WO2011027219A1

WO2011027219A1 - High throughput detection of small genomic deletions and insertions

Info

Publication number: WO2011027219A1
Application number: PCT/IB2010/002354
Authority: WO
Inventors: Marianne Stef; Diego Tejedor; Antonio Martinez; Laureano Simon
Original assignee: Progenika Biopharma, S.A.
Priority date: 2009-09-04
Filing date: 2010-09-03
Publication date: 2011-03-10

Abstract

The invention provides novel methods of making and designing nucleic acid probe libraries for accurate, reliable and specific detection and characterization of small nucleotide insertions or deletions (indels) or SNPs in any target nucleic acid sample. The invention further provides a probe library made by the methods and solid phase substrates coated with such probe libraries. The probe libraries of the invention allow detection of indels in a target nucleic acid segment also called a genetic variant segment. The invention further provides methods of using the probe library to detect the presence of indels in the test nucleic acid sample.

Description

HIGH THROUGHPUT DETECTION OF SMALL GENOMIC DELETIONS AND INSERTIONS

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit under 35 U.S.C. § 119(e) of the U.S. provisional application No. 61/239,872 filed September 4, 2009, the contents of which are expressly incorporated herein by reference in its entirety.

BACKGROUND OF INVENTION

[0002] The so-called "DNA-chips", also named "micro-arrays", "DNA-arrays" or "DNA bio- chips", and collections of beads with attached nucleic acids, are systems that functional genomics uses for large scale studies. One can also tailor these systems for specific mutation detection or detection of several mutations at the same time and thus for the use in functional genomics which studies the changes in the expression of genes due to environmental factors and to genetic characteristics of an individual.

[0003] Gene sequences present small inter-individual variations at one unique nucleotide called an SNP ("single nucleotide polymorphism"), which in a small percentage are involved in changes in the expression and/or function of genes that cause certain pathologies. The majority of studies which apply DNA-chips study gene expression, although chips are also used in the detection of SNPs. Other genetic variations such as differences in nucleotide repeat sequences are also involved in phenotypic variations. For example, aberrant numbers of trinucleotide repeats causes Huntington's disease, several ataxias, and fragile X syndrome. Large deletions and insertions are associated with multi-gene disorders, such as Down's syndrome.

[0004] The first DNA-chip was the "Southern blot" where labeled nucleic acid molecules were used to examine nucleic acid molecules attached to a solid support. The support was typically a nylon membrane.

[0005] Two breakthroughs marked the definitive beginning of DNA-chip. The use of a solid non-porous support, such as glass, enabled miniaturization of arrays thereby allowing a large number of individual probe features to be incorporated onto the surface of the support at a density of > 1,000 probes per cm². The adaptation of semiconductor photolithographic techniques enabled the production of DNA- chips containing more than 400,000 different oligonucleotides in a region of approximately 20 μπι², so- called high density DNA-chips.

[0006] For genetic expression studies, probes deposited on the solid surface, e.g. glass, are hybridized to cDNAs synthesized from mRNAs extracted from a given sample. In general the cDNA has been labeled with a fluorophore. The larger the number of cDNA molecules joined to their

complementary sequence in the DNA-chip, the greater the intensity of the fluorescent signal detected, typically measured with a laser. This measure is therefore a reflection of the number of mRNA molecules in the analyzed sample and consequently, a reflection of the level of expression of each gene represented in the DNA-chip. [0007] In the nucleic acid beads, a bead set is typically coats with a number of nucleic acid probes that are labeled such that different probes can be "seen" using visualization or capture of the beads after hybridization to a target nucleic acid.

[0008] Gene expression DNA-chips typically also contain probes for detection of expression of control genes, often referred to as "house-keeping genes", which allow experimental results to be standardized and multiple experiments to be compared in a quantitive manner. With the DNA-chip, the levels of expression of hundreds or thousands of genes in one cell can be determined in one single experiment. The cDNA of a test sample and that of a control sample can be labeled with two different fluorophores so that the same DNA-chip can be used to study differences in gene expression. DNA-chips for detection of genetic polymorphisms, changes or mutations (in general, genetic variations) in the DNA sequence, comprise a solid surface, typically glass, on which a high number of genetic sequences are deposited (the probes), complementary to the genetic variations to be studied. Using standard robotic printers to apply probes to the array a high density of individual probe features can be obtained, for example probe densities of 600 features per cm.sup.2 or more can be typically achieved. The positioning of probes on an array is precisely controlled by the printing device (robot, inkjet printer,

photolithographic mask etc) and probes are aligned in a grid. The organization of probes on the array facilitates the subsequent identification of specific probe -target interactions. Additionally it is common, but not necessary to divide the array features into smaller sectors, also grid-shaped, that are subsequently referred to as sub-arrays. Sub-arrays typically comprise 32 individual probe features although lower (e.g. 16) or higher (e.g. 64 or more) features can comprise each sub-array.

[0009] One strategy used to detect genetic variations involves hybridization to sequences which specifically recognize the normal and the mutant allele in a fragment of DNA derived from a test sample. Typically, the fragment has been amplified, e.g. by using the polymerase chain reaction (PCR), and labeled e.g. with a fluorescent molecule. A laser can be used to detect bound labeled fragments on the chip and thus an individual who is homozygous for the normal allele can be specifically distinguished from heterozygous individuals (in the case of autosomal dominant conditions then these individuals are referred to as carriers) or those who are homozygous for the mutant allele.

[0010] Another strategy to detect genetic variations comprises carrying out an amplification reaction or extension reaction on the DNA-chip itself.

[0011] For differential hybridization based methods there are a number of methods for analyzing hybridization data for genotyping. For example, one can analyze an increase in hybridization level, wherein the hybridization level of complementary probes to the normal and mutant alleles are compared. One can also analyze a decrease in hybridization level, wherein differences in the sequence between a control sample and a test sample can be identified by a fall in the hybridization level of the totally complementary oligonucleotides with a reference sequence. A complete loss is produced in mutant homozygous individuals while there is only 50% loss in heterozygotes. In DNA-chips for examining all the bases of a sequence of "n" nucleotides ("oligonucleotide") of length in both strands, a minimum of "2n" oligonucleotides that overlap with the previous oligonucleotide in all the sequence except in the nucleotide are necessary. Typically the size of the oligonucleotides is about 25 nucleotides. The increased number of oligonucleotides used to reconstruct the sequence reduces errors derived from fluctuation of the hybridization level. However, the exact change in sequence cannot be identified with this method; sequencing is later necessary in order to identify the mutation.

[0012] Where amplification or extension is carried out on the DNA-chip itself, three methods are presented by way of example:

[0013] In the mini-sequencing strategy, a mutation specific primer is fixed on the slide and after an extension reaction with fluorescent dideoxynucleotides, the image of the DNA-chip is captured with a scanner.

[0014] In the primer extension strategy, two oligonucleotides are designed for detection of the wild type and mutant sequences respectively. The extension reaction is subsequently carried out with one fluorescently labeled nucleotide and the remaining nucleotides unlabelled. In either case the starting material can be either an RNA sample or a DNA product amplified by PCR.

[0015] In the Tag arrays strategy, an extension reaction is carried out in solution with specific primers, which carry a determined 5' sequence or "tag". The use of DNA-chips with oligonucleotides complementary to these sequences or "tags" allows the capture of the resultant products of the extension. Examples of this include the high density DNA-chip "Flex-flex" (Affymetrix).

[0016] For genetic diagnosis, simplicity as well as accuracy must be taken into account. The need for amplification and purification reactions presents disadvantages for the on-chip

extension/amplification methods compared to the differential hybridization based methods.

[0017] Small duplications, insertions and deletions are genetic variations that are quite difficult to automatically detect in resequencing assays because they are not automatically identified by the software analyzing the data. Small duplications, insertions and deletions that are generally less than or equal tolO nucleotides are called indels. Only known indels can be detected because specific probes can be designed for their detection. In addition, novel indels are difficult to predict. In many diseases, indels represent from 10 to 40% of point mutations, and not detecting them can dramatically lead to the underestimation of the mutation rate and also the perceived mutation detection rate.

[0018] Alternative genotyping strategies for the detection of substitutions based mutations have been described, for example, in the International Patent application W095/11995, but genotyping strategies for the detection of indels are lacking in general.

SUMMARY OF THE INVENTION

[0019] The present invention provides methods for the designing and using probe sets that allow detection of single nucleotide polymorphisms, small deletions and insertions of a small number of nucleotides referred to herein as "indels". The methods are based on a novel design system that allows rapid detection and characterization of the indels in any selected nucleic acid sequence. [0020] Accordingly, in one embodiment, the invention provides a method of designing a library of probes for detecting at least one indel variation in a genetic variant segment, the method comprising the steps of (a) selecting a nucleic acid variant segment of N nucleotides long, wherein N can be any length between 25 and 5000; (b) selecting N number of probe sets each designed to hybridize to one of the N number of nucleotides in the nucleic acid variant segment; and (c) selecting at least one probe subset for the probe set, wherein the probe subset comprises at least two different probes forming a pair of probes, one designed to specifically hybridize to a normal/wild-type or a control sequence and one designed to specifically hybridize to a sequence with the at least one indel variation.

[0021] In some embodiments, the method further comprises a step of manufacturing the probe sets selected/designing through steps (a), (b) and (c).

[0022] In some embodiments, the method further comprises performing at least one of the steps

(a), (b), or (c) with a computer. Such computer implemented system can be performed by setting forth an algorithm with the novel selection rules set forth in the method and allowing a computer to automatically select the probes using input parameters for the desired length of the probe, the type of an indel, the desired target variant sequence and so forth.

[0023] In some embodiments, the method further comprises a step of attaching the probe on a solid surface.

[0024] In some embodiments, the at least one pair of probes consist of a normal/control probe and a variant probe, both of which interrogate the about same region on the genetic variant segment, wherein the both probes forming the probe sub-set have the same sequence length and are of the same type of nucleic acids.

[0025] In some embodiments, the normal (N) or control (C) probe comprises the normal sequence (which is the wild type sequence) or a known SNP polymorphism (which is the control sequence) of genetic variant segment and the variant probe comprises an indel-containing variant sequence of genetic variant segment

[0026] In some embodiments, the at least two different probes has the difference between them located in position -4, -3, -2, -1, 0, +1, +2, +3 or +4 position of the probe, wherein the position 0 is the center nucleotide of the probe when the probe has an odd number of nucleotides; and wherein the position -1 and +1 are the two central nucleotides of the probe when the probe has an even number of nucleotides.

[0027] In other embodiments where the probes are longer than 25 nt, e. g. 40 or 50 nt long, or

25-50 bp, the position of the indel variation can be between -25 and +25 position (inclusive) from the center of the probe, e. g. -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9,-8, - 7, -6, -5, -4, -3, -2, -1, 0, +1, +2, +3, +4, +5, +6, +7, +8, +9, +10, +11, +12, +13, +14, +15, +16, +17, +18, +20, +21, +22, +23, +24 or +25.

[0028] In some embodiments the probes are DNA, RNA or PNA. Pairs of probes that are of the same type of nucleic acid means that the probe members constituting the pair of probes are all DNA, RNA or PNA. The probe members constituting the pair of probes cannot be a mixture of one probe that is a DNA and the other probe is a RNA, a mixture of one probes that is a RNA and the other probe is a PNA, or a mixture of one probes that is a DNA and the other probe is a PNA. This ensures that the differences in the intensity are due to the presence of an indel and not due to the differences in binding affinity of the types of nucleic acid.

[0029] In some embodiments the indel variation is a deletion, an insertion or a duplication of nucleotide. The deletion, insertion or duplication can be 1-10, 1-20, 1-30, 1-40 or 1-50 nucleotides long. In some embodiments, the indel is 1-10 nucleotides long.

[0030] In other embodiments, the deletion can be up to 50 nt, e. g. 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 nt.

[0031] In other embodiments, the insertion can be up to 50 nt, e. g. 11, 12, 13, 14, 15, 16, 17,

18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 nt.

[0032] In other embodiments, the duplication can be up to 50 nt, e. g. 11, 12, 13, 14, 15, 16, 17,

[0033] In some embodiments the deletion is selected from a group consisting of one, two, three, four, five, six, seven, eight, nine, and ten nucleotides. In some embodiments, deletion of 1-10, 1-15, 1-

20, 1-50 nucleotides can be detected.

[0034] In some embodiments the insertion is selected from a group consisting of one, two, three, four, five, six, seven, eight, nine, and ten nucleotides.

[0035] In some embodiments the duplication is selected from a group consisting of one, two, three, four, five, six, seven, eight, nine, and ten nucleotides. In some embodiments, insertion of 1-10, 1- 15, 1-20, 1-50 nucleotides can be detected.

[0036] In some embodiments the probes of the at least one probe sub-set is complementary to the sense strand of the genetic variant segment.

[0037] In some embodiments probes of the at least one probe sub-set is complementary to the anti-sense strand of the genetic variant segment.

[0038] In some embodiments only one kind of indel is detected, the method comprising a step of selecting one set of probe sets and as many probe sets as the length or number of nt (or base pairs) in the variant segment under interrogation, wherein each probe set comprises a single probe sub-set, wherein each probe sub-set comprises at least a pair of probes consisting of one control (C) or normal (N) /wild type probe and one variation probe (V).

[0039] In some embodiments at least two types of indels are designed to be detected, the method comprising the step of designing each probe set to comprise at least two probe sub-sets, wherein each probe sub-set comprises at least one pair of probes, wherein each pair of probes consists of one control or normal or control probe and one variation probe, wherein the probes of each pair of probes making up the probe sub-set differ from each other in terms of length, indel variation location inside the probe and strand of interrogation of the variant segment.

[0040] In some embodiments more than two types of indels are designed to be detected, further comprising a step of designing as many probe sub-sets as there are indels that need to be detected, and wherein each pair of probes within a probe sub-set is designed to differ from each other in terms of length, interrogating position inside the probe and strand of interrogation of the variant segment.

[0041] The invention also provides a library of probes prepared by the methods described above.

[0042] In some embodiments, the probes are selected from the probes set forth in Table 1, SEQ

ID NOS: 1-4575, and consist of or consist essentially of the probes set forth in Table 1, SEQ ID NOS: 1- 4575.

[0043] In some embodiments the probes consist of, or consist essentially of SEQ ID NOS: 1-

4575.

[0044] The invention also provides for methods of using or use of the library of probes designed/selected according to any one of methods described above. One can use the libraries to identify the location and the type of an indel in any target nucleic acid sequence, such as a genetic variant segment.

[0045] The invention also provides a DNA-chip comprising the library of probes set forth above and use of the DNA chips, and well as a collection of microbeads comprising the library of probes and uses thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1A shows a pair of probes consisting of a control or normal/wild type probe and a variation probe (SEQ ID NOS: 4607 and 4608, respectively in the order of appearance); the pair of probes is used to investigate an indel located at nucleotide 16 which is the nucleotide of interest in a genetic variant segment. The indel here is a deletion of one base (G in position 16, illustrated in box) (Dell).

[0047] Figure IB shows a pair of probes consisting of a control or normal/wild type probe and a variation probe (SEQ ID NOS: 4609 and 4610, respectively in the order of appearance); the pair of probes is used to investigate an indel consisting of a deletion of four nucleotides located at nucleotide 16 which is the nucleotide of interest in a genetic variant segment. The indel here is a deletion of the nucleotide 16 as well as the three nucleotides adjacent in 3' (boxed) (Del4).

[0048] Figure 2 shows the possible differences in various pairs of probes making up a indel probe sub-set: differences in probe length, 21 and 25 nucleotides long; differences in strand interrogated by the probes, the sense or anti-sense strand; and differences in the position of the indel location within the probes such as at the 11 nucleotide (0 position) in a 21 nucleotide long probe or at the 13 nucleotide (0 position) in a 25 nucleotide long probe.

[0049] Figure 3 shows different pairs of probes making up a probe sub-set and a different probe sub-set make up a probe set (SEQ ID NOS: 4611-4615, 4612, 4616, 4614, 4617-4621, 4618, 4622, 4620 and 4623, respectively in the order of appearance).

[0050] Figure 4A shows an embodiment of a library of probes on a solid support for detecting a single indel. The library has N probe sets for interrogating a variant segment having a length of N basepair long, and each probe set comprises of one probe sub-set which comprises a pair of probes consisting of one control or normal/wild type probe (C) and one variation probe (V).

[0051] Figure 4B shows an embodiment of a library of probes on a solid support for detecting a single indel. The library has N probe sets for interrogating a variant segment having a length of N basepair long, and each probe set comprises of one probe sub-set which comprises several pair of probes, each of which consists of one control or normal/wild type probe (C) and one variation probe (V).

[0052] Figure 4C shows an embodiment of a library of probes on a solid support for detecting four distinct indels. The library has N probe sets for interrogating a variant segment having a length of N basepair long, and each probe set comprises of four probe sub-sets, one probe sub-set for each distinct indel, each probe sub-set comprises 32 pair of probes, each of which consists of one control or normal/wild type probe (C) and one variation probe (V).

[0053] Figure 5 shows one embodiment of the indel detection and analysis method.

[0054] Figure 6 shows one embodiment of the indel detection and analysis method.

[0055] Figure 7 shows one embodiment of the indel detection and analysis method.

[0056] Figure 8 illustrates three probes having 25, 23 and 20 nucleotide bases respectively showing the -3, -2, -1, 0 , +1, +2, +3 positions of the indel within the probes.

[0057] Figure 9 shows a schematic presentation of an embodiment of replicate probe features of the pair of probes comprising the probe sub-sets on a flat solid support.

[0058] Figure 10 shows is a block diagram showing an exemplary system for detecting an indel type of genetic variation.

[0059] Figure 11 shows an exemplary set of instructions on a computer readable storage medium for use with the systems described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0060] The present invention relates to an in vitro method of detecting genetic variations in an individual, specifically variations (e.g. duplications, insertions or deletions or loss of a small number of nucleotides collectively referred to as "indels") in a sequence segment in the genome. The inventors have developed a sensitive, specific and reproducible computer implemented method for simultaneously detecting and characterizing indel variations in a genome. The method does not require prior knowledge of any indel in the segment. Therefore, novel indels can be discovered by the method described herein. The inventors also developed methods for designing oligonucleotide probe sets for carrying out the method of detecting indel variations. Using the uniquely designed probe sets and analysis methods described herein, one can analyze any indels in a genome. The method is also useful for the development of products for commercial, fast and reliable genotyping methods to detect known indels. Such products, such as kits, can be used for, e.g., diagnostic and prognostic purposes and for the purposes of identifying individuals susceptible for, e.g., side effects associated with known indels or drug responsive individuals, wherein the drug response is associated with a known indel. In a preferred embodiment, the method is the detection of mutations responsible of the illness Hypercholesterolemia Familiar. The method is achieved with the use of a specially designed library of probes together with a computation algorithm for analysis of the data obtained from the library of probes.

[0061] Broadly, the invention provides methods and products for determining the presence of insertions or deletions of a small number of nucleotides (indels) in a genetic segment of interest, also named genetic variant segment, such as an exon, an intron or a promoter, in the target nucleic acid (NA) sample. The inventors showed that by using a specifically designed library of probes in hybridization experiments with a target NA sample to be genotyped, any indels harbored within a target NA sample can be detected with accuracy. Further, in the event that the indels are unknown, the type of indels found in the target NA sample can also be characterized. Because the method, in combination with the specially designed library of probes, facilitates simultaneous detection and characterization of the indels in a genetic variant segment, embodiments of the invention can therefore provide considerable efficiency in terms of savings in time and cost when compared to other methods of detecting and characterizing indels, for example, full NA sequencing of the genetic variant segment.

[0062] The method is unique in that it is based on a combination of (1) use of a solid support based array, such as NA-chips/microbeads genotyping strategy with some distinct modifications in the probe selection and array design, and (2) a sequential computation system (algorithm) amenable for electronically processing and interpreting the data generated by the genotyping strategy (based on a selection of the probes to be included in the computation of the genotype). This combination of genotyping strategy and a sequential computation system guarantees high level of specificity, sensitivity and reproducibility of results. This method is versatile because any solid support, such as, chips or microbeads that are coated with the selected unique probes can be used, for example, in clinical genetic diagnosis. The method is versatile for processing and interpreting of the data and it can be performed manually or by using a computer that is programmed to carry out the algorithm.

[0063] One specific advantage of the method is the availability of a library of probes for every nucleotide position of any genetic segment of interest. It is not necessary to have prior knowledge of the indels, for example, whether the indel variation is a deletion or an insertion, or the number of nucleotides (nt) deleted or inserted. The library of probes is specially designed to contain all probes that will detect all possible permutations of indels in a genetic variant segment. The genetic variant segment can be e.g., having a length of N nt, wherein N can be, for example, 100-2000 or 50-5000 nt long. In some embodiments shorter than 50, such as 10-15, 25-50 nucleic acid fragments can be analyzed.

Alternatively, one can also analyze fragments that are larger, such as about 50 or 100 to 2000, to 3000, to

4000, to 5000, to 6000, to 7000, to 8000, to 9000 or up to about 10,000 nucleotides long.

[0064] Another specific advantage is the fact that direct identification of indel changes can be achieved, while previously used methods only detect the possible presence of an indel, without actually identifying the exact genetic change (i.e. the identity of the sequence variation).

Definitions

[0065] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected here. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired in the art to which it pertains. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. 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.

[0066] The term "nucleic acid (NA)" refers to deoxyribonucleotides (DNA) or ribonucleotides

(RNA) and polymers thereof ("polynucleotides") in either single- or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Where the NA is a double stranded, the term "base pairs" (bp) are used to refer to the building block bases. Where the NA is a single stranded such as an oligonucleotide probe, the term "nucleotides" (nt) are used to refer to the building block bases.

[0067] As used herein, the term "peptide-nucleic acid" or "PNA" refers to any synthetic nucleic acid analog (deoxyribonucleic acid (DNA) mimics with a pseudopeptide backbone) which can hybridize to form double-stranded structures with DNA in a similar fashion as naturally occurring nucleic acids. PNA is an extremely good structural mimic of DNA (or of ribonucleic acid (RNA)), and PNA oligomers are able to form very stable duplex structures with Watson-Crick complementary DNA and RNA (or PNA) oligomers, and they can also bind to targets in duplex DNA by helix invasion. Other type of complementary base pairing, such as the Hoogsteen pairing is possible too. PNA may be an oligomer, linked polymer or chimeric oligomer. Methods for the chemical synthesis and assembly of PNAs are well known in the art and are described in U. S. Patents Nos: 5,539,082, 5,527,675, 5,623,049, 5,714,331, 5,736,336, 5,773,571, and 5,786,571. Uses of the PNA technology are also well known in the art; see U. S. patents Nos. 6,265,166, 6,596,486, and 6,949,343. These references are hereby incorporated by reference in their entirety.

[0068] As used herein, the phrase "same type of nucleic acid" with regards to the probes constituting a pair of probes(also referred to as member probes), refers to the member probes being all DNA, all RNA, or all PNA, and there is no mixture of RNA, DNA and/or PNA in a pair of probes. For this context of the make-up or composition of probes, the term "nucleic acid" also include PNA.

[0069] As used herein, the term "complementary base pair" refers to A:T and G:C in DNA and

A:U in RNA. Most DNA consists of sequences of nucleotide only four nitrogenous bases: base or base adenine (A), thymine (T), guanine (G), and cytosine (C) or pseudocytosine (J). The pairing is based on the Watson-Crick pairing or the Hoogsteen pairing. Together these bases form the genetic alphabet, and long ordered sequences of them contain, in coded form, much of the information present in genes. Most RNA also consists of sequences of only four bases. However, in RNA, thymine is replaced by uridine (U).

[0070] As used herein, the term "indels" refers to small duplications, deletions and/or insertions which involve anywhere between one to ten nucleotides (nt) and in other embodiments, the indels are duplications, deletions and/or insertions involving up to 50 nt. In one embodiment, the indel is a one nt deletion indel. In another embodiment, the indel is a two nt deletion indel. In other embodiments, the indel is a three nt deletion indel, a four nt deletion indel, a five nt deletion indel, a six nt deletion indel, a seven nt deletion indel, an eight nt deletion indel, a nine nt deletion indel, or a ten nt deletion indel. In other embodiments, the indel is a one nt insertion indel, a two nt insertion indel, a three nt insertion indel, a four nt insertion indel, a five nt insertion indel, a six nt insertion indel, a seven nt insertion indel, an eight nt insertion indel, a nine nt insertion indel, or a ten nt insertion indel. In the embodiments where the indels are up to 50 nt, the duplication, deletion or insertion can be up to 50 nt, e. g. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 nt. The term "indel" and "indel variation" are used interchangeably.

[0071] As used herein, the phrase "genetic variant segment" refers to a segment or region of nucleic acid (NA) wherein there may be or are commonly known sequence variations within a population of an animal species, including humans. Such allelic variations may be silent or causal, or disease or disease-risk causing mutations. In some embodiments, a "genetic variant segment" refers to or included a NA segment or NA region where there is a likelihood of sequence variations within a population of an animal species, e.g., a region prone to spontaneous mutations, a region of known genetic instability, and/or a region associated with a disease or disorder that is known to be linked to mutations in the gene. The NA can be DNA or RNA. The NA is typically a genomic DNA, but in some embodiments it can also be a primary transcript or fragments thereof or a messenger RNA or fragments thereof. In some embodiments, the sequence variation or genetic variant present in the "genetic variant segment" is an indel.

[0072] As used herein, the phrase "genetic non-variant segment" or "non-variant segment" refers to a segment or region of nucleic acid (NA) wherein the sequence is constant within a population of animal species, meaning that it is know that there is no allelic variation in the population in this region. While the "genetic non-variant segments" or "non-variant segment" do not have allelic variations among individuals in a population, they can have known mutations that result in very obvious and distinct phenotypes. Two normal individuals who are of the same gender and do not exhibit any of the obvious and distinct phenotypes (e.g. Down syndrome) that are associated with known mutations at these "genetic non-variant segments" would have identical "genetic non-variant segments". "Genetic non-variant segments" function as the reference/control segments in the present invention in the analysis of indels. Mutations in non-variant segments can be selected from known disease -causing regions, such the DSCR1 locus on chromosome 21, the PLP locus and F9 locus on chromosome X, or any other region, which results in an unmistakable phenotype, wherein an absence of a phenotype, such as a Down syndrome, indicates that this region does not have variations in the subject, such as a human individual or an animal, whose nucleic acid is to be analyzed or in the sample from an individual or an animal whose sample is used as a control. A skilled artisan can easily select these regions based on these criteria and common knowledge of genetic diseases. The "genetic non-variant segments" can be DNA or RNA. The NA can be genomic DNA, a primary transcript or fragments thereof or a messenger RNA or fragments thereof.

[0073] In one embodiment, the non-variant segment selected for analysis of human samples is derived from the human chromosome 21. In another embodiment, the non-variant segment is derived from the Down Syndrome Critical Region 1 (DSCR1) on chromosome 21. The gene DSCR1 is also called RCAN1 for Regulator of Calcineurin 1. DSCR1/RCAN1 is located at position 21q22.1-q22.2; chromosome 21 : 34,810,654-34,909,252 (SEQ ID NO: 4576) with respect to human genome assembly 18 March 2006 (GENBANK™ accession number for its mRNA: NM_004414.5, SEQ ID NO: 4577). It is involved in the development of the phenotype of the Down syndrome. Indeed a deletion of one copy this gene is lethal whereas the presence of an extra copy of this gene, i.e. a duplication of this gene, is responsible of the Down syndrome phenotype, which is easily recognizable. This gene, part of this gene or the region of the chromosome 21 wherein this gene is located can be used as the non- variant segment for the normalization in human samples in the presently claimed methods.

[0074] As used herein, the term "known genotype" when used in reference to control data of the genetic variant segment means that the type of indels, the number of nt involved, and the position or location, the bases or nt sequence(s) of the indel in the genetic variant segment are known, for example, one nt insertion at position K is the genetic variant in the segment. In some embodiments, the term "known genotype" when used in reference to control data means a SNP that is known, for example, it can be either a T nucleotide or a C nucleotide. In some embodiments, "known genotype" when used in reference to normal or wild type genotype data of the genetic variant segment which is the normal genotype in the population, meaning no indels at all in the genetic variant segment and the wild-type sequences are known.

[0075] As used herein, the term "a test nucleic acid (tNA)" refers to a nucleic acid (NA) sequence wherein the indels within the sequence is unknown. In some embodiments, the term "a test nucleic acid (tNA)" refers to a NA sequence wherein the indel within the sequence is of interest to the investigator and the tNA therefore is being studied, regardless of whether the indel is known or not. For example, the investigator would like to verify that the indicated indel in the tNA is accurate and valid. A "test nucleic acid (tNA) sample" refers to a NA sample comprising at least one tNA.

[0076] As used herein, the term "a control nucleic acid (cNA)" refers to a nucleic acid (NA) sequence wherein the indel within the sequence is known. In one embodiment, a cNA is a NA sequence that is normal/wild type and has no known indel within the sequence. In another embodiment, a cNA is a NA sequence that has a SNP that is known, for example, it can be either a T or a C, within the control sequence. A control NA can be used in parallel with a tNA in the methods described herein for the detection and analysis of the indel in the tNA. A "control nucleic acid (cNA)" sample refers to a NA sample comprising at least one cNA.

[0077] As used herein, the term "target nucleic acids (target NAs)" refers to the nucleic acids that are to be hybridized to the probes immobilized on solid support(s) described herein. Target NAs can comprise both the control nucleic acid and the test nucleic acid. In some embodiments, target NAs can be detectably labeled or fragmented to smaller segments of nucleic acid sequences.

[0078] As used herein, the term "probe" refers to a short sequence of NA, typically consisting between 15nt-50nt, including all of the whole integers between 15-50, wherein the short sequence is complementary to a small portion of a genetic variant segment or complementary to a small portion of a non-variant segment (the control segment) that is under interrogation such that the probe can hybridize to the segment by complementary base pairing. For example, one can use probes that are 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 nucleic acids long. In some embodiments shorter, such as 10-15 Nt or longer probes, such as 50-100 nt, can be used, but typically, one uses about 25 nucleic acids as a standard probe. The probe can be a DNA, RNA, peptide nucleic acid (PNA) or hybrids thereof. Modifications to the backbone of the NA are encompassed within the definition. In one embodiment, the probe is a DNA-probe. In another embodiment, the probe is an RNA-probe. In another embodiment, the probe is a PNA-probe. Probes are preferably single-stranded probes, but double-stranded or partially double-stranded probes can also be used.

[0079] As used herein, the term "variation affecting one nucleotide" refers to any of a plurality of insertions or deletions affecting one nt of interest, exclusively, and/or one nt of interest together with an addition of one to nine nt located contiguously at its Y side. In other embodiments, the additional nt can be one and up to 50 nt, e. g. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 nt. A deletion of only the nt of interest (one-nt deletion, or Dell) is an example of such a variation, i.e., affecting one nt. A deletion of the nt of interest together with one contiguous Y nucleotide (two-nt deletion, or Del2) is another example of such a variation affecting one nt. Other examples include Del3, a deletion of the nt of interest together with two contiguous Y nt; Del4, a deletion of the nt of interest together with three contiguous Y nt; Del5, a deletion of the nt of interest together with four contiguous Y nt; Del6, a deletion of the nt of interest together with five contiguous Y nt; Del7, a deletion of the nt of interest together with six contiguous Y nt; Del8, a deletion of the nt of interest together with seven contiguous Y nt; Del9, a deletion of the nt of interest together with eight contiguous Y nt; DellO, and a deletion of the nt of interest together with nine contiguous Y nt.

