal

Table AVC. CNS neurodegeneration vl .O

^•ACHN ca. CAPAN2 I

Renal ca. Pancreas

0.5 0.0 0.0 8.0 22.1 5.0 OJO-31 Pool

Table AVE. Panel 4. ID

Table AVF. gene ral oncology screening panel_v_2.4

AI_comprehensive panel_vl.O Summary: Ag4282 Highest expression ofthe

CGI 05201-01 gene is detected in sample derived from rheumatoid arthritis (RA) bone

(CT=27). High to moderate levels of expression of this gene is also seen in samples derived from osteoarthritic (OA) bone and adjacent bone, OA cartilage, OA synovium and OA synovial fluid samples, as well as from cartilage, bone, synovium and synovial fluid samples from RA patients. Low level expression is also detected in samples derived from normal lung samples, COPD lung, emphysema, atopic asthma, asthma, allergy, Crohn's disease (normal matched control and diseased), ulcerative colitis(normal matched control and diseased), and psoriasis (normal matched control and diseased). Therefore, therapeutic modulation of this gene product may ameliorate symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoartliritis

CNS_neurodegeneration_vl.O Summary: Ag4282 This panel confirms the expression ofthe CG105201-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4282 Three experiments with same probe and primer set are in excellent agreement, with highest expression ofthe CG105201-01 gene in spleen, colon cancer and bladder (CTs=29=30.8). Therefore, expression of this gene may be used to distinguish this sample from other samples in the panel and also as marker for detection of colon cancer. Furthermore therapeutic modulation of this gene may be useful in the treatment of colon cancer, allergies, autoimmune diseases, and inflammatory diseases.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, skeletal muscle, heart, and liver. Glucose phosphorylation, catalyzed by hexokinase, is the first committed step in glucose uptake in skeletal muscle and adipose. Glucose uptake into these tissues is compromised in obesity- related insulin resistance and Type 2 diabetes. Pharmacologic enhancement of hexokinase activity may be a treatment for the prevention and/or treatment of Type 2 diabetes. (Jimenez- Chillaron JC, Metabolism. 2002 Jan;51(l):121-6.) Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Ag4282 Results from one experiment (run 219274018) with this gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4.1D Summary: Ag4282 Highest expression ofthe CG105201-01 gene is detected in resting macrophage (CT=26). High to moderate levels of expression of this gene is also seen in neutrophils, macrophage, monocytes, dendritic cells, two way MLRs, PBMC and LAK cells. Therefore therapeutic modulation of this gene through the use of small molecule drug may be useful in the treatment of autoimmune and inflammatory diseases including Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, lupus erythematosus, or psoriasis. general oncology screening panel_v_2.4 Summary: Ag4282 Highest expression of the CG105201-01 gene is detected in kidney cancer (CT=31.6). Higher expression of this gene is seen in colon, lung, kidney, prostate and metastatic melanoma cancer samples as compared to the adjacent normal tissue. Therefore, expression of this gene may be used as diagnostic marker of detection of these cancers and therapeutic modulation of this gene may be beneficial in the treatment of colon, lung, kidney, prostate and metastatic melanoma cancers.

AW. CG105294-01: Human ortholog of mouse kinesin KIF21B Expression of gene CG105294-01 was assessed using the primer-probe set Ag4283, described in Table AWA. Results ofthe RTQ-PCR runs are shown in Tables AWB, AWC and A WD.

Table AWA. Probe Name Ag4283

Start SEQ ID iPrimers Sequences Length Position No

[Forward [5 ' -tctacaacgaggagatccttga- 3 ' 22 45: 442

[Probe ιTΞT- 5 ' -ctgtttgacagcacccgtgaccct- 3 ' [TAMRA 24 476 443

Reverse !5 ' -gtcctcgtggatcttgatgtt- 3 21 52] 444

Table AWB. CNS neurodegeneration vl.O

Table AWC. General_screeningjpanel_vl .4

'Lung ca. HOP-62 [ 0.6 [Cerebral Cortex Pool 6.0 [Brain (Substantia nigra)

Tung ca. NCI-H522 j 0.9 5.8 iPool

'Liver '^■ 0.1 iBrain (Thalamus) Pool 6.9 _jFetal Liver ] 0.3 Brain (whole) 15.4

[Liver ca. HepG2 j 0.1 [Spinal Cord Pool 2.0

.Kidney Pool 0.5 [Adrenal Gland o.: [Fetal Kidney 0.5 Pituitary gland Pool 0.1 iRenal ca. 786-0 0.0 [Salivary Gland

[Renal ca. A498 _ 0.2 [Thyroid (female) 0.1

•Pancreatic ca. Renal ca. ACHN 0.1 0.1 CAPAN2

Renal ca. UO-31 0.6 Pancreas Pool 0.5

Table AWD. Panel 4. ID

... _^ ......

'Macrophages TPS ! [Thymus [ 32.1

[HUVEC none i i 1.9 [Kidney [ 12.4

[HUVEC starved ^~T 2.1 1

CNS_neurodegeneration_vl.O Summary: Ag4283 This panel does not show differential expression of this gene in Alzheimer's disease. This gene encodes a homolog of kinesin, a microtubule-based motor protein involved in the transport of organelles. Axonal transport of APP in neurons is mediated by binding with kinesin. (Gunewardena S, Neuron 2001 Nov 8;32(3):389-401). Kamal et al. suggest that impaired APP transport leads to enhanced axonal generation and deposition of Abeta, resulting in disruption of neurotrophic signaling and neurodegeneration (Nature 2001 Dec 6;414(6864):643-8). Thus, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of Alzheimer's disease or other neurodegenerative disorders. General__screening_panel_vl.4 Summary: Ag4283 This gene is overexpressed in fetal brain (CT=25.6) when compared to expression in other samples on this panel. Thus, expression of this gene could be used to differentiate between fetal and adult brain tissue. Rapid organelle transport is required for growth and establishment of specialized structures during neuronal development. Morfini G et al. showed kinesin to be enriched in growing neurons. (Dev Neurosci 2001 ;23(4-5):364-76). Therefore, the higher levels of expression in the fetal brain suggest that this gene product, a kinesin homolog, may be involved in the developing brain. In addition, this gene is expressed at moderate levels in all regions ofthe CNS examined. Therefore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Among tissues with metabolic function, this gene is expressed at low levels in adipose, adrenal gland, pancreas, and fetal liver. This expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

Panel 4. ID Summary: Ag4283 This gene appears to be expressed mainly in hematopoietic cells, with highest expression in IL-2 treated LAK cells. This transcript is also found in T cells, particularly chronically activated Thl, Th2 and Tri cells. Macrophages, B cells, eosinophils, neutrophils and dendritic cells also express the transcript. The only non- hematopoietic cell type that expresses the transcript at moderate levels is dermal fibroblasts. Thymus and kidney also express low levels ofthe transcript. Thus, this transcript or the protein it encodes could be used to detect hematopoietically-derived cells. Furthermore, therapeutics designed with the protein encoded by this transcript could be important in the regulation the function of antigen presenting cells (macrophages and dendritic cells)or T cells and be important in the treatment of asthma, emphysema, psoriasis, arthrtis, and IBD.

AX. CG105334-01: peptidyl-prolyl cis-trans isomerase

Expression of gene CG105334-01 was assessed using the primer-probe set Ag4286, described in Table AXA. Results ofthe RTQ-PCR runs are shown in Tables AXB, AXC and AXD.

Table AXA. Probe Name Ag4286

Start SEQ ID

.Primers¹. Sequences Length

Po _sition _. No

Forward '5 ' -tgaacagctgaggacattgg-3 ' 20 ^" 445 lTET- 5 ' - cctagagttcctcgctgccatggag-

,Probe 25 [TAMRA 64 446

Reverse '5 ' - cttcttcctcaacagctgctt- 3 21 117 447

Table AXB. CNS_neurodegeneration_ vl .O

Table AXC. General_screening_panel_vl .4

Table AXD. Panel 4. ID

CNS_neurodegeneration_vl.0 Summary: Ag4286 This panel con irms t e expression ofthe CG105334-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders. General_screening_panel_vl.4 Summary: Ag4286 Highest expression ofthe

CGI 05334-01 gene is detected in breast cancer T47D cell line (CT=32.6). Significant expression of this gene is also seen in an ovarian cancer cell line. Thus, expression of this gene may be used as a marker to detect the presence of this cancer and therapeutic modulation of the expression or function of this gene may be useful in the treatment of breast and ovarian cancers.

In addition, this gene is expressed at low levels in substantia nigra. thalamus. and cerebral cortex. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Panel 4.1D Summary: Ag4286 Highest expression ofthe CG105334-01 gene is detected in kidney (Ct=32.2). In addition, low expression of this gene is also detected in thymus. Therefore, expression of this gene may be used to distinguish these two samples from other samples in the panel. In addition, therapeutic modulation of this gene product may be beneficial in the treatment of autoimmune and inflammatory diseases that affect kidney including lupus and glomerulonephritis.

AY. CG105503-01: Drosophila Melanogaster Separation Anxiety Protein

Expression of gene CG105503-01 was assessed using the primer-probe set Ag4289, described in Table AYA. Results ofthe RTQ-PCR runs are shown in Table AYB.

Table AYA. Probe Name Ag4289

Table AYB. Panel 4. ID

Tissue Name Rel. Exp.(%) Tissue Name Rel. Exp.(%)

gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

General_screening_panel_vl.4 Summary: Ag4289 Expression ofthe CG105503-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel 4.1D Summary: Ag4289 Moderate level of expression ofthe CG105503-01 gene is seen only in kidney (CT=31.9). Thus, expression of this gene may be used to distinguish kidney from other samples in the panel. Furthermore, small molecule therapies designed with the protein encoded for by this gene could modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis. AZ. CG105550-01: KINESIN 12

Expression of gene CG105550-01 was assessed using the primer-probe set Ag4291, described in Table AZA. Results ofthe RTQ-PCR runs are shown in Tables AZB and AZC.

Table AZA. Probe Name Ag4291

Table AZB. General_screening_jpanel_vl .4

Table AZC. Panel 4. ID

low/undetectable in all samples on this panel (CTs>35).

General_screening_panel_vl.4 Summary: Ag4291 Highest expression of this gene is seen in a breast cancer cell line (CT=30.9). Moderate levels of expression are also seen in brain, renal, ovarian and colon cancer cell lines. In addition, higher levels of expression of this gene are detected in fetal kidney (CT=31.4) when compared to expression in adult kidney (CT=37). Thus, expression of this gene could be used to differentiate between fetal and adult kidney and as a marker of these cancers. Significant levels of expression in cancer cell lines and fetal tissues also suggest that this gene product is necessary for cell growth. Members of the kinesin family are involved in the assembly and dynamics ofthe mitotic spindle (Blangy A. Cell 1995 Dec 29;83(7):1 159-69). Components ofthe mitotic apparatus are targets for drugs used in cancer therapy. Therefore, based on the homology of this gene to kinesin and its expression in cancer cell lines, therapeutic modulation ofthe expression or function of this gene product may be useful in the treatment of brain, renal, breast and colon cancers.

Panel 4.1D Summary: Ag4291 This gene is expressed at detectable levels in the kidney (CT=34.4). Therefore, antibody or small molecule therapies designed with the protein encoded for by this gene could modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis.

BA. CG105597-01: PUTATIVE FOUR REPEAT ION CHANNEL

Expression of gene CG105597-01 was assessed using the primer-probe sets Agl090, Ag4292 and Ag536, described in Tables BAA, BAB and BAC. Results ofthe RTQ-PCR runs are shown in Tables BAD, BAE, BAF, BAG, BAH and BAL

Table BAA. Probe Name Agl090

Table BAB. Probe Name Ag4292

Table BAC. Probe Name Ag536

Table BAD. CNS neurodegeneration vl.O

Table BAE. General_screening_panel_vl.4

Melanoma* Ml 4 0.0 Gastric ca. KATO III 0.0

.Melanoma* 0.5 Colon ca. SW-948 0.0 TOXIMVI

, SNB-19

CNS cancer (glio) SF-

Luns ca. SHP-77 0.1 9.9 295

Lung ca. A549 4.2 'Brain (Amygdala) Pool 20.2

Tung ca. NCI-H526 . 0.0 [Brain (cerebellum) 12.2 unTc^~.Tsl mTJ [Brain (fetal) 10.4

Table BAF. Panel 1.1

Table BAG. Panel 4. ID

HUVEC starved 5.4

Table BAH. Panel 5 Islet

'12pl_placenta j adenoma

94721_Donor 2 U - '

A Mesenchymal Stem [ 15.9 72410_Kidney_HRCE _! 13.5 i

^'Cells !

|94722_Donor 2 U - iβ Mesenchymal Stem 1 1.9 724 1 l_Kidney_HRE 5.1 iCells '

;94723 JDonor 2 U -^{""" """} 731 39_Uterus_Uterine smooth [C Mesenchymal Stem 37.1 0.0 mus 5cle cells ICells

Table BAL Panel CNS 1

CNS_neurodegeneration_vl.O Summary: Agl090/Ag4292 Two experiments with different probe and primer sets are in excellent agreement. This panel confirms the expression ofthe CG105597-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4292 Highest expression ofthe CGI 05597-01 gene, a putative ion channel protein, is detected in whole brain (CT=27). High expression of this gene is seen in all the region of central nervous system examined including amygdala, hippocampus, substantia nigra. thalamus, cerebellum, cerebral cortex, and spinal cord. All mutations known to cause seizure disorders are found in ion channels and to date ion channels are the primary target of antiepileptics. Therefore, this gene could potentially be used as a small molecule target for the treatment of seizure disorders (including epilepsy) or to screen small molecules for action as antiepileptics.

Moderate to low levels of expression of this gene is also seen in number of cancer cell lines derived from pancreatic, lung, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of pancreatic, lung, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Panel 1.1 Summary: Ag536 Highest expression ofthe CG105597-01 gene is detected in whole brain (CT=24.5). High expression of this gene is seen in all the region of central nervous system examined including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Moderate levels of expression of this gene is also seen in number of cancer cell lines derived from pancreatic, renal, colon, gastric lung, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of pancreatic, lung, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in adipose, pancrease adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Panel 4.1D Summary: Ag4292 Highest expression ofthe CG105597-01 gene is detected in IL-9 treated NCI-H292 (CT=29.9). In addition, moderate to low levels of expression of this gene is also seen in endothelial cells represented by HUVEC, microvascular lung and dermal endothelial cells, TNFalpha + IL-lbeta treated astrocytes, keratinocytes and NCI-H292 cells. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of multiple sclerosis or other inflammatory diseases ofthe CNS, lupus erythematosus, asthma, emphysema, Crohn's disease, ulcerative colitis, rheumatoid arthritis, osteoarthritis, and psoriasis. Panel 5 Islet Summary: Ag4292 Highest expression ofthe CGI 05597-01 gene is detected in adipose (CT=32.4). The novel four repeat ion channel is upregulated during adipocyte differentiation. The expression profile of the four repeat ion channel closely resembles that of PPARg.

PPARg is sufficient and necessary for adipogenesis (Lee et al., 2002, J Biol Chem 2002 Mar 4, PMID: 11877444 [epub ahead of print]). The novel four repeat ion channel may act downstream of PPARg in promoting adipogenesis. Inhibition of the novel four repeat ion channel may result in delayed adipocyte differentiation and reduction of body mass. Therefore, antagonist to the novel four repeat ion channel may be beneficial in the treatment of obesity. Panel CNS L Summary: Agl090 This panel confirms the expression ofthe

CG105597-01 gene at low levels in the brains of an independent group of individuals. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders. BB. CG105627-01 and CG105627-04: C-C CHEMOKINE RECEPTOR TYPE 5

Expression of gene CG105627-01 and CG105627-04 was assessed using the primer- probe sets Ag4309 and Ag6626, described in Tables BBA and BBB. Results ofthe RTQ-PCR runs are shown in Tables BBC, BBD, BBE and BBF.

Table BBA. Probe Name Ag4309

[ I _τ ,, Start SEQ ID

Primers [ Sequences Length' _ ... i Position No

'Forward |5 ' -caacattgtccttctcctgaac-3 22 546 463^"""

TET-5 ' -ccttccaggaattctttggcctgaat-3

Probe TAMRA 26 569 464

Reverse '5 ' -ttggtccaacctgttagagcta-3 22 603 465

Table BBB. Probe Name Ag6626

Table BBC. CNS_neurodegeneration_vl .0

Table BBD. General_screeι_ingjpanel_vl .4

Brain (Substantia nigra)

Lung ca. NCI-H522 0.0 4.2 Pool

Liver 4.8 Brain (Thalamus) Pool 10.9

Fetal Liver 13.3 Brain (whole) 6.7

[Liver ca. HepG2 0.0 Spinal Cord Pool 21.5

[Kidney Pool 43.8 Adrenal Gland 17.2 Fetal Kidney 1.9 Pituitary gland Pool 3.1

Ttenaϊ ca. 786-0 0.0 Salivary Gland 11.7

Renal ca. A498 0.0 Thyroid (female) 16.0

1 Pancreatic ca. jRenal ca. ACHN 0.0 0.0

1 CAPAN2 iRenal ca. UO-31 0.0 Pancreas Pool 52.9

Table BBE. General_screening_panel_vl .6

Table BBF. Panel 4. ID

CNS_neurodegeneration_vl.O Summary: Ag4309 Th s panel con irms the expression ofthe CGI 05627-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel__vl.4 Summary: Ag4309 Highest expression ofthe CGI 05627-01 gene is detected in bladder (CT=30.5). Significant expression of this gene is also seen in tissues with metabolic/endocrine function including pancreas, adipose, adrenal gland, thyroid, pituitary gland, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Moderate levels of expression of this gene is also seen in colon cancer sample. Therefore, expression of this gene may be used as marker for detecting the presence of colon cancer and therapeutic modulation of this gene may be beneficial in the treatment of colon cancer.

In addition, this gene is expressed at moderate levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

General_screening_panel_vl.6 Summary: Ag6626 Highest expression ofthe CG105627-01 gene is detected in bladder (CT=29.4). Significant expression of this gene is also seen in tissues with metabolic/endocrine function including pancreas, adipose, adrenal gland, thyroid, pituitary gland, heart, and liver. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Moderate level of expression of this gene is also seen in colon cancer sample. Therefore, expression of this gene may be used as marker for detecting the presence of colon cancer and therapeutic modulation of this gene may be beneficial in the treatment of colon cancer.

Panel 4. ID Summary: Ag4309/Ag6626 Two experiment with different probe and primer set are in excellent agreement with highest expression ofthe CGI 05627-01 in LPS treated monocytes (CTs=25 -25.7). The CGI 05627-01 gene encodes a CCR5 like molecule, which is a co-receptor for HIV, and a chemokine receptor important for the migration of T and mononuclear cells to the site of inflammation. Therefore, strategies aimed at targeting CCR5 would be crucial for controlling HIV invasion and the migration of inflammatory cells to site ofthe tissue damage. Therefore, small molecule drugs or antibodies that antagonzie the function of this gene product may reduce or eliminate the symptoms in patients with several types of autoimmune and inflammatory diseases, such as lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, or psoriasis.

BC. CG106074-01: Novel Mitochondrial enzyme containing

Oxidoreductase Domain Expression of gene CGI 06074-01 was assessed using the primer-probe set Ag4316, described in Table BCA. Results of the RTQ-PCR runs are shown in Tables BCB, BCC and BCD.

Table BCA. Probe Name Ag4316

Table BCB. CNS neurodegeneration vl .O

Table BCC. General screening panel _vl.4

Table BCD. Panel 4. ID

Rel. Exp.(%) ! Rel. Exp.(%)

Tissue Name Ag4316, Run Tissue Name ^[ Ag4316, Run

183714203 I 183714203

Secondary Thl act [HUVEC IL-lbeta ^". ^~"_ 8.3 ^[Secondary Th2 act ^{""'"' """}85.3 iHUVEC IFN gamma ^"[^{'" ~}3^~2lT ^~'~ ^"1

!^"HUV^"E^"C^""TNF^" alpha + IFN

[Secondary Tri act 65.1 i 7.1 jgamma

, iSecondar _y Thl r _e__s_t_ 24.: [HUVEC TNF alpha + IL4 12.8

^Secondary Th2 rest 52.: jHUVEC IL- 11 25.2

^■Secondary Tri rest 18.6 [Lung Microvascular EC none 11.4

^"HUVEC none __ __ ^: _ T² T ^!κidne ___ : _ 27.4 j

HUVEC starved ^{" " " " "} \ 47.6^" \ ^{~~" " " """ '} 1 ^"1

CNS_neurodegeneration_vl.O Summary: Ag4316 This panel confirms the expression of the CG106074-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gerie was detected between

Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag4316 Highest expression ofthe

CG106074-01 gene is detected in renal cancer TK-10 cell line (CT=28). Moderate levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Therefore, expressiono of this gene may be used as marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Interestingly, this gene is expressed at much higher levels in fetal (CT=30) when compared to adult liver (CT=35). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.

In addition, this gene is expressed at moderate levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as

Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Panel 4. ID Summary: Ag4316 Highest expression of the CGI 06074-01 gene is detected in basophils (CT=30.5). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

BD. CG 106166-01 and CG106166-02: novel protein kinase

Expression of gene CGI 06166-01 and CGI 06166-02 was assessed using the primer- probe set Ag4415, described in Table BDA. Results ofthe RTQ-PCR runs are shown in Tables BDB, BDC, BDD and BDE. Please note that CGI 06166-02 represents a full-length physical clone of the CG106166-01 gene, validating the prediction ofthe gene sequence.

Table BDA. Probe Name Ag4415

Start SEQ ID iPrimers: Sequences ;Length[ Position No

'Forward '5 ' -cttcccacctaaggaagagaag-3 ' 22 288 472

Probe jTET- 5 ' -attgtggactgcctcccttgcatact-3 ' -

[TAMRA 26 322 473

[Reverse J5 ' -ggcacttgacgttacaatcct-3 ' 21 559 474

Table BDB. AI_comprehensive panel_vl.0

Table BDC. CNS neurodegeneration vl.O

Table BDD. General_screening_panel_vl .4

Table BDE. Panel 4. ID

A comprehensive panel vl.O Summary: Ag4415 Highest expression ofthe CG106166-01 gene is detected in sample derived from matched control for psoriasis patient (CT=29). Moderate levels of expression of this gene are detected in samples derived from normal and orthoarthitis/ rheumatoid arthritis bone and adjacent bone, cartilage, synovium and synovial fluid, from normal lung samples, COPD lung, emphysema, atopic astlmia, asthma, allergy, Crohn's disease (normal matched control and diseased), ulcerative colitis(normal matched control and diseased), and psoriasis (normal matched control and diseased). Therefore, therapeutic modulation of this gene product may ameliorate symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, astlmia, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis

CNS_neurodegeneration_vl.0 Summary: Ag4415 This panel confirms the expression ofthe CGI 06166-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screening_j.anel_vl.4 Summary: Ag4415 Highest expression ofthe CGI 06166-01 gene is detected in melanoma M14 cell line(CT=25). Moderate to high levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Interestingly, this gene is expressed at much higher levels in fetal (CT=29.7) when compared to adult liver (CT=34.8). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation ofthe protein kinase encoded by this gene could be useful in treatment of liver related diseases.

Panel 4.1D Summary: Ag4415 Highest expression ofthe CG106166-01 gene is detected in activated secondary Th2 cells (CT=29). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

BE. CG106773-01: calmodulin-dependent protein kinase Il-delta Expression of gene CG106773-01 was assessed using the primer-probe set Ag4336, described in Table BEA. Results ofthe RTQ-PCR runs are shown in Tables BEB, BEC, BED and BEE.

Table BEA. Probe Name Ag4336

Table BEB. CNS_ neurodegeneration_vl.O

Table BED. Panel 4. ID

^''Dermal fibroblast CCD 1070

B lymphocytes PWM 16.5 ^!rest 29.9

;B lymphocytes CD40L and Dermal fibroblast CCD 1070

40.9 40.: .IL-4 TNF alpha

[Dermal fibroblast CCD 1070 lEOL-1 dbcAMP 1.6 13.6 [IL-1 beta

[EOL-1 dbcAMP

5.9 [Dermal fibroblast IFN gamma 30.1 jPMA/ionomycin iDendritic cells none 23.0 ;Dermal fibroblast IL-4 45.7

(Dendritic cells LPS ^"39^"θ 'Dermal Fibroblasts rest ^"37.9 ^" iDendritic cells anti-CD40 21.2 iNeutrophils TNFa+LPS ^" .2 ^'

₍Monocytes rest ^"l5.2 iNeutrophils rest ^" l .O

'Monocytes LPS ^"3.0 [Colon ^~ 875 ^~

'Macrophages rest 9.4_ jLung _ _ _ _ 9.9 ^"

'Macrophages LPS ^"4.6^" iThymus 14.4

' uVEC nόne^" 6.2 [Kidney ^'S ^"

ΗUVEC starved 9.5

Table BEE. Panel 5 Islet

CNS_neurodegeneration_vl.O Summary: Ag4336 This panel confirms the expression ofthe CG106773-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 14 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4336 Highest expression ofthe CG106773-01 gene is detected in breast cancer BT 549 cell line (CT=25). Moderate to high levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. The CGI 06773-01 gene codes for splice variant of calcium/calmodulin-dependent protein kinase type II delta chain (CaMK II). CaMK-II has been implicated in diverse neuronal and non-neuronal functions, including cell growth control. Splice variants of CaMK-II have been shown to be differentially expressed in tumor cells, especially neuroblastoma and mammary tumor cells (Tombes RM, Krystal GW., 1997, Biochim Biophys Acta 1355(3):2Sl-92, PMID: 9060999). Therefore, therapeutic modulation of this gene through the use of small molecule drug may be useful in the treatment of neuroblastoma and mammary tumors.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. CaMK-II is known to be highly expressed in pancreatic islets and associated with insulin secretion vesicles. Also, the suppression of CaMK II disturbs insulin secretion and insulin gene expression (Rochlitz et al., 2000, Diabetologia 43(4)465-73, PMID: 10819240). Activation of CaMK II and the concomitant phosphorylation of synapsin I contribute to insulin secretion from pancreatic beta-cells (Tabuchi et al., 2000, Endocrinology 141(7):2350-60, PMID: 10875234 ). Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at high levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Calmodulin (CaM) is a major Ca2+-binding protein in the brain, where it plays an important role in the neuronal response to changes in the intracellular Ca2+ concentration. Calmodulin modulates numerous Ca2+-dependent enzymes and participates in relevant cellular functions. Among the different CaM-binding proteins, the Ca2+/CaM dependent protein kinase II and the phosphatase calcineurin are especially important in the brain because of their abundance and their participation in numerous neuronal functions (Sola et al., 2001, Int J Biochem Cell Biol 33(5)439-55, PMID: 11331200). In addition, the alpha-CaMK II knock-out mouse and transgenic mice expressing a mutant form of CaMK II clearly demonstrate that CaMK II plays a prominent role in hippocampal LTP and hippocampus-dependent memory (Fukunaga K, Miyamoto E., 2000, Neurosci Res 38(1):3-17, PMID: 10997573). Therefore, therapeutic modulation of this gene product may be useful in the treatment of neurological disorders such as memmory loss, Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4336 Highest expression ofthe CG106773-01 gene is detected in IL-9 treated lung fibroblast cells (CT=27.3). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screeningjpanel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Panel 5 Islet Summary: Ag4336 Highest expression ofthe CG106773-01 gene is detected in skeletal muscle (CT=29.5). In addition, moderate expression of this gene is also seen in islet cells, adipose, skeletal muscle, uterus, placenta, kidney and small intestine. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Please see panel 1.4 for further references and discussion ofthe utility of this gene.

BF. CG108211-01: ECT2

Expression of gene CG10821 1-01 was assessed using the primer-probe set Ag4353, described in Table BFA.

Table BFA. Probe Name Ag4353

CNS_neurodegeneration_vl.O Summary: Ag4353 Expression ofthe CG108211-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel. General_screening_panel_vl.4 Summary: Ag4353 Expression of the CG108211-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel 4.1D Summary: Ag4353 Expression ofthe CG108211-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel. BG. CG108351-01: THIOREDOXIN REDUCTASE TR2

Expression of gene CG 108351-01 was assessed using the primer-probe set Ag4354, described in Table BGA. Results ofthe RTQ-PCR runs are shown in Tables BGB and BGC.

Table BGA. Probe Name Ag4354

Table BGB. General_screening_panel_vl 4

gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

General_screening_panel_vl.4 Summary: Ag4354 Highest expression ofthe CG108351-01 gene is detected in CNS cancer (astro) SNB-75 cell line (CT=27.9). Moderate to high levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. The CG108351-01 gene codes for thioredoxin reductase (TR). TR is a selenocysteine containing flavoenzyme that catalyzes the NADPH dependent reduction ofthe redox protein thioredoxin. Thioredoxin is over-expressed by a number of human tumors. Experimental studies have shown that thioredoxin is responsible for the growth and transformed phenotype of some human cancer cells. Thus, thioredoxin reductase presents an attractive target for anticancer drug development to regulate the activity ofthe thioredoxin system (Engman et al, 1997, Anticancer Res 17(6D):4599-605, PMID: 9494575). Therefore, therapeutic modulation ofthe expression or function of TR encoded by this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Panel 4.1D Summary: Ag4354 Highest expression of the CGI 08351-01 gene is detected in kidney and IFN gamma treated NCI-H292 (CTs=31.7). Low to moderate expression of this gene is seen in endothelial cells derived from dermal and lung epithelium, epithelial cells, astrocytes, lung and dermal fibroblasts, keratinocytes, basophils, dendritic cells, activated lymphocytes, activated primary and secondary T cells, and normal tissues represented by lung and thymus. Therefore, therapeutic modulation of this gene may be useful in the treatment of asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

BH. CG108462-01: Novle FKBP-type peptidyl-prolyl cis-trans isomerase

Expression of gene CG108462-01 was assessed using the primer-probe set Ag4364, described in Table BHA. Results ofthe RTQ-PCR runs are shown in Tables BHB, BHC and BHD.