[0080] A duplication of only the nt of interest (one-nt duplication, or Dupl) is another example of a variation affecting one nt. A duplication of the nt of interest together with one contiguous Y

nucleotide (two-nt duplication, or Dup2) is another example of such a variation affecting one nt. Other examples include Dup3, a duplication of the nt of interest together with two contiguous Y nt; Dup4, a duplication of the nt of interest together with three contiguous Y nt; Dup5, a duplication of the nt of interest together with four contiguous Y nt; Dup6, a duplication of the nt of interest together with five contiguous Y nt; Dup7, a duplication of the nt of interest together with six contiguous Y nt; Dup8, a duplication of the nt of interest together with seven contiguous Y nt; Dup9, a duplication of the nt of interest together with eight contiguous Y nt; DuplO, and a duplication of the nt of interest together with nine contiguous Y nt. The Fig. 1 shows graphically an example of Dell and Del4 variations affecting one nt, at position 16, of the wild type sequence. In some embodiment, the duplications are insertions, where the sequences of the inserted nt are different from that of the nt of interest.

[0081] As used herein, the term "indel probe sub-set" or "probe sub-set" refers to a collection of probes interrogating one kind of indel variation affecting one nt. For example, a first probe sub-set investigates the presence of a single nt insertion at K position in variant segment, a second probe sub-set investigates the presence of a two- nt insertion at K position, a third probe sub-set investigates the presence of a three-nt insertion at K position, a fourth probe sub-set investigates the presence of a single nt deletion at K position, a fifth probe sub-set investigates the presence of a two-nt delenios at K position, a sixth probe sub-set investigates the presence of a three-nt deletion at K position, a seventh probe sub-set investigates the presence of a single nt duplication at K position, a probe sub-set investigates the presence of a two-nt duplication at K position, and a eight probe sub-set investigates the presence of a three-nt duplication at K position. The collection of the entire eight probe sub-sets make up the probe set for the K position bp in the variant segment.

[0082] In one embodiment, an "indel probe sub-set" or "probe sub-set" comprises at least one pair of probes, wherein the pair of probes consist of one control or normal/wild type probe and one variation probe. In one embodiment, one control or normal/wild type probe and one variation probe making up a pair of probes that have the same length and sequence except for the indel variation, be it an insertion, deletion or duplication. For each kind of variation to be detected, probes can be designed with (1) different lengths, at (2) different positions in the probes wherein the indel variation to be detected are located; and (3) to hybridize to the sense strand solely, to the antisense strand solely, or to both strands. Any combination of the length, strand and position can be selected for a given indel probe sub-set. For example, a given indel probe sub-set can comprise probes of two different lengths, with sense and antisense probes of both lengths, and with two positions by which the variations will be detected in the probes of one length and three positions by which the variations will be detected in the probes of the other length.

[0083] All indels probe sub-sets should include the normal (i.e., wild type) probes matching the variation probes in terms of length, strand and position of the variation in the probe. Fig. 2 shows an example of ten variations designed for the variation probes making up the pairs of probes that would make up an indel probe sub-set. The variation probes are of two different lengths (21 nt and 25 nt long). Variation probes of both lengths are designed for either the sense or antisense strands or both. Probes which are 21 nt-long carry the variation-detecting nt at positions 9 and 11, while probes which are 25-nt long carry the variation-detecting nt at positions 11, 13 and 15. In this example, positions of variation- detecting nt are the same for the sense and antisense probes, but do not necessarily have to be so in all embodiments.

[0084] In the Fig. 2 example, sense and antisense variation probes are designed for both lengths, but it does not necessarily have to be so in all embodiments. In this example, the indel probe sub-set includes the normal (i.e., wild type) probes that match the 10 variation probes. In another embodiment, the indel probe sub-set includes the control probes that match the 10 variation probes. The match of each variation probe with its normal or control probe forms a pair of probes. Any probe sub-set comprises at least two probes for the nucleotide of interest, a probe harboring a variation and the corresponding normal or control probe. The number of distinct probes in a probe sub-set can range from one (in the case of a non-variant segment) to about 10,000, typically one uses about 2-200 probes per probe sub-set. The probes are all distinct probes. In one embodiment, there is at least a duplicate or replicate of a probe. In another embodiment, one uses triplicates of a probe. In one embodiment, four or five replicates of each of the different probes making up a probe sub-set can be used. In other embodiments, more than five replicates of each different probe are used on a solid support, in some embodiment, up to 10, or up to 50 replicates are used. In the case of a non-variant segment, the probe sub-set is only composed of normal (i.e., wild type) or control probes.

[0085] As used herein, the term "an indel probe set" refers to the collection of all the probe subsets selected for interrogating a nucleotide or nucleotide of interest where an indel variation can occur, and detecting all the kinds of variation affecting this nucleotide of interest. Any combination of indel probe sub-sets can be selected for a given probe set. Probe sub-sets in a given probe set can have different number of probes, and different combinations of length, strand hybridization and position of the variation to be detected in the probe. However, the process of designing the probe sub-set and probe set follows the novel selection method claimed herein and remains the same.

[0086] As used herein, the term "a set of indel probe sets" refers to the collection of all the probe sets (thus, all the probes) selected for interrogating a genetic variant segment or a non-variant segment. For example, a genetic variant segment where indels are known to occur encompassing 0.7 kilobases (kb) long is selected for interrogation. The investigator can select any number of probe sets covering these regions. The full length of the segment of interest can be covered by designing indel probe sets for all the nt of the variant segment, i. e. 700 nt. For example, one can decide to have 700 different indel probe sets. Each indel probe set can consist of any number of probes. In one

embodiment, each indel probe set consists, for example, of 180 probes; each indel probe set interrogating one base of the 700 base pair long variant segment. This would result in 700 x 180 = 126 000 different probes covering the variant segment. The number of distinct probes can be different for each probe set. The number of distinct probes in a set of probe sets can range from one to about 300,000, typically one uses about 25,000 - 200,000 probes per set of probe sets for a nucleic acid region covering 1 kb. The probes can be all distinct probes, and they complement and interrogate a single genetic variant segment or non-variant segment.

[0087] In one embodiment, "a set of indel probe sets" constitutes a library of probes. In one embodiment, the genetic variant segment where indels of interest can be found is between about 50 base- pair (bp) to about 5000 bp long. In one embodiment, the genetic variant segment where indels of interest can be found is between about 100 bp to about 2000 bp long.

[0088] In Fig. 3, a set of two probe sets is shown. The two probe sets affect respectively nt 16 and 17 of a variant segment which is 37 bp long. The first probe set is for interrogating variations of the 16^th nt. Two probe sub-sets making up the probe set for nt 16 are shown: one designed to detect a one-nt deletion (Dell) of the nt of interest (nt 16), and the other designed to detect a deletion of nt 16 and the nt immediately Y adjacent, i.e. nt 17 (Del2). The Dell variation 1 probe length is 30 nt, and the position of the nt of interest is position 16 (of the 30 nt). The Dell variation 2 probe also is 30 bp-long, but the position of the nt of interest is position 13 (of the 30 nt of the probe). The Del2 variation 1 of the second probe sub-set of this first probe set is the deletion of nt 16 and 17, the indel variation (16^th bp) is placed at position 16 of a 30 nt long fragment. The Del2 variation 2 is designed to detect the deletion of nt 16 and 17, in other words, a two-nt deletion at the 16^th nt position, but the indel variation is located in position 13 of a 30 nt long probe. The second probe set is designed to detect variations affecting the 17^th bp of the same variant segment. Two probe sub-sets make up this second probe set for the 17^th bp. As shown in Fig. 3, the same characteristics of probes have been designed, although this has not to be the case on other embodiments. Thus, for the variation 1 probe of the first probe sub- set (Dell), the nt of interest is in position 16 of a 30 nt-long probe. For the variation 2 probe, the indel variation is in position 13 of a 30 bp-long probe. In the second probe sub-set (Del2), deletions of 2 nt are interrogated, the indel variation is placed at position 16 of the 30 nt-long probe in variation 1, and in position 13 of the 30 nt- long probe in variation 2.

[0089] In some embodiments, probes are designed for the variant segment LDLR gene Exon 2, from position 68 -121, in intron 1, to nucleotide in position 190 +102 (reference sequence NM_000527.3, SEQ ID NO: 4579), a 345 nt- long sequence. The possible probes variety can be whether to have sense and antisense strands probes, have three different sizes of probes (probes of 21, 23 and 25 nt), 5 different positions of the indel variation in the probe , such as central (0), central-2 nt (-2), central-4 nt (-4), central+2 nt (+2), central+4 nt (+4) positions or more etc, for the detection of the deletion of one, two and three nt and the detection of the insertion of one, two and three nt. For this variant segment, the number of probes to be designed can be 103,500, including both normal and variation probes.

[0090] As used herein, the term "normal probe" or "control probe" refers to a probe that has no indel genetic variation, meaning that the probe has the wild type sequence with no deletions, insertions or duplications or has a known SNP respectively. In one embodiment, the "normal probe" or "control probe" interrogates the control nucleic acid (cNA). In another embodiment, the "normal probe" or "control probe" interrogates the non-variant segment. In one embodiment, the wild type sequence with no deletions, insertions or duplications in the control or normal sequence of the cNA or non-variant segment.

[0091] As used herein, the term "variation probe" or "variant probe" refers to a probe that has an indel genetic variation with respect to the normal/wild type or control sequence, meaning that the probe has a deletion, insertion or duplication within the sequence. In one embodiment, the "variation probe" interrogates the test nucleic acid (tNA). In another embodiment, the "variation probe" interrogates the genetic variant segment.

[0092] As used herein, the term "probe feature" refers to a localized and concentrated deposit of multiple copies of the same probe on a solid support surface (a defined "spot" on the glass surface or oligonucleotides on one bead). For example, for a flat solid support such as on the glass-chip surface, a probe feature is a spot or dot printed with multiple copies of the same probe. The multiple copies can range from tens to hundreds to thousands, e.g., about 10-10,000, or 100-10,000. All of the whole integers numbering from 10 to 10,000 are included. Typically the concentration of the oligonucleotide solution and the droplet size will determine the approximate copies of oligonucleotides printed on a "probe feature spot" on a flat solid support. For a spherical surface such as a glass bead, "a probe feature" refers to a single bead coated with at least about 100 copies of the same oligonucleotides probe that complement and interrogate a single genetic variant segment or non-variant segment. In this case, typically the concentration of the oligonucleotide solution determines the approximate copies of oligonucleotides coating the bead. In one embodiment, the bead can have about 100-10,000 copies of the same probe. All of the whole integers running from 100 to 10,000 are included. The raw value or signal intensity of the hybridization reaction in the methods herein is obtained from a probe feature, meaning from a "dot" or a single probe-coated bead. In other words, measuring the signal intensity after hybridization of the test sample or the control sample gives a raw signal value.

[0093] As used herein, the phrases "replicate feature" or "replicate probe feature" refer to a replicate or multiples of a probe feature all having a single/same type of probe to genetic variant segment or non-variant segment (parallel dots or spots with same probe or oligonucleotide sequence on a solid surface or parallel numbers of beads coated with the same probe). For a flat solid support such as a glass- chip, all replicate features of one probe feature have one type of probe and the replicate features can be arranged, for example in a row but not close to each other on the glass-chip surface. For a spherical solid support such as a glass bead, "replicate feature" refers to number of probe -coated beads. For example, 100 probe-coated beads are 100 replicate features or replicate probe features. On a solid flat surface, for each probe, there are at least four replicate features, at least five, at least six, at least seven, at least eight, at least nine, and at least ten replicate features. However, one can also use 11, 12, 13, 14, 15 16, 17, 18, 19, 20, 20-25, or even 25-50 replicates. In a typical analysis, one uses 10 replicate features. For a spherical solid surface, there are at least 100 replicate features, typically between about 100-5000 probe- coated beads. All of the whole integers going from 100 to 5,000 are included.

[0094] As used herein, the term "interrogation" refers to the examination, investigation or study of the nucleotide sequence information in a NA, i.e., the genotype.

[0095] As used herein, the term "comprising" means that other elements can also be present in addition to the defined elements presented. The use of "comprising" indicates inclusion rather than limitation.

[0096] The term "consisting" is a closed term, indicating that nothing else is considered to be included. The phrase "consisting essentially of is intended to cover situations, wherein the operational parts are included but one can also include non-essential or non-active ingredients or steps.

[0097] As used herein, the term "median" when used in the analysis of the data obtained from the probe feature replicas refers to general meaning when used in statistical analysis. Median is the 'middle value' in a list of values when arranged in increasing order. For example, for a list of the following numbers: 9, 3, 44, 17, 15 (odd amount of numbers), after lining up these numbers: 3, 9, 15, 17, 44 in increasing order (smallest to largest), the median is 15 which is the number in the middle of the ordered list. In the situation, wherein an even number of replicates are present, a median is found by finding the middle pair of numbers, and then find the value that would be half way between them. This is easily done by adding them together and dividing by two. In the present methods, the analysis of median is performed using computer-implemented software with the signal intensity values from the replicate features as an input and median as an output.

[0098] As used herein, the term "mean" when used in the analysis of the data obtained from the probe feature replicas refers to general meaning when used in statistical analysis. Median is the average of a list of values, calculated by the formula:

Average = Sum of the list of numbers

Number in list

For example, for a list of the following five numbers: 9, 3, 44, 17, 15

The mean = (9+3+44+17+15) = 17.6

5

[0099] As used herein, the term "solid support", on which the plurality of probes is deposited, can be any solid support to which oligonucleotides can be attached. Practically any support, to which an oligonucleotide can be joined or immobilized, and which may be used in the production of DNA probe arrays and particle suspensions, can be used in the invention. For example, the said support can be of a non-porous material, for example, glass, silicone, plastic, or a porous material such as a membrane or filter (for example, nylon, nitrocellulose) or a gel. In one embodiment, the said support is a glass support, such as a glass slide. In another embodiment, the support is a particle in suspension, as described above, such as a microparticle. Microparticles useful for the methods of the invention are commercially available for example from LUMINEX^® Inc., INVITROGEN^™ (Carlsbad, Calif.), and Polysciences Inc. (Warrington, Pa.). In one embodiment, the solid support is a non-porous solid support. In one embodiment the solid support is a porous solid support. Such supports are well known to one skilled in the art.

Analysis methods

[0100] Embodiments of the invention provide (1) a library of probes which allows the detection of indels in a genetic variant segment; (2) a method of designing such a library of probes; (3) the use of the library of probes to detect the presence of indels in the test NA sample, the method comprises the immobilization of the probes on a solid support, the hybridization of test and optionally normal or control NA samples on the probes, the determination of the intensity for each NA-hybridized probe, and the analysis process and interpretation of the data generated by the hybridization; and (4) a solid support chip or spherical microbeads comprising a library of probes which allows the detection and

analysis/characterization of indels in a genetic variant segment.

[0101] Accordingly, provided herein are method to design and a specifically designed library of probes for detecting at least one indel variation in a genetic variant segment having a length of N number of base pairs (wherein N is typically a number between 25 and 5000, for example 50-2000), the library comprising a set of probe sets which comprises N number of probe sets (i.e. the same number of probe sets as there are nucleotides in the segment to be analyzed), wherein there is one probe set for each nucleotide position of the genetic variant segment. Each probe set comprises at least one probe sub-set, wherein the at least one probe sub-set is for interrogating a single kind of indel; and further wherein the at least one probe sub-set comprises at least a pair of probes, a normal probe and a variant probe, both of which interrogate the same region on the genetic variant segment (i.e. are designed to bind to either to the normal or variant sequence in that specific location). These probes form a pair of probes that have the same sequence length and are of the same type of nucleic acids (except for the difference in the normal and variant sequence to be detected). The length of the probes is between 15-50 nucleotides. Thus, the normal probe comprises a sequence corresponding and binding to the normal / wild type or control sequence of genetic variant segment and the variant probe comprises an indel-containing variant sequence of genetic variant segment. Further, the indel in the variant probe is located at -4, -3, -2, -1, 0, +1, +2, +3 or +4 position in the variant probe or located up to 25 nt off the central nt for probes longer, e. g. up to 50nt, wherein the position 0 is the center nucleotide of the probe when the probe has an odd number of nucleotides; and wherein the position -1 and +1 are the two central nucleotides of the probe when the probe has an even number of nucleotides, e. g. -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, - 15, -14, -13, -12, -11, -10, -9,-8, -7, -6, -5, -4, -3, -2, -1, 0, +1, +2, +3, +4, +5, +6, +7, +8, +9, +10, +11, +12, +13, +14, +15, +16, +17, +18, +20, +21, +22, +23, +24 or +25. [0102] Since the indel variations in the genetic variant segment are of various types, i. e.

deletions, insertions and/or duplications, the library of probes can consist of the design of all the probes able to detect any one or all kinds of possible indels that one would desire or is likely to detect. If the indels are known indels that one looks for, e.g., as a disease screen or a drug resistance or tolerance screen, probes for only those specific indels can be included into the library. For example, if the genetic region of interest is 100 bp long in the genome, all possible indels for this region would encompass all indel types occurring at each of the 100 nt of this 100 bp-long sequence. For example, a deletion, an insertion and a duplication individually for the position 1 in this 100 bp-long sequence, and so forth for all the following 99 positions in this 100 bp-long sequence.

[0103] In one embodiment, the library of probes comprises or consists essentially of or consists of a control and/or a normal probe. In one embodiment, the control and/or normal probes are provided on a solid support. Control or normal/wild type probes for a known non-variant segment(s) on the X- chromosome exhibit gender dimorphism, meaning that the control, i.e. known nt at position x or the normal wild type nt at position x, is present depends on whether hybridization is performed on a male or female subject (one copy in males, two in females). Such control probes and their respective X chromosome non-variant segments can be used as controls to verify that the control nt, e.g. in SNP, or the normal/ wild type nt is detected in each hybridization, by comparing the test subject and a control subject of different gender. For example, an X chromosome non-variant segment(s) can be selected from two well characterized genes: the PLP locus and F9 locus on the human X-chromosome. These non-variant segments can be used for the normalization. The first gene is PLP (for Proteolipid Protein 1, located Xq22), a gene whose duplications and deletions are responsible of the Pelizaeus-Merzbacher disease (PMD). This disease is an X-linked recessive hypomyelinative leukodystrophy (HLD1) in which myelin is not formed properly in the central nervous system. PMD is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay. PLP1 is located at position chromosome X:

102,927,195-102,934,703 (SEQ ID NO: 4580) with respect to human genome assembly 18 March 2006 (GENBANK™ accession number for its mRNA: NM_000533.3, SEQ ID NO: 4581). The second gene is the F9 (for coagulation factor IX, located Xq22) which is responsible of Hemophilia B. Deletions of this gene cause Hemophilia B. These genes or part of these genes are the genetic variant segments in test samples. F9 is located at position chromosome X: 138,440,061-138,473,783 (SEQ ID NO: 4582) with respect to human genome assembly 18 March 2006 (GENBANK™ accession number for its mRNA: NM_000133.3; SEQ ID NO: 4583).

[0104] In some embodiments, the indel variation can be deletion of one, two, three, four, five, six, seven, eight, nine or ten adjacent nucleotides (nts). In other embodiments, the deletion can be up to 50 nt, e. g. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 nt.

[0105] In one embodiment, the indel variations also can be insertions of one, two, three, four, five, six, seven, eight, nine or ten adjacent nts. The insertions or deletions can be located at any of the nt in the sequence. In other embodiments, the insertion can be up to 50 nt, e. g. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 nt.

[0106] In some embodiments, the insertion of one or more nucleotides can be a duplication of one or more nt, up to ten nt, of the reference/control or wild type sequence, for example, two, three, four, five, six, seven, eight, nine or ten nts. In other embodiments, the duplication can be up to 50 nt, e. g. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 nt.

[0107] Better detection of the many kinds of indel variations in a genetic variant segment can be achieved by using many different types of probes and/or a greater number of probes. While it is not possible to perform an "a priori" analysis to assess the best design of the probes for the detection of an indel, or for the detection of various indels, the inventors have designed a novel strategy which ensures that the library comprises at least one probe for each potential indel for each nt position in the genetic variant segment and that there is a better, if not best, probe for an indel at each nt position among all the probes that are designed of that indel at that nt position. The different types of probes encompassed for each nt position in the genetic variant segment include: (1) probes with different length, e. g. probes that are anywhere from 15- 50 nt long, such as 21, 23, 25, 27, 30 and 32 nt long; (2) the probes that have the indel variation located at different interrogating position inside the variant probe, e. g. located at the interrogating position-4, -3, -2, -1, 0, +1, +2, +3 or +4 position of the variant probe wherein the position 0 is the center nucleotide of the probe when the probe has an odd number of nts; and wherein the position - 1 and +1 are the two central nts of the probe when the probe has an even number of nucleotides (see Fig. 8); and (3) probes that complement or hybridize to the sense strand or the anti-sense strand of the genetic variant segment. The strand to which the probe complements or hybridizes would be the stand interrogated by the probe of the variant segment. Thus, a great number of different types of probes can be designed for each specific indel at each specific nt position in the genetic variant segment according to the described novel design strategy. For example, for a deletion of a nt at a position k, the best probe for its detection might be a probe 25 bp long, interrogating the sense strand of the variant segment and the indel variation is located at the 0 position (i. e. nt number 13) of the 25 bp long probe (see Fig. 8), while for the deletion of one nt in position k+1, the best probe for its detection might be a probe 23 base-pair long, interrogating the anti-sense strand of the variant segment and with the indel variation is located at the -3 position (i. e. nt number 9) of the 23 bp-long probe (see Fig. 8).

[0108] In one embodiment of the at least one probe sub-set comprises more than one pair of probes, e. g. anywhere from 5-100 pairs of probes. Member probes constituting a pair of probes have the same length and interrogate the same region on the variant segment and they interrogate the same strand.

[0109] In one embodiment, the pairs of probes of the at least one probe set have different length, at least three different length, e. g. anywhere from 15-50 nt long. For example, there are pairs of probes that are 15, 20, 25, 30, 35, 40, 45 and 50 nt long making up the at least one probe sub-set. For example, there are pairs of probes that are 21, 23 and 25 nt long making up the at least one probe sub-set.

[0110] In some embodiments, the pairs of probes of the at least one probe set interrogate a different strand of the genetic variant segment, e.g. some pairs of probes interrogate the sense strand of the genetic variant segment and other pairs of probes interrogate the anti-sense strand of the genetic variant segment. These pairs of probes can have the same length or different length. In some

embodiments, the probes are all designed to hybridize to either the sense or the anti-sense strand.

[0111] In one embodiment, the pairs of probes of the at least one probe set have different positions of the indel variation located within the probe.

[0112] It is contemplated that in some embodiments, within a library of probes are probes for detecting and analysing/characterizing several combinations of indel variations in a genetic variant segment. This facilitates simultaneous detection and analysis of several indels in the genetic variant segment. For example, a library of probes can have probes for detecting and analysis/characterization insertions of one, two, and three nts at all the nt positions and probes for detecting and

analysing/characterization deletions of one, two, and three nts at all the nt positions in the genetic variant segment. Another library of probes can have probes for insertions of four and five nts at all the nt positions and probes for deletions of four and five nts at all the nt positions in the genetic variant segment. Libraries can have probes that detecting and analysing/characterization all possible

combinations of indel variations in a genetic variant segment described.

[0113] It is also contemplated that within a library of probes are probes for detecting and analysing/characterization of several combinations of indel variations if more than one indel is present in a genetic variant segment. In other embodiments, the library of probes can be used to detecting and analysing/characterization of several combinations of indel variations in more than one genetic variant segment, e. g. several genetic variant segments. For example, an investigator may wish to analyze several genetic variant segments found in a test NA sample. Such a library of probes will facilitate simultaneous detection and analysis of several indels in the test NA sample which may have only one or several genetic variant segments.

[0114] In one embodiment, only one kind of indel, for example, a deletion of one nt or an insertion of one nt located at an unknown position in a genetic variant segment, is investigated. For this embodiment, the library of probes comprises one set of probe sets and as many probe sets as the length or number of nt (or base pairs) in the variant segment under interrogation, wherein each probe set comprises a single probe sub-set, wherein each probe sub-set itself comprises a single pair of probes consisting of one control or normal/wild type probe (C) and one variation probe (V). Fig. 4 A shows an example of this embodiment of the library of probes for a single indel detection whether it is a one nt deletion or a one nt- insertion. The library is for interrogating a variant segment having a length of N bp-long (where N can be any number of nucleotides, such as, 25-5000 or any size as described already above in connection with some embodiments), and each probe sub-set itself comprises a single pair of probes. For this N bp-long segment, there should be N number of probe sets (i.e. as many probe sets as there are nucleotides in the segment that on wishes to analyze) making up the one set of probe sets. Replicas of each of the probes for each pair of probes can be placed on the solid support, e.g., replicas of the C and V probes (see Figure 4) of each pair of probes can be placed on the solid support.

[0115] In one embodiment, a library of probes is the set of probe sets or the entire collection of probe sets. The number of probe sets comprising in the library is as many as the length of nt (or base pairs) in the variant segment under interrogation. Each probe set comprises one or more probe sub-sets wherein each probe sub-set comprises one or more pairs of probes. A pair of probes consists of one control or normal/wild type probe and one variant probe. Each pair of probes making up a probe sub-set differ from the other pairs of probes within the same probe sub-set in term of the length, the location of the indel variation inside the variant probe, and/or the interrogation strand: sense strand or the anti-sense strand.

[0116] All pairs of probes making up a probe sub-set have the same type of indel variation under investigation, e. g. one deletion of one nt (see Fig. 3, probe sub-set nt 16 dell or nt 17 dell) or one deletion of one nt at X position and one 3 'contiguous nt (see Fig. 3, probe sub-set nt 16 del2 or nt 17 del2). Therefore, a probe sub-set is a collection of pairs of probes that investigates a single type of indel variation at a specific X position in a genetic variant segment.

[0117] A probe set is then a collection of probe sub-sets that investigates indel variations at a specific X position in a genetic variant segment (see Fig. 3, probe sub-set nt 16 dell and nt 16 del2 make up the probe set for nt 16). In one embodiment, the collection of probe sub-sets (i. e. a probe set) investigates at least one type of indel variation at a specific X position in a genetic variant segment. In another embodiment, the collection of probe sub-sets investigates more than one type of indel variation at a specific X position in a genetic variant segment (e.g. when an insertion of 2 nt, an insertion of 3 nt and a deletion of 4 nt in the same genetic location). Where more than one indel variation at X position is desired, the probe set can be the collection of probe sub-sets that investigates all the desired types of indel variation at X position. For example, a probe sub-set comprises pairs of probes that investigate a deletion of one nt at the 16^th position, probe sub-set nt 16, Dell. Another probe sub-set comprises pairs of probes that investigate an insertion of one nt at the 16^th position, probe sub-set nt 16, Insl. Another probe sub-set comprises pairs of probes that investigate a duplication of one nt at the 16^th position, probe sub-set nt 16, Dupl. Another probe sub-set comprises pairs of probes that investigate a duplication of two nt at the 16^th position, probe sub-set nt 16, Dup2. The collection of probe sub-sets for the 16^th nt: Dell, Insl, Dupl and Dup2 make up a probe set for nt at the 16^th position of the genetic variant segment.

[0118] In one embodiment, the control or normal/wild type probe and the variant probe making a pair of probe have the same length, i. e. both the normal and variant probes have the same number of bases or nt (Fig. 1 and Fig. 3).

[0119] In another embodiment, the control or normal/wild type probe and the variant probe making a pair of probe hybridize to the same strand of the genetic variant segment, i. e. both the normal and variant probes hybridize to the sense strand of the genetic variant segment or both hybridize to the anti-sense strand of the genetic variant segment.

[0120] In another embodiment, the normal/control probe and the variant probe interrogate about the same region in the genetic variant segment.

[0121] In one embodiment, each of these probe sub-sets comprises at least a pair of probes consisting of one control or normal probe and one variant probe. In other embodiments, each probe subset comprises several pairs of probes wherein each pair consists of one control or normal probe and one variant probe. For the multiples pairs of probes comprising a probe sub-set interrogating any particular indel variation located at any particular nt position in the genetic variant segment, the probes of the different pairs of probes can differ from each other by the length, the location of the indel variation inside the variant probe or the interrogation strand: sense strand or the anti-sense strand.

[0122] For example, Fig. 3 shows two pairs of probes for the probe sub-set nt 16 dell, two pairs of probes for the probe sub-set nt 16 del2, two pairs of probes for the probe sub-set nt 17 dell and two pairs of probes for the probe sub-set nt 17 del2. The two pairs of probes for the probe sub-set nt 16 dell investigates a single nt deletion at nt position 16. All four probes of these two pairs are 30 mers, meaning they each consist of 30 nt. However, the probes from the two pairs differ by the location of the deletion on the probe; in nt 16 dell variation 1, the deletion is located at position 16 of the 30 mer, or position +1, and in nt 16 dell variation 2, the deletion is located at position 13 of the 30 mer, or position -3. The two pairs of probes for the probe sub-set nt 16 del2 investigates a single nt deletion at nt position 16 and a deletion of one 3' contiguous of nt position 16. All four probes of these two pairs are 30 mers, meaning they each consist of 30 nt. However, the probes from the two pairs differ by the location of the deletion on the probe; in nt 16 dell variation 1, the deletion is located at position 16 of the 30 mer, or position +1, and in nt 16 dell variation 2, the deletion is located at position 13 of the 30 mer, or position -3.

[0123] In one embodiment, one can decides to detect one kind of indel, for example, only deletions of one nt in a genetic variant segment. For this embodiment, the library of probes comprises one set of probe sets and as many probe sets as the length of the variant segment under interrogation (e.g., if the length of the segment to be analyzed is 2000 base pairs, 2000 probe sets are designed according the novel system or rules set forth in this specification), wherein each probe set comprises a single probe sub-set, wherein the probe sub-set comprises at least one pair of probes, wherein each pair of probes consists of one normal/wild type probe and one variant probe, wherein the probes of each pair of probes making up the probe sub-set differ from each other in terms of length, indel variation location inside the probe and strand of interrogation of the variant segment. Fig. 4B shows one exemplary system how to make a library of probes for detecting a single type of indel present in a variant segment having a length of N bp-long. For each probe set, there is a single probe sub-set consisting of ten pairs of probes. For this N bp-long segment, there are N numbers of probe sets making up the one set of probe sets. Replica of the C and V probes of each pair of probes can be placed on the solid support. [0124] In this embodiment where there are only two probe sub-sets, one probe sub-set investigates the single nt deletion or insertion at position X in the genetic variant segment. The second probe sub-set investigates the single nt deletion or insertion plus another nt deletion or insertion 3 'side of position X in the genetic variant segment.

[0125] In one embodiment, if one decides to detect more than one type of indel, for example, two types of indels; e.g., a deletion of only one nt in a genetic variant segment and an insertion of only one nt in a genetic variant segment. The only one-nt deletion in a genetic variant segment and the only one-nt insertion in a genetic variant segment represent two distinct kinds or types of indels that can occur for each and every nt position in the variant segment. For this embodiment, the library of probes comprises one set of probe sets and as many probe sets as the length of the variant segment under interrogation, wherein each probe set comprises two probe sub-sets, wherein each probe sub-set comprises at least one pair of probes, wherein each pair of probes consists of one control or normal/wild- type probe and one variation probe, wherein the probes of each pair of probes making up the probe subset differ from each other in terms of length, indel variation location inside the probe and strand of interrogation of the variant segment. There is one probe sub-set for each distinct indel being investigated. For example, for the two indels investigation described, there is a first and a second probe sub-set for the probe set that correspond to the nt at the X position in the genetic variant segment; the first probe sub-set that investigates the single nt deletion at position X in the genetic variant segment and the second probe sub-set investigates the single nt insertion at position X in the genetic variant segment.

[0126] The application therefore provides various combinations of indels that can be investigated simultaneously with a library of probes, where the library of probes is designed according to the rules set forth in this specification and examples.

[0127] In one embodiment, one decides to detect several kinds of indel variation in a genetic variant segment, for example, deletions of one, two, three, four and five nts. A library of probes for detecting and analysis of a genetic variant segment with one, two, three, four and five nts deletions has one set of probes sets. There are as many probe sets as the length of the variant segment under interrogation, each probe set comprising of five probe sub-set, each probe sub-set for investigating each of the different type of indel, i. e. deletions of one, two, three, four and five nts; each probe sub-set comprising at least one pair of probes which consist of one normal probe and one variant probe. The probes of each pair of probes within a probe sub-set differ from each other in terms of length, interrogating position inside the probe and strand of interrogation of the variant segment.

[0128] In one embodiment, one can detect several kinds of indel variations in a genetic variant segment simultaneously with a library of probes, for example, deletions of one, two and three nts and an insertion of one nt, i. e. four distinct indel variations. A library of probes for detecting and analysis of a genetic variant segment with one, two, and three nt deletions and one nt insertion will have one set of probes sets. There are again as many probe sets as the length of the variant segment under interrogation. Each probe set comprising four probe sub-sets, each probe sub-set for investigating each of the different type of indel, i. e. deletions of one, two and three nt and insertion of one nt; each probe sub-set comprises at least one pair of probes which consist of one control or normal / wild type probe and one variant probe. The probes of each pair of probes within a probe sub-set differ from each other in terms of length, interrogating position inside the probe and strand of interrogation of the variant segment.

[0129] Fig. 4C shows one embodiment of the library of probes for detecting four types of indel present in a variant segment having a length of N bp-long. The library has four probe sub-sets, one probe sub-set for each of the different type of indel, i.e. deletions of one, two and three nt and insertion of one nt; each probe sub-set consisting of 32 pairs of probes. For this N bp-long segment, there are N numbers of probe sets making up the one set of probe sets. Replica of the C and V probes of a pair of probes can be placed on the solid support.

[0130] Methods of analysis for the detection of indels rely on, in general, comparisons of hybridization intensities among normal and variation probes, among tNA and cNA samples, among genetic variant and non-variant segments, and combinations thereof.

[0131] In one embodiment, the method of detection of indels relies solely on the hybridization intensities among normal and variation probes of at least one test sample. In this embodiment, probes comprising the probe sub sets should have the same characteristics (length, length, position of the indel variation of interest - i.e. at position +1 from the middle of the probe or as described above for other alternative positions, and strand hybridized - i.e., sense or anti-sense) across all probe sets. As used herein, the phrase "probe feature" refers to a localized and concentrated deposit of multiple copies of the same probe on a solid support surface (for example, a defined "spot" on the glass surface or

oligonucleotides on one bead).

[0132] In one embodiment, the method of detecting and analyzing an least one indel in a genetic variant segment having a length of N nucleotide bases comprises:

(a) designing and providing a library of probes on a solid support, wherein the library of probes comprises one set of probe sets for interrogating a genetic variant segment, wherein the set of probe sets comprise at least two probe sets, a first and a second probe set, wherein each the at least two probe sets comprises at least one probe sub-set, wherein the at least one probe sub-set comprise at least one pair of probes: a normal or control probe and a variation probe, wherein the normal probe of the pair is complementary to the normal (wild type) or control sequence of the genetic variant segment, and the variation probe is complementary to the normal sequence except for a position corresponding to the indel variation, wherein the type of indel variation probes of the at least two probe sets are the same, wherein the first probe set interrogates an indel located at position k in the genetic variant segment, and the second probe set interrogates the indel located position k+1 in the genetic variant segment, and wherein the probes are placed on the solid support as probe features;

(b) providing at least a tNA sample;

(c) amplifying the regions of interest of the at least one tNA sample ; (d) contacting the tNA with the solid support, thereby allowing NA hybridization between the tNA to the normal or control and variation probe features thereby forming NA-probe complexes, wherein each complex is detectably labeled;

(e) measuring an intensity of the detectable label for NA-probe complex at each probe feature; and

(f) applying an algorithm to the data from step (e), thereby determining the indel present in the genetic variant segment of the tNA sample, wherein algorithm comprises the steps of:

(i) . computing a first intensity ratio (Ratio 1) between the normal (N) or control (C) probe in the first probe set IN_(k) and the corresponding normal probe in the corresponding pair in the second probe set IN _k+i₎

Ratio 1 = IN_(k) ÷ ₎

(ii) . computing a second intensity ratio (Ratio 2) between the variation probe in the first probe set IV_(k) and the corresponding variation probe in the corresponding pair in the second probe set IV_(k+i₎

Ratio 2 = IV^-IV^D

wherein k has values from 1 to N-l where 1 represent the first oligonucleotide of the variant segment and N is the last base;

(iii) . computing a Ratio_(k/k+1) between the Ratio 1 and Ratio 2:

Ratio_(k/k+1) = INiki Nik₊r_!. = Ratio 1

Ratio 2

wherein if the Ratio_(k/k+1) is equal to about one, the genotype of the k nucleotide is normal

(i.e. wild type) or the indel variation addressed by the probe sub-set of nucleotide base k is the same as that of the k+1 nucleotide of the variant segment; if the Ratio^_+!) is at least two, preferentially more than 5, preferentially more than 10, this indicates a heterozygote indel variation at the position k+1 ; if the Ratio_(k/k+1) is more than 100, preferentially more than 200 fold, this indicates an homozygote indel variation at the position k+1.; Inversely, if the Ratio_(k/k+1) is less than 0.5, preferentially less than 0.2, preferentially less than 0.1 , this indicates an heterozygote indel variation at the position k, and if Ratio^_+!) is less than 0.01, preferentially less than 0.005, this indicates an homozygote indel variation at the position k.

[0133] It is understood that in the above described analysis method and other analysis methods described herein, when normal/wild type sequences are used in the analysis and comparison, the symbol

(N) is used; and when the control known sequences are used in the analysis and comparison, the symbol

(C) is used.

[0134] It is also understood that in the above described analysis method and other analysis methods described herein, when normal/wild type sequences are used in the analysis and comparison, normal/wild type probe sequences are designed/selected and used for the library. In the embodiments wherein /selected and used control, known sequences are used in the analysis and comparison, control probe sequences are designed/selected and used for the library.

[0135] In embodiments where the probe sub-sets comprises more than one pair of probes, the method comprises comparing all the ratios of each probe sub-set to confirm that they all indicate the same indel variation. An example of this embodiment of method is shown in Fig. 5 and some exemplary intensity data generated by the hybridization of the test NA and the probe features and the calculation of the can be found in Tables 2-5.

[0136] In one embodiment of the method, the probe sub-sets within the probe sets for each contiguous nt in the variant segment has the same number of pairs of probes and the same type of pair of probes in term of length, interrogating position inside the probe and strand of interrogation of the variant segment. The method compares results of a certain nucleotide with the results of the nucleotide to its right (k vs k+1). Thus the probes within each probe sub-set of a probe set must have matching probes in the probe sub-set of the adjacent probe set, matching in term of length, location of indel interrogation, and strand of interrogation between probe sub-sets in order to obtain the ratios for ratio comparison. The matching up is necessary for consecutive nt positions in the segment investigated. However, it is necessary for all the probe sub-sets have all the same number or variety of variation probes. For example, for a library with N number of probe sets, each with one probe sub-set, all the probe sub-set has two pairs of probes, one pair of 30 nt for the sense strand with the indel variation at the -2 position within the probe and the second pair of 25 nt for the sense strand with the indel variation at the -2 position within the probe. At the minimum, there should be at least one pair of probes for a probe sub-set for K position (in the K probe set) that matches up with at least one pair of probes of probe sub-set for K+1 position (in the K+1 probe set), and at least one pair of probes for a probe sub-set for K position that matches up with at least one pair of probes of probe sub-set for K-l position (in the K-l probe set). As used herein, matches up means that the matched pair of probes are of the same length, interrogate the approximately same region in the variant segment, interrogate the same type of indel and the indel is located at the same position within the probe (see Fig. 1 and 3).

[0137] In one embodiment, the method of detection and analysis of the indels relies on the hybridization of the tNA samples as well as one control NA sample. In this embodiment, the genetic variant segment and the non-variant segment form both the tNA and the cNA samples are used. The method of detecting and analyzing an indel in a genetic variant segment having a length of N nucleotide bases comprises:

(a) providing at least a tNA sample;

(b) providing one cNA sample;

(c) amplifying at least one genetic variant segment from the at least a tNA and amplifying at least one genetic variant segment from the cNA samples, wherein the amplifications optionally use the same primers; (d) amplifying at least one genetic non-variant segment from the at least a tNA and amplifying at least one genetic non-variant segment from the cNA samples, wherein the amplifications optionally use the same primers;

(d) providing one set of probe sets designed to hybridize to the at least one genetic variant segment and one set of probe sets designed to hybridize to at least one genetic non-variant segment, wherein the sets of probe sets are attached to a solid support, wherein each of the probe set for the genetic variant segment comprises at least one probe sub-set, wherein the at least one probe sub-set comprises at least one pair of probes: a normal or control probe and a variation probe, wherein the normal probe of the pair is complementary to the normal (wild type) or control (i. e. known variation) sequence of the genetic variant segment, and the variation probe is complementary to the normal sequence except for a position corresponding to the indel variation, wherein each of the probe set for the genetic non-variant comprises at least one probe sub-set, wherein the at least one probe sub-set comprises at least one probe: a normal (wild type) or control probe, and wherein the probes are placed on the solid support as probe features;

(e) contacting, optionally in parallel reactions, the at least one genetic variant segment from the at least one tNA and the at least one genetic variant segment from the control NA with the solid support, thereby allowing NA hybridization between the genetic variant segments from tNA and the cNA to the probe features for the genetic variant segment and the probe features for the non-variant segment thereby forming NA-probe complexes, wherein each complex is detectably labeled.

(f) measuring an intensity of the detectable label for NA-probe complex at each probe feature.

(g) applying an algorithm to the data from step (f), thereby determining the indel variation present in the genetic variant segment of the tNA sample, wherein algorithm comprises the steps of:

(i) . computing a median or a mean of the intensity from step (f) for the normal or control probe features of all the probe sets of the set of probe sets interrogating the at least one non-variant segment wherein the median or mean is used as a normalization factor for intensities of step (f);

(ii) . applying the normalization factor of step (i) to the intensities of step (f) to obtain a normalized intensity for all the probe features;

(iii) . computing a normal or control ratio (Ratio 1) between IN_(k)t over IN_(k)C where k can have values from 1 to N where 1 represent the first nucleotide base of the variant segment and N the last nucleotide base, where IN^ represents the value of intensity of the normal probe from the tNA sample and IN^ represents the intensity of the normal (N) or control (C) probe from the c NA sample:

Ratio 1 = IN^_t ÷ IN^ (iv) . pairing the probe feature of variation probes hybridized with the genetic variant segment from the tNA sample with the probe feature of variation probes hybridized with the genetic variant segment from the cNA sample for all the probe sub-sets of all probe sets; pairing of the normal or control probes are performed too;

(v) . computing a variation ratio (Ratio 2) between IV^ over IV^ where k can have values from 1 to N where 1 represent the first nucleotide base of the variant segment and n the last nucleotide base, where IV_(k)t represents the value of intensity of the variation probe from the tNA sample and IV_(k)C represents the intensity of the variation probe from the cNA sample:

Ratio 2 = IV_(k)t ÷ IV_(k)c

(vi) . pairing the ratio 1 and its corresponding ratio 2 from steps (iii) and (v) for each indel probe sub-set of each indel probe set according to the length, position of the nucleotide of interest, and interrogation strand; and

(vii) . computing the ratio between the ratio N over the ratio V for each pair in step (vi):

Ratio _(t/c)(k) =

= Ratio 1

IVoot / IV_(k)c Ratio 2

wherein if a Ratio _{(t/C) (k)} is equal to about one, the indel variation of the nucleotide k position is normal (i.e. wild type); if the Ratio _{(t/C) (k)} is more than two, preferentially more than 5, preferentially more than 10, this indicates a heterozygote indel variation at the nucleotide k position; if the ratio is more than 100, preferentially more than 200 fold, this indicates an homozygote indel variation at the nucleotide in k position.

[0138] In this method, the comparison is between each probe set of the tNA and probe set of the control tNA (for instance, probe set for nt 16 for tNA versus the probe set control for nt 16 for cNA, and probe set for nt 17 for tNA versus probe set for nt 17 for cNA). Thus, all the probes in a sub-set for the tNA must have a corresponding probe in the cNA. The number of pairs of probes for the probe sub-set need not be the same, e. g. three pairs of probes in a sub-set of set 16, 4 totally different pairs of probes (in terms of length, location of indel interrogation, and strand of interrogation) in the corresponding subset of set 17, and compare both of them to the control as long as the corresponding pairs are in the control too, in this case, the control should have at least 7 probes, 3 matching the ones of set 16 and 4 matching the ones of set 17.

[0139] In some embodiments, the probe features of normal probes hybridized with the genetic variant segment from the tNA sample are paired with the probe features of normal probes hybridized with the genetic variant segment from the cNA sample for all the probe sub-sets of all probe sets.

[0140] In embodiments where the probe sub-sets comprises more than one pair of probes, the method comprises comparing all the ratios of each probe sub-set to confirm that they all indicate the same indel variation. An example of this embodiment of method is shown in Fig. 6.

[0141] In one embodiment, more than one control NA sample can be used for the method of detection and analysis of indels described. Those skilled in the art can readily adopt the above described method to calculate the normalization factor of step (f) by using data from the various control NA samples, instead of data from just one cNA sample.

[0142] In one embodiment, the normalization factor is computed by the median or the mean of all the normal probe features of the variant segment when several, preferentially more than 10, preferentially more than 50, preferentially more than 100 probe sub sets are used.

[0143] In one embodiment, the method of detection of indels relies on the hybridization of the test samples as well as various control samples. In this embodiment, only the genetic variant segment is used. The method of detecting and analyzing an indel in a genetic variant segment having a length of N nucleotide bases comprises:

(a) providing at least a tNA sample.

(b) providing at least two cNA samples.

(c) amplifying at least one genetic variant segment from the at least a test NA and amplifying at least one genetic variant segment from the at least two control NA samples, wherein the amplification of the genetic variant segments from the test NA samples and the control NA samples optionally use the same primers;

(d) providing a set of probe sets designed to hybridize to the at least one genetic variant segment, wherein the set of probe sets comprising at least one probe set, wherein the at least one probe set for the genetic variant segment comprises at least one probe sub-set, wherein the at least one probe sub-sets comprise at least one pair of probes: a normal probe and a variation probe, wherein the normal probe of the pair is complementary to the normal (wild type or control) sequence of the genetic variant segment, and the variation probe is complementary to the normal sequence except for a position corresponding to the indel variation, and wherein the probes are placed on the solid support as probe features;

(e) contacting optionally in parallel the at least one genetic variant segment from the at least tNA sample and the at least one genetic variant segment from the at least two cNA samples with the solid support, thereby allowing NA hybridization between the genetic variant segments from the tNA and the cNAs to the genetic variant probe features thereby forming NA -probe complexes, wherein each complex is detectably labeled;

(g) applying an algorithm to the data from step (f), thereby determining the indel present in the genetic variant segment of the tNA sample, wherein algorithm comprises the steps of:

(i). computing a ratio for each pair of probes:

Ratio_(k) = intensity value for normal probe

(intensity value for normal probe + intensity value for variation probe)

(ii). computing the mean and the standard deviation of the ratios obtained for all the control NA samples; and (iii). comparing the ratios obtained for each of the tNA sample with the mean ratio obtained for the cNA samples in step (ii), wherein if the ratio of the tNA sample is at least 5 standard deviations away from the mean ratio obtained with the cNA sample, the test NA has the indel variation at position k, either in an heterozygous or a homozygous state; wherein k has values from 1 to N-l where 1 represent the first oligonucleotide of the variant segment and N is the last base.

[0144] An example of this embodiment of method is shown in Fig. 7.

[0145] In some embodiments of the methods, probes features of each pair of probes comprising the at least one probe sub-set are grouped together according to their length, position of the nucleotide of interest, and interrogation strand.

[0146] In some embodiments of the methods, the normal or control probe and their

corresponding variation probe features are paired according to their length, position of the nucleotide of interest, and interrogation strand for the at least tNA sample and the cNA samples.

[0147] In one embodiment of the methods, there is as many probe sets as there are bp in the genetic variant segment under investigation. For example, if the genetic variant segment has N bp, then the library has N number of probe sets.

[0148] In some embodiments of the methods, probe features are grouped together according to their probe sub-set.

[0149] In some embodiments of the methods, the normal and their corresponding variation probe features are paired according to the probe feature groups.

[0150] In embodiments where the probe sub-sets comprise more than one pair of probes, the method comprises comparing all the ratios of each probe sub-set to confirm that they all indicate the same indel variation.

[0151] In some embodiments of the methods, one can use several test samples with the same control samples.

[0152] For any single indel, any of the method described can be used. It is contemplated that more than one described method is use for any given indel investigated. In some embodiments, one can use one of the four methods of indel detection. In some embodiments, two, three or all methods described are used for indel detection.

[0153] In some embodiments, one can use three of the four methods of indel detection.

[0154] In some embodiments, one can use four of the four methods of indel detection.

[0155] In some embodiments, one can use replicates of the probes or probe features.

[0156] In one embodiment, each probe of pairs of probes comprising the probe sub-sets are attached to a solid support to form probe features. In one embodiment, replicates of each probe features on the solid support are exemplified in Fig. 9. In some embodiments, the number of replicates for each probe is between 1-50, from 1 and up to 5, or from 1 up to 10. In one embodiment, there are four replicate features for each probe. In another embodiment, there are ten replicate features for each probe. [0157] In one embodiment, the methods comprise measuring an intensity of the detectable label in non-probe positions of the solid support to obtain a background intensity value.

[0158] In one embodiment, the methods comprise transforming the intensity of the detectable label obtained into a raw value for each probe or probe feature and the solid support background using a quantitation software.

[0159] One embodiment of the methods comprises amending the raw value for each of the probe feature or replicate probe feature by deducting the background raw value, thereby obtaining a net value for the each probe feature or replicate probe feature for both the at least one genetic variant segment and the at least one genetic non-variant segment.

[0160] One embodiment of the methods comprises selecting for subsequent analysis the probe features whose net values pass quality control thresholds or values signal to noise ratio of, typically, over three (SNR>3), in the probe feature positions wherein a signal is detected.

[0161] In one embodiment, one can use one or more control NA samples.

[0162] In one embodiment, the method is computer implemented.

[0163] The NA samples can be obtained from any appropriate biological sample which contains

NA. The sample may be taken from a fluid or tissue, secretion, cell or cell line derived from the human body.

[0164] For example, samples may be taken from blood, including serum, lymphocytes, lymphoblastoid cells, fibroblasts, platelets, mononuclear cells or other blood cells, from saliva, liver, kidney, pancreas or heart, urine or from any other tissue, fluid, cell or cell line derived from the human body. For example, a suitable sample may be a sample of cells from the buccal cavity. One can also use hair follicle samples.

[0165] In one embodiment, the NA is obtained from a blood sample.

[0166] In general, NA can be extracted and isolated from the biological sample using conventional techniques. The nucleic acid to be extracted from the biological sample may be DNA, or RNA, typically total RNA. Typically RNA is extracted if the genetic variation to be studied is situated in the coding sequence of a gene. Where RNA is extracted from the biological sample, the methods further comprise a step of obtaining cDNA from the RNA. This may be carried out using conventional methods, such as reverse transcription using suitable primers. Subsequent procedures are then carried out on the extracted DNA or the cDNA obtained from extracted RNA. The term DNA, as used herein, may include both DNA and cDNA.

[0167] One can also use lab-on-a-chip methods wherein separate isolation step is not necessary because the raw sample, such as blood or urine sample, can be inserted into the micro-channel, the genetic variant and sos-variant segment amplified thereon and be hybridized to the designed chip either within the micro-channel or after exiting the micro-channel. Such lab-on-a-chip systems are well known to one skilled in the art. [0168] In general, any genetic variant segment can be analyzed using the computer- implemented algorithm as described. The genetic variations to be tested are located within known nucleic acid sequences and well characterized.

[0169] In one aspect, the NA samples which contain the genetic segment or segments of interest are subjected to an amplification reaction prior to analysis in order to obtain amplification products which contain the genetic variations to be identified. The amplified nucleic acid regions are typically the variant and/or non-variant segment to be interrogated. Any suitable technique or method can be used for amplification. In general, the technique allows the multiplex amplification of all the DNA sequences containing the genetic variations to be identified. In other words, where multiple genetic variations are to be analyzed, it is preferable to simultaneously amplify all of the corresponding target DNA regions in one reaction (comprising the variations). Carrying out the amplification in a single step (or as few steps as possible) simplifies the method. PCR amplification conditions are such that the final copy number after amplification reflects the initial copy number of the segments in the NA samples.

[0170] For example, multiplex PCR can be carried out, using appropriate pairs of

oligonucleotide PCR primers which are capable of amplifying the target regions containing the genetic variations to be identified. Here each genetic variant segment is amplified together with a genetic non- variant segment in the multiplex PCR reaction using the test or control NA sample as the DNA template. The genetic variant and the genetic non-variant segments amplified together form an amplification group. Any suitable pair of primers which allow specific amplification of a target DNA region may be used. In one aspect, the primers allow amplification in the least possible number of PCR reactions. Thus, by using appropriate pairs of oligonucleotide primers and appropriate conditions, all of the target DNA regions necessary for genotyping the genetic variations can be amplified for genotyping (e.g. DNA-array or particle suspension) analysis with the minimum number of reactions. . The present method can comprise the use of one or more of these primers or one or more of the listed primer pairs. Examples presented in the present application provide additional exemplary primers.

[0171] In one embodiment, several independent multiplex PCR amplification reactions are carried out for the test NA sample and the control sample. In one embodiment, at least four independent multiplex PCR amplification reactions are carried out for the test NA sample and the control sample. In one embodiment, about four independent multiplex PCR amplification reactions are carried out for the test NA sample and the control NA sample. The PCR products from the independent amplifications for the test NA sample are pooled together. Likewise, those of the control NA samples are pooled together.

[0172] In parallel with each genetic variant segment comprising the indel provided, no or at least one genetic non-variant segment can be selected. The genetic non-variant segment is encompassed within the test NA and control NA samples. For example, if neither the test nor the control exhibit Down syndrome, a test region from the Down syndrome region of chromosome 21 can be selected as a non- variant segment. [0173] In one embodiment, the NA in the test NA and control samples are detectably-labeled.

The aim is to be able to later detect hybridization between the genetic variant or non-variant segments and probe features fixed on a solid support. The greater the extent of hybridization of labeled segment to a probe feature, the greater the intensity of detectable label at that probe position. Methods of labeling NA are well known to one skill in the art, e. g. US Patent No. 6,573,374 and US Patent No. 5,700,647 describe suitable labeling methods. The attached label is detected by various methods known in the art, e.g. optically, wherein a photonic signal is converted to an electronic signal and registered by a computer, which outputs a signal in, for example, a numeric value. For example, a labeled nucleotide can be incorporated during the amplification reaction or labeled primers can be used for amplification. In some embodiments, the labeled nucleotide is a biotinylated nucleotide. In other embodiments, the labeled primer is a biotinylated primer.

[0174] Labeling can be direct using for example, fluorescent or radioactive markers or any other marker known by persons skilled in the art. Examples of fluorophores, include for example, Cy3 or Cy5. Alternatively enzymes may be used for sample labeling, for example alkaline phosphatase or peroxidase. Examples of radioactive isotopes which can be used include for example ³³P, ¹²⁵I, or any other marker known by persons skilled in the art. In one instance, labeling of amplification products is carried out using a nucleotide which has been labeled directly or indirectly with one or more fluorophores. In another example, labeling of amplification products is carried out using primers labeled directly or indirectly with one or more fluorophores.

[0175] Labeling may also be indirect, using, for example, chemical or enzymatic methods. For example, an amplification product may incorporate one member of a specific binding pair, for example avidin or streptavidin, conjugated with a fluorescent marker and the probe to which it will hybridize may be joined to the other member of the specific binding pair, for example biotin (indicator), allowing the probe/target binding signal to be measured by fluorimetry. In another example, an amplification product may incorporate one member of a specific binding pair, for example, an anti-dioxigenin antibody combined with an enzyme (marker) and the probe to which it will hybridise may be joined to the other member of the specific binding pair, for example dioxigenin (indicator). On hybridization of

amplification product to probe the enzyme substrate is converted into a luminous or fluorescent product and the signal can be read by, for example, chemi-luminescence or fluorometry.

[0176] The NA or the amplification products can further undergo a fragmentation reaction, thereby obtaining some fragmentation products which comprise or contain the genetic variations to be identified or analyzed. Typically fragmentation increases the efficiency of the hybridization reaction. Fragmentation may be carried out by any suitable method known in the art, for example, by contacting the nucleic acid, e.g. the amplification products with a suitable enzyme such as a DNase.

[0177] In some embodiments, the PCR products are fragmented to smaller sizes and then detectably labeled prior to hybridization with probes on a solid support. In one embodiment, the PCR products are fragmented to between about 12 -250nt in size. In one embodiment, the PCR products are fragmented to between about 25 -200nt in size. In one embodiment, the PCR products are fragmented to between about 25 -150nt in size. In one embodiment, the PCR products are fragmented to between about 25 -lOOnt in size. In one embodiment, the PCR products are fragmented to between about 25 -75nt in size. In one embodiment, the PCR products are fragmented to between about 25 -50nt in size.

[0178] On can also use method as described in U.S. S.N. 12/499,076 in the methods of the present application.

[0179] If the NA has not been previously labeled, e.g. during the amplification reaction, (and, typically, where no post-hybridization amplification or ligation is carried out on the solid support) then labeling with a detectable label may be carried out pre-hybridization by labeling the fragmentation products. Suitable labeling techniques are known in the art and may be direct or indirect as described herein. Direct labeling may comprise the use of, for example, fluorophores, enzymes or radioactive isotopes. In one embodiment, the direct labeling comprises the use of biotin. Indirect labeling may comprise the use of, for example, specific binding pairs that incorporate e.g. fluorophores, enzymes, etc. For example, if amplification products have not been labeled during the amplification reaction the fragmentation products may undergo a direct or indirect labeling with one or various markers, for example biotin or one or various fluorophores, although other known markers can be used by those skilled in the art.

[0180] In some embodiments, hybridization intensity values, for use in analysis methods, can be amended for each of the probe features by deducting the background raw value from the raw value, thereby obtaining a net value.

[0181] In one embodiment, at least one oligonucleotide probe is designed and synthesize for each of the variant and non-variant segment to be interrogated. In a preferred embodiment, at least two unique probes are designed and synthesize for each segment. In other embodiments, at least five, at least ten, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, and at least 100, including all the whole integers between 2-100,000 unique probes are designed and synthesize for each segment. All of the probes are unique, although they can have overlapping sequences.

[0182] In one embodiment, the collection of unique probes designed and synthesized for each segment constitutes a set of probe set. In one embodiment, the set of probe sets for a segment that is interrogated comprises at least two unique probe sets for that segment. In other embodiments, a set of probe sets for a segment that is interrogated comprises at least five, at least ten, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least70, at least 75, at least 80, at least 85, at least 90, at least 95, and at least 100, including all the whole integers between 2-100, unique probe sets. In one embodiment, for the practice of the method described herein, a first set of probe sets is provided for a genetic variant segment (form the test NA sample) to be interrogated. In one embodiment, for the practice of the method, a second set of probe sets is provided for a genetic non-variant segment (from the control NA sample) to be interrogated. DNA chips or microbeads

[0183] In one embodiment, the library of probe is attached to a solid support as probe features in a specific arrangement wherein the location of each probe feature is known. In one embodiment, a probe feature is provided on a solid support; the probe feature being a localized and concentrated sample having multiple copies of the same probe is deposited and attached on a solid surface. For example, for a flat solid support such as on the glass-chip surface, a probe feature is a minute spot or dot printed with multiple copies of the same probe (see Fig. 9). The multiple copies can range from hundreds to thousands, e.g. 100-10000. All of the whole integers between 100 to 10,000 are included is a single probe feature. For a spherical surface such as a glass bead, "a probe feature" refers to a single probe -coated bead. All the beads are coated with the multiple copies of same probe that complements and interrogates a single genetic variant segment or non-variant segment. The range of numbers of probe-coated beads in "a probe feature" is between 100-1000, including all of the whole integers between 10-10000.

[0184] In one embodiment, replicates of a probe feature are made on a solid support. For a flat solid support such as a glass-chip, all replicate features of one probe feature type have one type of probe and the replicates can be arranged in a row on the glass-chip surface. Multiple rows can be made and distributed in fix and known coordinates on the glass chip (see Fig. 9). For a spherical solid support such as a glass bead, replicate features of one probe are many probe -coated beads, about 100 probe -coated beads. These beads all have probes of a single type. For each probe on a flat solid support, there are at least four replicate features, at least five, at least six, at least seven, at least eight, at least nine, and at least ten replicate features, sometimes more. In some embodiments, the solid support has between 10- 50 replicate features for each unique probe. All whole integers between 10-50 are considered. For each probe on a spherical solid support, there are at least about 100 replicate features or probe -coated beads.

[0185] In one embodiment, for the practice of the methods, replicates of probe features of a first set of probe sets are provided for a genetic variant segment (form the test NA sample) to be interrogated. In one embodiment, for the practice of the methods, replicates of probe features of a second set of probe sets are provided for a genetic non-variant segment (from the control NA sample) to be interrogated. The replicates of probe features of the first and second set of probe sets are attached on same solid support.

[0186] In accordance with some methods, two or more identical solid supports are used, each solid support having probe features. One solid support is used to hybridize with the test NA sample and the other solid support is used to hybridize with the control NA sample (Fig. 6 and 7).

[0187] In accordance with the method where two identical solid supports are used, each solid support having all the replicates of a first and a second set of probe sets, wherein the first set of probe sets interrogates a genetic variant segment and the second set of probe sets interrogates a genetic non-variant segment. One solid support is used to hybridize with the test NA sample and the other solid support is used to hybridize with the control NA sample (see Fig. 6 and 7).

[0188] In one embodiment, each probe feature is provided in at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 9, at least 10 replicates and the probe features are attached to the flat surface at positions according to a known uniform spatial distribution, i.e., a support or surface with an ordered array of binding (e.g. hybridization) sites or probes. In other embodiments, anywhere form 10-50 replicate probe features are provided. Thus, the arrangement of replicate features on the support is predetermined. Each probe replicate is located at a known predetermined position on the solid support such that the identity (i.e. the sequence) of each probe can be determined from its position on the array. Typically, the probes are uniformly distributed in a predetermined pattern.

[0189] In one embodiment, the solid support is a flat surface. For example, for a flat solid support is a glass-chip surface.

[0190] In addition to DNA-arrays in the form of DNA-chips to detect genetic variations, the present invention also contemplates the use of DNA particle or bead suspensions.