Table BHA. Probe Name Ae4364 jPrimers Sequences (Length Start T SEQ ID Position No

Forwards ' -ccaagccagtcacctgtaag-3 ' 20 3880 484

ITET- 5 ' -agtcctgtcctctgccagactttt- 3 ' ^■

^'Probe [TAMRA 24 Ϊ900 485

[Reverse [5 ' -tcccaggtcagtctgagagtta-3 ' 22 3936 486

Table BHB. CNS neurodegeneration vl .O

Control 3 Temporal jControl (Path) 2

11.2 17.9 Ctx Parietal Ctx

Table BHC. General_screeningjpanel__vl.4

Table BHD. Panel 4. ID

_neuro egenerat on_vl. ummary: g43 4 s pane con irms the expression of this gene at low levels in the brain in an independent group of individuals. This gene is found to be upregulated in the temporal cortex of Alzheimer's disease patients.

Therefore, therapeutic modulation ofthe expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease.

General_screening_panel_vl.4 Summary: Ag4364 Highest expression of this gene is seen in a brain cancer cell line (CT=27). Significant levels of expression are also seen in a cluster of brain cancer cell lines. This gene is widely expressed in this panel, with moderate expression also seen in brain, colon, gastric, lung, breast, ovarian, pancreatic and melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

Among tissues with metabolic function, this gene is expressed at moderate to low significant levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

This gene is also expressed at moderate levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Panel 4.1D Summary: Ag4364 Highest expression of this gene is seen in resting monocytes (CT=27.9). This gene is also expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

BI. CG108723-01, CG108723-02 and CG108723-03: Sodium- and chloride- dependent GABA transporter. Expression of gene CG108723-01, CG108723-02 and CG108723-03 was assessed using the primer-probe sets Ag4408, Ag5971 and Ag6397, described in Tables BIA, BIB and BIC. Please note that probe Ag6397 is specific for variant CGI 08723-03. Please also note that CG108723-02 represents a full-length physical clone ofthe CG108723-01 gene, validating the prediction ofthe gene sequence. Results ofthe RTQ-PCR runs are shown in Table BID.

Table BIA. Probe Name Ag4408

Table BIB. Probe Name Ag5971

Table BIC. Probe Name Ag6397

Table BID. CNS_neurodegeneration_vl .0

CNS_neurodegeneration_vl.0 Summary: Ag4408 Two experiments with same probe and primer sets are in good agreement. This panel confirms the expression of the CGI 08723-01 gene at low levels in the brain in an independent group of individuals. This gene is found to be slightly down-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia, memory loss, and neuronal death associated with this disease.

Ag6397 This probe is specific for CG108723-03 and expression of this gene is low/undetectable (CTs > 35) across all ofthe samples on this panel. General_screening_panel_vl.6 Summary: Ag6397 Expression ofthe CG108723-03 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel 4.1D Summary: Ag6397 Expression ofthe CGI 08723-03 gene is low/undetectable (CTs > 35) across all of the samples on this panel.

Panel 5 Islet Summary: Ag4408 Expression ofthe CG108723-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Ag6397 This probe is specific for CGI 08723-03 and expression of this gene is also low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel 5D Summary: Ag5971 Expression ofthe CGI 08723-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel. Panel CNS_1 Summary: Ag4408 Results from one experiment with the CGI 08723-

01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

BJ. CG108870-01: HS1 BINDING PROTEIN 3

Expression of gene CG108870-01 was assessed using the primer-probe set Ag4382, described in Table BJA. Results ofthe RTQ-PCR runs are shown in Tables BJB, BJC and BJD.

Table BJA. Probe Name Ag4382

Table BJB. CNS_neurodegeneration_vl .0

Table BJC. General_screening__panel_vl .4

Table BJD. Panel 4. ID

ionomycin i * g—amma

1 _. , [Dermal fibroblast [

B lymphocytes PWM jCCDl 070 rest i

B lymphocytes CD40L ₁ _ r. [Dermal fibroblast

27.4 'and IL-4 JCCD1070 TNF alpha

! Dermal fibroblast iEOL-1 dbcAMP 15.0 27.7 CCD 1070 IL-1 beta

^■EOL-1 dbcAMP Dermal fibroblast IFN

17.9 55.5 PMA/ionomycin gamma

.Dendritic cells none 46.7 Dermal fibroblast IL-4 ioo.o

Dendritic cells LPS 31.2 Dermal Fibroblasts rest 67.8 ^~

Dendritic cells anti-

49.0 Neutrophils TNFa+LPS 13.6 GD40

'Monocytes rest ^™ 48?6 Neutrophils rest ^{" ~ "} 28.9 ^"

.Monocytes LPS 97.3 ^{"" "} Colon ^{'" "}2O.9^"

[Macrophages rest ) 59.0 Lung 27.0 ^Macrophages LPS j 24.1 Thymus ^"Ϊ6A

JHUVEC none | ^~26.6^~ Kidney 87.1 ^"""

ΗUVEC starved ^{" ~ "}| 463 ^{" " "}

CNS_neurodegeneration_\T.O Summary: Ag4382 This panel confirms the expression of this gene at low levels in the brain in an independent group of individuals. This gene appears to be slightly upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation ofthe expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease.

General_screening_panel_vl.4 Summary: Ag4382 Highest expression is seen in a breast cancer cell line (CT=27). High to moderate levels of expression are seen in cell lines derived from brain, colon, liver, lung, breast, ovarian, and skin cancers. In addition, this gene is expressed at much higher levels in fetal lung (CTs=30) when compared to expression in the adult counteφart (CT=33). Thus, expression of this gene may be used to differentiate between the fetal and adult sources of these tissues. The high levels of expression in fetal tissue and cancer cell lines p suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. This gene is also expressed at moderate levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Panel 4. ID Summary: Ag4382 Highest expression is seen in activated dermal fibroblasts (CT=29.7). This gene is also expressed at moderate to low levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.5 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

BK. CG109487-01: VOLTAGE-DEPENDENT ANION CHANNEL 2

Expression of gene CG109487-01 was assessed using the primer-probe set Ag4385, described in Table BKA. Results ofthe RTQ-PCR runs are shown in Tables BKB, and BKC.

Table BKA. Probe Name Ag4385

Start SEQ ID

[Primers Sequences Length Position No

Forward [5 ' -tgtacacagccagtgtgtcttc-3 ' 22 50 499

[Probe ITET- 5 ' -cctccatcatacgctcaccttgtcaa- 3 ' TAMRA 26 500 jReverse 5 ' -aaccaaatcctttgttgaaacc-3 ' 22 102 501

Table BKB. General_screening_panel_vl.4

Table BKC. Panel 4. ID

CNS_neurodegeneration_vl.O Summary: Ag4385 Expression ofthe CGI 09487-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

General_screening_panel_vl.4 Summary: Ag4385 ITighest expression ofthe CGI 09487-01 gene is detected in trachea (CT=32.9). Therefore, therapeutic modulation of this gene may be useful in the treatment of diseases related to trachea.

In addition, significant expression of this gene is also seen in number of cancer cell lines including CNS, colon, gastric, and breast cancer cell lines. Therefore, expression of this gene may be used as diagnostic marker to detect the presence of these cancers and therapeutic modulation of this gene through the use of small molecule target may be beneficial in the treatment of CNS, colon, gastric, and breast cancer.

Panel 4.1D Summary: Ag4385 Highest expression ofthe CG109487-01 gene is detected in kidney (CT=30.4). Therefore, expression of this gene may be used to distinguish kidney from other samples used in this panel. In addition, therapeutic modulation of this gene may be beneficial in the treatment of autoimmune of inflammatory disease that affect kidney including lupus and glomeruloneplrritis.

Moderate to low levels of expression of this gene is also seen in thymus, basophils, eosinophils and cytokine treated LAK cells. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of asthma, allergies, hypersensitivity reactions, inflammatory bowel disease, viral infections and autoimmune diseases.

Panel CNS_1 Summary: Ag4385 Expression ofthe CG109487-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel. Panel CNSJL.l Suraraarj': Ag43S5 Expression ofthe CG109487-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

BL. CG109594-01: Phospholipase

Expression of gene CGI 09594-01 was assessed using the primer-probe set Ag4393, described in Table BLA. Results of the RTQ-PCR runs are shown in Table BLB.

Table BLA. Probe Name Ag4393

L _A | Start j SEQ ID

Primers! Sequences Length! _, .... ^

! ^te ; Position No

Forward 15 ' -tcattaatgctgcaaagactga- 3 22 68 502

|TET- 5 ' -aataaggcacccaggagctcaactga- 3 '

Probe 'TA RA 26 102 503 'Reverse 15 ' -ggacagaaggggtcctgtataa-3 ' 22^" Ϊ46 504

Table BTB. General_screening_panel_vl .4

[Pancreatic ca.

Renal ca. ACHN 0.0

! [CAPAN2 0.0 iRenal ca. UO-31 0.0 [Pancreas Pool 0.0

CNS_neurodegeneration_vl.0 Summary: Ag4393 Expression ofthe CG109594-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

General_screening_panel_vl.4 Summary: Ag4393 High expression of the CGI 09594-01 gene is seen only in lung cancer A549 cell line (CT=26.3). Therefore, expression of this gene could be used to differentiate between this sample from other samples on this panel and as a marker to detect the presence of lung cancer. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of lung cancer.

Panel 4.1D Summary: Ag4393 Expression ofthe CG109594-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel 5 Islet Summary: Ag4393 Results from one experiment with the CGI 09594- 01 gene are not included. The amp plot indicates that there were experimental difficulties with this run. general oncology screening panel_v_2.4 Summary: Ag4393 Expression ofthe CG109594-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

BM. CG109733-01: Guanylate kinase-Iike

Expression of gene CG109733-01 was assessed using the primer-probe set Ag4401, described in Table BMA.

Table BMA. Probe Name Ag4401

CNS_neurodegeneration_vl.O Summary: Ag4401 Expression ofthe CGI 09733-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

General_screening_panel_vl.4 Summary: Ag4401 Results from one experiment with the CGI 09733 -01 gene are not included. The amp plot indicates that there were experimental difficulties with this run. Panel 4. ID Summary: Ag4401 Expression ofthe CGI 09733-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel CNS_1 Summary: Ag4401 Expression ofthe CGI 09733-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel CNS_1.1 Summary: Ag4401 Expression of the CG109733-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

BN. CG109835-01: GTP-BINDING PROTEIN REM2

Expression of gene CGI 09835-01 was assessed using the primer-probe set Ag4405, described in Table BNA. Results ofthe RTQ-PCR runs are shown in Tables BNB, BNC, BND. BNE and BNF.

T _^ a „b_.l_e~ B __^N ,A. _^.. P _ ro_•b_•e- N .. ,a„m_*_..e_. A - _*ae4.405

Primers _i Sequences Length Start Position [SEQ ID No

Forward 5 ' - cgtttatgacatctgggaacag- 3 ' 22 357 ! 508

Probe ιTET- 5 ' -cttcagaccggggacgcctttct - 3 ' -TAMRA 23 412 : 509

Reverse |5 ' -gtcggtgactgagaagacgat- 3 ' 21 436 ! 510

Table BNB. CNS neurodegeneration vl.O

Table BNC. General _creening_panel_ l .4

Uterus Pool [Colon ca. SW1116 ! ^{— ~ ~~~}4^{~ '}

Fetal Liver 1 5.4 Brain (whole) 12.0

Liver ca. HepG2 j 0.0 Spinal Cord Pool j 3.8

Kidney Pool ! 8.9 Adrenal Gland _j 0.0 Fetal Kidney [ ^{" ~}9 Pituitary gland Pool J ^{" ~}ιό.^"o^" [Renal ca.^" 786-6 1 0.9 Salivary Gland 1 ^"""~ϊ.5^~"""~

'Renal ca. A498 i ^{l A} Thyroid (female) _ _0;6

Pancreatic ca.

^■Renal ca. ACHN | 1.0

! CAPAN2 2.7

Renal ca. UO-31 0.8 Pancreas Pool 1 7.1

Table BND. Pane T 4.1D

Table BNE. Panel CNS 1

Table BNF. Panel CNS 1.1

CNS_neurodegeneration_vl.O Summary: Ag4405 This panel confirms the expression of the CG109835-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screening__panel_vl.4 Summary: Ag4405 Highest expression ofthe CG109835-01 gene is detected in cerebellum (CT=28.5). High to moderate levels of expression of this gene is seen in all regions of central nervous system examined including including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. The CGI 09835-01 gene codes for a homolog of rat GTP-binding protein REM2. The rat REM2 was identified on the basis of its homology with the Rem, Rad, Gem and Kir (RGK) family of Ras-related small GTP-binding protems. Rem2 mRNA was detected in rat brain and kidney (Finlin et al, 2000, Biochem J 347 Pt 1 :223-31, PMID: 10727423). Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Moderate to low levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adipose, pituitary gland, skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=32.7) when compared to adult liver (CT=40). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation ofthe REM2 protein encoded by this gene could be useful in treatment of liver related diseases.

Panel 4. ID Summary: Ag4405 Highest expression ofthe CG109835-01 gene is detected in resting neutrophils. Moderate levels of expression of this gene is also seen in TNF alpha + LPS treated neutrophils. Therefore, expression of this gene may be used to distinguish neutrophils from other samples in this panel. Low levels of expression of this gene is also seen in thymus, IL-4 treated dermal fibroblasts, PMA/ionomycin treated basophils, dendritic cells, monocytes, CD40L and IL-4 activated B lymphocytes, NK cells, LAK cells, anti-CD95 CHI 1 treated secondary Thl/Th2/Trl cells, and CD4 lymphocytes. Therefore, small molecule drugs that antagonzie the function of this gene product may reduce or eliminate the symptoms in patients with several types of autoimmune and inflammatory diseases, such as lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, or psoriasis. Panel CNS_1 Summary: Ag4405 This panel confirms the expression ofthe

CGI 09835-01 gene at low levels in the brains of an independent group of individuals. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders. Panel CNS_1.1 Summary: Ag4405 This panel confirms the expression ofthe CGI 09835-01 gene at low levels in the brains of an independent group of individuals. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

BO. CG110114-01 and CG110114-02: Aldose Reductase-Related Protein

Expression of gene CGI 10114-01 and CGI 10114-02 was assessed using the primer- probe set Ag5947, described in Table BOA. Results ofthe RTQ-PCR runs are shown in Table BOB. Please note that CGI 10114-02 represents a full-length physical clone o the CGI 101 14- 01 gene, validating the prediction of the gene sequence.