[0191] In one embodiment, the solid support is a micron-size particle. In one embodiment, the beads are uniquely identifiable. Examples of particle identifiers on a particle are a bar code and a fluorescent dye. In one embodiment, the beads are bar-coded. These beads such as polymer or magnetic beads have unique spectroscopic signatures. Beads can be synthesized by dispersion polymerization of a family of styrene monomers and methacrylic acid to generate a spectroscopically encoded bead library. Raman spectroscopy is used to monitor complexing events on the barcoded beads. The genotyping assays from ILLUMINA^®, Inc. uses the particles that are cylindrical beads encoded with a barcode, which are then read by a barcode scanner. Platforms such as the XMAP^™ technology from LUMINEX^® is have the particles that are microspheres encoded with fluorescent dyes. The particles are read by a flow cytometer.

[0192] In one embodiment, the solid supports form particle suspensions. It has been found that these particle suspensions should comply with a number of requirements in order to be used in the present methods, for example in terms of the design of the probes, the number of probes provided for each genetic variation to be detected and the distribution of probes on the support. These are described in detail herein.

[0193] In one embodiment, wherein the solid support is a micron-size particle, each probe is attached to at least 10 units of each particle species, wherein each particle species is distinguishable by a unique code from all other particle species.

[0194] In one embodiment, wherein the solid support is a micron-size particle, each probe is attached to at least 1000 units of each particle species.

[0195] In practicing the method described herein, the labeled NA are contacted with a solid support having attached probes in a specified arrangement described herein as replicate features, allowing NA hybridization between the tNA and the cNA (collective hereby termed as target NA) with the probes in the replicate features and the formation of target-probe complexes. Under conditions which allow hybridization to occur between target NA and the corresponding probes, specific hybridization complexes are formed between target NA and corresponding probes. Since the NAs are labeled, the target-probe complexes formed can therefore be detected. [0196] Typically, the hybridization conditions allow specific hybridization between probes and corresponding target NA to form specific probe/target hybridization complexes while minimizing hybridization between probes carrying one or more mismatches to the DNA. Such conditions may be determined empirically, for example by varying the time and/or temperature of hybridization and/or the number and stringency of the array washing steps that are performed following hybridization and are designed to eliminate all probe -DNA interactions that are non-specific. For example, the melting temperature of the probe/target complexes may occur at 75-85°C. In some embodiments, hybridizations can be for one hour, although higher and lower temperatures and longer or shorter hybridizations may also suffice. A skilled artisan can optimize these conditions using routine methods.

[0197] The hybridization can be carried out using conventional methods and devices. In one instance, hybridization is carried out using an automated hybridization station. For hybridization to occur, the segments are placed in contact with the probes under conditions which allow hybridization to take place. Using stable hybridization conditions allows the length and sequence of the probes to be optimized in order to maximize the discrimination between genetic variations A and B, e.g. between wild type and mutant sequences, as described herein.

[0198] In general a chip DNA array has from 300 to 40000 probe features, for example, from

400 to 30000 or 400 to 20000. The chip can have from 1000 to 20000 probes, such as 1000 to 15000 or 1000 to 10000, or 1000 to 5000. A suitable chip may have from 2000 to 20000, 2000 to 10000 or 2000 to 5000 probe features. For example, a chip may have 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 14000, 16000, 18000 or 20000 probes. Smaller chips 400 to 1000 probes, such as 400, 500, 600, 700, 800, 900 or 950 probes are also envisaged. The number of probes in a particle suspension will vary depending on the number of individually identifiable particles.

[0199] In general the chip DNA array of the invention comprises a support or surface with an ordered array of binding (e.g. hybridization) sites or probe features. Thus the arrangement of probes on the support is predetermined. Each probe (i.e each replicate feature) is located at a known predetermined position on the solid support such that the identity (i.e. the sequence) of each probe can be determined from its position in the array. Typically the probes are uniformly distributed in a predetermined pattern.

[0200] Preferably, the probes deposited on the support, although they maintain a predetermined arrangement, are not grouped by genetic variation but have a random distribution. Typically they are also not grouped within the same genetic variation. If desired, this random distribution can be always the same. Therefore, typically the probes are deposited on the solid support (in an array) following a predetermined pattern so that they are uniformly distributed, for example, between the two areas that may constitute a DNA-chip, but not grouped according to the genetic variation to be characterized.

Distributing probe replicates across the array in this way helps to reduce or eliminate any distortion of signal and data interpretation, e.g. arising from a non-uniform distribution of background noise across the array. [0201] In some embodiments, probe features are arranged on the support in subarrays.

Microarrays are in general prepared by selecting probes which comprise a given polynucleotide sequence, and then immobilizing such probes to a solid support or surface. Probes may be designed, tested and selected as described herein. In general, the probes can comprise DNA sequences. In some embodiments the probes may comprise RNA sequences, or copolymer sequences of DNA and RNA. The polynucleotide sequences of the probes may also comprise DNA and/or RNA analogues, or combinations thereof. For example, the polynucleotide sequences of the probes may be full or partial fragments of genomic DNA. The polynucleotide sequences of the probes may also be synthesized nucleotide sequences, such as synthetic oligonucleotide sequences. The probe sequences can be synthesized either enzymatically in vivo, enzymatically in vitro (e.g., by PCR), or non-enzymatically in vitro.

[0202] Microarrays or chips can be made in a number of ways. However produced, microarrays typically share certain characteristics. The arrays are reproducible, allowing multiple copies of a given array to be produced and easily compared with each other. Preferably, microarrays are made from materials that are stable under binding (e.g., nucleic acid hybridization) conditions. The microarrays are preferably small, e.g., between 0.25 to 25 or 0.5 to 20 cm², such 0.5 to 20 cm² or 0.5 to 15 cm², for example, 1 to 15 cm² or 1 to 10 cm², such as 2, 4, 6 or 9 cm².

[0203] Replicate probe features can be attached to the solid support using conventional techniques for immobilization of oligonucleotides on the surface of the supports. The techniques used depend, amongst other factors, on the nature of the support used - porous (membranes, micro-particles, etc.) or non-porous (glass, plastic, silicone, etc.) In general, the probes can be immobilized on the support either by using non-covalent immobilization techniques or by using immobilization techniques based on the covalent binding of the probes to the support by chemical processes.

[0204] Preparation of non-porous supports (e.g., glass, silicone, plastic) requires, in general, either pre-treatment with reactive groups (e.g., amino, aldehyde) or covering the surface of the support with a member of a specific binding pair (e.g. avidin, streptavidin). Likewise, in general, it is advisable to pre-activate the probes to be immobilized by means of corresponding groups such as thiol, amino or biotin, in order to achieve a specific immobilization of the probes on the support.

[0205] The immobilization of the probes on the support can be carried out by conventional methods, for example, by means of techniques based on the synthesis in situ of probes on the support (e.g., photolithography, direct chemical synthesis, etc.) or by techniques based on, for example, robotic arms which deposit the corresponding pre-synthesized probe (e.g. printing without contact, printing by contact) (See U. S. Patent No. 7,281,419 for example).

[0206] In one embodiment, the support is a glass slide and in this case, the probes, in the number of established replicates (for example, 6, 8 or 10) are printed on pre-treated glass slides, for example coated with aminosilanes, using equipment for automated production of DNA -chips by deposition of the oligonucleotides on the glass slides ("micro-arrayer"). Deposition is carried out under appropriate conditions, for example, by means of crosslinking with ultraviolet radiation and heating (80°C), maintaining the humidity and controlling the temperature during the process of deposition, typically at a relative humidity of between 40-50% and typically at a temperature of 20°C.

[0207] The replicate probe features are distributed uniformly amongst the areas or sectors (sub- arrays), which typically constitute a DNA-chip. The number of replicas and their uniform distribution across the DNA-chip minimizes the variability arising from the printing process that can affect experimental results.

[0208] To control the quality of the manufacturing process of the DNA-chip, in terms of hybridization signal, background noise, specificity, sensitivity and reproducibility of each replica as well as differences caused by variations in the morphology of the spotted probe features after printing, a commercially synthesize NA can be used.

[0209] In contrast to chip DNA array technology, in which the probes are attached to the solid support at known locations, particle suspension technology allows for the detection of probes in a single vessel, with individual probes attached to a particle with a distinguishable characteristic. In some embodiments the particles are encoded with one or more optically distinguishable dyes, a detectable label, or other identifying characteristic such as a bar code. Other labeling methods include, but are not limited to a combination of fluorescent and non-fluorescent dyes, or avidin coating for binding of biotinylated ligands. Such methods of encoding particles are known in the art.

[0210] Once hybridization has taken place, the intensity of detectable label at each probe position (including control probes) can be determined. The intensity of the signal (the raw intensity value) is a measure of hybridization at each replicate feature.

[0211] The intensity of detectable label at each probe position (each probe feature replica) can be determined using any suitable means. The means chosen will depend upon the nature of the label. In general an appropriate device, for example, a scanner, collects the image of the hybridized and developed DNA-chip. An image is captured and quantified.

[0212] In one instance, e.g. where fluorescent labeling is used, after hybridization, the hybridized and developed DNA-chip is placed in a scanner in order to quantify the intensity of labeling at the points where hybridization has taken place. Although practically any scanner can be used, in one embodiment a fluorescence confocal scanner is used. In this case, the DNA-chip is placed in the said apparatus and the signal emitted by the fluorpohore due to excitation by a laser is scanned in order to quantify the signal intensity at the points where hybridization has taken place. Non-limiting examples of scanners which can be used according to the present invention include scanners marketed by the following companies: Axon, Agilent, Perkin Elmer, etc.

[0213] In one aspect of the invention, the signal from the particles is detected by the use of a flow cytometer. In other embodiments, detection of fluorescent labels may also be carried out using a microscope or camera that will read the image on the particles. Flow cytometric software for detection and analysis of the signal is available for example from Luminex, Inc. (Austin, TX). [0214] In one embodiment, wherein the measuring intensity of the detectable label for each probe is performed using scanning.

[0215] In one embodiment, wherein the measuring intensity of the detectable label for each probe is performed using flow measuring systems.

[0216] Typically, in determining the intensity of detectable label at each probe position (i.e for each probe feature replica), account is taken of background noise, which is eliminated. Background noise arises because of non-specific binding to the probe array and can be determined by means of controls included in the array. Once the intensity of the background signal has been determined, this can be subtracted from the raw intensity value for each probe replica in order to obtain a clean intensity value. Typically the local background, based on the signal intensity detected in the vicinity of each individual feature is subtracted from the raw signal intensity value. This background is determined from the signal intensity in a predetermined area surrounding each feature (e.g. an area of X, Y or Z μπι² centered on the position of the probe). The background signal is typically determined from the local signal of "blank" controls (solvent only). In many instances the device, e.g. scanner, which is used to determine signal intensities will provide means for determining background signal.

[0217] Thus, for example, where the label is a fluorescent label, absolute fluorescence values

(raw intensity values) can be gathered for each probe replica and the background noise associated with each probe replica can also be assessed in order to produce "clean" values for signal intensity at each replicate feature position.

[0218] Once the test DNA has been hybridized to the chip and the intensity of detectable label has been determined at the probe feature replica positions on the chip (the raw intensity values), it is necessary to provide a method (model) which can relate the intensity data from the chip to the genotype of the individual.

[0219] The inventors have found that this can be done by applying a specific algorithm to the intensity data. The algorithm and computer software developed by the inventors allows analysis of the genetic variations with sufficient sensitivity and reproducibility as to allow use in a clinical setting.

[0220] Typically, amending the raw intensity value to obtain the clean intensity value for each probe replica comprises subtracting background noise from the raw value. Background noise is typically determined using appropriate controls such as area of chip with no NA or probe.

[0221] The inventors have found that the use of replicas and median calculated from replicas is important for reliable working of the invention.

[0222] The algorithm as described herein is designed to be computer implemented, and thus in some embodiments, the methods described herein comprise the use of a computer system and a computer program.

Systems for analysis of indel genetic variation

[0223] Embodiments of the invention can be described through functional modules, which are defined by computer executable instructions recorded on computer readable media and which cause a computer to perform method steps when executed. The modules are segregated by function for the sake of clarity. However, it should be understood that the modules/systems need not correspond to discreet blocks of code and the described functions can be carried out by the execution of various code portions stored on various media and executed at various times. Furthermore, it should be appreciated that the modules may perform other functions, thus the modules are not limited to having any particular functions or set of functions.

[0224] The computer readable storage media can be any available tangible media that can be accessed by a computer. Computer readable storage media includes volatile and nonvolatile, removable and non-removable tangible media implemented in any method or technology for storage of information such as computer readable instructions, data structures, program modules or other data. Computer readable storage media includes, but is not limited to, RAM (random access memory), ROM (read only memory), EPROM (eraseable programmable read only memory), EEPROM (electrically eraseable programmable read only memory), flash memory or other memory technology, CD-ROM (compact disc read only memory), DVDs (digital versatile disks) or other optical storage media, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage media, other types of volatile and nonvolatile memory, and any other tangible medium which can be used to store the desired information and which can accessed by a computer including and any suitable combination of the foregoing.

[0225] Computer-readable data embodied on one or more computer-readable media may define instructions, for example, as part of one or more programs that, as a result of being executed by a computer, instruct the computer to perform one or more of the functions described herein, and/or various embodiments, variations and combinations thereof. Such instructions may be written in any of a plurality of programming languages, for example, Java, J#, Visual Basic, C, C#, C++, Fortran, Pascal, Eiffel, Basic, COBOL assembly language, and the like, or any of a variety of combinations thereof. The computer-readable media on which such instructions are embodied may reside on one or more of the components of either of a system, or a computer readable storage medium described herein, may be distributed across one or more of such components.

[0226] The computer-readable media can be transportable such that the instructions stored thereon can be loaded onto any computer resource to implement the aspects of the present invention discussed herein. In addition, it should be appreciated that the instructions stored on the computer- readable medium, described above, are not limited to instructions embodied as part of an application program running on a host computer. Rather, the instructions may be embodied as any type of computer code (e.g., software or microcode) that can be employed to program a computer to implement aspects of the present invention. The computer executable instructions may be written in a suitable computer language or combination of several languages. Basic computational biology methods are known to those of ordinary skill in the art and are described in, for example, Setubal and Meidanis et al., Introduction to Computational Biology Methods (PWS Publishing Company, Boston, 1997); Salzberg, Searles, Kasif, (Ed.), Computational Methods in Molecular Biology, (Elsevier, Amsterdam, 1998); Rashidi and Buehler, Bioinformatics Basics: Application in Biological Science and Medicine (CRC Press, London, 2000) and Ouelette and Bzevanis Bioinformatics: A Practical Guide for Analysis of Gene and Proteins (Wiley & Sons, Inc., 2nd ed., 2001).

[0227] The functional modules of certain embodiments of the invention include at minimum a measuring module #40, a storage module #30, a comparison module #80, and an output module #110 (Fig. 10). The functional modules can be executed on one, or multiple, computers, or by using one, or multiple, computer networks. The measuring module has computer executable instructions to provide e.g., expression information in computer readable form.

[0228] The measuring module #40, can comprise any system for detecting a signal representing the detectable label from a target NA-probe complex (Fig. 10). Such systems can include DNA microarray readers, RNA expression array reader, flow cytometer or any other system which produces an electronic signal converted from the original label, such as a photonic signal or a radioactive signal. The original signal intensity or frequency determines the electronic signal intensity or frequency.

[0229] The information determined in the determination system can be read by the storage module #30 (Fig. 10). As used herein the "storage module" is intended to include any suitable computing or processing apparatus or other device configured or adapted for storing data or information. Examples of electronic apparatus suitable for use with the present invention include stand-alone computing apparatus, data telecommunications networks, including local area networks (LAN), wide area networks (WAN), Internet, Intranet, and Extranet, and local and distributed computer processing systems. Storage modules also include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage media, magnetic tape, optical storage media such as CD-ROM, DVD, electronic storage media such as RAM, ROM, EPROM, EEPROM and the like, general hard disks and hybrids of these categories such as magnetic/optical storage media. The storage module is adapted or configured for having recorded thereon genetic variation information. Such information may be provided in digital form that can be transmitted and read electronically, e.g., via the Internet, on diskette, via USB (universal serial bus) or via any other suitable mode of communication.

[0230] As used herein, "stored" refers to a process for encoding information on the storage module. Those skilled in the art can readily adopt any of the presently known methods for recording information on known media to generate manufactures comprising genetic variation information.

[0231] In one embodiment, the reference data stored in the storage module to be read by the comparison module is e.g., genetic variation data from normal subjects.

[0232] The "comparison module" #80 (Fig. 10) can use a variety of available software programs and formats for the comparison operative to compare genetic variation data determined in the measuring module for the variant and non-variant segment. In one embodiment, the comparison module is configured to use pattern recognition techniques to compare information from one or more entries to one or more reference data patterns. The comparison module may be configured using existing commercially-available or freely-available software for comparing patterns, and may be optimized for particular data comparisons that are conducted. The comparison module provides computer readable information related to normalized ratios of intensities, median log₂ of intensities etc in the analysis and interpretation of the genetic variation in an individual.

[0233] The comparison module, or any other module of the invention, can include an operating system (e.g., UNIX) on which runs a relational database management system, a World Wide Web application, and a World Wide Web server. World Wide Web application includes the executable code necessary for generation of database language statements (e.g., Structured Query Language (SQL) statements). Generally, the executables will include embedded SQL statements. In addition, the World Wide Web application can include a configuration file which contains pointers and addresses to the various software entities that comprise the server as well as the various external and internal databases which must be accessed to service user requests. The Configuration file also directs requests for server resources to the appropriate hardware— as may be necessary should the server be distributed over two or more separate computers. In one embodiment, the World Wide Web server supports a TCP/IP protocol. Local networks such as this are sometimes referred to as "Intranets." An advantage of such Intranets is that they allow easy communication with public domain databases residing on the World Wide Web (e.g., the GENBANK or Swiss Pro World Wide Web site). Thus, in a particular preferred embodiment of the present invention, users can directly access data (via Hypertext links for example) residing on Internet databases using a HTML interface provided by Web browsers and Web servers.

[0234] The comparison module provides a computer readable comparison result that can be processed in computer readable form by predefined criteria, or criteria defined by a user, to provide a content-based in part on the comparison result that may be stored and output as requested by a user using an output module #110 (Fig. 10).

[0235] The content based on the comparison result, can be an expression value compared to a reference showing the

in a genetic variant segment of the test NA sample.

[0236] In one embodiment of the invention, the content based on the comparison result is displayed on a computer monitor #120. In one embodiment of the invention, the content based on the comparison result is displayed through printable media #130, #140. The display module can be any suitable device configured to receive from a computer and display computer readable information to a user. Non-limiting examples include, for example, general-purpose computers such as those based on Intel PENTIUM-type processor, Motorola PowerPC, Sun UltraSPARC, Hewlett-Packard PA-RISC processors, any of a variety of processors available from Advanced Micro Devices (AMD) of Sunnyvale, California, or any other type of processor, visual display devices such as flat panel displays, cathode ray tubes and the like, as well as computer printers of various types.

[0237] In one embodiment, a World Wide Web browser is used for providing a user interface for display of the content based on the comparison result. It should be understood that other modules of the invention can be adapted to have a web browser interface. Through the Web browser, a user may construct requests for retrieving data from the comparison module. Thus, the user will typically point and click to user interface elements such as buttons, pull down menus, scroll bars and the like conventionally employed in graphical user interfaces.

[0238] The present invention therefore provides for systems (and computer readable media for causing computer systems) to perform methods for analyzing genetic variations in a tNA sample.

[0239] Systems and computer readable media described herein are merely illustrative embodiments of the invention for detecting indel genetic variation in an individual, and are not intended to limit the scope of the invention. Variations of the systems and computer readable media described herein are possible and are intended to fall within the scope of the invention.

[0240] The modules of the machine, or those used in the computer readable medium, may assume numerous configurations. For example, function may be provided on a single machine or distributed over multiple machines.

[0241] In one embodiment, provided herein is a system for detecting analyzing an indel variation in NA sample, comprising:

a. a measuring module measuring the raw intensity comprising a detectable signal from a replicate feature indicating the presence or level of a NA-probe complex on a solid support comprising the replicate feature;

b. a storage module configured to store data output from the measuring module; c. a comparison module adapted to compare the data stored on the storage module with reference and/or control data, and to provide a retrieved content, and d. an output module for displaying the retrieved content for the user, wherein the retrieved content the Ratio^₎ or Ratio_(k)/(k+1) for the kth nucleotide of the genetic variant segment indicates that the presence of an indel in the NA sample.

[0242] In one embodiment, provided herein is a computer readable storage medium comprising:

a. a storing data module containing a detectable signal from a replicate feature indicating the presence or level of a NA-probe complex on a solid support comprising the replicate feature

b. a comparison module that compares the data stored on the storing data module with a reference data and/or control data, and to provide a comparison content, and c. an output module displaying the comparison content for the user, wherein the retrieved content the

for the kth nucleotide of the genetic variant segment indicates that the presence of an indel in the NA sample..

[0243] In one embodiment, the control data comprises data from an individual with normal / wild type genotype at the genetic variant segment under interrogation.

Design and selection of probe sets and variant segments for indel analysis and an indel-chip

[0244] In one embodiment, genes or genetic variant segments are selected on the basis of the pathogenicity of indels they may contain. The probes for detecting indels are oligonucleotide NA ranging from 15 to 50 nt and are designed for interrogating genes or genetic variant segments. Indels to be detected can be deletions of one nt, deletions of two nt, deletions of three nt, duplications of one nt, insertions of one nt, insertions of more than one nt. The deletion, insertions or duplications can be anywhere from one to ten nt at any of the nt positions in the genes or genetic variant segments. In other embodiments, the deletion insertions or duplications can be up to 50 nt, e. g. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 nt.

[0245] As an exemplary, the gene having genetic variant segments to be interrogated is the gene encoding LDLR (for Low Density Lipoprotein Receptor, located 19pl3.2). It is involved in the phenotype of Hypercholesterolemia, Autosomic Dominant (HAD mainly called Familial

Hypercholesterolemia, hereafter named FH), all the regions known to be possibly affected by indels are selected as genetic variant segments for interrogations. These regions are listed below:

Genetic variant segment 1: Promoter and exon 1 of LDLR gene (SEQ ID NO: 4585).

[0246] From position (-377), considering the first nucleotide of the initiating methionine in position 1 of the protein as the origin, until 67+ 106, localized in intron 1 (reference sequence LDLR mRNA is NM_000527.3, SEQ ID NO: 4579). This region includes transcription regulatory elements (2 TATA box and 3 imperfect repetitions of elements regulated by sterol (SER elements).

Genetic variant segment 2: Exon 2 (SEQ ID NO: 4586).

[0247] From position 68 -121, in intron 1, until nucleotide in position 190 +102.

Genetic variant segment 3: Exon 3 (SEQ ID NO: 4587).

[0248] From position 191 -124, in intron 2, until nucleotide in position 313 +121.

Genetic variant segment 4: Exon 4 (SEQ ID NO: 4588).

[0249] From position 314 -77, in intron 3, until nucleotide in position 694 +81.

Genetic variant segment 5: Exon 5 (SEQ ID NO: 4589).

[0250] From position 695 -71, in intron 4, until nucleotide in position 817 +78.

Genetic variant segment 6: Exon 6 (SEQ. ID. NO: 4590).

[0251] From position 818 -71, in intron 5, until nucleotide in position 940 +83.

Genetic variant segment 7: Exon 7 (SEQ ID NO: 4591).

[0252] From position 941 -84, in intron 6, until nucleotide in position 1060 +146.

Genetic variant segment 8: Exon 8 (SEQ ID NO: 4592).

[0253] From position 1061- 94, in intron 7, until nucleotide in position 1186 +106.

Genetic variant segment 9: Exon 9, intron 9 and exon 10 (SEQ ID NO: 4593).

[0254] From position 1187 -93, in intron 8, until nucleotide in position 1586 +111. This region includes full intron 9.

Genetic variant segment 10: Exon 11 (SEQ ID NO: 4594).

[0255] From position 1587 -96, in intron 10, until nucleotide in position 1705 +107.

Genetic variant segment 11: Exon 12 (SEQ ID NO: 4595).

[0256] From position 1706 -130, in intron 11, until nucleotide in position 1845 +79. Genetic variant segment 12: Exon 13, intron 13 and exon 14 (SEQ ID NO: 4596).

[0257] From position 1846 -78, in intron 12, until nucleotide in position 2140 +150. This region includes full intron 13.

Genetic variant segment 13: Exon 15 (SEQ ID NO: 4597).

[0258] From position 2141 -71, in intron 14, until nucleotide in position 2311 +84.

Genetic variant segment 14: Exon 16 (SEQ ID NO: 4598).

[0259] From position 2312 -116, in intron 15, until nucleotide in position 2389 +105.

Genetic variant segment 15: Exon 17 (SEQ ID NO: 4599).

[0260] From position 2390 -105, in intron 16, until nucleotide in position 2547 +80.

[0261] One embodiment of a library of probes designed according to the system described herein is found in Table 1, comprising SEQ ID NO: 1-4575. This library of probe is designed to detect all possible indels for the exon 2 of the human LDLR gene.

Genetic variant segment 16: Exon 18 (SEQ ID NO: 4600).

[0262] From position 2548 -146, in intron 17, until nucleotide in position 2580 +96.

[0263] Other genes having genetic variant segments that can be interrogated are the human apolipoprotein B (including Ag(x) antigen) (APOB) gene (SEQ ID NO: 4584), the various exons in PCSK9 (Proprotein convertase subtilisin/kexin type 9) gene, in particular, exons 2, 4, 7 and 10, as provided in SEQ ID NOS: 4602-4605, respectively and the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsible for the genetic disorder cystic fibrosis. This gene is located on chromosome 7: 116907153-117096054 (approx. 188kb) (SEQ ID NO: 4606).

Genetic variant segment 17: Exon 26 APOB (SEQ ID NO: 4601).

[0264] From position 10453, exon 26, until nucleotide in position 10740 (reference sequence

NM_000384.2).

[0265] The nomenclature formula for the positions of the bases are as described in den Dunnen and Antonarakis, Human Mutation, 2000,15:7-12. The first number within each position formula XXX- YYY or XXX+YYY, e. g. position 2141 -71 or position 2547 +80 refers to the position of the base on the mRNA human LDLR sequence (SEQ ID NO: 4579) wherein the position number 1 is the "A" of the ATG of the signal peptide" in SEQ ID NO: 4576. In SEQ. ID. NO: 4, the "A" of the ATG of the signal peptide" or base position number 1 is the 469th nucleotide in the genomic sequence of human LDLR sequence (SEQ ID NO: 4579). In other words, the base position in the LDLR genomic sequence that corresponds to the 1st base position in the LDLR mRNA is 469. The second number within each position formula refers to the number of the bases that is to be added or subtracted from the base position in the genomic where that base position corresponds to the first number of the position formula which is that in the mRNA. The sequences of a number of indel oligonucleotide probes are selected from these variant segments. These probes are synthesized and then spotted on a solid support in an array as probe feature replicas. [0266] The patient's NA, such as DNA, to be genotyped, called test NA sample, is amplified to produce various genetic variant segments as listed herein and can be complementary of the entire size of the probes. Together with the patient's DNA, one or more control NA sample is amplified under the same conditions of the test target NA.

[0267] Once amplified, the targets (test and control) are fragmented and labeled and then hybridized onto the probes that are immobilized on solid supports. Solid supports such as flat glass chips or beads are scanned to obtain intensities of each single probe.

[0268] Additional embodiments of the invention provides a DNA chip comprising a plurality of probe features deposited on a solid support, the chip being suitable for use in a method of the invention described herein; a computational method for obtaining a genotype from DNA-chip hybridization intensity data wherein the method comprises using ratios for each segment to be genotyped; a computer system comprising a processor and means for controlling the processor to carry out a computational method of the invention; and a computer program comprising computer program code which when run on a computer or computer network causes the computer or computer network to carry out a

computational method of the invention.

Design and selection of probe sets for idel analysis

[0269] In one embodiment, the invention provides a library of probes for detecting at least one indel variation in a genetic variant segment having a length of N number of base pairs, the library comprising (a) a set of probe sets which comprises N number of probe sets, wherein there is one probe set for each nucleotide position of the genetic variant segment; wherein each probe set comprise of at least one probe sub-set, wherein the at least probe sub-set is for interrogating a single kind of indel; wherein the at least probe sub-set comprises at least a pair of probes, a normal or control probe and a variant probe, both of which interrogate a substantially similar region on the genetic variant segment, wherein the both probes forming the pair of probes have the same sequence length, interrogated the same strand of genetic variant segment and are of the same type of nucleic acids, and wherein the length of the probes are between 15-50 nucleotides; wherein the normal probe comprises the normal / wild type or control sequence of genetic variant segment and the variant probe comprises an indel-containing variant sequence of genetic variant segment; wherein the indel in the variant probe is located at -25, -24, -23, - 22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9,-8, -7, -6, -5, -4, -3, -2, -1, 0, +1, +2, +3, +4, +5, +6, +7, +8, +9, +10, +11, +12, +13, +14, +15, +16, +17, +18, +20, +21, +22, +23, +24 or +25 nucleotide position in the variant probe; wherein the position 0 is the center nucleotide of the probe when the probe has an odd number of nucleotides; and wherein the position -1 and +1 are the two central nucleotides of the probe when the probe has an even number of nucleotides.

[0270] This invention is further illustrated by the following example for selecting and designing a library of probes which should not be construed as limiting.

[0271] In one embodiment, control probes are designed and selected for the library.

[0272] In one embodiment, normal / wild type probes are designed and selected for the library. [0273] In one embodiment, the library comprises only control probes and not normal probes, in addition to the corresponding variant probes.

[0274] In one embodiment, the library comprises only normal probes and not control probes, in addition to the corresponding variant probes.

[0275] In one embodiment, for the detection of indels, oligonucleotide probes are designed for each position to be tested in the genetic variant segment. In one embodiment, for each position of the segment to be interrogated, 36 probes are designed to detect changes from the normal or control sequence.

[0276] In one embodiment, all these probes are to be oriented in the 3' to 5' direction on the solid support. In another embodiment, all these probes are to be oriented in the 3' to 5' direction on the solid support.

[0277] In one embodiment, indels of 2 or more nts are always considered to the "right" (i.e., 30 of the nt interrogated in the genetic variant segment.

[0278] The following are the designs of these 36 probe sets for each indel position with reference to the probes in the 3' to 5' direction:

[0279] In one embodiment, the oligonucleotide probes can be about 15-50 nt long. The probes typically have the base to be examined (the site of the indel genetic variation) at the center of the probe, i.e., in the middle, such that for example a probe of 25 nucleotides long has the location of the genetic variation as nucleic acid 13 from the 5'end. In other words, the indel variation is located at the "0" position within the probe, "0" refers to the central nt in the oligonucleotide probe. In one embodiment, the indel variation can also be 2-4 nucleic acids 3' or 5' of the center of the probe, i. e. at the -4, -3, -2, -1, +1, +2, +3 or +4 position within the probe, wherein the probe oriented in the 3' to 5' direction on the solid support.

[0280] In one embodiment, one oligonucleotide probe where the base of interest (i. e. indel variation) located at the central base is deleted with respect to the normal or wild type allele. This probe detects a single nt deletion. The indel variation is located at the "0" position within the probe. The same oligonucleotide probe is also designed but on the other strand of the fragment is to be analyzed.

Therefore, a pair of complementary probes is made. In this design, both the sense and anti-sense strand will be interrogated by this pair of complementary probes.

[0281] In one embodiment, one oligonucleotide probe where the base of interest is in an offset position of 4 nucleotides with respect to the central base towards the 5' end and is deleted compared to the normal or wild type allele. This probe detects a single nt deletion. This probe has the indel variation located at the -4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0282] In one embodiment, one oligonucleotide probe where the base of interest is in an offset position of 4 nucleotides with respect to the central base towards the 3' end and is deleted from the normal or wild type allele. This probe detects a single nt deletion. This probe has the indel variation located at the +4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0283] In one embodiment, one oligonucleotide probe where the base of interest is located at the central base and its adjacent base on the 5' side is deleted with respect to the normal or wild type allele. This probe detects two nt deletion. The indel variation is located at the "0" position within the probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0284] In one embodiment, one oligonucleotide probe where the two bases of interest are in an offset position of 4 nucleotides towards the 5' with respect to the base in the central position and its adjacent base on the 5' side and are deleted respect to the normal or wild type allele. This probe detects two nt deletions. This probe has the indel variation located at the -4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0285] In one embodiment, one oligonucleotide probe where the two bases of interest are in an offset position of 4 nucleotides towards the 3' respect to the base in the central position and its adjacent base on the 5' side and are deleted respect to the normal or wild type allele. This probe detects two nt deletions. This probe has the indel variation located at the +4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0286] In one embodiment, one oligonucleotide probe where the bases of interest located the central base and its adjacent 2 base on the 5' side are deleted respect to the normal or wild type allele. This probe detects three nt deletions. The indel variation is located at the "0" position within the probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0287] In one embodiment, one oligonucleotide probe where the three bases of interest are in an offset position of 4 nucleotides towards the 5' respect to the base in the central position and its adjacent base on the 5' side and are deleted respect to the normal or wild type allele. This probe detects three nt deletions. This probe has the indel variation located at the -4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0288] In one embodiment, one oligonucleotide probe where the three bases of interest are in an offset position of 4 nucleotides towards the 3' respect to the base in the central position and its adjacent base on the 5' side and are deleted respect to the normal or wild type allele. This probe detects three nt deletions. This probe has the indel variation located at the +4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0289] In one embodiment, one oligonucleotide probe where the base of interest located at the central base is duplicated respect to the normal or wild type allele. This probe detects a single nt duplication. The indel variation is located at the "0" position within the probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0290] In one embodiment, one oligonucleotide probe where the base of interest is in an offset position of 4 nucleotides respects to the central base towards the 5' end and is duplicated respect from the normal or wild type allele. This probe detects a single nt duplication. This probe has the indel variation located at the -4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0291] In one embodiment, one oligonucleotide probe where the base of interest is in an offset position of 4 nucleotides respects to the central base towards the 3' end and is duplicated respect from the normal or wild type allele. This probe detects a single nt duplication. This probe has the indel variation located at the +4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0292] In one embodiment, one oligonucleotide probe where the bases of interest being the central base and its adjacent base on the 5' side are duplicated respect to the normal or wild type allele. This probe detects a two- nt duplication. The indel variation is located at the "0" position within the probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0293] In one embodiment, one oligonucleotide probe where the two bases of interest are in an offset position of 4 nucleotides towards the 5' respect to the base in the central position and its adjacent base on the 5' side and are duplicated respect to the normal or wild type allele. This probe detects a two- nt duplication. This probe has the indel variation located at the -4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0294] In one embodiment, one oligonucleotide probe where the two bases of interest are in an offset position of 4 nucleotides towards the 3' respect to the base in the central position and its adjacent base on the 5' side and are duplicated respect to the normal or wild type allele. This probe detects a two- nt duplication. This probe has the indel variation located at the +4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0295] In one embodiment, one oligonucleotide probe where the bases of interest being the central base and its adjacent 2 base on the 5' side are duplicated respect to the normal or wild type allele. This probe detects a three -nt duplication. The indel variation is located at the "0" position within the probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0296] In one embodiment, one oligonucleotide probe where the three bases of interest are in an offset position of 4 nucleotides towards the 5' respect to the base in the central position and its adjacent base on the 5' side and are duplicated respect to the normal or wild type allele. This probe detects a three - nt duplication. This probe has the indel variation located at the -4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0297] In another embodiment, the library of probes comprises of oligonucleotide oligos of three different length, 21 nt, 23 nt, and 25 nt, all of which have the indel variation located in central (0) position and oligonucleotide probes interrogating the sense and the anti-sense strand are represented.

[0298] In one embodiment, one oligonucleotide probe where the three bases of interest are in an offset position of 4 nucleotides towards the 3' respect to the base in the central position and its adjacent base on the 5' side and are duplicated respect to the normal or wild type allele. This probe detects a three - nt duplication. This probe has the indel variation located at the +4 position with respect to the central nt in the oligonucleotide probe. A similar oligonucleotide probe is also designed but this probe hybridizes to the other strand of the fragment to be analyzed.

[0299] Unless otherwise explained, 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 disclosure belongs. Definitions of common terms in genomics and molecular biology can be found in The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); Robert A.

Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8); and Discovering Genomics, Proteomics and

Bioinformatics 2nd edition - by A. Malcolm Campbell and Laurie J. Heyer. (ISBN 0-8053-4722-4;

published by Cold Spring Harbor Laboratory Press and Benjamin Cummings: 2006). Definitions of common terms in molecular biology may be found in Benjamin Lewin, Genes IX, published by Jones & Bartlett Publishing, 2007 (ISBN-13: 9780763740634); Kendrew et al. (eds.).

[0300] Unless otherwise stated, the present invention was performed using standard procedures, as described, for example in Microarrays Methods and Applications (Nuts & Bolts series) by Gary Hardiman (Ed.), DNA Press; 1st edition (2003; ISBN-13: 978-0966402766), Analytical Tools for DNA, Genes and Genomes : Nuts & Bolts (Nuts & Bolts series) by Arseni Markoff (Ed.), DNA Press, (2005, ISBN-13: 978-0974876511); and DNA Microarrays, Part B: Databases and Statistics, Volume 411 (Methods in Enzymology) by Alan R. Kimmel and Brian Oliver (Eds), Academic Press, 1^st edition (2006; ISBN-13: 978-0121828165) which are all incorporated by reference herein in their entireties.

[0301] It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0302] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term "about." The term "about" when used in connection with percentages may mean ±1%.

[0303] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. It is further to be understood that all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, "e.g." is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g." is synonymous with the term "for example."

[0304] All patents and other publications identified in the specification are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[0305] The contents of all references cited throughout this application, as well as the figures and tables are incorporated herein by reference.

Table 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27 68 123 30) _100_ _dO_r 1 TCCCGTCTTGGCACTGGAACTCGTT 2 CCCGTCTTGG CACTG G AACTCGT 3 CCGTCTTGGCACTGGAACTCG

LDLRex2(27 68 123 30) _101. _dO_f 4 ACGAGTTCCAGTGCCAAGACGGGAA 5 CG AGTTCCAGTG CCAAG ACG G G A 6 GAGTTCCAGTGCCAAGACGGG

LDLRex2(27 68 123 30) _101. _dO_r 7 TTCCCGTCTTGGCACTGGAACTCGT 8 TCCCGTCTTGGCACTGGAACTCG 9 CCCGTCTTGG CACTG GAACTC

LDLRex2(27 68 123 30) _102. _dO_f 10 CGAGTTCCAGTGCCAAGACGGGAAA 11 GAGTTCCAGTGCCAAGACGGGAA 12 AGTTCCAGTGCCAAGACGGGA

LDLRex2(27 68 123 30) _102. _dO_r 13 TTTCCCGTCTTGGCACTGGAACTCG 14 TTCCCGTCTTGGCACTGGAACTC 15 TCCCGTCTTGGCACTGGAACT

LDLRex2(27 68 123 30) _103_ _dO_f 16 GAGTTCCAGTGCCAAGACGGGAAAT 17 AGTTCCAGTGCCAAGACGGGAAA 18 GTTCCAGTG CCAAG ACGG GAA

LDLRex2(27 68 123 30) _103_ _dO_r 19 ATTTCCCGTCTTGGCACTGGAACTC 20 TTTCCCGTCTTGGCACTGGAACT 21 TTCCCGTCTTGGCACTGGAAC

LDLRex2(27 68 123 30) _104_ _dO_f 22 AGTTCCAGTGCCAAGACGGGAAATG 23 GTTCCAGTGCCAAGACGGGAAAT 24 TTCCAGTGCCAAGACGGGAAA

LDLRex2(27 68 123 30) _104_ _dO_r 25 CATTTCCCGTCTTGG CACTG G AACT 26 ATTTCCCGTCTTGG CACTG G AAC 27 TTTCCCGTCTTGGCACTGGAA

LDLRex2(27 68 123 30) _105. _dO_f 28 GTTCCAGTG CCAAG ACGG G AAATG C 29 TTCCAGTGCCAAGACGGGAAATG 30 TCCAGTGCCAAGACGGGAAAT

LDLRex2(27 68 123 30) _105. _dO_r 31 GCATTTCCCGTCTTGGCACTGGAAC 32 CATTTCCCGTCTTGG CACTG G AA 33 ATTTCCCGTCTTGGCACTGGA

LDLRex2(27 68 123 30) _106_ _dO_f 34 TTCCAGTGCCAAGACGGGAAATGCA 35 TCCAGTG CCAAG ACGG G AAATG C 36 CCAGTG CCAAG ACGG G AAATG

LDLRex2(27 68 123 30) _106_ _dO_r 37 TG CATTTCCCGTCTTG G CACTG G AA 38 GCATTTCCCGTCTTGGCACTGGA 39 CATTTCCCGTCTTGG CACTG G

LDLRex2(27 68 123 30) _107_ _dO_f 40 TCCAGTG CCAAG ACGG G AAATG CAT 41 CCAGTG CCAAG ACGG G AAATG CA 42 CAGTG CCAAG ACGG G AAATG C

LDLRex2(27 68 123 30) _107_ _dO_r 43 ATGCATTTCCCGTCTTGGCACTGGA 44 TG CATTTCCCGTCTTG GCACTG G 45 G CATTTCCCGTCTTG GCACTG

LDLRex2(27 68 123 30) _108. _dO_f 46 CCAGTG CCAAG ACGG G AAATG CATC 47 CAGTG CCAAG ACGG G AAATG CAT 48 AGTG CCAAG ACGG G AAATG CA

LDLRex2(27 68 123 30) _108. _dO_r 49 GATG CATTTCCCGTCTTGG CACTG G 50 ATGCATTTCCCGTCTTGGCACTG 51 TG CATTTCCCGTCTTG G CACT

LDLRex2(27 68 123 30) _109. _dO_f 52 CAGTG CCAAG ACGG G AAATG CATCT 53 AGTG CCAAG ACGG G AAATG CATC 54 GTGCCAAGACGGGAAATGCAT

LDLRex2(27 68 123 30) _109. _dO_r 55 AGATGCATTTCCCGTCTTGGCACTG 56 GATGCATTTCCCGTCTTGGCACT 57 ATGCATTTCCCGTCTTGGCAC

LDLRex2(27 68 123 30) _110. _dO_f 58 AGTG CCAAG ACGG G AAATG CATCTC 59 GTGCCAAGACGGGAAATGCATCT 60 TG CCAAG ACGG G AAATG CATC

LDLRex2(27 68 123 30) _110. _dO_r 61 GAGATGCATTTCCCGTCTTGGCACT 62 AGATGCATTTCCCGTCTTGGCAC 63 GATGCATTTCCCGTCTTGGCA

LDLRex2(27 68 123 30) _111. _dO_f 64 GTGCCAAGACGGGAAATGCATCTCC 65 TG CCAAG ACGG G AAATG CATCTC 66 G CCAAG ACGG G AAATG CATCT

LDLRex2(27 68 123 30) _111. _dO_r 67 GGAGATGCATTTCCCGTCTTGGCAC 68 GAGATGCATTTCCCGTCTTGGCA 69 AGATGCATTTCCCGTCTTGGC

LDLRex2(27 68 123 30) _112. _dO_f 70 TG CCAAG ACGG G AAATG CATCTCCT 71 G CCAAG ACGG G AAATG CATCTCC 72 CCAAGACGGGAAATGCATCTC

LDLRex2(27 68 123 30) _112. _dO_r 73 AGGAGATGCATTTCCCGTCTTGGCA 74 GGAGATGCATTTCCCGTCTTGGC 75 GAGATGCATTTCCCGTCTTGG

LDLRex2(27 68 123 30) _113. _dO_f 76 G CCAAG ACGG G AAATG CATCTCCTA 77 CCAAGACGGGAAATGCATCTCCT 78 CAAGACGGGAAATGCATCTCC

LDLRex2(27 68 123 30) _113. _dO_r 79 TAGGAGATGCATTTCCCGTCTTGGC 80 AGGAGATGCATTTCCCGTCTTGG 81 G GAG ATG CATTTCCCGTCTTG

LDLRex2(27 68 123 30) _114. _dO_f 82 CCAAGACGGGAAATGCATCTCCTAC 83 CAAGACGGGAAATGCATCTCCTA 84 A AG ACG G G AAATG CATCTCCT

LDLRex2(27 68 123 30) _114. _dO_r 85 GTAG G AG ATG CATTTCCCGTCTTG G 86 TAGGAGATGCATTTCCCGTCTTG 87 AGGAGATGCATTTCCCGTCTT

LDLRex2(27 68 123 30) _115. _dO_f 88 CAAGACGGGAAATGCATCTCCTACA 89 AAGACGGGAAATGCATCTCCTAC 90 AG ACGG G AAATG CATCTCCTA

LDLRex2(27;68;123;30) _115. _dO_r 91 TGTAGGAGATGCATTTCCCGTCTTG 92 GTAG GAG ATG CATTTCCCGTCTT 93 TAGGAGATGCATTTCCCGTCT

able 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27 68 123 30) _116. _d0_f 94 AAGACGGGAAATG C ATCTCCTACA A 95 AG ACGG G AAATG CATCTCCTACA 96 GACGGGAAATGCATCTCCTAC

LDLRex2(27 68 123 30) _116. _d0_r 97 TTGTAGGAGATGCATTTCCCGTCTT 98 TGTAGGAGATGCATTTCCCGTCT 99 GTAG GAG ATG CATTTCCCGTC

LDLRex2(27 68 123 30) _117. _d0_f 100 AG ACGG G AAATG CATCTCCTACAAG 101 GACGGGAAATGCATCTCCTACAA 102 ACGG G AAATG CATCTCCTACA

LDLRex2(27 68 123 30) _117. _d0_r 103 CTTGTAGGAGATGCATTTCCCGTCT 104 TTGTAGGAGATGCATTTCCCGTC 105 TGTAGGAGATGCATTTCCCGT

LDLRex2(27 68 123 30) _118_ _d0_f 106 GACGGGAAATGCATCTCCTACAAGT 107 ACGG G AAATG CATCTCCTACAAG 108 CGGGAAATGCATCTCCTACAA

LDLRex2(27 68 123 30) _118_ _d0_r 109 ACTTGTAG GAG ATG CATTTCCCGTC 110 CTTGTAGGAGATGCATTTCCCGT 111 TTGTAGGAGATGCATTTCCCG

LDLRex2(27 68 123 30) _119. _d0_f 112 ACGG G AAATG CATCTCCTACAAGTG 113 CGGGAAATGCATCTCCTACAAGT 114 GGGAAATGCATCTCCTACAAG

LDLRex2(27 68 123 30) _119. _d0_r 115 CACTTGTAG GAG ATG CATTTCCCGT 116 ACTTGTAG GAG ATG CATTTCCCG 117 CTTGTAGGAGATGCATTTCCC

LDLRex2(27 68 123 30) _120. _d0_f 118 CGGGAAATGCATCTCCTACAAGTGG 119 GGGAAATGCATCTCCTACAAGTG 120 G G AAATG CATCTCCTACAAGT

LDLRex2(27 68 123 30) _120. _d0_r 121 CCACTTGTAG GAG ATG CATTTCCCG 122 CACTTGTAG GAG ATG CATTTCCC 123 ACTTGTAG GAG ATG CATTTCC

LDLRex2(27 68 123 30) _121. _d0_f 124 GGGAAATGCATCTCCTACAAGTGGG 125 G G AAATG CATCTCCTACAAGTGG 126 GAAATGCATCTCCTACAAGTG

LDLRex2(27 68 123 30) _121. _d0_r 127 CCCACTTGTAGGAGATGCATTTCCC 128 CCACTTGTAG GAG ATG CATTTCC 129 CACTTGTAG GAG ATG CATTTC

LDLRex2(27 68 123 30) _122. _d0_f 130 G G AAATG CATCTCCTACAAGTGG GT 131 GAAATGCATCTCCTACAAGTGGG 132 AAATGCATCTCCTACAAGTGG

LDLRex2(27 68 123 30) _122. _d0_r 133 ACCCACTTGTAGGAGATGCATTTCC 134 CCCACTTGTAGGAGATGCATTTC 135 CCACTTGTAG GAG ATG CATTT

LDLRex2(27 68 123 30) _123. _d0_f 136 GAAATGCATCTCCTACAAGTGGGTC 137 AAATG CATCTCCTACAAGTGG GT 138 AATGCATCTCCTACAAGTGGG

LDLRex2(27 68 123 30) _123. _d0_r 139 G ACCCACTTGTAG GAG ATG CATTTC 140 ACCCACTTGTAGGAGATGCATTT 141 CCCACTTGTAGGAGATGCATT

LDLRex2(27 68 123 30) _124. _d0_f 142 AAATG CATCTCCTACAAGTGG GTCT 143 AATG CATCTCCTACAAGTG GGTC 144 ATGCATCTCCTACAAGTGGGT

LDLRex2(27 68 123 30) _124. _d0_r 145 AGACCCACTTGTAGGAGATGCATTT 146 G ACCCACTTGTAG GAG ATG CATT 147 ACCCACTTGTAGGAGATGCAT

LDLRex2(27 68 123 30) _125. _d0_f 148 AATGCATCTCCTACAAGTGGGTCTG 149 ATGCATCTCCTACAAGTGGGTCT 150 TG CATCTCCTACAAGTG GGTC

LDLRex2(27 68 123 30) _125. _d0_r 151 CAGACCCACTTGTAGGAGATGCATT 152 AGACCCACTTGTAGGAGATGCAT 153 G ACCCACTTGTAG GAG ATG CA

LDLRex2(27 68 123 30) _126. _d0_f 154 ATGCATCTCCTACAAGTGGGTCTGC 155 TG CATCTCCTACAAGTGG GTCTG 156 G CATCTCCTACAAGTGG GTCT

LDLRex2(27 68 123 30) _126. _d0_r 157 G CAG ACCCACTTGTAG GAG ATG CAT 158 CAGACCCACTTGTAGGAGATGCA 159 AGACCCACTTGTAGGAGATGC

LDLRex2(27 68 123 30) _127. _d0_f 160 TGCATCTCCTACAAGTGGGTCTGCG 161 GCATCTCCTACAAGTGGGTCTGC 162 CATCTCCTACAAGTGGGTCTG

LDLRex2(27 68 123 30) _127_ _d0_r 163 CGCAGACCCACTTGTAGGAGATGCA 164 G CAG ACCCACTTGTAG GAG ATG C 165 CAGACCCACTTGTAGGAGATG

LDLRex2(27 68 123 30) _128. _d0_f 166 GCATCTCCTACAAGTGGGTCTGCGA 167 CATCTCCTACAAGTG GGTCTG CG 168 ATCTCCTACAAGTG GGTCTG C

LDLRex2(27 68 123 30) _128. _d0_r 169 TCG CAG ACCCACTTGTAG GAG ATG C 170 CG CAG ACCCACTTGTAG GAG ATG 171 G CAG ACCCACTTGTAG GAG AT

LDLRex2(27 68 123 30) _129. _d0_f 172 CATCTCCTACAAGTG GGTCTG CG AT 173 ATCTCCTACAAGTG GGTCTG CG A 174 TCTCCTACAAGTGGGTCTGCG

LDLRex2(27 68 123 30) _129. _d0_r 175 ATCGCAGACCCACTTGTAGGAGATG 176 TCG CAG ACCCACTTGTAG GAG AT 177 CG CAG ACCCACTTGTAG GAGA

LDLRex2(27 68 123 30) _130_ _d0_f 178 ATCTCCTACAAGTG GGTCTG CG ATG 179 TCTCCTACAAGTGGGTCTGCGAT 180 CTCCTACAAGTGGGTCTGCGA

LDLRex2(27 68 123 30) _130. _d0_r 181 CATCGCAGACCCACTTGTAGGAGAT 182 ATCGCAGACCCACTTGTAGGAGA 183 TCG CAG ACCCACTTGTAG GAG

LDLRex2(27;68;123;30) _131. _d0_f 184 TCTCCTACAAGTGGGTCTGCGATGG 185 CTCCTACAAGTGG GTCTG CG ATG 186 TCCTACAAGTGGGTCTGCGAT

able 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27 68 123 30) _131_ _d0_r 187 CCATCGCAGACCCACTTGTAGGAGA 188 CATCGCAGACCCACTTGTAGGAG 189 ATCGCAGACCCACTTGTAGGA

LDLRex2(27 68 123 30) _132_ _d0_f 190 CTCCTACAAGTG G GTCTG CG ATG GC 191 TCCTACAAGTGG GTCTG CG ATG G 192 CCTACAAGTG GGTCTG CG ATG

LDLRex2(27 68 123 30) _132_ _d0_r 193 G CCATCG CAG ACCCACTTGTAG GAG 194 CCATCGCAGACCCACTTGTAGGA 195 CATCGCAGACCCACTTGTAGG

LDLRex2(27 68 123 30) _133_ _d0_f 196 TCCTACAAGTGG GTCTG CG ATG GCA 197 CCTACAAGTG GGTCTG CG ATGG C 198 CTACAAGTGG GTCTG CG ATG G

LDLRex2(27 68 123 30) _133_ _d0_r 199 TG CCATCG CAG ACCCACTTGTAG G A 200 GCCATCGCAGACCCACTTGTAGG 201 CCATCGCAGACCCACTTGTAG

LDLRex2(27 68 123 30) _134_ _d0_f 202 CCTACAAGTG GGTCTG CG ATGG CAG 203 CTACAAGTG G GTCTG CG ATG GCA 204 TACAAGTGG GTCTG CG ATG GC

LDLRex2(27 68 123 30) _134_ _d0_r 205 CTG CCATCG CAG ACCCACTTGTAG G 206 TG CCATCG CAG ACCCACTTGTAG 207 G CCATCG CAG ACCCACTTGTA

LDLRex2(27 68 123 30) _135_ _d0_f 208 CTACAAGTG G GTCTG CG ATG GCAGC 209 TACAAGTGG GTCTG CG ATG GCAG 210 ACAAGTG GGTCTG CG ATGG CA

LDLRex2(27 68 123 30) _135_ _d0_r 211 GCTGCCATCGCAGACCCACTTGTAG 212 CTG CCATCG CAG ACCCACTTGTA 213 TG CCATCG CAG ACCCACTTGT

LDLRex2(27 68 123 30) _136_ _d0_f 214 TACAAGTGGGTCTGCGATGGCAGCG 215 ACAAGTG GGTCTG CG ATGG CAG C 216 CAAGTGGGTCTGCGATGGCAG

LDLRex2(27 68 123 30) _136_ _d0_r 217 CGCTGCCATCGCAGACCCACTTGTA 218 GCTGCCATCGCAGACCCACTTGT 219 CTG CCATCG CAG ACCCACTTG

LDLRex2(27 68 123 30) _137_ _d0_f 220 ACAAGTGGGTCTGCGATGGCAGCGC 221 CAAGTGGGTCTGCGATGGCAGCG 222 AAGTGGGTCTGCGATGGCAGC

LDLRex2(27 68 123 30) _137_ _d0_r 223 G CG CTG CCATCG CAG ACCCACTTGT 224 CGCTGCCATCGCAGACCCACTTG 225 GCTGCCATCGCAGACCCACTT

LDLRex2(27 68 123 30) _138. _d0_f 226 CAAGTGGGTCTGCGATGGCAGCGCT 227 AAGTGGGTCTGCGATGGCAGCGC 228 AGTG GGTCTG CG ATGG CAG CG

LDLRex2(27 68 123 30) _138. _d0_r 229 AGCGCTGCCATCGCAGACCCACTTG 230 G CG CTG CCATCG CAG ACCCACTT 231 CGCTGCCATCGCAGACCCACT

LDLRex2(27 68 123 30) _139. _d0_f 232 AAGTGGGTCTGCGATGGCAGCGCTG 233 AGTGGGTCTGCGATGGCAGCGCT 234 GTGGGTCTGCGATGGCAGCGC

LDLRex2(27 68 123 30) _139. _d0_r 235 CAGCGCTGCCATCGCAGACCCACTT 236 AGCGCTGCCATCGCAGACCCACT 237 G CGCTG CCATCG CAG ACCCAC

LDLRex2(27 68 123 30) _140. _d0_f 238 AGTGGGTCTGCGATGGCAGCGCTGA 239 GTGGGTCTGCGATGGCAGCGCTG 240 TGGGTCTGCGATGGCAGCGCT

LDLRex2(27 68 123 30) _140. _d0_r 241 TCAGCGCTGCCATCGCAGACCCACT 242 CAGCGCTGCCATCGCAGACCCAC 243 AGCGCTGCCATCGCAGACCCA

LDLRex2(27 68 123 30) _141. _d0_f 244 GTGGGTCTGCGATGGCAGCGCTGAG 245 TGGGTCTGCGATGGCAGCGCTGA 246 GGGTCTGCGATGGCAGCGCTG

LDLRex2(27 68 123 30) _141. _d0_r 247 CTCAGCGCTGCCATCGCAGACCCAC 248 TCAGCGCTGCCATCGCAGACCCA 249 CAGCGCTGCCATCGCAGACCC

LDLRex2(27 68 123 30) _142. _d0_f 250 TGGGTCTGCGATGGCAGCGCTGAGT 251 GGGTCTGCGATGGCAGCGCTGAG 252 GGTCTGCGATGGCAGCGCTGA

LDLRex2(27 68 123 30) _142. _d0_r 253 ACTCAG CGCTG CCATCG CAG ACCCA 254 CTCAGCGCTGCCATCGCAGACCC 255 TCAGCGCTGCCATCGCAGACC

LDLRex2(27 68 123 30) _143. _d0_f 256 GGGTCTGCGATGGCAGCGCTGAGTG 257 GGTCTGCGATGGCAGCGCTGAGT 258 GTCTGCGATGGCAGCGCTGAG

LDLRex2(27 68 123 30) _143. _d0_r 259 CACTCAG CGCTG CCATCG CAG ACCC 260 ACTCAG CGCTG CCATCG CAG ACC 261 CTCAGCGCTGCCATCGCAGAC

LDLRex2(27 68 123 30) _144. _d0_f 262 G GTCTG CG ATG GCAGCG CTG AGTG C 263 GTCTGCGATGGCAGCGCTGAGTG 264 TCTGCGATGGCAGCGCTGAGT

LDLRex2(27 68 123 30) _144. _d0_r 265 GCACTCAGCGCTGCCATCGCAGACC 266 CACTCAG CGCTG CCATCG CAG AC 267 ACTCAGCGCTGCCATCGCAGA

LDLRex2(27 68 123 30) _145. _d0_f 268 GTCTGCGATGGCAGCGCTGAGTGCC 269 TCTGCGATGGCAGCGCTGAGTGC 270 CTGCGATGGCAGCGCTGAGTG

LDLRex2(27 68 123 30) _145. _d0_r 271 GGCACTCAGCGCTGCCATCGCAGAC 272 GCACTCAGCGCTGCCATCGCAGA 273 CACTCAG CGCTG CCATCG CAG

LDLRex2(27 68 123 30) _146. _d0_f 274 TCTGCGATGGCAGCGCTGAGTGCCA 275 CTGCGATGGCAGCGCTGAGTGCC 276 TGCGATGGCAGCGCTGAGTGC

LDLRex2(27;68;123;30) _146. _d0_r 277 TGGCACTCAGCGCTGCCATCGCAGA 278 G GCACTCAG CGCTG CCATCG CAG 279 GCACTCAGCGCTGCCATCGCA

able 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27 68 123 30) _147. _d0_f 280 CTGCGATGGCAGCGCTGAGTGCCAG 281 TGCGATGGCAGCGCTGAGTGCCA 282 GCGATGGCAGCGCTGAGTGCC

LDLRex2(27 68 123 30) _147. _d0_r 283 CTG GCACTCAG CGCTG CCATCG CAG 284 TG GCACTCAG CGCTG CCATCG CA 285 GGCACTCAGCGCTGCCATCGC

LDLRex2(27 68 123 30) _148_ _d0_f 286 TGCGATGGCAGCGCTGAGTGCCAGG 287 GCGATGGCAGCGCTGAGTGCCAG 288 CGATGGCAGCGCTGAGTGCCA

LDLRex2(27 68 123 30) _148_ _d0_r 289 CCTG GCACTCAG CGCTG CCATCG CA 290 CTG GCACTCAG CGCTG CCATCG C 291 TGGCACTCAGCGCTGCCATCG

LDLRex2(27 68 123 30) _149_ _d0_f 292 GCGATGGCAGCGCTGAGTGCCAGGA 293 CGATGGCAGCGCTGAGTGCCAGG 294 GATGGCAGCGCTGAGTGCCAG

LDLRex2(27 68 123 30) _149_ _d0_r 295 TCCTG GCACTCAG CGCTG CCATCG C 296 CCTG GCACTCAG CGCTG CCATCG 297 CTGGCACTCAGCGCTGCCATC

LDLRex2(27 68 123 30) _150. _d0_f 298 CGATGGCAGCGCTGAGTGCCAGGAT 299 GATGGCAGCGCTGAGTGCCAGGA 300 ATGGCAGCGCTGAGTGCCAGG

LDLRex2(27 68 123 30) _150. _d0_r 301 ATCCTGGCACTCAGCGCTGCCATCG 302 TCCTG GCACTCAG CGCTG CCATC 303 CCTGGCACTCAGCGCTGCCAT

LDLRex2(27 68 123 30) _151. _d0_f 304 GATGGCAGCGCTGAGTGCCAGGATG 305 ATGGCAGCGCTGAGTGCCAGGAT 306 TGGCAGCGCTGAGTGCCAGGA

LDLRex2(27 68 123 30) _151. _d0_r 307 CATCCTGGCACTCAGCGCTGCCATC 308 ATCCTGGCACTCAGCGCTGCCAT 309 TCCTG GCACTCAG CGCTG CCA

LDLRex2(27 68 123 30) _152. _d0_f 310 ATGGCAGCGCTGAGTGCCAGGATGG 311 TGGCAGCGCTGAGTGCCAGGATG 312 GGCAGCGCTGAGTGCCAGGAT

LDLRex2(27 68 123 30) _152. _d0_r 313 CCATCCTGGCACTCAGCGCTGCCAT 314 CATCCTGGCACTCAGCGCTGCCA 315 ATCCTGGCACTCAGCGCTGCC

LDLRex2(27 68 123 30) _153. _d0_f 316 TGGCAGCGCTGAGTGCCAGGATGGC 317 GGCAGCGCTGAGTGCCAGGATGG 318 GCAGCGCTGAGTGCCAGGATG

LDLRex2(27 68 123 30) _153_ _d0_r 319 G CCATCCTG GCACTCAG CGCTG CCA 320 CCATCCTGGCACTCAGCGCTGCC 321 CATCCTGGCACTCAGCGCTGC