Table BOA. Probe Name Ag5947

Start SEQ ID

Primers Sequences [Length Position _ . __ N_o ..

Forward [5 ' -caaatgagagaattccttgaa-3 21 920 jTET- 5 ' -tccagtttctgttgaagctgagta- 3 ' -

Probe [TAMRA 24 S85 512

■Reverse ι5 ' -ttgagaacattcaggtcttt- 3 20 831 513

Table BOB. General_screeningjpanel_vl .5

-— - - - — -

Liver ca. HepG2 j [Spinal Cord Pool 0.0

Kidney Pool j 0.0 _lAdrenal Gland 0.0

'Fetal Kidney J 0.0 [Pituitary gland Pool

0.0 [Salivary Gland ^"T 0.0 JRenal ca. 786-0^{" "} f^" ^" o.o JRenaϊ ca. A498 } 79.0 [Thyroid (female) 1 0.0 jPancreatic ca.

Renal ca. ACHN j 0.0 0.0 JCAPAN2 1

JRenai ca. UO-31 ] 0.0 Pancreas Pool . 0.0

CNS_neurodegeneration_vl.O Summary: Ag5947 Expression ofthe CGI 10114-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Summary: Ag5947 Highest expression ofthe CGI 10114-01 gene is detected in lung cancer NCI-H460 cell line (CT=32.6). In addition, moderate levels of expression of this gene is also seen in lung cancer A549 and renal cancer A498 cell lines. Therefore, expression of this gene may be used to distinguish these samples from other samples in this panel and also as diagnostic marker for detection of these cancers. Furthermore, therapeutic modulation of this gene through the use of small molecule drug may be beneficial in the treatment of these cancers. The CG 110114-01 gene codes for a homolog of Aldo-Keto reductase. Aldo-keto reductases (AKRs) are a family of monomeric oxido-reductases with molecular weight ranging from 35-40 kDa and currently includes upwards of 60 members. They are expressed in a wide variety of tissues, where they catalyze the NADPH-dependent reduction of various aliphatic and aromatic aldehydes and ketones. Members of AKR family have been shown to be overexpressed in hepatocellular carcinoma (HCC) and contribute to drug resistance (Scuric et al., 1998, Hepatology 27(4):943-50, PMID: 9537432; Lee et al., 2001, Anticancer Drugs 12(2); 129-32, PMID: 11261885).

Two members of AKR family, aldehyde reductase (AKRIA) and aldose reductase (AKRIB), have been extensively studied, as they have relevance to the complications of diabetes mellitus. AKRIB is up-regulated during hyperglycemia, and at the same time there is an increased activity ofthe sorbitol pathway and non-enzymatic glycation of proteins with ensuing damage in various tissues. Unlike the other AKR family members that are ubiquitously expressed, recently a renal-specific oxio-reductase has been described that is expressed exclusively in the proximal tubules. Although, it has no homology with other AKR members, it binds to NADPH with high affinity and is up-regulated in streptozotocin-induced diabetes in mice. It is also developmentally regulated and seems to selectively modulate renal tubulogenesis during embryonic life (Wallner et al., 2001, Ren Fail 23(3-4):311-20, PMID: 11499547 ). Therefore, AKR protein encoded by this gene may also have a functional relevance with to the complications of diabetes and therapeutic modulation of this gene may be beneficial in the treatment of diabetes.

Panel 4. ID Summary: Ag5947 Expression ofthe CGI 10114-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel 5 Islet Summary: Ag5947 Results from one experiment with the CGI 10114- 01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

BP. CG110123-01: Kinesin Family Member C2 (Kinesin Motor Protein) Expression of gene CGI 10123-01 was assessed using the primer-probe set Ag4409, described in Table BPA. Results ofthe RTQ-PCR runs are shown in Tables BPB, BPC and BPD.

Table BPA. Probe Name Ag4409

.Primers' Sequences [Length [Start Position [SEQ ID No

[Forward '5 ' -accatgtagggtgcagtcttta-3 I 22 j 2795 __ J 514 fProbe TET-5' -ctc ^"c^""ctaacccgtttcccgaaaa-3 ' -TAMRA] 23 [ 2817 | 515 Reverse [5 ' -tctctcatctgtctggaaagga-3 ' 22 ; 2850 i 516

Table BPB. CNS_neurodegeneration_vl.0

Table BPC. General_screening_panel_vl .4

68. Brain (Substantia nigra)

Tung ca. NCI-H522 17.3 48.0 Pool

'^■Liver 0.1 Brain (Thalamus) Pool j 43.2

'Fetal Liver 1.2 Brain (whole) \ 33.9

[Liver ca. HepG2 [ 10.4 Spinal Cord Pool 5.9

.Kidney Pool ] 10.2 Adrenal Gland 1.7 .Fetal Kidney ] 5.6 Pituitary gland Pool 3.9 Renal ca. 786-0 [ 32.3 Salivary Gland 1.1

'Renal ca. A498 7.6 Thyroid (female) 0.9

Pancreatic ca.

_.Renal ca. ACHN 6.4 11.4 CAPAN2

Renal ca. UO-31 10.4 Pancreas Pool | 5.7

Table BPD. Panel 4. ID

HUVEC none | | 6.3 •Kidney 1 100.0

HUVEC starved i 5.3

CNS_neurodegeneration_vl.O Summary: Ag4409 This panel confirms the expression of this gene at low levels in the brain in an independent group of individuals. This gene is found to be down-regulated in the temporal cortex of Alzheimer's disease patients. This gene encodes a homolog of kinesin, a microtubule-based motor protein involved in the transport of organelles, including axonal transport of APP in neurons. (Gunewardena S,

Neuron 2001 Nov 8;32(3):389-401). Kamal et al. suggest that impaired APP transport leads to enhanced axonal generation and deposition of Abeta, resulting in disruption of neurotrophic signaling and neurodegeneration (Nature 2001 Dec 6;414(6864):643-8). Therefore, based on the pattern of expression of this kinesin homolog, up-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia, memory loss, and neuronal death associated with this disease.

General_screening_panel_vl.4 Summary: Ag4409 This gene is ubiquitously expressed in this panel, with highest expression in a breast cancer cell line (CT=28.8). Moderate levels of expression are also seen in all the cancer cell lines on this panel. Thus, expression of this gene could be used as a marker of cancer. Significant levels of expression in cancer cell lines suggest that this gene product, a kinesin homolog, is necessary for cell growth. Members ofthe kinesin family are involved in the assembly and dynamics ofthe mitotic spindle (Blangy A. Cell 1995 Dec 29;83(7):1159-69). Components of he mitotic apparatus are targets for drugs used in cancer therapy. Therefore, based on the homology of this gene to kinesin and its expression in cancer cell lines, therapeutic modulation ofthe expression or function of this gene product may be useful in the treatment of cancer.

In addition, a cluster of prominent expression is detected in all the samples derived from the CNS. A kinesin C. elegans ortholog has been shown to be involved in axonal transport. Furthermore, null mutants present several behavioral defects. (Jamain S. Genomics 2001 May 15;74(l):36-44). Thus, modulation ofthe expression or function of this kinesin may be effective in the treatment of neurological disorders.

Panel 4.1D Summary: Ag4409 Expression of this gene is widespread at low but significant levels in this panel. Highest expression is seen in kidney (CT=31.1). This gene is also expressed in members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening__panel__vl .5 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as astlmia, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

BQ. CG110132-01: Novel MMKIF17 Protein (Kinesin Motor Protein )

Expression of gene CGI 10132-01 was assessed using the primer-probe set Ag4410, described in Table BQA. Results ofthe RTQ-PCR runs are shown in Tables BQB, BQC and BQD.

Table BQA. Probe Name Ag4410

Table BQB. CNS_neurodegeneration_vl .0

Table BQC. General_screening__panel_vl .4

Tiver 0.0 [Brain (Thalamus) Pool ^{30 6}

'Fetal Liver [Brain (whole) n n → JD . I

,Liver ca. HepG2 4.6 [Spinal Cord Pool 1.7 Kidney Pool ^~5 J ^" [Adrenal Gland O. ^" jFetal Kidney ^"Tf [Pituitary gland Pool ^"θ^".9 JRenal ca. 786-0 _T__ [Salivary Gland ^"67ό^" [Renal ca. A498 [Thyroid (female) ^"2.7^{" "} i^{" ~"} Pancreatic ca.

IRenal ca. ACHN 23.2 1.1 CAPAN2

[Renal ca. UO-31 ^~15.0^~ [Pancreas Pool ^"6T

Table BOD. Panel 4. ID

CNS_neurodegeneration_\T.0 Summary: Ag4410 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. General_screening_panel_vl.4 Summary: Ag4410 Expression of this gene appears to be brain specific, with highest expression of this gene in the cerebellum (CT=28.9). Moderate levels of expression are seen throughout the CNS, including hippocampus, cerebral cortex, substantia nigra, thalamus, and amygdala. A kinesin C. elegans ortholog has been shown to be involved in axonal transport. Furthermore, null mutants present several behavioral defects. (Jamain S. Genomics 2001 May 15;74(l):36-44). Thus, modulation ofthe expression or function of this kinesin may be effective in the treatment of neurological disorders.

Prominent levels of expression are also seen in breast and lung cancer cell lines. Members of the kinesin family are involved in the assembly and dynamics ofthe mitotic spindle, a target for drugs used in cancer therapy (Blangy A. Cell 1995 Dec 29;83(7): 1159- 69). Therefore, based on the homology of this gene to kinesin and its expression in cancer cell lines, therapeutic modulation ofthe expression or function of this gene product may be useful in the treatment of breast and lung cancers.

Panel 4.1D Summary: Ag4410 Highest expression of this gene is seen in the kidney (CT=30.1). Thus, expression of this gene could be used to differentiate between the kidney sample and other samples on this panel and as a marker of kidney tissue. The prominent expression in the kidney suggests that this kinesin may play a role in in kidney function including microtubule-based vesicle transport of ion channels and transporters to and from the apical plasma membranes. The putative membrane trafficking activity of this protein may contribute to the specific function ofthe kidney, including maintenance of ion channel and transporter composition in apical membranes. In addition, defects in microtubule-based transport may contribute to diseases ofthe kidney. (Hamm-Alvarez SF, Physiol Rev 1998 Oct;78(4):l 109-29) Therefore, small molecule therapies designed with the protein encoded by this gene could modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis.

BR. CG110160-01 and CG110160-02: novel globin-like protein

Expression of gene CGI 10160-01 and CGI 10160-02 was assessed using the primer- probe set Ag4411, described in Table BRA. Results ofthe RTQ-PCR runs are shown in Tables BRB, BRC and BRD. Please note that CGI 10160-02 represents a full-length physical clone ofthe CGI 10160-01 gene, validating the prediction ofthe gene sequence.

Table BRA. ProDe Name Ag4411 _τ ,, , Start SEQ ID

'Primers Sequences Length¹ _γ, ._... ; ^to ; Position No

'Forward s ' -ccatcctggtgaggttcttt-3 20 191 _520_

, TET-5 ' -aacttcccctcggccaagcagtactt-3 ' -

Probe [TAMRA 26 214 521

.Reverse _'5 ' -gatcctccatgtgcttgaact-3 245 522

Table BRB. CNS_neurodegeneration_vl .0

Control 1 Temporal Control 2 Parietal

9.6 76.8 €tx Gtx

Control 2 Temporal Control 3 Parietal [

50.3 28.: Ctx iCtx [

Control 3 Temporal [Control (Path) 1

25.9 73.2 Ox iParietal Ctx

IControl 4 Temporal Gontrol (Path) 2

21.2 22.5 JCtx jParietal Ctx

Control (Path) 1 jControl (Path) 3 57.8 6.2 _|Temporal Ctx ■Parietal Ctx___ Control (Path) 2 JControl (Path) 4 52.9 50.3 Temporal Ctx 'Parietal Ctx

Table BRC. General_screening_panel_vl .4

Table BRD. Panel 4. ID

_neurodegeneration_\T.O Summary: Ag4411 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag4411 Highest expression of this gene is seen in a brain cancer cell line (CT=24.4). High levels of expression are also seen in cell lines derived from ovarian cancer and melanoma. This protein is homologous to stellate cell activation-associated protein, a novel peroxidase that may play an antifibrotic role in the liver by scavenging peroxides (KawadaN, J Biol Chem 2001 Jul 6;276(27):25318-23). Therefore, expression of this gene could be used to differentiate between these samples and other samples on this panel. Furthermore, modulation of the expression or function of this gene may be useful in the treatment of these cancers.

Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. This gene is also expressed at high levels in the cerebellum and at moderate levels throughout the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, and cerebral cortex. Therefore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy, as well as pathologies that affect the cerebellum, including autism and the ataxias.

Panel 4. ID Summary: Ag441 1 Highest expression of this gene is seen in keratinocytes (CTs=30). Moderate levels are also seen in activated lung fibroblasts, dermal fibroblasts and bronchial epithelium, treated and untreated small airway epithelium and coronary artery SMCs, and normal lung. Thus, expression of this gene could be used to differentiate between keratinocytes and other samples on this panel. Furthermore, the expression of this gene in cells derived from or within the lung and skin suggests that this gene may be involved in normal conditions as well as pathological and inflammatory lung and skin disorders that include chronic obstructive pulmonary disease, asthma, allergy, emphysema, psoriasis and wound healing.

BS. CGI10350-01: PHOTORECEPTOR OUTER SEGMENT ALL- TRANS RETINOL DEHYDROGENASE

Expression of gene CGI 10350-01 was assessed using the primer-probe set Ag5915, described in Table BSA.

Table BSA. Probe Name Ag5915

I TAMRA

Reverse _j5 ' -ccagtgtctcagctgtatcca-3 ' 21 535 525

General_screening_panel_vl.5 Summary: Ag5915 Expression ofthe CGI 10350-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel 5 Islet Summary: Ag5915 Expression ofthe CGI 10350-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

BT. CG59693: Trans-l,2-Dihydrobenzene-l,2-Diol Dehydrogenase

Expression of NOV70 variants CG59693-01 and CG59693-02 were assessed using the primer-probe set Ag3562, described in Table BTA. Results ofthe RTQ-PCR runs for CG59693-02 are shown in Tables BTB, BTC, BTD, BTE, BTF, BTG, BTH and BTI. Results ofthe RTQ-PCR runs for CG59693-01 are shown in Tables BTJ, BTK, BTL and BTM.