LDLRex2(27 68 123 30) _154. _d0_f 322 GGCAGCGCTGAGTGCCAGGATGGCT 323 GCAGCGCTGAGTGCCAGGATGGC 324 CAGCGCTGAGTGCCAGGATGG

LDLRex2(27 68 123 30) _154. _d0_r 325 AGCCATCCTGGCACTCAGCGCTGCC 326 G CCATCCTG GCACTCAG CGCTG C 327 CCATCCTGGCACTCAGCGCTG

LDLRex2(27 68 123 30) _155. _d0_f 328 GCAGCGCTGAGTGCCAGGATGGCTC 329 CAGCGCTGAGTGCCAGGATGGCT 330 AGCGCTGAGTGCCAGGATGGC

LDLRex2(27 68 123 30) _155. _d0_r 331 GAGCCATCCTGGCACTCAGCGCTGC 332 AGCCATCCTGGCACTCAGCGCTG 333 G CCATCCTG GCACTCAG CGCT

LDLRex2(27 68 123 30) _156. _d0_f 334 CAGCGCTGAGTGCCAGGATGGCTCT 335 AGCGCTGAGTGCCAGGATGGCTC 336 GCGCTGAGTGCCAGGATGGCT

LDLRex2(27 68 123 30) _156. _d0_r 337 AGAGCCATCCTGGCACTCAGCGCTG 338 GAGCCATCCTGGCACTCAGCGCT 339 AGCCATCCTGGCACTCAGCGC

LDLRex2(27 68 123 30) _157. _d0_f 340 AGCG CTG AGTG CCAG G ATG GCTCTG 341 GCGCTGAGTGCCAGGATGGCTCT 342 CG CTG AGTG CCAG G ATG GCTC

LDLRex2(27 68 123 30) _157. _d0_r 343 CAGAGCCATCCTGGCACTCAGCGCT 344 AGAGCCATCCTGGCACTCAGCGC 345 GAGCCATCCTGGCACTCAGCG

LDLRex2(27 68 123 30) _158. _d0_f 346 GCGCTGAGTGCCAGGATGGCTCTGA 347 CGCTG AGTG CCAG G ATG GCTCTG 348 G CTG AGTGCCAG G ATG GCTCT

LDLRex2(27 68 123 30) _158. _d0_r 349 TCAG AGCCATCCTGG CACTCAG CG C 350 CAGAGCCATCCTGGCACTCAGCG 351 AGAGCCATCCTGGCACTCAGC

LDLRex2(27 68 123 30) _159. _d0_f 352 CGCTGAGTGCCAGGATGGCTCTGAT 353 G CTG AGTG CCAG G ATG GCTCTG A 354 CTGAGTGCCAGGATGGCTCTG

LDLRex2(27 68 123 30) _159. _d0_r 355 ATCAGAGCCATCCTGGCACTCAGCG 356 TCAGAGCCATCCTGGCACTCAGC 357 CAGAGCCATCCTGGCACTCAG

LDLRex2(27 68 123 30) _160. _d0_f 358 GCTGAGTGCCAGGATGGCTCTGATG 359 CTGAGTGCCAGGATGGCTCTGAT 360 TGAGTGCCAGGATGGCTCTGA

LDLRex2(27 68 123 30) _160. _d0_r 361 CATCAGAGCCATCCTGGCACTCAGC 362 ATCAGAGCCATCCTGGCACTCAG 363 TCAGAGCCATCCTGGCACTCA

LDLRex2(27 68 123 30) _161. _d0_f 364 CTGAGTGCCAGGATGGCTCTGATGA 365 TGAGTGCCAGGATGGCTCTGATG 366 GAGTGCCAGGATGGCTCTGAT

LDLRex2(27 68 123 30) _161. _d0_r 367 TCATCAGAGCCATCCTGGCACTCAG 368 CATCAGAGCCATCCTGGCACTCA 369 ATCAGAGCCATCCTGGCACTC

LDLRex2(27;68;123;30) _162. _d0_f 370 TGAGTGCCAGGATGGCTCTGATGAG 371 GAGTGCCAGGATGGCTCTGATGA 372 AGTGCCAGGATGGCTCTGATG

able 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27 68 123 30) _162. _d0_r 373 CTCATCAGAGCCATCCTGGCACTCA 374 TCATCAGAGCCATCCTGGCACTC 375 CATCAGAGCCATCCTGGCACT

LDLRex2(27 68 123 30) _163_ _d0_f 376 GAGTGCCAGGATGGCTCTGATGAGT 377 AGTG CCAG G ATG GCTCTG ATG AG 378 GTGCCAGGATGGCTCTGATGA

LDLRex2(27 68 123 30) _163_ _d0_r 379 ACTCATCAGAGCCATCCTGGCACTC 380 CTCATCAGAGCCATCCTGGCACT 381 TCATCAGAGCCATCCTGGCAC

LDLRex2(27 68 123 30) _164. _d0_f 382 AGTG CCAG G ATG GCTCTG ATG AGTC 383 GTGCCAGGATGGCTCTGATGAGT 384 TGCCAGGATGGCTCTGATGAG

LDLRex2(27 68 123 30) _164. _d0_r 385 GACTCATCAGAGCCATCCTGGCACT 386 ACTCATCAGAGCCATCCTGGCAC 387 CTCATCAG AG CCATCCTG G CA

LDLRex2(27 68 123 30) _165. _d0_f 388 GTGCCAGGATGGCTCTGATGAGTCC 389 TGCCAGGATGGCTCTGATGAGTC 390 GCCAGGATGGCTCTGATGAGT

LDLRex2(27 68 123 30) _165. _d0_r 391 G G ACTCATCAG AG CCATCCTG GCAC 392 GACTCATCAGAGCCATCCTGGCA 393 ACTCATCAG AG CCATCCTG GC

LDLRex2(27 68 123 30) _166. _d0_f 394 TGCCAGGATGGCTCTGATGAGTCCC 395 GCCAGGATGGCTCTGATGAGTCC 396 CCAGGATGGCTCTGATGAGTC

LDLRex2(27 68 123 30) _166. _d0_r 397 GGGACTCATCAGAGCCATCCTGGCA 398 G G ACTCATCAG AG CCATCCTG GC 399 GACTCATCAGAGCCATCCTGG

LDLRex2(27 68 123 30) _167. _d0_f 400 GCCAGGATGGCTCTGATGAGTCCCA 401 CCAGGATGGCTCTGATGAGTCCC 402 CAGGATGGCTCTGATGAGTCC

LDLRex2(27 68 123 30) _167. _d0_r 403 TGGGACTCATCAGAGCCATCCTGGC 404 GGGACTCATCAGAGCCATCCTGG 405 G G ACTCATCAG AG CCATCCTG

LDLRex2(27 68 123 30) _168. _d0_f 406 CCAGGATGGCTCTGATGAGTCCCAG 407 CAGGATGGCTCTGATGAGTCCCA 408 AGGATGGCTCTGATGAGTCCC

LDLRex2(27 68 123 30) _168. _d0_r 409 CTGGGACTCATCAGAGCCATCCTGG 410 TGGGACTCATCAGAGCCATCCTG 411 GGGACTCATCAGAGCCATCCT

LDLRex2(27 68 123 30) _169. _d0_f 412 CAGGATGGCTCTGATGAGTCCCAGG 413 AGGATGGCTCTGATGAGTCCCAG 414 GGATGGCTCTGATGAGTCCCA

LDLRex2(27 68 123 30) _169. _d0_r 415 CCTGGGACTCATCAGAGCCATCCTG 416 CTGGGACTCATCAGAGCCATCCT 417 TGGGACTCATCAGAGCCATCC

LDLRex2(27 68 123 30) _170. _d0_f 418 AGGATGGCTCTGATGAGTCCCAGGA 419 GGATGGCTCTGATGAGTCCCAGG 420 GATGGCTCTGATGAGTCCCAG

LDLRex2(27 68 123 30) _170. _d0_r 421 TCCTGGGACTCATCAGAGCCATCCT 422 CCTGGGACTCATCAGAGCCATCC 423 CTGGGACTCATCAGAGCCATC

LDLRex2(27 68 123 30) _171. _d0_f 424 GGATGGCTCTGATGAGTCCCAGGAG 425 GATGGCTCTGATGAGTCCCAGGA 426 ATGGCTCTGATGAGTCCCAGG

LDLRex2(27 68 123 30) _171. _d0_r 427 CTCCTGGGACTCATCAGAGCCATCC 428 TCCTGGGACTCATCAGAGCCATC 429 CCTGGGACTCATCAGAGCCAT

LDLRex2(27 68 123 30) _172. _d0_f 430 GATGGCTCTGATGAGTCCCAGGAGA 431 ATGGCTCTGATGAGTCCCAGGAG 432 TGGCTCTGATGAGTCCCAGGA

LDLRex2(27 68 123 30) _172. _d0_r 433 TCTCCTGGGACTCATCAGAGCCATC 434 CTCCTGGGACTCATCAGAGCCAT 435 TCCTGGGACTCATCAGAGCCA

LDLRex2(27 68 123 30) _173. _d0_f 436 ATGGCTCTGATGAGTCCCAGGAGAC 437 TGGCTCTGATGAGTCCCAGGAGA 438 GGCTCTGATGAGTCCCAGGAG

LDLRex2(27 68 123 30) _173. _d0_r 439 GTCTCCTGGGACTCATCAGAGCCAT 440 TCTCCTGGGACTCATCAGAGCCA 441 CTCCTGGGACTCATCAGAGCC

LDLRex2(27 68 123 30) _174. _d0_f 442 TGGCTCTGATGAGTCCCAGGAGACG 443 GGCTCTGATGAGTCCCAGGAGAC 444 G CTCTG ATG AGTCCCAG GAGA

LDLRex2(27 68 123 30) _174. _d0_r 445 CGTCTCCTGGGACTCATCAGAGCCA 446 GTCTCCTGGGACTCATCAGAGCC 447 TCTCCTGGGACTCATCAGAGC

LDLRex2(27 68 123 30) _175. _d0_f 448 GGCTCTGATGAGTCCCAGGAGACGT 449 G CTCTG ATG AGTCCCAG G AG ACG 450 CTCTGATGAGTCCCAGGAGAC

LDLRex2(27 68 123 30) _175. _d0_r 451 ACGTCTCCTGGGACTCATCAGAGCC 452 CGTCTCCTGGGACTCATCAGAGC 453 GTCTCCTGGGACTCATCAGAG

LDLRex2(27 68 123 30) _176. _d0_f 454 G CTCTG ATG AGTCCCAG GAG ACGTG 455 CTCTGATGAGTCCCAGGAGACGT 456 TCTGATGAGTCCCAGGAGACG

LDLRex2(27 68 123 30) _176. _d0_r 457 CACGTCTCCTGGGACTCATCAGAGC 458 ACGTCTCCTGGGACTCATCAGAG 459 CGTCTCCTGGGACTCATCAGA

LDLRex2(27 68 123 30) _177. _d0_f 460 CTCTGATGAGTCCCAGGAGACGTGC 461 TCTGATGAGTCCCAGGAGACGTG 462 CTGATGAGTCCCAGGAGACGT

LDLRex2(27;68;123;30) _177. _d0_r 463 GCACGTCTCCTGGGACTCATCAGAG 464 CACGTCTCCTGGGACTCATCAGA 465 ACGTCTCCTGGGACTCATCAG

able 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27 68 123 30) _178_d0_f 466 TCTGATGAGTCCCAGGAGACGTGCT 467 CTGATGAGTCCCAGGAGACGTGC 468 TGATGAGTCCCAGGAGACGTG

LDLRex2(27 68 123 30) _178_d0_r 469 AGCACGTCTCCTGGGACTCATCAGA 470 G CACGTCTCCTGG GACTCATCAG 471 CACGTCTCCTGGGACTCATCA

LDLRex2(27 68 123 30) _179_d0_f 472 CTGATGAGTCCCAGGAGACGTGCTG 473 TGATGAGTCCCAGGAGACGTGCT 474 GATGAGTCCCAGGAGACGTGC

LDLRex2(27 68 123 30) _179_d0_r 475 CAGCACGTCTCCTGGGACTCATCAG 476 AGCACGTCTCCTGGGACTCATCA 477 G CACGTCTCCTGG GACTCATC

LDLRex2(27 68 123 30) _180_d0_f 478 TGATGAGTCCCAGGAGACGTGCTGT 479 GATGAGTCCCAGGAGACGTGCTG 480 ATGAGTCCCAGGAGACGTGCT

LDLRex2(27 68 123 30) _180_d0_r 481 ACAG CACGTCTCCTGG G ACTCATCA 482 CAGCACGTCTCCTGGGACTCATC 483 AGCACGTCTCCTGGGACTCAT

LDLRex2(27 68 123 30) _181_d0_f 484 GATGAGTCCCAGGAGACGTGCTGTG 485 ATGAGTCCCAGGAGACGTGCTGT 486 TGAGTCCCAGGAGACGTGCTG

LDLRex2(27 68 123 30) _181_d0_r 487 CACAG CACGTCTCCTGG GACTCATC 488 ACAG CACGTCTCCTGG G ACTCAT 489 CAGCACGTCTCCTGGGACTCA

LDLRex2(27 68 123 30) _182_d0_f 490 ATGAGTCCCAGGAGACGTGCTGTGA 491 TGAGTCCCAGGAGACGTGCTGTG 492 GAGTCCCAGGAGACGTGCTGT

LDLRex2(27 68 123 30) _182_d0_r 493 TCACAG CACGTCTCCTGG G ACTCAT 494 CACAG CACGTCTCCTGG GACTCA 495 ACAG CACGTCTCCTGG GACTC

LDLRex2(27 68 123 30) _183_d0_f 496 TGAGTCCCAGGAGACGTGCTGTGAG 497 GAGTCCCAGGAGACGTGCTGTGA 498 AGTCCCAGGAGACGTGCTGTG

LDLRex2(27 68 123 30) _183_d0_r 499 CTCACAG CACGTCTCCTGG GACTCA 500 TCACAG CACGTCTCCTGG GACTC 501 CACAG CACGTCTCCTGG G ACT

LDLRex2(27 68 123 30) _184_d0_f 502 GAGTCCCAGGAGACGTGCTGTGAGT 503 AGTCCCAGGAGACGTGCTGTGAG 504 GTCCCAG GAG ACGTG CTGTG A

LDLRex2(27 68 123 30) _184_d0_r 505 ACTCACAGCACGTCTCCTGGGACTC 506 CTCACAG CACGTCTCCTGG G ACT 507 TCACAG CACGTCTCCTGG G AC

LDLRex2(27 68 123 30) _185_d0_f 508 AGTCCCAGGAGACGTGCTGTGAGTC 509 GTCCCAG GAG ACGTG CTGTG AGT 510 TCCCAGGAGACGTGCTGTGAG

LDLRex2(27 68 123 30) _185_d0_r 511 GACTCACAGCACGTCTCCTGGGACT 512 ACTCACAGCACGTCTCCTGGGAC 513 CTCACAG CACGTCTCCTGG G A

LDLRex2(27 68 123 30) _186_d0_f 514 GTCCCAG G AG ACGTG CTGTG AGTCC 515 TCCCAGGAGACGTGCTGTGAGTC 516 CCCAGGAGACGTGCTGTGAGT

LDLRex2(27 68 123 30) _186_d0_r 517 GGACTCACAGCACGTCTCCTGGGAC 518 GACTCACAGCACGTCTCCTGGGA 519 ACTCACAGCACGTCTCCTGGG

LDLRex2(27 68 123 30) _187_d0_f 520 TCCCAGGAGACGTGCTGTGAGTCCC 521 CCCAGGAGACGTGCTGTGAGTCC 522 CCAGGAGACGTGCTGTGAGTC

LDLRex2(27 68 123 30) _187_d0_r 523 GGGACTCACAGCACGTCTCCTGGGA 524 GGACTCACAGCACGTCTCCTGGG 525 GACTCACAGCACGTCTCCTGG

LDLRex2(27 68 123 30) _188_d0_f 526 CCCAGGAGACGTGCTGTGAGTCCCC 527 CCAGGAGACGTGCTGTGAGTCCC 528 CAGGAGACGTGCTGTGAGTCC

LDLRex2(27 68 123 30) _188_d0_r 529 GGGGACTCACAGCACGTCTCCTGGG 530 GGGACTCACAGCACGTCTCCTGG 531 GGACTCACAGCACGTCTCCTG

LDLRex2(27 68 123 30) _189_d0_f 532 CCAGGAGACGTGCTGTGAGTCCCCT 533 CAGGAGACGTGCTGTGAGTCCCC 534 AGGAGACGTGCTGTGAGTCCC

LDLRex2(27 68 123 30) _189_d0_r 535 AGGGGACTCACAGCACGTCTCCTGG 536 GGGGACTCACAGCACGTCTCCTG 537 GGGACTCACAGCACGTCTCCT

LDLRex2(27 68 123 30) _190 + l_d0_f 538 AGGAGACGTGCTGTGAGTCCCCTTT 539 G GAG ACGTG CTGTG AGTCCCCTT 540 GAGACGTGCTGTGAGTCCCCT

LDLRex2(27 68 123 30) _190 + l_d0_ - 541 AAAGGGGACTCACAGCACGTCTCCT 542 AAGGGGACTCACAGCACGTCTCC 543 AGGGGACTCACAGCACGTCTC

LDLRex2(27 68 123 30) _190 + 10_d0. . 544 GCTGTGAGTCCCCTTTGGGCATGAT 545 CTGTGAGTCCCCTTTGGGCATGA 546 TGTGAGTCCCCTTTGGGCATG

LDLRex2(27 68 123 30) _190 + 10_d0. . 547 ATCATG CCCAAAG GG G ACTCACAG C 548 TCATGCCCAAAGGGGACT CACAG 549 CATGCCCAAAGGGGACTCACA

LDLRex2(27 68 123 30) _190 + ll_d0_ . 550 CTGTGAGTCCCCTTTGGGCATGATA 551 TGTGAGTCCCCTTTGGGCATGAT 552 GTGAGTCCCCTTTGGGCATGA

LDLRex2(27 68 123 30) _190 + ll_d0. . 553 TATCATGCCCAAAGGGGACTCACAG 554 ATCATG CCCAAAG GG G ACTCACA 555 TCATGCCCAAAGGGGACTCAC

LDLRex2(27;68;123;30) _190 + 12_d0. . 556 TGTGAGTCCCCTTTGGGCATGATAT 557 GTGAGTCCCCTTTGGGCATGATA 558 TGAGTCCCCTTTGGGCATGAT

able 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27 68 123 30) _190 + 12_d0_ 559 ATATCATG CCCAAAG GG G ACTCACA 560 TATCATGCCCAAAGGGGACTCAC 561 ATCATGCCCAAAGGGGACTCA

LDLRex2(27 68 123 30) _190 + 13_d0_ 562 GTGAGTCCCCTTTGGGCATGATATG 563 TGAGTCCCCTTTGGGCATGATAT 564 GAGTCCCCTTTGGGCATGATA

LDLRex2(27 68 123 30) _190 + 13_d0_ 565 CATATCATG CCCAAAG GG G ACTCAC 566 ATATCATG CCCAAAG GG GACTCA 567 TATCATGCCCAAAGGGGACTC

LDLRex2(27 68 123 30) _190 + 14_d0_ 568 TGAGTCCCCTTTGGGCATGATATGC 569 GAGTCCCCTTTGGGCATGATATG 570 AGTCCCCTTTGGGCATGATAT

LDLRex2(27 68 123 30) _190 + 14_d0_ 571 GCATATCATGCCCAAAGGGGACTCA 572 CATATCATG CCCAAAG GG GACTC 573 ATATCATG CCCAAAG GG G ACT

LDLRex2(27 68 123 30) _190 + 15_d0_ 574 GAGTCCCCTTTGGGCATGATATGCA 575 AGTCCCCTTTGGGCATGATATGC 576 GTCCCCTTTGGGCATGATATG

LDLRex2(27 68 123 30) _190 + 15_d0_ 577 TGCATATCATGCCCAAAGGGGACTC 578 GCATATCATGCCCAAAGGGGACT 579 CATATCATG CCCAAAG GG G AC

LDLRex2(27 68 123 30) _190 + 2_d0_f 580 G G AG ACGTG CTGTG AGTCCCCTTTG 581 GAGACGTGCTGTGAGTCCCCTTT 582 AG ACGTG CTGTGAGTCCCCTT

LDLRex2(27 68 123 30) _190 + 2_d0_r 583 CAAAGGGGACTCACAGCACGTCTCC 584 AAAGGGGACTCACAGCACGTCTC 585 AAGGGGACTCACAGCACGTCT

LDLRex2(27 68 123 30) _190 + 3_d0_f 586 GAGACGTGCTGTGAGTCCCCTTTGG 587 AG ACGTG CTGTG AGTCCCCTTTG 588 GACGTGCTGTGAGTCCCCTTT

LDLRex2(27 68 123 30) _190 + 3_d0_r 589 CCAAAGGGGACTCACAGCACGTCTC 590 CAAAGGGGACTCACAGCACGTCT 591 AAAGGGGACTCACAGCACGTC

LDLRex2(27 68 123 30) _190 + 4_d0_f 592 AG ACGTG CTGTG AGTCCCCTTTGG G 593 GACGTGCTGTGAGTCCCCTTTGG 594 ACGTG CTGTG AGTCCCCTTTG

LDLRex2(27 68 123 30) _190 + 4_d0_r 595 CCCAAAG G GG ACTCACAG CACGTCT 596 CCAAAGGGGACTCACAGCACGTC 597 CAAAGGGGACTCACAGCACGT

LDLRex2(27 68 123 30) _190 + 5_d0_f 598 GACGTGCTGTGAGTCCCCTTTGGGC 599 ACGTG CTGTG AGTCCCCTTTG G G 600 CGTGCTGTGAGTCCCCTTTGG

LDLRex2(27 68 123 30) _190 + 5_d0_r 601 G CCCAAAG GG G ACTCACAGCACGTC 602 CCCAAAG G GG ACTCACAG CACGT 603 CCAAAGGGGACTCACAGCACG

LDLRex2(27 68 123 30) _190 + 6_d0_f 604 ACGTGCTGTGAGTCCCCTTTGGGCA 605 CGTGCTGTGAGTCCCCTTTGGGC 606 GTGCTGTGAGTCCCCTTTGGG

LDLRex2(27 68 123 30) _190 + 6_d0_r 607 TG CCCAAAG GG GACTCACAGCACGT 608 G CCCAAAG GG GACTCACAGCACG 609 CCCAAAGGGGACTCACAGCAC

LDLRex2(27 68 123 30) _190 + 7_d0_f 610 CGTGCTGTGAGTCCCCTTTGGGCAT 611 GTGCTGTGAGTCCCCTTTGGGCA 612 TGCTGTGAGTCCCCTTTGGGC

LDLRex2(27 68 123 30) _190 + 7_d0_r 613 ATGCCCAAAGGGGACTCACAGCACG 614 TG CCCAAAG GG GACTCACAGCAC 615 G CCCAAAG GG GACTCACAGCA

LDLRex2(27 68 123 30) _190 + 8_d0_f 616 GTGCTGTGAGTCCCCTTTGGGCATG 617 TGCTGTGAGTCCCCTTTGGGCAT 618 GCTGTGAGTCCCCTTTGGGCA

LDLRex2(27 68 123 30) _190 + 8_d0_r 619 CATGCCCAAAGGGGACTCACAGCAC 620 ATGCCCAAAGGGGACTCACAGCA 621 TG CCCAAAG GG GACTCACAGC

LDLRex2(27 68 123 30) _190 + 9_d0_f 622 TGCTGTGAGTCCCCTTTGGGCATGA 623 GCTGTGAGTCCCCTTTGGGCATG 624 CTGTGAGTCCCCTTTGGGCAT

LDLRex2(27 68 123 30) _190 + 9_d0_r 625 TCATGCCCAAAGGGGACTCACAGCA 626 CATGCCCAAAGGGGACTCACAGC 627 ATGCCCAAAGGGGACTCACAG

LDLRex2(27 68 123 30) _190_d0_f 628 CAGGAGACGTGCTGTGAGTCCCCTT 629 AGGAGACGTGCTGTGAGTCCCCT 630 GGAGACGTGCTGTGAGTCCCC

LDLRex2(27 68 123 30) _190_d0_r 631 AAGGGGACTCACAGCACGTCTCCTG 632 AGGGGACTCACAGCACGTCTCCT 633 GGGGACTCACAGCACGTCTCC

LDLRex2(27 68 123 30) _68 - l_dO_f 634 TCCTCTCTCTCAGTGGGCGACAGAT 635 CCTCTCTCTCAGTG GGCGACAGA 636 CTCTCTCTCAGTGGGCGACAG

LDLRex2(27 68 123 30) _68 - l_dO_r 637 ATCTGTCGCCCACTGAGAGAGAGGA 638 TCTGTCGCCCACTGAGAGAGAGG 639 CTGTCGCCCACTGAGAGAGAG

LDLRex2(27 68 123 30) _68 - 10_d0_f 640 TTCTCCTTTTCCTCTCTCTCAGTG G 641 TCTCCTTTTCCTCTCTCTCAGTG 642 CTCCTTTTCCTCTCTCTCAGT

LDLRex2(27 68 123 30) _68 - 10_d0_r 643 CCACTGAGAGAGAGGAAAAGGAGAA 644 CACTGAGAGAGAGGAAAAGGAGA 645 ACTGAGAGAGAGGAAAAGGAG

LDLRex2(27 68 123 30) _68 - ll_dO_f 646 TTTCTCCTTTTCCTCTCTCTCAGTG 647 TTCTCCTTTTCCTCTCTCTCAGT 648 TCTCCTTTTCCTCTCTCTCAG

LDLRex2(27;68;123;30) _68 - ll_dO_r 649 CACTGAGAGAGAGGAAAAGGAGAAA 650 ACTGAGAGAGAGGAAAAGGAGAA 651 CTGAGAGAGAGGAAAAGGAGA

e 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27;68;123;30) _68 - 12 _dO_ f 652 CTTTCTCCTTTTCCTCTCTCTCAGT 653 TTTCTCCTTTTCCTCTCTCTCAG 654 TTCTCCTTTTCCTCTCTCTCA

LDLRex2(27;68;123;30) _68 - 12 _dO_ r 655 ACTGAGAGAGAGGAAAAGGAGAAAG 656 CTGAGAGAGAGGAAAAGGAGAAA 657 TGAGAGAGAGGAAAAGGAGAA

LDLRex2(27;68;123;30) _68 - 13 _dO_ f 658 CCTTTCTCCTTTTCCTCTCTCTCAG 659 CTTTCTCCTTTTCCTCTCTCTCA 660 TTTCTCCTTTTCCTCTCTCTC

LDLRex2(27;68;123;30) _68 - 13 _dO_ r 661 CTGAGAGAGAGGAAAAGGAGAAAGG 662 TGAGAGAGAGGAAAAGGAGAAAG 663 GAGAGAGAGGAAAAGGAGAAA

LDLRex2(27;68;123;30) _68 - 14 _dO_ f 664 CCCTTTCTCCTTTTCCTCTCTCTCA 665 CCTTTCTCCTTTTCCTCTCTCTC 666 CTTTCTCCTTTTCCTCTCTCT

LDLRex2(27;68;123;30) _68 - 14 _dO_ r 667 TGAGAGAGAGGAAAAGGAGAAAGGG 668 GAGAGAGAGGAAAAGGAGAAAGG 669 AGAGAGAGGAAAAGGAGAAAG

LDLRex2(27;68;123;30) _68 - 15 _dO_ f 670 ACCCTTTCTCCTTTTCCTCTCTCTC 671 CCCTTTCTCCTTTTCCTCTCTCT 672 CCTTTCTCCTTTTCCTCTCTC

LDLRex2(27;68;123;30) _68 - 15 _dO_ r 673 GAGAGAGAGGAAAAGGAGAAAGGGT 674 AGAGAGAGGAAAAGGAGAAAGGG 675 GAGAGAGGAAAAGGAGAAAGG

LDLRex2(27;68;123;30) _68 - 2_ dO_f 676 TTCCTCTCTCTCAGTGGGCGACAGA 677 TCCTCTCTCTCAGTGGGCGACAG 678 CCTCTCTCTCAGTG G GCG ACA

LDLRex2(27;68;123;30) _68 - 2_ dO_r 679 TCTGTCGCCCACTGAGAGAGAGGAA 680 CTGTCGCCCACTGAGAGAGAGGA 681 TGTCGCCCACTGAGAGAGAGG

LDLRex2(27;68;123;30) _68 - 3_ dO_f 682 TTTCCTCTCTCTCAGTGGGCGACAG 683 TTCCTCTCTCTCAGTGGGCGACA 684 TCCTCTCTCTCAGTGGGCGAC

LDLRex2(27;68;123;30) _68 - 3_ dO_r 685 CTGTCGCCCACTGAGAGAGAGGAAA 686 TGTCGCCCACTGAGAGAGAGGAA 687 GTCGCCCACTGAGAGAGAGGA

LDLRex2(27;68;123;30) _68 - 4_ dO_f 688 TTTTCCTCTCTCTCAGTG GG CG ACA 689 TTTCCTCTCTCTCAGTGGGCGAC 690 TTCCTCTCTCTCAGTGGGCGA

LDLRex2(27;68;123;30) _68 - 4_ dO_r 691 TGTCGCCCACTGAGAGAGAGGAAAA 692 GTCGCCCACTGAGAGAGAGGAAA 693 TCGCCCACTGAGAGAGAGGAA

LDLRex2(27;68;123;30) _68 - 5_ dO_f 694 CTTTTCCTCTCTCTCAGTGGGCGAC 695 TTTTCCTCTCTCTCAGTGGGCGA 696 TTTCCTCTCTCTCAGTGGGCG

LDLRex2(27;68;123;30) _68 - 5_ dO_r 697 GTCGCCCACTGAGAGAGAGGAAAAG 698 TCGCCCACTGAGAGAGAGGAAAA 699 CGCCCACTGAGAGAGAGGAAA

LDLRex2(27;68;123;30) _68 - 6_ dO_f 700 CCTTTTCCTCTCTCTCAGTG GG CG A 701 CTTTTCCTCTCTCTCAGTG GG CG 702 TTTTCCTCTCTCTCAGTG GG C

LDLRex2(27;68;123;30) _68 - 6_ dO_r 703 TCGCCCACTGAGAGAGAGGAAAAGG 704 CGCCCACTGAGAGAGAGGAAAAG 705 GCCCACTGAGAGAGAGGAAAA

LDLRex2(27;68;123;30) _68 - 7_ dO_f 706 TCCTTTTCCTCTCTCTCAGTG GG CG 707 CCTTTTCCTCTCTCTCAGTG GG C 708 CTTTTCCTCTCTCTCAGTGGG

LDLRex2(27;68;123;30) _68 - 7_ dO_r 709 CGCCCACTGAGAGAGAGGAAAAGGA 710 GCCCACTGAGAGAGAGGAAAAGG 711 CCCACTGAGAGAGAGGAAAAG

LDLRex2(27;68;123;30) _68 - 8_ dO_f 712 CTCCTTTTCCTCTCTCTCAGTG GG C 713 TCCTTTTCCTCTCTCTCAGTGGG 714 CCTTTTCCTCTCTCTCAGTG G

LDLRex2(27;68;123;30) _68 - 8_ dO_r 715 GCCCACTGAGAGAGAGGAAAAGGAG 716 CCCACTGAGAGAGAGGAAAAGGA 717 CCACTG AG AG AG AG GAAAAG G