Table BTA. Probe Name Ag3562

Table BTB. CNS neurodegeneration vl .O

Table BTC. General_screening_panel_vl .4

____. .„^ . .

Renal ca. UO-31 Pancreas Pool 0.2

Table BTD. General screening_panel_ _vl.6

._ __ ^. iLung ca. SHP-77 [ ^!CNS cancer (glio) SF-295 j 3.4

[Lung ca. A549 [ 100.0 [Brain (Amygdala) Pool j 0.1

Tung ca. NCI-H526 [ 0.0 [Brain (cerebellum) [ 0.2

Tung ca. NCI-H23 J 0.2 JBrain (fetal) | 0.4

JLung ca. NCI-H460 j . ._ 13_.7._ __ _jBrain (Hippocampus) Pool J 0.1

[Lung ca. HOP-62 1 [Cerebral Cortex Pool | 0.1

[Lung ca. NCI-H522 j 0.7 [Brain (Substantia nigra) Pool j 0.1 iver i 0.6 jBrain (Thalamus) Pool 1 0.2

[Fetal Liver j 4.6 iBrain (whole) 1 0.4 iLiver ca. HepG2 [ 1.9 [Spinaϊ Cord^" Pool | 0.4

[Kidney Pool j 0.2 [Adrenal Gland 6.2 [Fetal Kidney j 0.1 Pituitary gland Pool [ 0.0 ' !Renal ca.^"786-0^{~ '"} ^{" "}θ.3 ^{"" " "} [Salivary Gland j 0.1

;Renal ca. A498 i 11.3 [Thyroid (female) j 0.1 [Renal ca. ACHN ^{" "} | ^" 0.2 [Pancreatic ca.^""CAPAN2 ] 0.1

^!Renaϊ ca. UO-31 ! 0.1 [Pancreas Pool | 0.1

Table BTE. HASS Panel vl.O

) Rel. Exp.(%) Ag3562, Rel. Exp.(%) Ag3562, j Tissue Name Tissue Name

1 Run 276044499 Run 276044499

^■MCF-7 Cl 8.5 U87-MG Fl (B) 19.6

[MCF-7 C2 12.0 U87-MG F2 5.2

'MCF-7 C3 15.7 U87-MG F3 15.8

,MCF-7 C4 13.2 U87-MG F4 10.2

[MCF-7 C5 20.2 U87-MG F5 40.3

[MCF-7 C6 10.4 U87-MG F6 92.7

[MCF-7 C7 8.8 U87-MG F7 5.9 jMCF-7 C9 6.9 U87-MG F8 9.1

JMCF-7 C10 10.2 U87-MG F9 1.9

^•MCF-7 Cl l 5.8 U87-MG F10 57.4

[MCF-7 Cl 2 8.7 U87-MG F11 100.0

'MCF-7 Cl 3 7.6 U87-MG F12 30.4

JMCF-7 C15 7^"ό^{"" ""} U87-MG F13 10.2

[MCF-7 CΪ6 13.2 U87-MG F14 16.7

JMCF-7 C17 9.8 U87-MG F15 9.5

[T24 DΪ 32.8 U87-MG F16 66.4 jT24 D2 12.2 U87-MG F17 67.4

T24 D3 26.4 . LnCAP Al 0.2

JT24 D4 48.3 LnCAP A2 0.2

|T24 D5 18.2 LnCAP A3 0.1

|T24 D6 0.2 LnCAP A4 0.1

Table BTF. Oncology_cell_line_screening_panel_v3.1

Table BTG. Panel 2D

Table BTH. Panel 4. ID

HUVEC starved 0.9

Table BTI. Panel 5 Islet

12pljplacenta adenoma

94721 Donor 2 U -

,A Mesenchymal Stem 3.8 72410_Kidney_HRCE [ 1 1.6 Cells

[94722_Donor 2 U - t 1 ]B Mesenchymal Stem 4.3 |72411_Kidney_ HRE [ 1.3 'Cells ι94723_Donor 2 U - [73139_Uterus_Uterine smooth ' jC Mesenchymal Stem 6.0 0.4 [muscle cells [ 'Cells

Table BTJ. General screening panel \ '1.5

Lung ca.(small cell)_LX-l ^"7^".6 ^~ '94919_Small cell carcinoma ofthe lung .1 ^{""" "} o.ϊ

Lung ca.(s.cell var.)_SHP-77

95268_Lung (Large eel¹ carcinoma) i 100

<94920_Small cell carcinoma ofthe lung 1 0

[Lung ca.(non-s.cell)_NCI-H23 0.2

'Lung ca.(large cell)_NCI-H460 1 13.7

Tung ca.(non-s.cell)_HOP-62 | 0

Lung ca.(non-s.cl)_NCI-H522 1 0.7

'103392 Liver [ 0.6

103393 Fetal Liver 1 4.6

Liver ca.(hepatoblast)JHepG2 ! 1.9

113465_Kidney Pool 1 0.2

103373_Fetal Kidney 0.1

■Renal ca. 786-0 1 0.3

,1 12188_renal cell carcinoma I 1 1.3

Renal ca._ACHN ] 0.2

112190_Renal cell carcinoma 1 0.1

Renal ca._TK- 10 1 1.5

[Bladder i i 0.8

Gastric ca. (liver met)__NCI-N87 ^~ r 0.1

1 12197_Stomach 0.3

94938 Colon Adenocarcinoma ! 0.5

.Colon ca._SW480 1 0

Colon ca.(SW480 met)_SW620 ( 0.6

Colon ca. HT29 ] 0.6

•Colon ca._HCT-l 16 ^"1 ^"" 0

Colon ca._CaCo-2 ^{~ " "}2^".4^~

83219_CC Well to Mod Diff (OD03866) 1 0.4

^'94936_Colon Adenocarcinoma ] 0

94930_Colon I 4.7

_|94935_Colon Adenocarcinoma I 0.9

[l l3468_Colon Pool 1 0.1

[113457_Small Intestine Pool ] 0.1

,1 13460_Stomach Pool . ! . _ . . .. 0.1

^'' 113467 Bone Marrow Pool ^"""""7^"" j 103371 JFetal Heart o.i ^"

11345 l_Heart Pool _ 0.1 jl 13466_Lymρh Node Pool 0.1

'103372_Fetal Skeletal Muscle l 13456 Skeletal Muscle Pool ]—.- 0 — . i 0.2 T l3459_Spleen Poo_l [717462 ^" Thvmus Pool 0.1

'CNS ca. (glio/astro)_U87-MG 4.7

[CNs7a. (_g7o/as^"t^"ro7U-l^"i 8-MG

JCNS ca. (neuro;met)_SK-N-AS 17 9.5264_Brain astrocytoma 0.1 |CNS^~caT(as-O) B-77_^{" "}9.5^" jCN^"7ca7_gϊϊo^")^"__s^"NB-77 0.4 jCNS ca.^'(giio SF-29l 3.4 ϊl 13447 JBrain (Amygdala) Pool ^"θ^".ϊ^"

[l 2303^~ Brainfcerebellum #64035- ϊ ^"o^".7

[64019- l_b^"rain(fetal) ^"0.7

[l 13448 JBrain (Hippocampus) Pool o7

[7^"l3464__Cerebraϊ Cortex Pool ^"o.i^"

|l 13449_Brain (Substantia nigra) Pool ^"o.i jiIΪ45 Brain (Thalamus) Pool ^"0.2 j 103384 JBrain (whole) 0.4^"

7l 345Ϊ 7pϊnarCord Pool ^" ^"0.4^"

[103377 Adrenal^" Gland ^" 0.2^" fl Ϊ3454_Pituitary gland Pool ^" ό

[ 103397_Sa_i^"vary Gland^{" " ~ ~ "} ^"oτ

[l03369_Thyroid (female) OT

.Pancreatic ca._CAPAN2 o.i^"

''113453 Pancreas Pool ^"o^"τ

Table BTK. Panel 3D

Rel. Expr., %

3.1x4tm7672f_

Tissue Name ag3562_a2

94905_Daoy_Medulloblastoma/Cerebellum_sscDNA ^"7 ^""""""

94906_TE671_Medulloblastom/Cerebellum_sscDNA 0.2 j94907_D283 Med_Medulloblastoma/Cerebellum_sscDNA 0

94908_PFSK-l_Primitive Neuroectodermal/Cerebellum_sscDNA 0.1

[94909_XF-498_CNS_sscDNA 0

94910_SNB-78_CNS/glioma_sscDNA 0.3

94911_SF-268_CNS/glioblastoma_sscDNA 0

94912_T98G_Glioblastoma_sscDNA 33.1

96776_SK-N-SH_Neuroblastoma (metastasis)_sscDNA 0

94913_SF-295_CNS/glioblastoma_sscDNA 2.3

[94914_Cerebellum_sscDNA 0.4

196777 Cerebellum sscDNA 0.1 .94916JS(CI-H292_Mucoepidermoid lung carcinoma_sscDNA 0.3

94917JDMS-1 14_Small cell lung cancer_sscDNA 0

94918_DMS-79_Small cell lung cancer/neuroendocrine_sscDNA 0

94919_NCI-H146_Small cell lung cancer/neuroendocrine_sscDNA 2.2

[94920_NCI-H526_Small cell lung cancer/neuroendocrine_sscDNA o ^"1

[94921_NCI-N417_Small cell lung cancer/neuroendocrine_sscDNA 0

[94923_NCI-H82_Small cell lung cancer/neuroendocrine_sscDNA 0

94924_NCI-H157_Squamous cell lung cancer (metastasis)_sscDNA ^{" "} 0

94925_NCI-H1155__Large cell lung cancer/neuroendocrine_sscDNA 0

94926_NCI-H1299JLarge cell lung cancer/neuroendocrine_sscDNA ! 0

[94927_NCI-H727_Lung carcinoid_sscDNA 1.2

!94928_NCi-UMC-l 1 JLung carcinoiα_sscDNA 100 ι94929_LX-l_Small cell lung cancer_sscDNA 1.6

;94930_Colo-205_Colon cancer__sscDNA 7.5

,9493 l_KM12_Colon cancer_sscDNA 0.1

^!94932 KM20L2 Colon cancer sscDNA 0.1

94933 NCI-H716 Colon cancer sscDNA 19.2

,94935_SW-48_Colon adenocarcinoma_sscDNA 2.3

94936 SWl l l 6 Colon adenocarcinoma sscDNA 0 _j94937_LS 174T_Colon adenocarcinoma_sscDNA 0.9

[94938_S W-948_Colon adenocarcinoma_sscDNA 0.3

94939_SW-480_Colon adenocarcinoma_sscDNA 0.5

94940 JSfCI-SNU-5_Gastric carcinoma_sscDNA 0

Il 12197J_ATO III_Stomach_sscDNA 0.1

[94943_NCI-SNU-16_Gastric carcinoma_sscDNA 2.7

94944_NCI-SNU-l_Gastric carcinoma_sscDNA 16.8

,94946_RF-l_Gastric adenocarcinoma_sscDNA 0.5

,94947_RF-48_Gastric adenocarcinoma_sscDNA o

:96778_MKN-45_Gastric carcinoma_sscDNA 1.6

^,94949_NCI-N87_Gastric carcinoma_sscDNA 0.8

'9495 l_ VCAR-5_Ovarian carcinoma_sscDNA 0.4

94952_RL95-2_Uterine carcinoma_sscDNA 0.4

•94953 HelaS3 Cervical adenocarcinoma sscDNA 0.9

[94954_Ca Ski_Cervical epidermoid carcinoma (metastasis)_sscDNA 0.3

94955_ES-2_Ovarian clear cell carcinoma_sscDNA ^" o ^"""""

[94957_Ramos/6h stim_ Stimulated with PMA/ionomycin 6h__sscDNA o

[94958_Ramos/14h stim_ Stimulated with PMA/ionomycin ]l4h_sscDNA 0

94962_MEG-01_Chronic myelogenous leukemia ^(megokaryoblast)_sscDNA 0.1

!94963_Raji_Burkitt's lymphoma_sscDNA 0 l94964_Daudi_Burkitt's lymphoma_sscDNA 0 (94965_U266_B-cell plasmacytoma/myeloma_sscDNA 0

|94968_CA46_Burkitt's 1> mphoma_sscDNA ^"o j94970_RL_non-Hodgkin's B-cell lyn phoma_sscDNA 0

;94972_JMl_pre-B-cell lymphoma/leukemia_sscDNA o

[94973 jurkat JT cell ieukemiajsscDNA 0

!94974_TF- 1 _Erythroleukemia__sscDNA 1.6

[94975_HUT 78_T-cell lymphoma_sscDNA 0

[94977_U937_Histiocytic lymphoma_sscDN A 0

[94980_KU-812_Myelogenous leukemia_sscDNA 0.9 ι94981 J769-P_Clear cell renal carcinoma_sscDNA 1

[94983_Caki-2_Clear cell renal carcinoma_sscDNA 63.5 j94984_SW 839_Clear cell renal carcinoma_sscDNA 0.4

[94986_G40 l_Wilms' tumor_sscDNA 0

[94987_Hs766T_Pancreatic carcinoma (LN metastasis)_sscDNA 0.2 j94988_CAPAN-l_Pancreatic adenocarcinoma (liver

^■metastasis) sscDNA 0.3

[94989_SU86.86_Pancreatic carcinoma (liver metastasis)_sscDNA ^" i^"7 ^{" ""}

_94990JBxPC-3 JPancreatic adenocarcinoma_sscDNA 3.6

,9499 l_HPAC_Pancreatic adenocarcinoma_sscDNA 3.1

_|94992_MIA PaCa-2_Pancreatic carcinoma_sscDNA 0

[94993 CFPAC-1 Pancreatic ductal adenocarcinoma sscDNA 3.9

•94994JPANC-1 JPancreatic epithelioid ductal carcinoma_sscDNA 0 j94996_T24__Bladder carcinma (transitional cell)_sscDNA 1.9

[94997_5637_Bladder carcinoma_sscDNA 0.1 ι94998_HT-l 197_Bladder carcinoma_sscDNA 0 _j94999_UM-UC-3_Bladder carcinma (transitional cell)_sscDNA 0.1 j95000__A204_Rlιabdomyosarcoma_sscDNA 0.8

,95001_HT-1080_Fibrosarcoma_sscDNA 0

J95602_MG-63_Osteosarcoma (bone)_ssc ^"NA ^"""7^{"" ""}

J95003_SK-LMS-i_Leiomyosarcoma (vuϊva)_ssc ^"NA 0

95004_SJRH30_Rlιabdomyosarcoma (met to bone marrow)_sscDNA i 0.1

|95005_A431_Epidermoid carcinoma_sscDNA 3.8

|95007_ M266-4_Melanoma_sscDNA 0.1

|112195_DU 145_Prostate_sscDNA 0.1

|95012_MDA-MB-468_Breast adenocarcinoma_sscDNA [ 0.5 jl 12196_SSC-4_Tongue_sscDNA 0.4

[Tl 2194_SSC-9_Tongue_sscDNA 0.2 jl 12191_SSC-15_Tongue_sscDNA 0.3

J95017_CAL 27_Squamous cell carcinoma of tongue_sscDNA 0.1 Table BTL. Panel 4D

Table BTM. Panel Ardias

1

Rel. Expr , %

Tissue Name tm9754fam_ ag3562

[136799 JLung cancer(362) 52.9

T36800_Lung NAT(363) 0.8

₍136813_Lung cancer(372) 100 iΪ36814_Lung NAT(373) 0.4

136815_Lung cancer(374) 1.1 _f136816_Lung NAT(375) 1.6

|136791_Lung cancer(35A) 0.4

[136795_Lung cancer(35E) f 1.6 ^"

;136797_Lung cancer(360) 0.4

^!136794_lung NAT(35D) 1.2

J136818_Lung NAT(377) 0.5

T36787Jung cancer(356) 0.1

|l36788Jung NAT(357) 17

[136806 JLung cancer(36B) 0.1

,136807_Lung NAT(36C) 0.4

136789 ung cancer(358) 0.4

136802_Lung cancer(365) 1.6

136803_Lung cancer(368) 0.5

136804 JLung cancer(369) 1.4

13681 l_Lung cancer(370) 64.2 136810_Lung NAT(36F) 3.9 j

CNS_neurodegeneration_vl.O Summary: Ag3562 This panel confirms the expression ofthe CG59693-02 gene at low levels in the brain in an independent group of individuals. This gene is found to be upregulated in the temporal cortex of Alzheimer's disease patients when analyzed by ANCOVA, (p = 0.002). Therefore, treatment with antagonists or agonists may therefore prevent or slow the progression of Alzheimer's disease.