LDLRex2(27;68;123;30) _68 - 9_ dO_f 718 TCTCCTTTTCCTCTCTCTCAGTGGG 719 CTCCTTTTCCTCTCTCTCAGTG G 720 TCCTTTTCCTCTCTCTCAGTG

LDLRex2(27;68;123;30) _68 - 9_ dO_r 721 CCCACTGAGAGAGAGGAAAAGGAGA 722 CCACTGAGAGAGAGGAAAAGGAG 723 CACTGAGAGAGAGGAAAAGGA

LDLRex2(27;68;123;30) _68. _d0. J 724 CCTCTCTCTCAGTGGGCGACAGATG 725 CTCTCTCTCAGTGGGCGACAGAT 726 TCTCTCTCAGTGGGCGACAGA

LDLRex2(27;68;123;30) _68. _d0. j 727 CATCTGTCGCCCACTGAGAGAGAGG 728 ATCTGTCGCCCACTGAGAGAGAG 729 TCTGTCGCCCACTGAGAGAGA

LDLRex2(27;68;123;30 _69. _d0. J 730 CTCTCTCTCAGTGGGCGACAGATGC 731 TCTCTCTCAGTGGGCGACAGATG 732 CTCTCTCAGTGGGCGACAGAT

LDLRex2(27;68;123;30 _69 -dO. j 733 GCATCTGTCGCCCACTGAGAGAGAG 734 CATCTGTCGCCCACTGAGAGAGA 735 ATCTGTCGCCCACTGAGAGAG

LDLRex2(27;68;123;30 _70. -dO. J 736 TCTCTCTCAGTGGGCGACAGATGCG 737 CTCTCTCAGTGGGCGACAGATGC 738 TCTCTCAGTGGGCGACAGATG

LDLRex2(27;68;123;30 _70. .dO j 739 CGCATCTGTCGCCCACTGAGAGAGA 740 GCATCTGTCGCCCACTGAGAGAG 741 CATCTGTCGCCCACTGAGAGA

LDLRex2(27;68;123;30 _71 .dO J 742 CTCTCTCAGTGGGCGACAGATGCGA 743 TCTCTCAGTGGGCGACAGATGCG 744 CTCTCAGTGGGCGACAGATGC

able 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27 68 123 30) _71. _d0_r 745 TCGCATCTGTCGCCCACTGAGAGAG 746 CGCATCTGTCGCCCACTGAGAGA 747 GCATCTGTCGCCCACTGAGAG

LDLRex2(27 68 123 30) _72. _d0_f 748 TCTCTCAGTGGGCGACAGATGCGAA 749 CTCTCAGTGGGCGACAGATGCGA 750 TCTCAGTGGGCGACAGATGCG

LDLRex2(27 68 123 30) _72. _d0_r 751 TTCGCATCTGTCGCCCACTGAGAGA 752 TCG CATCTGTCG CCCACTG AG AG 753 CGCATCTGTCGCCCACTGAGA

LDLRex2(27 68 123 30) _73. _d0_f 754 CTCTCAGTGGGCGACAGATGCGAAA 755 TCTCAGTGGGCGACAGATGCGAA 756 CTCAGTGGGCGACAGATGCGA

LDLRex2(27 68 123 30) _73. _d0_r 757 TTTCGCATCTGTCGCCCACTGAGAG 758 TTCGCATCTGTCGCCCACTGAGA 759 TCG CATCTGTCG CCCACTG AG

LDLRex2(27 68 123 30) _74. _d0_f 760 TCTCAGTGGGCGACAGATGCGAAAG 761 CTCAGTGGGCGACAGATGCGAAA 762 TCAGTGGGCGACAGATGCGAA

LDLRex2(27 68 123 30) _74. _d0_r 763 CTTTCGCATCTGTCGCCCACTGAGA 764 TTTCG CATCTGTCG CCCACTG AG 765 TTCG CATCTGTCG CCCACTG A

LDLRex2(27 68 123 30) _75. _d0_f 766 CTCAGTGGGCGACAGATGCGAAAGA 767 TCAGTGGGCGACAGATGCGAAAG 768 CAGTGGGCGACAGATGCGAAA

LDLRex2(27 68 123 30) _75. _d0_r 769 TCTTTCGCATCTGTCGCCCACTGAG 770 CTTTCG CATCTGTCG CCCACTG A 771 TTTCGCATCTGTCGCCCACTG

LDLRex2(27 68 123 30) _76. _d0_f 772 TCAGTGGGCGACAGATGCGAAAGAA 773 CAGTGGGCGACAGATGCGAAAGA 774 AGTGGGCGACAGATGCGAAAG

LDLRex2(27 68 123 30) _76. _d0_r 775 TTCTTTCGCATCTGTCGCCCACTGA 776 TCTTTCGCATCTGTCGCCCACTG 111 CTTTCG CATCTGTCG CCCACT

LDLRex2(27 68 123 30) _77. _d0_f 778 CAGTGGGCGACAGATGCGAAAGAAA 779 AGTGGGCGACAGATGCGAAAGAA 780 GTGGGCGACAGATGCGAAAGA

LDLRex2(27 68 123 30) _77. _d0_r 781 TTTCTTTCGCATCTGTCGCCCACTG 782 TTCTTTCGCATCTGTCGCCCACT 783 TCTTTCGCATCTGTCGCCCAC

LDLRex2(27 68 123 30) _78. _d0_f 784 AGTGGGCGACAGATGCGAAAGAAAC 785 GTGGGCGACAGATGCGAAAGAAA 786 TGGGCGACAGATGCGAAAGAA

LDLRex2(27 68 123 30) _78. _d0_r 787 GTTTCTTTCGCATCTGTCGCCCACT 788 TTTCTTTCGCATCTGTCGCCCAC 789 TTCTTTCGCATCTGTCGCCCA

LDLRex2(27 68 123 30 _79. _d0_f 790 GTGGGCGACAGATGCGAAAGAAACG 791 TGGGCGACAGATGCGAAAGAAAC 792 GGGCGACAGATGCGAAAGAAA

LDLRex2(27 68 123 30 _79. _d0_r 793 CGTTTCTTTCGCATCTGTCGCCCAC 794 GTTTCTTTCGCATCTGTCGCCCA 795 TTTCTTTCG CATCTGTCG CCC

LDLRex2(27 68 123 30 _80. _d0_f 796 TGGGCGACAGATGCGAAAGAAACGA 797 GGGCGACAGATGCGAAAGAAACG 798 GGCGACAGATGCGAAAGAAAC

LDLRex2(27 68 123 30 _80. _d0_r 799 TCGTTTCTTTCGCATCTGTCGCCCA 800 CGTTTCTTTCGCATCTGTCGCCC 801 GTTTCTTTCGCATCTGTCGCC

LDLRex2(27 68 123 30 _81. _d0_f 802 GGGCGACAGATGCGAAAGAAACGAG 803 GGCGACAGATGCGAAAGAAACGA 804 GCGACAGATGCGAAAGAAACG

LDLRex2(27 68 123 30 _81. _d0_r 805 CTCGTTTCTTTCGCATCTGTCGCCC 806 TCGTTTCTTTCGCATCTGTCGCC 807 CGTTTCTTTCGCATCTGTCGC

LDLRex2(27 68 123 30 _82. _d0_f 808 GGCGACAGATGCGAAAGAAACGAGT 809 GCGACAGATGCGAAAGAAACGAG 810 CGACAGATGCGAAAGAAACGA

LDLRex2(27 68 123 30 _82. _d0_r 811 ACTCGTTTCTTTCG CATCTGTCG CC 812 CTCGTTTCTTTCGCATCTGTCGC 813 TCGTTTCTTTCGCATCTGTCG

LDLRex2(27 68 123 30 _83. _d0_f 814 GCGACAGATGCGAAAGAAACGAGTT 815 CGACAGATGCGAAAGAAACGAGT 816 GACAGATGCGAAAGAAACGAG

LDLRex2(27 68 123 30 _83. _d0_r 817 AACTCGTTTCTTTCGCATCTGTCGC 818 ACTCGTTTCTTTCG CATCTGTCG 819 CTCGTTTCTTTCGCATCTGTC

LDLRex2(27 68 123 30 _84. _d0_f 820 CGACAGATGCGAAAGAAACGAGTTC 821 GACAGATGCGAAAGAAACGAGTT 822 ACAGATGCGAAAGAAACGAGT

LDLRex2(27 68 123 30 _84. _d0_r 823 GAACTCGTTTCTTTCGCATCTGTCG 824 AACTCGTTTCTTTCGCATCTGTC 825 ACTCGTTTCTTTCG CATCTGT

LDLRex2(27 68 123 30 _85. _d0_f 826 GACAGATGCGAAAGAAACGAGTTCC 827 ACAGATGCGAAAGAAACGAGTTC 828 CAG ATG CG AAAG AAACG AGTT

LDLRex2(27 68 123 30 _85. _d0_r 829 GGAACTCGTTTCTTTCGCATCTGTC 830 GAACTCGTTTCTTTCGCATCTGT 831 AACTCGTTTCTTTCGCATCTG

LDLRex2(27 68 123 30 _86. _d0_f 832 ACAGATGCGAAAGAAACGAGTTCCA 833 CAGATGCGAAAGAAACGAGTTCC 834 AGATGCGAAAGAAACGAGTTC

LDLRex2(27;68;123;30 _86. _d0_r 835 TG G AACTCGTTTCTTTCG CATCTGT 836 GGAACTCGTTTCTTTCGCATCTG 837 GAACTCGTTTCTTTCGCATCT

able 1

SEQ ID SEQ ID

normal NO: 25 nt NO: 23 nt SEQ ID NO: 21 nt

LDLRex2(27 68 123 30) _87. _d0_f 838 CAGATGCGAAAGAAACGAGTTCCAG 839 AGATGCGAAAGAAACGAGTTCCA 840 GATGCGAAAGAAACGAGTTCC

LDLRex2(27 68 123 30) _87. _d0_r 841 CTGGAACTCGTTTCTTTCGCATCTG 842 TGGAACTCGTTTCTTTCGCATCT 843 GGAACTCGTTTCTTTCGCATC

LDLRex2(27 68 123 30) _88. _d0_f 844 AGATGCGAAAGAAACGAGTTCCAGT 845 GATGCGAAAGAAACGAGTTCCAG 846 ATGCGAAAGAAACGAGTTCCA

LDLRex2(27 68 123 30) _88. _d0_r 847 ACTGGAACTCGTTTCTTTCGCATCT 848 CTGGAACTCGTTTCTTTCGCATC 849 TGGAACTCGTTTCTTTCGCAT

LDLRex2(27 68 123 30) _89. _d0_f 850 GATGCGAAAGAAACGAGTTCCAGTG 851 ATGCGAAAGAAACGAGTTCCAGT 852 TGCGAAAGAAACGAGTTCCAG

LDLRex2(27 68 123 30) _89. _d0_r 853 CACTGGAACTCGTTTCTTTCGCATC 854 ACTGGAACTCGTTTCTTTCGCAT 855 CTGGAACTCGTTTCTTTCGCA

LDLRex2(27 68 123 30) _90. _d0_f 856 ATGCGAAAGAAACGAGTTCCAGTGC 857 TGCGAAAGAAACGAGTTCCAGTG 858 G CG AAAG AAACG AGTTCCAGT

LDLRex2(27 68 123 30) _90. _d0_r 859 G CACTG G AACTCGTTTCTTTCGCAT 860 CACTGGAACTCGTTTCTTTCGCA 861 ACTGGAACTCGTTTCTTTCGC

LDLRex2(27 68 123 30) _91. _d0_f 862 TG CG AAAG AAACG AGTTCCAGTG CC 863 GCGAAAGAAACGAGTTCCAGTGC 864 CGAAAGAAACGAGTTCCAGTG

LDLRex2(27 68 123 30) _91. _d0_r 865 GGCACTGGAACTCGTTTCTTTCGCA 866 G CACTG G AACTCGTTTCTTTCGC 867 CACTGGAACTCGTTTCTTTCG

LDLRex2(27 68 123 30) _92. _d0_f 868 G CG AAAG AAACG AGTTCCAGTG CCA 869 CGAAAGAAACGAGTTCCAGTGCC 870 GAAAGAAACGAGTTCCAGTGC

LDLRex2(27 68 123 30) _92. _d0_r 871 TGGCACTGGAACTCGTTTCTTTCGC 872 GGCACTGGAACTCGTTTCTTTCG 873 G CACTG G AACTCGTTTCTTTC

LDLRex2(27 68 123 30) _93. _d0_f 874 CGAAAGAAACGAGTTCCAGTGCCAA 875 GAAAGAAACGAGTTCCAGTGCCA 876 AAAGAAACGAGTTCCAGTGCC

LDLRex2(27 68 123 30) _93. _d0_r 877 TTG GCACTG G AACTCGTTTCTTTCG 878 TGGCACTGGAACTCGTTTCTTTC 879 GGCACTGGAACTCGTTTCTTT

LDLRex2(27 68 123 30) _94. _d0_f 880 GAAAGAAACGAGTTCCAGTGCCAAG 881 AAAG AAACG AGTTCCAGTG CCAA 882 AAGAAACGAGTTCCAGTGCCA

LDLRex2(27 68 123 30) _94. _d0_r 883 CTTGGCACTGGAACTCGTTTCTTTC 884 TTG GCACTG G AACTCGTTTCTTT 885 TGGCACTGGAACTCGTTTCTT

LDLRex2(27 68 123 30) _95. _d0_f 886 AAAG AAACG AGTTCCAGTG CCAAG A 887 AAGAAACGAGTTCCAGTGCCAAG 888 AGAAACGAGTTCCAGTGCCAA

LDLRex2(27 68 123 30) _95. _d0_r 889 TCTTGG CACTG G AACTCGTTTCTTT 890 CTTGGCACTGGAACTCGTTTCTT 891 TTG GCACTG G AACTCGTTTCT

LDLRex2(27 68 123 30) _96. _d0_f 892 AAGAAACGAGTTCCAGTGCCAAGAC 893 AGAAACGAGTTCCAGTGCCAAGA 894 GAAACGAGTTCCAGTGCCAAG

LDLRex2(27 68 123 30) _96. _d0_r 895 GTCTTGGCACTGGAACTCGTTTCTT 896 TCTTG G CACTG G AACTCGTTTCT 897 CTTGGCACTGGAACTCGTTTC

LDLRex2(27 68 123 30) _97. _d0_f 898 AGAAACGAGTTCCAGTGCCAAGACG 899 GAAACGAGTTCCAGTGCCAAGAC 900 AAACGAGTTCCAGTGCCAAGA

LDLRex2(27 68 123 30) _97. _d0_r 901 CGTCTTGGCACTGGAACTCGTTTCT 902 GTCTTGGCACTGGAACTCGTTTC 903 TCTTGG CACTG G AACTCGTTT

LDLRex2(27 68 123 30) _98. _d0_f 904 GAAACGAGTTCCAGTGCCAAGACGG 905 AAACGAGTTCCAGTGCCAAGACG 906 AACGAGTTCCAGTGCCAAGAC

LDLRex2(27 68 123 30) _98. _d0_r 907 CCGTCTTGG CACTG G AACTCGTTTC 908 CGTCTTGGCACTGGAACTCGTTT 909 GTCTTGGCACTGGAACTCGTT

LDLRex2(27 68 123 30) _99. _d0_f 910 AAACGAGTTCCAGTGCCAAGACGGG 911 AACGAGTTCCAGTGCCAAGACGG 912 ACGAGTTCCAGTGCCAAGACG

LDLRex2(27;68;123;30) _99. _d0_r 913 CCCGTCTTGG CACTG G AACTCGTTT 914 CCGTCTTGG CACTG G AACTCGTT 915 CGTCTTGGCACTGGAACTCGT

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _100. .dl_r 916 TTCCCGTCTTGGCCTGGAACTCGTT 917 TCCCGTCTTGGCCTGGAACTCGT 918 CCCGTCTTG GCCTG GAACTCG

LDLRex2(27 68 123 30 _101_ .dlj 919 ACGAGTTCCAGTCCAAGACGGGAAA 920 CGAGTTCCAGTCCAAGACGGGAA 921 GAGTTCCAGTCCAAGACGGGA

LDLRex2(27 68 123 30 _101_ .dl_r 922 TTTCCCGTCTTGGACTGGAACTCGT 923 TTCCCGTCTTGGACTGGAACTCG 924 TCCCGTCTTG GACTG GAACTC

LDLRex2(27 68 123 30 _102. .dlj 925 CGAGTTCCAGTGCAAGACGGGAAAT 926 GAGTTCCAGTGCAAGACGGGAAA 927 AGTTCCAGTGCAAGACGGGAA

LDLRex2(27 68 123 30 _102. .dl_r 928 ATTTCCCGTCTTG CACTG GAACTCG 929 TTTCCCGTCTTGCACTGGAACTC 930 TTCCCGTCTTGCACTGGAACT

LDLRex2(27 68 123 30 _103. .dlj 931 GAGTTCCAGTGCAAGACGGGAAATG 932 AGTTCCAGTG CAAG ACGG G AAAT 933 GTTCCAGTGCAAGACGGGAAA

LDLRex2(27 68 123 30 _103. .dl_r 934 CATTTCCCGTCTTG CACTG GAACTC 935 ATTTCCCGTCTTG CACTG G AACT 936 TTTCCCGTCTTGCACTGGAAC

LDLRex2(27 68 123 30 _104 .dlj 937 AGTTCCAGTGCCAGACGGGAAATGC 938 GTTCCAGTGCCAGACGGGAAATG 939 TTCCAGTGCCAGACGGGAAAT

LDLRex2(27 68 123 30 _104 .dl_r 940 G CATTTCCCGTCTG GCACTG G AACT 941 CATTTCCCGTCTGGCACTGGAAC 942 ATTTCCCGTCTGGCACTGGAA

LDLRex2(27 68 123 30 _105. .dlj 943 GTTCCAGTGCCAGACGGGAAATGCA 944 TTCCAGTGCCAGACGGGAAATGC 945 TCCAGTGCCAGACGGGAAATG

LDLRex2(27 68 123 30 _105. .dl_r 946 TG CATTTCCCGTCTGG CACTG G AAC 947 GCATTTCCCGTCTGGCACTGGAA 948 CATTTCCCGTCTGG CACTG G A

LDLRex2(27 68 123 30 _106. .dlj 949 TTCCAGTGCCAAACGGGAAATGCAT 950 TCCAGTGCCAAACG G G AAATG CA 951 CCAGTGCCAAACGGGAAATGC

LDLRex2(27 68 123 30 _106. .dl_r 952 ATGCATTTCCCGTTTGGCACTGGAA 953 TG CATTTCCCGTTTGG CACTG G A 954 G CATTTCCCGTTTG G CACTG G

LDLRex2(27 68 123 30 _107. .dlj 955 TCCAGTGCCAAGCGGGAAATGCATC 956 CCAGTGCCAAGCGGGAAATGCAT 957 CAGTGCCAAGCGGGAAATGCA

LDLRex2(27 68 123 30 _107. .dl_r 958 GATG CATTTCCCGCTTG G CACTG G A 959 ATGCATTTCCCGCTTGGCACTGG 960 TGCATTTCCCGCTTGGCACTG

LDLRex2(27 68 123 30 _108. .dlj 961 CCAGTG CCAAG AGG G AAATG CATCT 962 CAGTG CCAAG AGG G AAATG CATC 963 AGTG CCAAG AGG G AAATG CAT

LDLRex2(27 68 123 30 _108. .dl_r 964 AGATGCATTTCCCTCTTGGCACTGG 965 GATGCATTTCCCTCTTGGCACTG 966 ATGCATTTCCCTCTTG G CACT

LDLRex2(27 68 123 30 _109. .dlj 967 CAGTGCCAAGACGGAAATGCATCTC 968 AGTGCCAAGACGGAAATGCATCT 969 GTGCCAAGACGGAAATGCATC

LDLRex2(27 68 123 30 _109. .dl_r 970 G AG ATG C ATTTCCGTCTTG G CACTG 971 AGATGCATTTCCGTCTTGGCACT 972 GATG CATTTCCGTCTTGG CAC

LDLRex2(27 68 123 30 _110. .dlj 973 AGTGCCAAGACGGAAATGCATCTCC 974 GTGCCAAGACGGAAATGCATCTC 975 TGCCAAGACGGAAATGCATCT

LDLRex2(27 68 123 30 _110. .dl_r 976 GGAGATGCATTTCCGTCTTGGCACT 977 GAGATGCATTTCCGTCTTGGCAC 978 AGATGCATTTCCGTCTTGGCA

LDLRex2(27 68 123 30 _111_ .dlj 979 GTGCCAAGACGGAAATGCATCTCCT 980 TGCCAAGACGGAAATGCATCTCC 981 GCCAAGACGGAAATGCATCTC

LDLRex2(27 68 123 30 _111_ .dl_r 982 AG GAG ATG CATTTCCGTCTTGG CAC 983 GGAGATGCATTTCCGTCTTGGCA 984 GAG ATG CATTTCCGTCTTG G C

LDLRex2(27 68 123 30) _112. .dlj 985 TG CCAAG ACG G G AATG CATCTCCTA 986 GCCAAGACGGGAATGCATCTCCT 987 CCAAGACGGGAATGCATCTCC

LDLRex2(27 68 123 30) _112. .dl_r 988 TAGGAGATGCATTCCCGTCTTGGCA 989 AG GAG ATG CATTCCCGTCTTG GC 990 GGAGATGCATTCCCGTCTTGG

LDLRex2(27 68 123 30) _113. .dlj 991 GCCAAGACGGGAATGCATCTCCTAC 992 CCAAGACGGGAATGCATCTCCTA 993 CAAGACGGGAATGCATCTCCT

LDLRex2(27 68 123 30) _113. .dl_r 994 GTAGGAGATGCATTCCCGTCTTGGC 995 TAG GAG ATG CATTCCCGTCTTG G 996 AG GAG ATG CATTCCCGTCTTG

LDLRex2(27 68 123 30) _114. .dlj 997 CCAAGACGGGAATGCATCTCCTACA 998 CAAGACGGGAATGCATCTCCTAC 999 AAGACGGGAATGCATCTCCTA

LDLRex2(27 68 123 30) _114. .dl_r 1000 TGTAG GAG ATG CATTCCCGTCTTG G 1001 GTAGGAGATGCATTCCCGTCTTG 1002 TAG GAG ATG CATTCCCGTCTT

LDLRex2(27 68 123 30) _115. .dlj 1003 CAAGACGGGAAAGCATCTCCTACAA 1004 AAG ACGG G AAAG CATCTCCTACA 1005 AGACGGGAAAGCATCTCCTAC

LDLRex2(27 68 123 30) _115. .dl_r 1006 TTGTAG GAG ATG CTTTCCCGTCTTG 1007 TGTAGGAGATGCTTTCCCGTCTT 1008 GTAGGAGATGCTTTCCCGTCT

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _116_ .dlj 1009 AAGACGGGAAATCATCTCCTACAAG 1010 AGACGGGAAATCATCTCCTACAA 1011 GACGGGAAATCATCTCCTACA

LDLRex2(27 68 123 30 _116_ .dl_r 1012 CTTGTAGGAGATGATTTCCCGTCTT 1013 TTGTAGGAGATGATTTCCCGTCT 1014 TGTAG G AG ATG ATTTCCCGTC

LDLRex2(27 68 123 30 _117. .dlj 1015 AGACGGGAAATGATCTCCTACAAGT 1016 GACGGGAAATGATCTCCTACAAG 1017 ACGGGAAATGATCTCCTACAA

LDLRex2(27 68 123 30 _117. .dl_r 1018 ACTTGTAGGAGATCATTTCCCGTCT 1019 CTTGTAG G AG ATCATTTCCCGTC 1020 TTGTAG G AG ATCATTTCCCGT

LDLRex2(27 68 123 30 _118. .dlj 1021 G ACGG G AAATG CTCTCCTACAAGTG 1022 ACGGGAAATGCTCTCCTACAAGT 1023 CG G G AAATG CTCTCCT AC A AG

LDLRex2(27 68 123 30 _118. .dl_r 1024 CACTTGTAGGAGAGCATTTCCCGTC 1025 ACTTGTAGGAGAGCATTTCCCGT 1026 CTTGTAGGAGAGCATTTCCCG

LDLRex2(27 68 123 30 _119. .dlj 1027 ACGGGAAATGCACTCCTACAAGTGG 1028 CGGGAAATGCACTCCTACAAGTG 1029 GGGAAATGCACTCCTACAAGT

LDLRex2(27 68 123 30 _119. .dl_r 1030 CCACTTGTAGGAGTGCATTTCCCGT 1031 CACTTGTAGGAGTGCATTTCCCG 1032 ACTTGTAGGAGTGCATTTCCC

LDLRex2(27 68 123 30 _120. .dlj 1033 CGGGAAATGCATTCCTACAAGTGGG 1034 GGGAAATGCATTCCTACAAGTGG 1035 G G AAATG CATTCCTACAAGTG

LDLRex2(27 68 123 30 _120. .dl_r 1036 CCCACTTGTAGGAATGCATTTCCCG 1037 CCACTTGTAGGAATGCATTTCCC 1038 CACTTGTAGGAATGCATTTCC

LDLRex2(27 68 123 30 _121_ .dlj 1039 GGGAAATGCATCCCTACAAGTGGGT 1040 G G AAATG CATCCCTACAAGTGG G 1041 GAAATGCATCCCTACAAGTGG

LDLRex2(27 68 123 30 _121_ .dl_r 1042 ACCCACTTGTAGG G ATG CATTTCCC 1043 CCCACTTGTAGGGATGCATTTCC 1044 CCACTTGTAGGGATGCATTTC

LDLRex2(27 68 123 30 _122. .dlj 1045 G G AAATG CATCTCTACAAGTGG GTC 1046 GAAATGCATCTCTACAAGTGGGT 1047 AAATG CATCTCTACAAGTGG G

LDLRex2(27 68 123 30 _122. .dl_r 1048 GACCCACTTGTAGAGATGCATTTCC 1049 ACCCACTTGTAGAGATGCATTTC 1050 CCCACTTGTAGAGATGCATTT

LDLRex2(27 68 123 30 _123. .dlj 1051 GAAATGCATCTCTACAAGTGGGTCT 1052 AAATG CATCTCTACAAGTGG GTC 1053 AATG CATCTCTACAAGTG GGT

LDLRex2(27 68 123 30 _123. .dl_r 1054 AG ACCCACTTGTAG AG ATG CATTTC 1055 GACCCACTTGTAGAGATGCATTT 1056 ACCCACTTGTAGAGATGCATT

LDLRex2(27 68 123 30 _124. .dlj 1057 AAATG CATCTCCACAAGTG GGTCTG 1058 AATG CATCTCCACAAGTGG GTCT 1059 ATGCATCTCCACAAGTGGGTC

LDLRex2(27 68 123 30 _124. .dl_r 1060 CAGACCCACTTGTGGAGATGCATTT 1061 AGACCCACTTGTGGAGATGCATT 1062 G ACCCACTTGTG GAG ATG CAT

LDLRex2(27 68 123 30 _125_ .dlj 1063 AATG CATCTCCTCAAGTG GGTCTG C 1064 ATGCATCTCCTCAAGTGGGTCTG 1065 TG CATCTCCTCAAGTG GGTCT

LDLRex2(27 68 123 30 _125_ .dl_r 1066 GCAGACCCACTTGAGGAGATGCATT 1067 CAGACCCACTTGAGGAGATGCAT 1068 AGACCCACTTGAGGAGATGCA

LDLRex2(27 68 123 30 _126_ .dlj 1069 ATGCATCTCCTAAAGTGGGTCTGCG 1070 TGCATCTCCTAAAGTGGGTCTGC 1071 GCATCTCCTAAAGTGGGTCTG

LDLRex2(27 68 123 30 _126_ .dl_r 1072 CGCAG ACCCACTTTAG GAG ATG CAT 1073 GCAG ACCCACTTTAG GAG ATG CA 1074 CAGACCCACTTTAGGAGATGC

LDLRex2(27 68 123 30 _127_ .dlj 1075 TGCATCTCCTACAGTGGGTCTGCGA 1076 GCATCTCCTACAGTGGGTCTGCG 1077 CATCTCCTACAGTG GGTCTG C

LDLRex2(27 68 123 30) _127. .dl_r 1078 TCGCAGACCCACTGTAGGAGATGCA 1079 CGCAGACCCACTGTAGGAGATGC 1080 GCAGACCCACTGTAGGAGATG

LDLRex2(27 68 123 30) _128. .dlj 1081 GCATCTCCTACAGTGGGTCTGCGAT 1082 CATCTCCTACAGTG GGTCTG CG A 1083 ATCTCCTACAGTG GGTCTG CG

LDLRex2(27 68 123 30) _128. .dl_r 1084 ATCG CAG ACCCACTGTAG GAG ATG C 1085 TCGCAGACCCACTGTAGGAGATG 1086 CGCAGACCCACTGTAGGAGAT

LDLRex2(27 68 123 30) _129. .dlj 1087 CATCTCCTACAATG GGTCTG CG ATG 1088 ATCTCCTACAATG GGTCTG CG AT 1089 TCTCCTACAATGGGTCTGCGA

LDLRex2(27 68 123 30) _129. .dl_r 1090 CATCG CAG ACCCATTGTAG GAG ATG 1091 ATCGCAGACCCATTGTAGGAGAT 1092 TCGCAGACCCATTGTAGGAGA

LDLRex2(27 68 123 30) _130. .dlj 1093 ATCTCCTACAAG GG GTCTG CG ATG G 1094 TCTCCTACAAGGGGTCTGCGATG 1095 CTCCTACAAGGGGTCTGCGAT

LDLRex2(27 68 123 30) _130. .dl_r 1096 CCATCGCAGACCCCTTGTAGGAGAT 1097 CATCGCAGACCCCTTGTAGGAGA 1098 ATCGCAGACCCCTTGTAGGAG

LDLRex2(27 68 123 30) _131. .dlj 1099 TCTCCTACAAGTG GTCTG CG ATG GC 1100 CTCCTACAAGTGGTCTGCGATGG 1101 TCCTACAAGTG GTCTG CG ATG

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _131_ .dl_r 1102 GCCATCGCAGACCACTTGTAGGAGA 1103 CCATCG CAG ACCACTTGTAG GAG 1104 CATCG CAG ACCACTTGTAG G A

LDLRex2(27 68 123 30 _132_ .dlj 1105 CTCCTACAAGTG GTCTG CG ATG GCA 1106 TCCTACAAGTG GTCTG CG ATG GC 1107 CCTACAAGTGGTCTGCGATGG

LDLRex2(27 68 123 30 _132_ .dl_r 1108 TGCCATCGCAGACCACTTGTAGGAG 1109 GCCATCGCAGACCACTTGTAGGA 1110 CCATCG CAG ACCACTTGTAG G

LDLRex2(27 68 123 30 _133. .dlj 1111 TCCTACAAGTG GTCTG CG ATG GCAG 1112 CCTACAAGTGGTCTGCGATGGCA 1113 CTACAAGTGGTCTGCGATGGC

LDLRex2(27 68 123 30 _133. .dl_r 1114 CTGCCATCGCAGACCACTTGTAGGA 1115 TGCCATCGCAGACCACTTGTAGG 1116 G CCATCG CAG ACCACTTGTAG

LDLRex2(27 68 123 30 _134 .dlj 1117 CCTACAAGTGGGCTGCGATGGCAGC 1118 CTACAAGTGGGCTGCGATGGCAG 1119 TACAAGTGGGCTGCGATGGCA

LDLRex2(27 68 123 30 _134 .dl_r 1120 G CTG CCATCG CAG CCCACTTGTAG G 1121 CTGCCATCGCAGCCCACTTGTAG 1122 TGCCATCGCAGCCCACTTGTA