General_screening_panel_ l.4 Summary: Ag3562 Highest expression ofthe CG59693-02 gene is detected in lung cancer A549 cell line (CT=20.01). High expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Among tissues with metabolic or endocrine function, this gene is expressed at moderate to high levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. In addition, this gene is expressed at high levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. General_screening_panel_vl.ό Summary: Ag3562 Highest expression ofthe

CG59693-02 gene is detected in lung cancer A549 cell line (CT=207). High expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Among tissues with metabolic or endocrine function, this gene is expressed at moderate to high levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. In addition, this gene is expressed at high levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and please see panel 1.4 for a discussion ofthe potential utility of this gene

HASS Panel vl.O Summary: Ag3562. The expression of CG59693-02 gene is not increased by oxygen deprivation, acidic or a serum starved environment in the breast , bladder, pancreatic and prostate cell line in this panel.

However expression is increased in a glioblastoma/ astrocytoma cell line when these cells are subjected to an acidic environment (Maximum expression U87-MG Fl 1; CT=23.96)which suggests that expression may also be upregulated in the acidic regions of brain cancers. Moderate to low expression is also shown in 2 of 5 glioma and 2 of 4 meduUoblastoma tissue samples in this panel. Therapeutic modulation of this gene product using small molecule drugs may be useful in the treatment of brain cancer.

Oncology_cell ine_screening_panel_y3.1 Summary: Ag3562 Highest expression ofthe CG59693-02 gene is detected in lung carcinoid sample (CT=21.7). High to moderate levels of expression of this gene is also seen in number of cancer samples including tongue, breast, prostate, melanoma, bone marrow, bladder, pancreatic, renal, lymphoma, ovarian, cervical, uterine, gastric, lung and brain cancer. Therefore, therapeutic modulation of this gene through the use of small molecule drug may be beneficial in the treatment of these cancers.

Panel 2D Summary: Ag3562 Highest expression ofthe CG59693-02 gene is detected in lung cancer (CT=23.5). High expression of this gene is seen in number of lung cancer samples. Expression of this gene is higher in cancer sample as compared to corresponding adjacent control samples. Therefore, expression of this gene may be used as marker to detect the presence of lung cancer and therapeutic modulation of this gene through the use of small molecule drug may be useful in the treatment of lung cancer.

High to moderate levels of expression of this gene is also seen in number of cancer samples including colon, gastric, ovarian, liver, breast, thyroid, kidney, and prostate cancers. Therefore, therapeutic modulation of this gene through the use of small molecule drug may be beneficial in the treatment of these cancers.

Panel 4. ID Summary: Ag3562 Highest expression ofthe CG59693-02 gene is detected in IL-4 treated dermal fibroblasts (CT=25.2). This gene is expressed at moderate to low levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening__panel_vl.5 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Panel 5 Islet Summary: Ag3562 Highest expression ofthe CG59693-02 gene is detected in islet cells (Bayer patient 1) (CT=25.3). High to moderate levels of expression of this gene is also seen in adipose, skeletal muscle, placenta, uterus, liver, heart, small intestine and kidney. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

BU. CG93541-01, CG93541-03, CG93541-04, CG93541-05 and CG93541- 06: Autotaxin-t (atx-t) Expression of gene CG93541-01, CG93541-03, CG93541-04, CG93541-05, and

CG93541-06 was assessed using the primer-probe set Ag3857, described in Table BUA. Results ofthe RTQ-PCR runs are shown in Tables BUB, BUC, BUD, BUE, BUF and BUG.

Table BUA. Probe Name Ag3857

Table BUB. CNS_neurodegeneration_vl .0

Table BUC. General_screening__panel_vl .5

Table BUD. Panel 2.2

Table BUE. Panel 4. ID

Table BUF. Panel 5 Islet

Table BUG. Panel 5D

CNSjπteurodegeneration vT.O Summary: Ag3857 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag3857 Results from one experiment with this gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screeningjpanel_vl.5 Summary: Ag3857 Highest expression ofthe CG93541-01 gene is seen in spinal cord (CT=25.1). This gene is also expressed at high regions throughout the CNS. Thus, expression of this gene may be used to differentiate between brain derived samples and other samples on this panel and as a marker of brain tissue. This gene is homologous to autotaxin, a gene that is enriched in the spinal cord and brain of rats and may be involved in oligodendrocyte function (Fuss B. J Neurosci 1997 Dec 1;17(23):9095-103). Therefore, the strong association of this gene with the CNS and its homology to autotaxin suggest that therapeutic modulation of this gene or gene product may be useful in the treatment of neurologic disease and specifically demyelinating diseases such as multiple sclerosis.

In addition, this gene is expressed at much higher levels in fetal lung and liver tissue (CTs=26.5-27.5) when compared to expression in the adult counterpart (CTs=31-33). Thus, expression of this gene may be used to differentiate between the fetal and adult sources of these tissues. The relative overexpression of this gene in these fetal tissues also suggests that the protein product may enhance growth or development of these organs in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation ofthe protein encoded by this gene may be useful in the treatment of diseases that affect these organs.

Among metabolic tissues, this gene is highly expressed in pancreas, adrenal, fetal liver, and adipose. It is expressed at moderate levels in pituitary, thyroid, heart and fetal and adult skeletal muscle, with low but significant expression in liver and fetal heart.

Panel 2.2 Summary: Ag3857 Highest expression is seen in kidney cancer (CT=28.2). In addition, this gene is more highly expressed in kidney cancer than in the corresponding normal adjacent tissue. Thus, expression of this gene could be used as a marker of this cancer. Furthemore, therapeutic modulation ofthe expression or function of this gene product may be useful in the treatment of kidney cancer.

Panel 4. ID Summary: Ag3857 Highest expression of this gene is seen in dermal fibroblasts treated with IL-4 (CT=25.3). In addition, high levels of expression are seen in a cluster of samples derived from dermal fibroblasts. Thus, expression of this gene may be used as a marker of this cell. In addition, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of skin disorders, including psoriasis.

Panel 5 Islet Summary: Ag 3857 (Autotaxin-t) is expressed in human islets (CT = 30). Autotaxin has been found to hydrolyze the type I phosphodiesterase substrate p- nitrophenyl thymidine-5'-monophosphate (J Biol Chem 1994 Dec 2;269(48):30479-84) and is a phosphodiesterase (PDE). In CuraGen GeneCalling studies, the rat orthologue (PDE1) was found to be down-regulated in good insulin-secreting versus poor-secreting cell lines. Thus, an antagonist for this autotaxin may improve insulin secretion in Type 2 diabetes. Panel 5D Summary: Ag 3857 Highest expression of this gene is seen in adipose (CT=287). Moderate levels of expression are seen in other metabolic tissues on this panel, including skeletal muscle. Overall, these results are in agreement with the results in Panel 51. Please see that panel for further discussion of utility of this gene in metabolic disease.

BV. CG93541-02: Autotaxin-Iike

Expression of gene CG93541-02 was assessed using the primer-probe set Ag6912, described in Table BVA. Results ofthe RTQ-PCR runs are shown in Table BVB.

Table BVA. Probe Name Ag6912 _τ .. i Start [SEQ ID

Primers ι Sequences Length i „ ._.. i -r ^& I Position No

[Forward |5 ' -gtggatggcttccgaaagac-3 ' 20 560 532

'_p ι [TET-5 ' -cagctacccagaaatcctgacactcaagacatacct- 'ODe j₃ , __TAMRA 586 ijj

_'Reverse ι5 ' -cagaaagttaaatctcgctctcatatg-3 ' 27 627 534

Table BVB. General_screening_panel_vl .6

General_screening_panel__vl.6 Summary: Ag6912 Highest expression ofthe CG93541-02 gene is seen in the spinal cord (CT=30.3). In addition, moderate to low levels of expression are seen in the amygdala, cerebellum, cerebral cortex, thalamas, substantia nigra and whole brain. This gene encodes a protein that is homologous to autotaxin. A variant of autotaxin has been found to be enriched in the brain and spinal cord, with expression seen in oligodendrocytes. Expression of this autotaxin is highest in the adult. (Fuss, B. J Neurosci 1997 Dec 1 ;17(23):9095-103). Based on the homology of this gene to autotaxin and the expression profile in this panel, expression of this gene may be used as a marker of neuronal tissue. In addition, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Among metabolic tissues, this gene is expressed at low but significant levels in adipose, fetal liver, heart, adrenal and pituitary. This expression suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

Moderate levels of expression are also seen in a cluster of samples derived from melanoma cell lines. Thus, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of melanoma.

BW. CG95872-02: AURORA-RELATED KINASE 2

Expression of gene CG95872-02 was assessed using the primer-probe set Ag6958, described in Table BWA. Results ofthe RTQ-PCR runs are shown in Table BWB.

Table BWA. Probe Name Ag6958

General screening panel vl.ό Summary: Ag6958 Highest expression ofthe

CG95872-02 gene is seen in a colon cancer cell line (CT=257). Overall, expression of this gene appears to be associated with cancer cell lines, with high to moderate levels of expression in all the cell lines on this panel. In addition, moderate levels of expression are seen in all the fetal tissues on this panel, while expression in the corresponding adult tissue is low/undetectable. This gene encodes a protein that has homology to aurora kinases, which have been implicated in chromosome segregation and cytokinesis. Members of this family have been shown to be expressed in cells with a high mitotic index, including fetal liver and cancer cell lines. (Bischoff J. R. Trends in Cell Biology 1999, 9:454-459). In addition, members ofthe aurora kinase family have been shown to bind the SH3 domain of RasGAP, which is involved in the regulation of cell proliferation and has an anti-apoptotic effect. (Gigoux V. J Biol Chem 2002 Apr 25). Based on the homology of this gene to aurora kinase and the predominant expression in proliferating tissues, expression of this gene could be used as a marker of cancer. Furthermore, therapeutic modulation ofthe expression or function of this protein may be effective in the treatment of cancer.

Example D. Identification of Single Nucleotide Polymorphisms (SNPs) in NOVX nucleic acid sequences Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration ofthe amino acid encoded by the gene at the position ofthe SNP. Intragenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result ofthe redundancy ofthe genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation ofthe expression pattern. Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message. SeqCalling assemblies produced by the exon linking process were selected and extended using the following criteria. Genomic clones having regions with 98% identity to all or part ofthe initial or extended sequence were identified by BLASTN searches using the relevant sequence to query human genomic databases. The genomic clones that resulted were selected for further analysis because this identity indicates that these clones contain the genomic locus for these SeqCalling assemblies. These sequences were analyzed for putative coding regions as well as for similarity to the known DNA and protein sequences. Programs used for these analyses include Grail, Genscan, BLAST, HMMER, FASTA, Hybrid and other relevant programs. Some additional genomic regions may have also been identified because selected SeqCalling assemblies map to those regions. Such SeqCalling sequences may have overlapped with regions defined by homology or exon prediction. They may also be included because the location ofthe fragment was in the vicinity of genomic regions identified by similarity or exon prediction that had been included in the original predicted sequence. The sequence so identified was manually assembled and then may have been extended using one or more additional sequences taken from CuraGen Corporation's human SeqCalling database. SeqCalling fragments suitable for inclusion were identified by the CuraTools™ program SeqExtend or by identifying SeqCalling fragments mapping to the appropriate regions ofthe genomic clones analyzed.

The regions defined by the procedures described above were then manually integrated and corrected for apparent inconsistencies that may have arisen, for example, from miscalled bases in the original fragments or from discrepancies between predicted exon junctions, EST locations and regions of sequence similarity, to derive the final sequence disclosed herein. When necessary, the process to identify and analyze SeqCalling assemblies and genomic clones was reiterated to derive the full length sequence (Alderborn et al., Determination of Single Nucleotide Polymorphisms by Real-time Pyrophosphate DNA Sequencing. Genome Research. 10 (8) 1249-1265, 2000).

Variants are reported individually but any combination of all or a select subset of variants are also included as contemplated NOVX embodiments ofthe invention.

RESULTS:

NOV2a SNP Data Sixteen polymorphic variants of NOV2a have been identified and are shown in

Table 2S.

NOV3a SNP Data

Two ol moi hic variants of NOV3a have been identified and are shown in Table 3S.

NOV8a SNP Data

One polymorphic variant of NOV8a has been identified and is shown in Table 8S.

NOVlla SNP Data

One polymorphic variant of NOVl la has been identified and is shown in Table 11 S.

NOV15a SNP Data Five polymoiphic variants of NOVl 5a have been identified and are shown in Table 15S.

NOVlόa SNP Data

One polymorphic variant of NOVl 6a has been identified and is shown in Table 16S.

NOVl 7a SNP Data

Eighteen polymorphic variants of NOV 17a have been identified and are shown in

Table 17S.

NOV20a SNP Data

Fifteen polymorphic variants of NOV20a have been identified and are shown in

Table 20S.

NOV21 SNP Data

Seven polymorphic variants of NOV21a have been identified and are shown in

Table 2 IS.

NOV23a SNP Data

One polymorphic variant of NOV23a has been identified and is shown in Table 23S.

NOV25a SNP Data

One polymorphic variant of NOV25a has been identified and is shown in Table 25S.

NOV26a SNP Data Two polymoφhic variants of NOV26a have been identified and are shown in

Table 26S.

NOV27a SNP Data One polymoiphic variant of NOV27a has been identified and is shown in Table 27S.

NOV30a SNP Data

One polymorphic variant of NOV30a has been identified and is shown in Table 3 OS.

NOV31a SNP Data

Five polymorphic variants of NOV31a have been identified and are shown in

Table 3 OS.

NOV38a SNP Data

Nine polymoiphic variants of NO V38a have been identified and are shown in

Table 38S.

NOV39a SNP Data

Four polymoiphic variants of NOV39a have been identified and are shown in

Table 39S.

NOV40a SNP Data

One polymoiphic variant of NOV40a has been identified and is shown in Table 40S.

NOV42a SNP Data

One polymoφhic variant of NOV42a has been identified and is shown in Table 42S.

NOV46a SNP Data

Five polymoφhic variants of NOV46a have been identified and are shown in

Table 46S. ^' •

NOV50a SNP Data

One polymoiphic variant of NOV50a has been identified and is shown in Table 50S.

NOV51a SNP Data

One polymorphic variant of NOV51a has been identified and is shown in Table 51 S.

NOV57a SNP Data

One polymoiphic variant of NOV57a has been identified and is shown in Table 57S.

NOVόόa SNP Data

Seven polymoφhic variants of NOVόόa have been identified and are shown in

Table 66S.

NOV70a SNP Data

Four polymorphic variants of NOV70a have been identified and are shown in Table 70S.

NOV71a SNP Data

Five polymorphic variants of NO V7 la have been identified and are shown in

Table 7 IS.

Example E. NOV45 - Method of Use

The present invention is partially based on the identification of biological macromolecules differentially modulated in a pathologic state, disease, or an abnormal condition or state, and/or based on novel associations of proteins and polypeptides and the nucleic acids that encode them, as identified in a yeast 2-hybrid screen using a cDNA library or one-by-one matrix reactions. Among the pathologies or diseases of present interest include metabolic diseases including those related to endocrinologic disorders, cancers, various tumors and neoplasias, inflammatory disorders, central nervous system disorders, and similar abnormal conditions or states. Important metabolic disorders with which the biological macromolecules are associated include obesity and diabetes mellitus, especially obesity and Type II diabetes. It is believed that obesity predisposes a subject to Type II diabetes. In very significant embodiments ofthe present invention, the biological macromolecules implicated in these pathologies and conditions are proteins and polypeptides, and in such cases the present invention is related as well to the nucleic acids that encode them. Methods that may be. employed to identify relevant biological macromolecules include any procedures that detect differential expression of nucleic acids encoding proteins and polypeptides associated with the disorder, as well as procedures that detect the respective proteins and polypeptides themselves. Significant methods that have been employed by the present inventors, include GeneCalling ® technology and SeqCalling TM technology, disclosed respectively, in U. S. Patent No. 5,871,697, and in U. S. Ser. No. 09/417,386, filed Oct. 13, 1999, each of which is incoφorated herein by reference in its entirety. GeneCalling^® is also described in Shimkets, et al, Nature Biotechnology 17:198-803 (1999).

The invention provides polypeptides and nucleotides encoded thereby that have been identified as having novel associations with a disease or pathology, or an abnormal state or condition, in a mammal. Included in the invention are nucleic acid sequences and their encoded polypeptides. The sequences are collectively referred to as "obesity and/or diabetes nucleic acids" or "obesity and/or diabetes polynucleotides" and the corresponding encoded polypeptide is referred to as an "obesity and/or diabetes polypeptide" or "obesity and/or diabetes protein". For example, an obesity and/or diabetes nucleic acid according to the invention is a nucleic acid including an obesity and/or diabetes nucleic acid, and an obesity and/or diabetes polypeptide according to the invention is a polypeptide that includes the amino acid sequence of an obesity and/or diabetes polypeptide. Unless indicated otherwise, "obesity and/or diabetes" is meant to refer to any ofthe sequences having novel associations disclosed herein. The present invention identifies a set of proteins and polypeptides, including naturally occurring polypeptides, precursor forms or proproteins, or mature forms ofthe polypeptides or proteins, which are implicated as targets for therapeutic agents in the treatment of various diseases, pathologies, abnormal states and conditions. A target may be employed in any of a variety of screening methodologies in order to identify candidate therapeutic agents which interact with the target and in so doing exert a desired or favorable effect. The candidate therapeutic agent is identified by screening a large collection of substances or compounds in an important embodiment ofthe invention. Such a collection may comprise a combinatorial library of substances or compounds in which, in at least one subset of substances or compounds, the individual members are related to each other by simple structural variations based on a particular canonical or basic chemical structure. The variations may include, by way of nonlimiting example, changes in length or identity of a basic framework of bonded atoms; changes in number, composition and disposition of ringed structures, bridge structures, alicyclic rings, and aromatic rings; and changes in pendent or substituents atoms or groups that are bonded at particular positions to the basic framework of bonded atoms or to the ringed structures, the bridge structures, the alicyclic structures, or the aromatic structures.

The present invention discloses novel associations of proteins and polypeptides and the nucleic acids that encode them, as identified in a yeast 2-hybrid screen using a cDNA library or one -by-one matrix reactions. The proteins and related proteins that are similar to them are encoded by a cDNA and/or by genomic DNA and were identified in some cases by CuraGen Corporation.

In the current invention, protein interactions may include the interaction of a protein fragment with full-length protein, a protein fragment with another protein fragment, or full- length proteins with each other. The protein interactions disclosed in the present invention may also represent significant discoveries of functional importance to specific diseases or pathological conditions in which novel proteins are found to be components of known pathways, known proteins are found to be components of novel pathways, or novel proteins are found to be components of novel pathways.

A polypeptide or protein described herein, and that serves as a target in the screening procedure, includes the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, e.g., the full-length gene product, encoded by the corresponding gene. The naturally occurring polypeptide also includes the polypeptide, precursor or proprotein encoded by an open reading frame described herein. A "mature" form of a polypeptide or protein arises as a result of one or more naturally occurring processing steps as they may occur within the cell, including a host cell. The processing steps occur as the gene product arises, e.g., via cleavage ofthe amino-terminal methionine residue encoded by the initiation codon of an open reading frame, or the proteolytic cleavage of a signal peptide or leader sequence. Thus, a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N- terminal methionine, would have residues 2 tlirough N remaining. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an amino-terminal signal sequence from residue 1 to residue M is cleaved, includes the residues from residue M+l to residue N remaining. A "mature" form of a polypeptide or protein may also arise from non-proteolytic post-translational modification. Such non-proteolytic processes include, e.g., glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or the combination of any of them.

As used herein, "identical" residues correspond to those residues in a comparison between two sequences where the equivalent nucleotide base or amino acid residue in an alignment of two sequences is the same residue. Residues are alternatively described as "similar" or "positive" when the comparisons between two sequences in an alignment show that residues in an equivalent position in a comparison are either the same amino acid or a conserved amino acid as defined below. As used herein, a "chemical composition" relates to a composition including at least one compound that is either synthesized or extracted from a natural source. A chemical compound may be the product of a defined synthetic procedure. Such a synthesized compound is understood herein to have defined properties in terms of molecular formula, molecular structure relating the association of bonded atoms to each other, physical properties such as electropherographic or spectroscopic characterizations, and the like. A compound extracted from a natural source is advantageously analyzed by chemical and physical methods in order to provide a representation of its defined properties, including its molecular formula, molecular structure relating the association of bonded atoms to each other, physical properties such as electropherographic or spectroscopic characterizations, and the like. As used herein, a "candidate therapeutic agent" is a chemical compound that includes at least one substance shown to bind to a target biopolymer. In important embodiments ofthe invention, the target biopolymer is a protein or polypeptide, a nucleic acid, a polysaccharide or proteoglycan, or a lipid such as a complex lipid. The method of identifying compounds that bind to the target effectively eliminates compounds with little or no binding affinity, thereby increasing the potential that the identified chemical compound may have beneficial therapeutic applications. In cases where the "candidate therapeutic agent" is a mixture of more than one chemical compound, subsequent screening procedures may be carried out to identify the particular substance in the mixture that is the binding compound, and that is to be identified as a candidate therapeutic agent.

As used herein, a "pharmaceutical agent" is provided by screening a candidate therapeutic agent using models for a disease state or pathology in order to identify a candidate exerting a desired or beneficial therapeutic effect with relation to the disease or pathology. Such a candidate that successfully provides such an effect is termed a pharmaceutical agent herein. Nonlimiting examples of model systems that may be used in such screens include particular cell lines, cultured cells, tissue preparations, whole tissues, organ preparations, intact organs, and nonhuman mammals. Screens employing at least one system, and preferably more than one system, may be employed in order to identify a pharmaceutical agent. Any pharmaceutical agent so identified may be pursued in further investigation using human subjects.

The following sections describe the study design(s) and the techniques used to identify the four repeat ion channel-encoded NOV45 protein, and any variants thereof, and to demonstrate its suitability as diagnostic markers, targets for an antibody therapeutic and targets for a small molecule drugs for Obesity and Diabetes. Four repeat ion channel CG105597-01

The four repeat ion channel is a novel calcium channel expressed exclusively during adipocyte differentiation and in the brain.

Pharmacological interference with the storage of fat has been recognized as a powerful approach to anti-obesity treatment. Peroxisome proliferator activated receptor gamma (PPARγ) is a nuclear hormone receptor that has been shown to be sufficient and necessary for the development of new adipocytes. Activation of PPARγ leads to a decrease in circulating free fatty acids (FFA) and improved insulin sensitivity in the periphery. Various PPARγ ligands, all of them thiazolidinediones, are on the market for the treatment of type II diabetes. However, these compounds are not effective against obesity and, on the contrary, might promote weight gain. Inhibitors ofthe PPARγ pathway can be considered for the treatment of obesity because they are expected to inhibit the recruitment of new adipocytes.

Intracellular calcium [Ca²⁺]ι has been implicated in regulating adipogenesis. Increasing [Ca²⁺]j exerts a biphasic regulatory role in human adipocyte differentiation, serving to inhibit the early stages of differentiation, while promoting the late stages of differentiation and lipid filling. Increasing [Ca ⁺]j has been shown to result in marked increase in the expression of PPARγ. Increased expression of PPARγ may subsequently accelerate adipocyte differentiation by directly acting upon and eliciting late differentiation gene expression, such as aP2, steroyl- CoA desaturase (SCD-1), phosphoeπolpyruvate carboxykinase (PEPCK), and FAS. On the other hand, in late differentiation, preadipocytes become more committed to terminal differentiation after the expression of several critical differentiation transcriptional factors, such as CCAAT/enhancer binding protein beta and delta (C/EBPβ and C/EBPΔ), PPARγ, and sterol regulatory element binding protein- 1 /adipocyte determination and differentiation factor- 1 (SREBP-l/ADD-1). [Ca²⁺]j may synergize with these transcriptional factors to promote the differentiation program by stimulating late differentiation gene expression. Consistent with this, [Ca²⁺]-, acts as a lipogenic and antilipolytic signaling factor in regulating adipocyte metabolism in both rodent and human adipocytes. Increasing [Ca^~ ]_. has been shown to stimulate the expression and activity of FAS, a key enzyme in de novo lipogenesis and thereby to promote triglycei'ide storage. In addition, increasing [Ca²⁺]i has been shown to inhibit basal and agonist-stimulated lipolysis in primary cultured human adipocytes. These effects can be completely blocked by calcium channel antagonism. Therefore, increasing [Ca^" ]. appears to promote triglycei'ide accumulation in adipocytes by exerting a coordinated control over lipogenesis and lipolysis, serving to simultaneously stimulate the former and suppress the latter, thereby resulting in lipid filling and adipocyte hypertrophy. Accordingly, the lipogenic and anti-lipolytic effects of [Ca²⁺]i, coupled with increased expression of a differentiation transcriptional factor such as PPARγ, may contribute to the stimulatory effect of [Ca²⁺]j in the late stages of differentiation. Thus, decrease in intracellular calcium in the late stages of adipocyte differentiation by antagonisms ofthe four repeat ion channel may be beneficial in the treatment of obesity. See generally, Rosen et al. 2002 Genes Dev 16(l):22-26; Ren et al., 2002 Genes Dev 116(1): 27-32; Lazar 2002 Genes Dev. 16(l):l-5; Shi et al, 2000 Physiol Genomics 3(2)75-82; Spiegelman and Flier 1996 Cell 87: 377-389.

NOV45 expression and clustering analysis

CG105597-01 (also referred to as NOV45) was identified based on its up-regulation during adipocyte differentiation in quantitative expression analysis of clones in various cells and tissues. CGI 05597-01 was upregulated 3-5 fold in mid-way differentiated adipocytes when compared to non-differentiated mesenchymal cells. The expression of CGI 05597-01 was lower in fully differentiated adipocytes. In clustering analysis, CG105597-01 showed a similar expression profile to PPARγ, suggesting that CGI 05597-01 and PPARγ may function in the same pathway regulating adipocyte differentiation.

Clustering analysis was performed by comparing the metabolic panel 51 expression profile of all CuraGen RTQ-PCR probes with the expression profile of CG105597-01 probe Ag4292. Results are shown in Table El.

Table El . Query: CGI 05597-01

²

CGI 05597-01 expression profile is very similar to that of PPARγ, suggesting that CGI 05597-01 may function in the PPARγ pathway in regulating adipocyte differentiation.

Cellular pathways

In one embodiment, the four repeat ion channel protein NOV45 is involved in adipocyte differentiation. Pharmacololgical interference with the storage of fat has been recognized as a powerful approach to anti-obesity treatment. Peroxisome proliferator activated receptor gamma (PPARγ) is a nuclear hormone receptor that has been shown to be sufficient and necessary for the development of new adipocytes. Activation of PPARγ leads to a decrease in circulating free fatty acids (FFA) and improved insulin sensitivity in the periphery. Various PPARγ ligands, all of them thiazolidinediones, are on the market for the treatment of type II diabetes. However, these compounds are not effective against obesity and, on the contrary, might promote weight gain. Inhibitors ofthe PPARγ pathway can be considered for the treatment of obesity because they are expected to inhibit the recruitment of new adipocytes. Intracellular calcium [Ca ]_. has been implicated in regulating adipogenesis. Increasing [Ca²⁺]j exerts a biphasic regulatory role in human adipocyte differentiation, serving to inhibit the early stages of differentiation, while promoting the late stages of differentiation and lipid filling. Pathways relevant to the etiology and pathogenesis of obesity and/or diabetes.

The following illustration suggests how alterations in expression ofthe human NOV45 four repeat ion channel gene and associated gene products function in the etiology and pathogenesis of obesity and/or diabetes. The scheme incoφorates the unique findings of these discovery studies in conjunction with what has been reported in the literature. The outcome of inhibiting the action ofthe human four repeat ion channel would be inhibition of de novo adipocyte differentiation and formation of new adipocytes, phenomenon contributing to increase in body mass and obesity. The adipogenesis pathway is shown in Table E2.

Table E2. Cellular pathway for Adipogenesis.

Mesenchymal stem cell

pre-adipocyte

pre-adipocyte Inhibitor for

Adip 1ogenesis

Adipocyte

Rationale for use as a diagnostic and/or target for small molecule drugs and antibody therapeutics.

The following is a summary ofthe findings from the discovery studies, supplementary investigations and assays that also incorporates knowledge in the scientific literature. Taken in total, the data indicates that an inhibitor/antagonist ofthe human four repeat ion channel is likely beneficial in the treatment of obesity and/or diabetes.

The four repeat ion channel is upregulated during adipocyte differentiation. The expression profile ofthe four repeat ion channel closely resembles that of PPARγ. PPARγ is sufficient and necessary for adipogenesis. The four repeat ion channel may act downstream of PPARγ in promoting adipogenesis. Inhibition ofthe four repeat ion channel may result in delayed adipocyte differentiation, inhibition of de novo adipocyte synthesis and reduction of body mass. Therefore, antagonist to the novel four repeat ion channel is also likely beneficial in the treatment of obesity.

Antibodies

The invention further encompasses antibodies and antibody fragments, such as Fab, (Fab)₂ or single chain Fv constructs, that bind immunospecifically to any ofthe proteins ofthe invention. Also encompassed within the invention are peptides and polypeptides comprising sequences having high binding affinity for any ofthe proteins ofthe invention, including such peptides and polypeptides that are fused to any carrier particle (or biologically expressed on the surface of a carrier) such as a bacteriophage particle.

Uses of the Compositions of the Invention

The protein similarity information, expression pattern, cellular localization, protein interaction complexes and map location for the protein and nucleic acid disclosed herein suggest that this protein may have important structural and/or physiological functions characteristic of the four repeat ion channel family. Therefore, the nucleic acids and proteins ofthe invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed. These also include potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), (v) an agent promoting tissue regeneration in vitro and in vivo, and (vi) a biological defense weapon.

The nucleic acids and proteins ofthe invention have applications in the diagnosis and/or treatment of various diseases and disorders. For example, the compositions ofthe present invention will have efficacy for the treatment of patients suffering from Obesity and/or Diabetes. These materials are further useful in the generation of antibodies that bind immunospecifically to the substances ofthe invention for use in diagnostic and/or therapeutic methods. Example F. NOV70 Utility in Tumorgenesis

SAGE analysis, cellular and in vivo validation assays, knockdown cell validation, was performed, as disclosed below.

Potential Role(_.) of CG59693-01 in Tumorgenesis: There is a subset of lung tumors, especially non-small cell lung tumors, associated with a marked worse outcome. This phenotype is strongly associated with the ability of these tumors to acquired resistance to the chemotherapy. As shown above, this gene is overexpressed in that subset of lung tumors (see TaqMan data and Hsu et al Cancer Res 2001 Mar 15;61(6):2727-31). The antisense data shows that decreasing the activity of this enzyme reduce the level of drug resistance. This reduction should correlate with an improve clinical outcome.

Impact of therapeutic targeting of CG59693-01: Therapeutic targeting ofthe enzymatic activity ofthe protein encoded by CG59693-01 with a small molecule inhibitor is anticipated to reduce or abolish the extent of resistance to chemotherapy in lung cancers, especially non-small cell lung tumors. Serial Analysis of Gene Expression of CG59693-01 in various cells and tissues.

Serial Analysis of Gene Expression (SAGE) uses a SAGE tag, a short polynucleotide sequence, generally under about 20 nucleotides, that occurs in a certain position in messenger RNA. The SAGE tag can be used to identify the corresponding transcript and gene from which it was transcribed. SAGE analysis begins with providing complementary deoxyribonucleic acid (cDNA) from tumor cell-line derived libraries. cDNAs can be linked to primer sites. Sequence tags are then created, for example, using the appropriate primers to amplify the DNA. By measuring the differences in these tags between the cDNA libraries, sequences which are aberrantly expressed in the tumor cell lines can be identified. SAGE was performed on a CG59693-01 nucleic acid, as shown in Table Fl.

Table Fl. SAGE data

H? 201967 : aldo-keto reductase family 1, member C2 (dihydrodiol dehydrosεnase 2 bile acid binding protein; 3-aIpha hydro_ysteroid delr drogenasej type HTJ

SAGE library data and reliable tae summsT.

Reliable tags found in SAGE libraries:

ΛGGTCTGCCA Tagsper Tag

Library name million counts Total tags

SAGE Duke 1273 51 2 38836

S GE Duke BB542 normal

17 1 58662 ceiebellum

SAGE Caco 2 32 2 61601

SAGE Chen LNCaP 32 2 62267

SAGE Chen Tumor Pr 29 2 683S4

SAGE CAP AN1 26 1 37926

SAGE CAPAH2 26 1 38240

SAGE HS766T 31 1 31506

SAGE Duke H392 104 6 57529

SAGE cooled GEM 16 1 61841

SAGE BB542 white nafter 10 1 94806

SAGE _IHA(5th. 19 1 52196

SAGE normal .■ o .j. lh) 15 1 63064

SAGE HCI 19 1 50115

SAGE Duke irJih-l 593 «•»^• 29 43488

SAGE lacZ 107 2 18528

SAGE TEN 106 1 9380

SAGE 35-347 29 2 67240

SAGE 95-348 16 1 60484

SAGE Disk. H341 22 1 44563

SAGE M.usePS PGCP 16 1 61240

SAGE Duke Kidney 169 ^{■ '} 7 41413

SAGE pastric cancer-G234 15 1 65291

SAGE normal luns 11 1 88901

SAGE normal _ artπc body

40 1 24972 epithelial

SAGE normal liver 405 •">» 27 66588

SAGE normal heart 47 4 84072

SAGE Duke H VEC 152 ^• •- 8 52532

SAGE Duke m_VEC+V_.GF 155 ^> - 0 57928

SAGE marn nar v epithelium 305 «■» 15 49167

SAGE Duke 7.7 205 ^■•^•■ - 4 19503

SAGE normal cerebellum 19 1 51135

SAGE Duke 4 ON 280 ** 2 7142

SAGE Duke 4_W 165 • 2 12091

SAGE Duke H1043 13 1 76673

G .TGGACCCG Tagsper Tag

Library name imllion counts Total tags

SAGE Chen LNCaP no-DHT 15 1 64631

SAGE Duke Kidney 24 1 41413

SAGE Duke HMVEC+VEGF 17 1 57928

SAGE Er N 26 1 37558

EST analysis data:

Positive signals were obtained in fetal liver/spleen; liver; gall bladder; infant brain; colon; pancreatic islets; brain; fetal lung; fetal heart.

Suggested cellular and in vivo validation assays

CG59693-01 was further analyzed in the following assays. Two cellular assays were performed to test for chemo sensitivity. In the first was, knockdown of CG59693-01 expression was assayed in NCI-H460 (positive cell line). In the second, CG59693-01 was stably transfected into NCI-H460 and NCI-N417 (null cell line) and assayed. Further data was obtained in an in vivo assay utilizing a drug resistance animal model. Knock-in cell lines were NCI-H1299, NCI-H157 and NCI-N417. Knock-out cell lines were NCI-H460.

Knockdown cell validation:

All oligonucleotides were mixed-backbone oligonucleotides containing modified phosphorothioate segments at 5' and 3' ends and 2'-O-methyl RNA oligoribonucleotide segments located in the middle. The oligonucleotides were synthesized by Midland, Inc. All oligonucleotides were desalted and gel purified. The purity ofthe oligonucleotides was confirmed by mass spectrometry.

Untransfected, scramble oligonucleotide transfected NCI-H460 cells and CG59693-01 antisense oligonucleotide transfected NCI-H460 cells were treated with Paclitaxel for 48h. Cellular viability was determined as ratio of absorbance of drug treated to untreated cells.

Knockdown assays for CG 59693-01 showed little effect on cell growth in NCI-H460 cells after 48 hr. See also, e.g., Hsu et al, Cancer Res 2001 Mar 15;61(6):2727-31 ; Matsuura et al, Biochem J 1991 Apr 1;323 ( Pt l):61-4; Deng et al., JBiol Chem 2002 Feb 12; (electronic publication ahead of print); Miyabe Y et al, Yakiigaku Zasshi 1997 Mar; 117(3): 167-77

Table F2. NOV70e Knockdown assay

Knockdown of CG59693-01 has little effect on cell growth NCI-H460, 48 hr

AS1 AΞ2 AS3 \S1-5 SC LC UC Table F3. NOV70e Knockdown assay - 48 hr Paclitaxel treatment

Table F4. NOV70e Knockdown assay - Cell Viability

Knockdown of CG59693-€1 sensitizes

Paclitaxel - IQn , NCI-B460, 8 hr

Table F5. NOV70e Knockdown assay - 72 hr Paclitaxel treatment

Knockdown of CG59693-01 sensitizes CI-H460 cells to Paclitaxel (72 hr)

Q untreated

□ aclitaxel 10n. .

AS1 AΞ2 AS3 AS4 AS5 AS ti S k S C LC UC

Table Fό. NOV70e Knockdown assay - Cell Viability

Knockdown of CG59693-01 sensitizes NCUH460 cells to Paclitaxel

Paclitaxel - 10r_M, HCI-H460, 72 hr

OTHER EMBODIMENTS

Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope ofthe appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope ofthe invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the embodiments described herein. Other aspects, advantages, and modifications considered to be within the scope ofthe following claims. The claims presented are representative ofthe inventions disclosed herein. Other, unclaimed inventions are also contemplated. Applicants reserve the right to pursue such inventions in later claims.

Claims

What is claimed is:

1. An isolated polypeptide comprising the mature form of an amino acid sequenced selected from the group consisting of SEQ ID NO:2n and SEQ ID NO:539, wherein n is an integer between 1 and 129.

2. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2n and SEQ ID NO:539, wherein n is an integer between

1 and 129.

3. An isolated polypeptide comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:2n and SEQ ID NO:239, wherein n is an integer between 1 and 129.

4. An isolated polypeptide, wherein the polypeptide comprises an amino acid sequence comprising one or more conservative substitutions in the amino acid sequence selected from the group consisting of SEQ ID NO:2n and SEQ ID NO:539, wherein n is an integer between 1 and 129.

5. The polypeptide of claim 1 wherein said polypeptide is naturally occurring.

6. A composition comprising the polypeptide ofclaim 1 and a carrier.

7. A kit comprising, in one or more containers, the composition of claim 6.

8. The use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1 , wherein the therapeutic comprises the polypeptide of claim 1.

9. A method for deteπriining the presence or amount ofthe polypeptide of claim 1 in a sample, the method comprising:

(a) providing said sample; (b) introducing said sample to an antibody that binds immunospecifically to the polypeptide; and

(c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.

10. A method for determining the presence of or predisposition to a disease associated with altered levels of expression ofthe polypeptide of claim 1 in a first mammalian subject, the method comprising: a) measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and b) comparing the expression of said polypeptide in the sample of step (a) to the expression ofthe polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease, wherein an alteration in the level of expression of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.

11. A method of identifying an agent that binds to the polypeptide of claim 1 , the method comprising:

(a) introducing said polypeptide to said agent; and

(b) determining whether said agent binds to said polypeptide.

12. The method of claim 11 wherein the agent is a cellular receptor or a downstream effector.

13. A method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions ofthe polypeptide of claim 1, the method comprising:

(a) providing a cell expressing the polypeptide of claim 1 and having a property or function ascribable to the polypeptide;

(b) contacting the cell with a composition comprising a candidate substance; and

(c) determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition in the absence of the substance, the substance is identified as a potential therapeutic agent.

14. A method for screening for a modulator of activity of or of latency or predisposition to a pathology associated with the polypeptide of claim 1, said method comprising:

(a) administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of claim 1, wherein said test animal recombinantly expresses the polypeptide ofclaim 1;

(b) measuring the activity of said polypeptide in said test animal after administering the compound of step (a); and

(c) comparing the activity of said polypeptide in said test animal with the activity of said polypeptide in a control animal not administered said polypeptide, wherein a change in the activity of said polypeptide in said test animal relative to said control animal indicates the test compound is a modulator activity of or latency or predisposition to, a pathology associated with the polypeptide of claim 1.

15. The method of claim 14, wherein said test animal is a recombinant test animal that expresses a test protein transgene or expresses said transgene under the control of a promoter at an increased level relative to a wild-type test animal, and wherein said promoter is not the native gene promoter of said transgene.

16. A method for modulating the activity ofthe polypeptide of claim 1, the method comprising contacting a cell sample expressing the polypeptide of claim 1 with a compound that binds to said polypeptide in an amount, sufficient to modulate the activity ofthe polypeptide.

17. A method of treating or preventing a pathology associated with the polypeptide of claim 1, the method comprising administering the polypeptide of claim 1 to a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject.

18. The method of claim 17, wherein the subj ect is a human.

19. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n and SEQ ID NO:539, wherein n is an integer between 1 and 129 or a biologically active fragment thereof.

20. An isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129.

21. The nucleic acid molecule of claim 20, wherein the nucleic acid molecule is naturally

22. A nucleic acid molecule, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129.

23. An isolated nucleic acid molecule encoding the mature form of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:2n and SEQ ID NO:539, wherein n is an integer between 1 and 129.

24. An isolated nucleic acid molecule comprising a nucleic acid selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129.

25. The nucleic acid molecule ofclaim 20, wherein said nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129, or a complement of said nucleotide sequence.

26. A vector comprising the nucleic acid molecule of claim 20.

27. The vector of claim 26, further comprising a promoter operably linked to said nucleic acid molecule.

28. A cell comprising the vector of claim 26.

29. An antibody that immunospecifically binds to the polypeptide of claim 1.

30. The antibody of claim 29, wherein the antibody is a monoclonal antibody.

31. The antibody of claim 29, wherein the antibody is a humanized antibody.

32. A method for determining the presence or amount ofthe nucleic acid molecule of claim 20 in a sample, the method comprising:

(a) providing said sample;

(b) introducing said sample to a probe that binds to said nucleic acid molecule; and

(c) determining the presence or amount of said probe bound to said nucleic acid molecule, thereby determining the presence or amount ofthe nucleic acid molecule in said sample.

33. The method of claim 32 wherein presence or amount ofthe nucleic acid molecule is used as a marker for cell or tissue type.

34. The method of claim 33 wherein the cell or tissue type is cancerous.

35. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the nucleic acid molecule of claim 20 in a first mammalian subject, the method comprising: a) measuring the level of expression ofthe nucleic acid in a sample from the first mammalian subject; and b) comparing the level of expression of said nucleic acid in the sample of step (a) to the level of expression ofthe nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of expression ofthe nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

36. A method of producing the polypeptide ofclaim 1 , the method comprising culturing a cell under conditions that lead to expression ofthe polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129.

37. The method of claim 36 wherein the cell is a bacterial cell.

38. The method of claim 36 wherein the cell is an insect cell.

39. The method ofclaim 36 wherein the cell is a yeast cell.

40. The method of claim 36 wherein the cell is a mammalian cell.

41. A method of producing the polypeptide ofclaim 2, the method comprising culturing a cell under conditions that lead to expression ofthe polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 2n-l and SEQ ID NO:538, wherein n is an integer between 1 and 129.

42. The method of claim 41 wherein the cell is a bacterial cell.

43. The method ofclaim 41 wherein the cell is an insect cell.

44. The method of claim 41 wherein the cell is a yeast cell.

45. The method ofclaim 41 wherein the cell is a mammalian cell.