LDLRex2(27 68 123 30 _135. .dlj 1123 CTACAAGTGGGTTGCGATGGCAGCG 1124 TACAAGTGGGTTGCGATGGCAGC 1125 ACAAGTGGGTTGCGATGGCAG

LDLRex2(27 68 123 30 _135. .dl_r 1126 CGCTGCCATCGCAACCCACTTGTAG 1127 GCTGCCATCGCAACCCACTTGTA 1128 CTG CCATCG CAACCCACTTGT

LDLRex2(27 68 123 30 _136. .dlj 1129 TACAAGTGGGTCGCGATGGCAGCGC 1130 ACAAGTGGGTCGCGATGGCAGCG 1131 CAAGTGGGTCGCGATGGCAGC

LDLRex2(27 68 123 30 _136. .dl_r 1132 GCGCTG CCATCG CG ACCCACTTGTA 1133 CGCTGCCATCGCGACCCACTTGT 1134 GCTGCCATCGCGACCCACTTG

LDLRex2(27 68 123 30 _137_ .dlj 1135 ACAAGTGGGTCTCGATGGCAGCGCT 1136 CAAGTGGGTCTCGATGGCAGCGC 1137 AAGTGGGTCTCGATGGCAGCG

LDLRex2(27 68 123 30 _137_ .dl_r 1138 AGCGCTGCCATCGAGACCCACTTGT 1139 GCGCTGCCATCGAGACCCACTTG 1140 CGCTGCCATCGAGACCCACTT

LDLRex2(27 68 123 30 _138. .dlj 1141 CAAGTGGGTCTGGATGGCAGCGCTG 1142 AAGTGGGTCTGGATGGCAGCGCT 1143 AGTGGGTCTGGATGGCAGCGC

LDLRex2(27 68 123 30 _138. .dl_r 1144 CAGCGCTGCCATCCAGACCCACTTG 1145 AGCGCTGCCATCCAGACCCACTT 1146 GCGCTG CCATCCAG ACCCACT

LDLRex2(27 68 123 30 _139. .dlj 1147 AAGTGGGTCTGCATGGCAGCGCTGA 1148 AGTGGGTCTGCATGGCAGCGCTG 1149 GTGGGTCTGCATGGCAGCGCT

LDLRex2(27 68 123 30 _139. .dl_r 1150 TCAGCGCTGCCATGCAGACCCACTT 1151 CAGCGCTGCCATGCAGACCCACT 1152 AGCGCTGCCATGCAGACCCAC

LDLRex2(27 68 123 30 _140. .dlj 1153 AGTGGGTCTGCGTGGCAGCGCTGAG 1154 GTGGGTCTGCGTGGCAGCGCTGA 1155 TGGGTCTGCGTGGCAGCGCTG

LDLRex2(27 68 123 30 _140. .dl_r 1156 CTCAGCGCTGCCACGCAGACCCACT 1157 TCAGCGCTGCCACGCAGACCCAC 1158 CAG CGCTG CCACG CAG ACCCA

LDLRex2(27 68 123 30 _141_ .dlj 1159 GTGGGTCTGCGAGGCAGCGCTGAGT 1160 TGGGTCTGCGAGGCAGCGCTGAG 1161 GGGTCTGCGAGGCAGCGCTGA

LDLRex2(27 68 123 30 _141_ .dl_r 1162 ACTCAG CG CTG CCTCGCAG ACCCAC 1163 CTCAGCGCTGCCTCGCAGACCCA 1164 TCAGCGCTGCCTCGCAGACCC

LDLRex2(27 68 123 30 _142. .dlj 1165 TGGGTCTGCGATGCAGCGCTGAGTG 1166 GGGTCTGCGATGCAGCGCTGAGT 1167 GGTCTGCGATGCAGCGCTGAG

LDLRex2(27 68 123 30 _142. .dl_r 1168 CACTCAGCGCTGCATCGCAGACCCA 1169 ACTCAG CG CTG CATCG CAG ACCC 1170 CTCAGCGCTGCATCGCAGACC

LDLRex2(27 68 123 30) _143. .dlj 1171 GGGTCTGCGATGCAGCGCTGAGTGC 1172 GGTCTGCGATGCAGCGCTGAGTG 1173 GTCTGCGATGCAGCGCTGAGT

LDLRex2(27 68 123 30) _143. .dl_r 1174 GCACTCAGCGCTGCATCGCAGACCC 1175 CACTCAGCGCTGCATCGCAGACC 1176 ACTCAGCGCTGCATCGCAGAC

LDLRex2(27 68 123 30) _144. .dlj 1177 GGTCTGCGATGGAGCGCTGAGTGCC 1178 GTCTGCGATGGAGCGCTGAGTGC 1179 TCTGCGATGGAGCGCTGAGTG

LDLRex2(27 68 123 30) _144. .dl_r 1180 GGCACTCAGCGCTCCATCGCAGACC 1181 GCACTCAGCGCTCCATCGCAGAC 1182 CACTCAGCGCTCCATCGCAGA

LDLRex2(27 68 123 30) _145. .dlj 1183 GTCTGCGATGGCGCGCTGAGTGCCA 1184 TCTGCGATGGCGCGCTGAGTGCC 1185 CTGCGATGGCGCGCTGAGTGC

LDLRex2(27 68 123 30) _145. .dl_r 1186 TGGCACTCAGCGCGCCATCGCAGAC 1187 GGCACTCAGCGCGCCATCGCAGA 1188 GCACTCAGCGCGCCATCGCAG

LDLRex2(27 68 123 30) _146. .dlj 1189 TCTGCGATGGCACGCTGAGTGCCAG 1190 CTGCGATGGCACGCTGAGTGCCA 1191 TGCGATGGCACGCTGAGTGCC

LDLRex2(27 68 123 30) _146. .dl_r 1192 CTGGCACTCAGCGTGCCATCGCAGA 1193 TGGCACTCAGCGTGCCATCGCAG 1194 GGCACTCAGCGTGCCATCGCA

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _147_ .dlj 1195 CTGCGATGGCAGGCTGAGTGCCAGG 1196 TGCGATGGCAGGCTGAGTGCCAG 1197 GCGATGGCAGGCTGAGTGCCA

LDLRex2(27 68 123 30 _147_ .dl_r 1198 CCTGG CACTCAGCCTG CCATCG CAG 1199 CTGG CACTCAGCCTG CCATCG CA 1200 TGGCACTCAGCCTGCCATCGC

LDLRex2(27 68 123 30 _148_ .dlj 1201 TGCG ATG G CAG CCTG AGTG CCAG G A 1202 GCGATGGCAGCCTGAGTGCCAGG 1203 CGATGGCAGCCTGAGTGCCAG

LDLRex2(27 68 123 30 _148_ .dl_r 1204 TCCTGGCACTCAGGCTGCCATCGCA 1205 CCTGGCACTCAGGCTGCCATCGC 1206 CTGGCACTCAGGCTGCCATCG

LDLRex2(27 68 123 30 _149_ .dlj 1207 GCGATGGCAGCGTGAGTGCCAGGAT 1208 CGATGGCAGCGTGAGTGCCAGGA 1209 GATGGCAGCGTGAGTGCCAGG

LDLRex2(27 68 123 30 _149_ .dl_r 1210 ATCCTGGCACTCACGCTGCCATCGC 1211 TCCTGGCACTCACGCTGCCATCG 1212 CCTG GCACTCACG CTG CCATC

LDLRex2(27 68 123 30 _150_ .dlj 1213 CGATGGCAGCGCGAGTGCCAGGATG 1214 GATGGCAGCGCGAGTGCCAGGAT 1215 ATGGCAGCGCGAGTGCCAGGA

LDLRex2(27 68 123 30 _150_ .dl_r 1216 CATCCTGGCACTCGCGCTGCCATCG 1217 ATCCTGGCACTCGCGCTGCCATC 1218 TCCTGG CACTCG CG CTG CCAT

LDLRex2(27 68 123 30 _151_ .dlj 1219 GATGGCAGCGCTAGTGCCAGGATGG 1220 ATGGCAGCGCTAGTGCCAGGATG 1221 TGG CAG CG CTAGTG CCAG GAT

LDLRex2(27 68 123 30 _151_ .dl_r 1222 CCATCCTGG CACTAG CG CTG CCATC 1223 CATCCTG GCACTAG CGCTG CCAT 1224 ATCCTGGCACTAGCGCTGCCA

LDLRex2(27 68 123 30 _152_ .dlj 1225 ATGGCAGCGCTGGTGCCAGGATGGC 1226 TG G CAG CG CTG GTG CCAG GATGG 1227 GGCAGCGCTGGTGCCAGGATG

LDLRex2(27 68 123 30 _152_ .dl_r 1228 G CCATCCTG GCACCAG CGCTG CCAT 1229 CCATCCTGGCACCAGCGCTGCCA 1230 CATCCTGGCACCAGCGCTGCC

LDLRex2(27 68 123 30 _153. .dlj 1231 TGGCAGCGCTGATGCCAGGATGGCT 1232 GGCAGCGCTGATGCCAGGATGGC 1233 GCAGCGCTGATGCCAGGATGG

LDLRex2(27 68 123 30 _153. .dl_r 1234 AGCCATCCTGG CATCAG CG CTG CCA 1235 G CCATCCTG GCATCAG CGCTG CC 1236 CCATCCTGGCATCAGCGCTGC

LDLRex2(27 68 123 30 _154. .dlj 1237 GGCAGCGCTGAGGCCAGGATGGCTC 1238 GCAGCGCTGAGGCCAGGATGGCT 1239 CAGCGCTGAGGCCAGGATGGC

LDLRex2(27 68 123 30 _154. .dl_r 1240 GAGCCATCCTGGCCTCAGCGCTGCC 1241 AGCCATCCTGGCCTCAGCGCTGC 1242 GCCATCCTGGCCTCAGCGCTG

LDLRex2(27 68 123 30 _155. .dlj 1243 GCAGCGCTGAGTCCAGGATGGCTCT 1244 CAGCGCTGAGTCCAGGATGGCTC 1245 AGCGCTGAGTCCAGGATGGCT

LDLRex2(27 68 123 30 _155. .dl_r 1246 AGAGCCATCCTGGACTCAGCGCTGC 1247 GAG CCATCCTG GACTCAG CGCTG 1248 AGCCATCCTGGACTCAGCGCT

LDLRex2(27 68 123 30 _156. .dlj 1249 CAG CGCTG AGTG CAG G ATG GCTCTG 1250 AGCG CTG AGTG CAG G ATG GCTCT 1251 GCGCTGAGTGCAGGATGGCTC

LDLRex2(27 68 123 30 _156. .dl_r 1252 CAGAGCCATCCTGCACTCAGCGCTG 1253 AGAGCCATCCTGCACTCAGCGCT 1254 GAG CCATCCTG CACTCAGCG C

LDLRex2(27 68 123 30 _157_ .dlj 1255 AGCGCTGAGTGCAGGATGGCTCTGA 1256 GCGCTGAGTGCAGGATGGCTCTG 1257 CGCTGAGTGCAGGATGGCTCT

LDLRex2(27 68 123 30 _157_ .dl_r 1258 TCAGAGCCATCCTGCACTCAGCGCT 1259 CAGAGCCATCCTGCACTCAGCGC 1260 AGAGCCATCCTGCACTCAGCG

LDLRex2(27 68 123 30 _158. .dlj 1261 GCGCTGAGTGCCGGATGGCTCTGAT 1262 CGCTGAGTGCCGGATGGCTCTGA 1263 GCTGAGTGCCGGATGGCTCTG

LDLRex2(27 68 123 30 _158. .dl_r 1264 ATCAGAGCCATCCGGCACTCAGCGC 1265 TCAGAGCCATCCGGCACTCAGCG 1266 CAGAGCCATCCGGCACTCAGC

LDLRex2(27 68 123 30) _159. .dlj 1267 CGCTGAGTGCCAGATGGCTCTGATG 1268 GCTGAGTGCCAGATGGCTCTGAT 1269 CTGAGTGCCAGATGGCTCTGA

LDLRex2(27 68 123 30) _159. .dl_r 1270 CATCAG AG CCATCTG GCACTCAG CG 1271 ATCAG AG CCATCTG GCACTCAG C 1272 TCAGAGCCATCTGGCACTCAG

LDLRex2(27 68 123 30) _160. .dlj 1273 GCTGAGTGCCAGATGGCTCTGATGA 1274 CTGAGTGCCAGATGGCTCTGATG 1275 TGAGTGCCAGATGGCTCTGAT

LDLRex2(27 68 123 30) _160. .dl_r 1276 TCATCAG AG CCATCTG GCACTCAG C 1277 CATCAGAGCCATCTGGCACTCAG 1278 ATCAGAGCCATCTGGCACTCA

LDLRex2(27 68 123 30) _161. .dlj 1279 CTGAGTGCCAGGTGGCTCTGATGAG 1280 TGAGTGCCAGGTGGCTCTGATGA 1281 G AGTG CCAG GTGG CTCTG ATG

LDLRex2(27 68 123 30) _161. .dl_r 1282 CTCATCAGAGCCACCTGGCACTCAG 1283 TCATCAG AG CCACCTGG CACTCA 1284 CATCAGAGCCACCTGGCACTC

LDLRex2(27 68 123 30) _162. .dlj 1285 TGAGTGCCAGGAGGCTCTGATGAGT 1286 GAGTGCCAGGAGGCTCTGATGAG 1287 AGTGCCAGGAGGCTCTGATGA

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _162. .dlj 1288 ACTCATCAGAGCCTCCTGGCACTCA 1289 CTCATCAG AG CCTCCTG G CACTC 1290 TCATCAG AG CCTCCTGG CACT

LDLRex2(27 68 123 30 _163_ .dlj 1291 G AGTG CCAG G ATG CTCTG ATG AGTC 1292 AGTGCCAGGATGCTCTGATGAGT 1293 GTG CCAG G ATG CTCTG ATG AG

LDLRex2(27 68 123 30 _163_ .dlj 1294 G ACTCATCAG AG CATCCTG GCACTC 1295 ACTCATCAGAGCATCCTGGCACT 1296 CTCATCAGAGCATCCTGGCAC

LDLRex2(27 68 123 30 _164 .dlj 1297 AGTGCCAGGATGCTCTGATGAGTCC 1298 GTG CCAG GATGCTCTG ATG AGTC 1299 TGCCAGGATGCTCTGATGAGT

LDLRex2(27 68 123 30 _164 .dl_r 1300 GGACTCATCAGAGCATCCTGGCACT 1301 GACTCATCAGAGCATCCTGGCAC 1302 ACTCATCAGAGCATCCTGGCA

LDLRex2(27 68 123 30 _165_ .dlj 1303 GTGCCAGGATGGTCTGATGAGTCCC 1304 TGCCAGGATGGTCTGATGAGTCC 1305 G CCAG G ATG GTCTG ATG AGTC

LDLRex2(27 68 123 30 _165_ .dl_r 1306 G GG ACTCATCAG ACCATCCTG G CAC 1307 GGACTCATCAGACCATCCTGGCA 1308 GACTCATCAGACCATCCTGGC

LDLRex2(27 68 123 30 _166_ .dlj 1309 TGCCAGGATGGCCTGATGAGTCCCA 1310 GCCAGGATGGCCTGATGAGTCCC 1311 CCAGGATGGCCTGATGAGTCC

LDLRex2(27 68 123 30 _166_ .dl_r 1312 TGGGACTCATCAGGCCATCCTGGCA 1313 GGGACTCATCAGGCCATCCTGGC 1314 GGACTCATCAGGCCATCCTGG

LDLRex2(27 68 123 30 _167. .dlj 1315 GCCAGGATGGCTTGATGAGTCCCAG 1316 CCAGGATGGCTTGATGAGTCCCA 1317 CAGGATGGCTTGATGAGTCCC

LDLRex2(27 68 123 30 _167. .dl_r 1318 CTGGGACTCATCAAGCCATCCTGGC 1319 TG G G ACTCATCAAG CCATCCTGG 1320 GGGACTCATCAAGCCATCCTG

LDLRex2(27 68 123 30 _168_ .dlj 1321 CCAGGATGGCTCGATGAGTCCCAGG 1322 CAGGATGGCTCGATGAGTCCCAG 1323 AGGATGGCTCGATGAGTCCCA

LDLRex2(27 68 123 30 _168_ .dl_r 1324 CCTGGGACTCATCGAGCCATCCTGG 1325 CTGGGACTCATCGAGCCATCCTG 1326 TGGGACTCATCGAGCCATCCT

LDLRex2(27 68 123 30 _169_ .dlj 1327 CAGGATGGCTCTATGAGTCCCAGGA 1328 AGGATGGCTCTATGAGTCCCAGG 1329 G G ATGG CTCTATG AGTCCCAG

LDLRex2(27 68 123 30 _169_ .dl_r 1330 TCCTGGGACTCATAGAGCCATCCTG 1331 CCTGGGACTCATAGAGCCATCCT 1332 CTGGGACTCATAGAGCCATCC

LDLRex2(27 68 123 30 _170_ .dlj 1333 AGGATGGCTCTGTGAGTCCCAGGAG 1334 GGATGGCTCTGTGAGTCCCAGGA 1335 GATGGCTCTGTGAGTCCCAGG

LDLRex2(27 68 123 30 _170_ .dl_r 1336 CTCCTGGGACTCACAGAGCCATCCT 1337 TCCTGGGACTCACAGAGCCATCC 1338 CCTGGGACTCACAGAGCCATC

LDLRex2(27 68 123 30 _171. .dlj 1339 GGATGGCTCTGAGAGTCCCAGGAGA 1340 GATGGCTCTGAGAGTCCCAGGAG 1341 ATGGCTCTGAGAGTCCCAGGA

LDLRex2(27 68 123 30 _171. .dl_r 1342 TCTCCTGGGACTCTCAGAGCCATCC 1343 CTCCTGGGACTCTCAGAGCCATC 1344 TCCTGGGACTCTCAGAGCCAT

LDLRex2(27 68 123 30 _172. .dlj 1345 GATGGCTCTGATAGTCCCAGGAGAC 1346 ATGGCTCTGATAGTCCCAGGAGA 1347 TGGCTCTGATAGTCCCAGGAG

LDLRex2(27 68 123 30 _172. .dl_r 1348 GTCTCCTGGGACTATCAGAGCCATC 1349 TCTCCTGGGACTATCAGAGCCAT 1350 CTCCTGGGACTATCAGAGCCA

LDLRex2(27 68 123 30 _173_ .dlj 1351 ATGGCTCTGATGGTCCCAGGAGACG 1352 TGGCTCTGATGGTCCCAGGAGAC 1353 GGCTCTGATGGTCCCAGGAGA

LDLRex2(27 68 123 30 _173. .dl_r 1354 CGTCTCCTGGGACCATCAGAGCCAT 1355 GTCTCCTGGGACCATCAGAGCCA 1356 TCTCCTGGGACCATCAGAGCC

LDLRex2(27 68 123 30) _174. .dlj 1357 TGGCTCTGATGATCCCAGGAGACGT 1358 GGCTCTGATGATCCCAGGAGACG 1359 GCTCTGATGATCCCAGGAGAC

LDLRex2(27 68 123 30) _174. .dl_r 1360 ACGTCTCCTGGGATCATCAGAGCCA 1361 CGTCTCCTGGGATCATCAGAGCC 1362 GTCTCCTG G G ATCATCAG AG C

LDLRex2(27 68 123 30) _175. .dlj 1363 GG CTCTG ATG AG CCCAG GAG ACGTG 1364 GCTCTGATGAGCCCAGGAGACGT 1365 CTCTG ATG AG CCCAG GAGACG

LDLRex2(27 68 123 30) _175. .dl_r 1366 CACGTCTCCTGGGCTCATCAGAGCC 1367 ACGTCTCCTGGGCTCATCAGAGC 1368 CGTCTCCTGGGCTCATCAGAG

LDLRex2(27 68 123 30) _176. .dlj 1369 GCTCTGATGAGTCCAGGAGACGTGC 1370 CTCTGATGAGTCCAGGAGACGTG 1371 TCTGATGAGTCCAGGAGACGT

LDLRex2(27 68 123 30) _176. .dl_r 1372 GCACGTCTCCTGGACTCATCAGAGC 1373 CACGTCTCCTGGACTCATCAGAG 1374 ACGTCTCCTGGACTCATCAGA

LDLRex2(27 68 123 30) _177. .dlj 1375 CTCTGATGAGTCCAGGAGACGTGCT 1376 TCTGATGAGTCCAGGAGACGTGC 1377 CTG ATG AGTCCAG GAG ACGTG

LDLRex2(27 68 123 30) _177. .dlj 1378 AGCACGTCTCCTGGACTCATCAGAG 1379 GCACGTCTCCTGGACTCATCAGA 1380 CACGTCTCCTGGACTCATCAG

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _178_dl_ _f 1381 TCTGATGAGTCCAGGAGACGTGCTG 1382 CTGATGAGTCCAGGAGACGTGCT 1383 TGATGAGTCCAGGAGACGTGC

LDLRex2(27 68 123 30 _178_dl_ _r 1384 CAGCACGTCTCCTGGACTCATCAGA 1385 AGCACGTCTCCTGGACTCATCAG 1386 GCACGTCTCCTGGACTCATCA

LDLRex2(27 68 123 30 _179_dl_ .f 1387 CTGATGAGTCCCGGAGACGTGCTGT 1388 TGATGAGTCCCGGAGACGTGCTG 1389 GATGAGTCCCGGAGACGTGCT

LDLRex2(27 68 123 30 _179_dl_ _r 1390 ACAGCACGTCTCCGGGACTCATCAG 1391 CAG CACGTCTCCGG G ACTCATCA 1392 AG CACGTCTCCGG GACTCATC

LDLRex2(27 68 123 30 _180_dl_ f 1393 TGATGAGTCCCAGAGACGTGCTGTG 1394 GATGAGTCCCAGAGACGTGCTGT 1395 ATGAGTCCCAGAGACGTGCTG

LDLRex2(27 68 123 30 _180_dl_ _r 1396 CACAGCACGTCTCTGGGACTCATCA 1397 ACAGCACGTCTCTGGGACTCATC 1398 CAGCACGTCTCTGGGACTCAT

LDLRex2(27 68 123 30 _181_dl_ f 1399 GATGAGTCCCAGAGACGTGCTGTGA 1400 ATGAGTCCCAGAGACGTGCTGTG 1401 TGAGTCCCAGAGACGTGCTGT

LDLRex2(27 68 123 30 _181_dl_ _r 1402 TCACAGCACGTCTCTGGGACTCATC 1403 CACAGCACGTCTCTGGGACTCAT 1404 ACAGCACGTCTCTGGGACTCA

LDLRex2(27 68 123 30 _182_dl_ f 1405 ATGAGTCCCAGGGACGTGCTGTGAG 1406 TGAGTCCCAGGGACGTGCTGTGA 1407 GAGTCCCAGGGACGTGCTGTG

LDLRex2(27 68 123 30 _182_dl_ _r 1408 CTCACAG CACGTCCCTGG G ACTCAT 1409 TCACAGCACGTCCCTGGGACTCA 1410 CACAG CACGTCCCTGG G ACTC

LDLRex2(27 68 123 30 _183_dl_ f 1411 TGAGTCCCAGGAACGTGCTGTGAGT 1412 G AGTCCCAG GAACGTG CTGTG AG 1413 AGTCCCAGGAACGTGCTGTGA

LDLRex2(27 68 123 30 _183_dl_ _r 1414 ACTCACAGCACGTTCCTGGGACTCA 1415 CTCACAGCACGTTCCTGGGACTC 1416 TCACAGCACGTTCCTGGGACT

LDLRex2(27 68 123 30 _184_dl_ f 1417 GAGTCCCAGGAGCGTGCTGTGAGTC 1418 AGTCCCAGGAGCGTGCTGTGAGT 1419 GTCCCAGGAGCGTGCTGTGAG

LDLRex2(27 68 123 30 _184_dl_ _r 1420 G ACTCACAG CACG CTCCTGG G ACTC 1421 ACTCACAGCACGCTCCTGGGACT 1422 CTCACAG CACG CTCCTGG G AC

LDLRex2(27 68 123 30 _185_dl_ f 1423 AGTCCCAGGAGAGTGCTGTGAGTCC 1424 GTCCCAGGAGAGTGCTGTGAGTC 1425 TCCCAGGAGAGTGCTGTGAGT

LDLRex2(27 68 123 30 _185_dl_ r 1426 GGACTCACAGCACTCTCCTGGGACT 1427 GACTCACAGCACTCTCCTGGGAC 1428 ACTCACAGCACTCTCCTGGGA

LDLRex2(27 68 123 30 _186_dl_ f 1429 GTCCCAGGAGACTGCTGTGAGTCCC 1430 TCCCAGGAGACTGCTGTGAGTCC 1431 CCCAG G AG ACTG CTGTG AGTC

LDLRex2(27 68 123 30 _186_dl_ r 1432 GGGACTCACAGCAGTCTCCTGGGAC 1433 G G ACTCACAGCAGTCTCCTG G G A 1434 GACTCACAGCAGTCTCCTGGG

LDLRex2(27 68 123 30 _187_dl_ f 1435 TCCCAGGAGACGGCTGTGAGTCCCC 1436 CCCAGGAGACGGCTGTGAGTCCC 1437 CCAGGAGACGGCTGTGAGTCC

LDLRex2(27 68 123 30 _187_dl_ r 1438 GGGGACTCACAGCCGTCTCCTGGGA 1439 GGGACTCACAGCCGTCTCCTGGG 1440 GGACTCACAGCCGTCTCCTGG

LDLRex2(27 68 123 30 _188_dl_ f 1441 CCCAGGAGACGTCTGTGAGTCCCCT 1442 CCAGGAGACGTCTGTGAGTCCCC 1443 CAGGAGACGTCTGTGAGTCCC

LDLRex2(27 68 123 30 _188_dl_ r 1444 AGGGGACTCACAGACGTCTCCTGGG 1445 GGGGACTCACAGACGTCTCCTGG 1446 GGGACTCACAGACGTCTCCTG

LDLRex2(27 68 123 30 _189_dl_ f 1447 CCAG G AG ACGTGTGTG AGTCCCCTT 1448 CAGGAGACGTGTGTGAGTCCCCT 1449 AGGAGACGTGTGTGAGTCCCC

LDLRex2(27 68 123 30) _189_dl_ r 1450 AAGGGGACTCACACACGTCTCCTGG 1451 AG GG G ACTCACACACGTCTCCTG 1452 GGGGACTCACACACGTCTCCT

LDLRex2(27 68 123 30) _190 + 1_ dl_f 1453 AGGAGACGTGCTTGAGTCCCCTTTG 1454 GGAGACGTGCTTGAGTCCCCTTT 1455 GAGACGTGCTTGAGTCCCCTT

LDLRex2(27 68 123 30) _190 + 1_ dl_r 1456 CAAAG GG G ACTCAAG CACGTCTCCT 1457 AAAG G GG ACTCAAG CACGTCTCC 1458 AAGGGGACTCAAGCACGTCTC

LDLRex2(27 68 123 30) _190 + 10 _dlj 1459 GCTGTGAGTCCCTTTGGGCATGATA 1460 CTGTGAGTCCCTTTGGGCATGAT 1461 TGTGAGTCCCTTTGGGCATGA

LDLRex2(27 68 123 30) _190 + 10 _dl_r 1462 TATCATG CCCAAAG GG ACTCACAG C 1463 ATCATGCCCAAAGGGACTCACAG 1464 TCATGCCCAAAGGGACTCACA

LDLRex2(27 68 123 30) _190 + 11 _dlj 1465 CTGTGAGTCCCCTTGGGCATGATAT 1466 TGTG AGTCCCCTTG GG CATG ATA 1467 GTGAGTCCCCTTGGGCATGAT

LDLRex2(27 68 123 30) _190 + 11 _dl_r 1468 ATATCATGCCCAAGGGGACTCACAG 1469 TATCATGCCCAAGGGGACTCACA 1470 ATCATGCCCAAGGGGACTCAC

LDLRex2(27 68 123 30) _190 + 12 _dlj 1471 TGTGAGTCCCCTTGGGCATGATATG 1472 GTGAGTCCCCTTGGGCATGATAT 1473 TG AGTCCCCTTG G GCATG ATA

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _190 + 12_dl_r 1474 CATATCATGCCCAAGGGGACTCACA 1475 ATATCATGCCCAAGGGGACTCAC 1476 TATCATGCCCAAGGGGACTCA

LDLRex2(27 68 123 30 _190 + 13_dl_f 1477 GTGAGTCCCCTTGGGCATGATATGC 1478 TGAGTCCCCTTGGGCATGATATG 1479 G AGTCCCCTTG GG CATG ATAT

LDLRex2(27 68 123 30 _190 + 13_dl_r 1480 GCATATCATGCCCAAGGGGACTCAC 1481 CATATCATGCCCAAGGGGACTCA 1482 ATATCATGCCCAAGGGGACTC

LDLRex2(27 68 123 30 _190 + 14_dl_f 1483 TGAGTCCCCTTTGGCATGATATGCA 1484 GAGTCCCCTTTGGCATGATATGC 1485 AGTCCCCTTTGGCATGATATG

LDLRex2(27 68 123 30 _190 + 14_dl_r 1486 TGCATATCATG CCAAAG GG G ACTCA 1487 G CAT ATCATG CCAAAG GG GACTC 1488 CATATCATGCCAAAGGGGACT

LDLRex2(27 68 123 30 _190 + 15_dl_f 1489 GAGTCCCCTTTGGCATGATATGCAT 1490 AGTCCCCTTTGGCATGATATGCA 1491 GTCCCCTTTGGCATGATATGC

LDLRex2(27 68 123 30 _190 + 15_dl_r 1492 ATGCATATCATGCCAAAGGGGACTC 1493 TGCATATCATG CCAAAG GG G ACT 1494 G CAT ATCATG CCAAAG GG G AC

LDLRex2(27 68 123 30 _190 + 2_dl_f 1495 GGAGACGTGCTGGAGTCCCCTTTGG 1496 GAGACGTGCTGGAGTCCCCTTTG 1497 AGACGTGCTGGAGTCCCCTTT

LDLRex2(27 68 123 30 _190 + 2_dl_r 1498 CCAAAGGGGACTCCAGCACGTCTCC 1499 CAAAG GG G ACTCCAG CACGTCTC 1500 AAAG GG G ACTCCAG CACGTCT

LDLRex2(27 68 123 30 _190 + 3_dl_f 1501 GAGACGTGCTGTAGTCCCCTTTGGG 1502 AGACGTGCTGTAGTCCCCTTTGG 1503 GACGTGCTGTAGTCCCCTTTG

LDLRex2(27 68 123 30 _190 + 3_dl_r 1504 CCCAAAGGGGACTACAGCACGTCTC 1505 CCAAAGGGGACTACAGCACGTCT 1506 CAAAGGGGACTACAGCACGTC

LDLRex2(27 68 123 30 _190 + 4_dl_f 1507 AGACGTGCTGTGGTCCCCTTTGGGC 1508 GACGTGCTGTGGTCCCCTTTGGG 1509 ACGTG CTGTGGTCCCCTTTG G

LDLRex2(27 68 123 30 _190 + 4_dl_r 1510 G CCCAAAG GG GACCACAGCACGTCT 1511 CCCAAAGGGGACCACAGCACGTC 1512 CCAAAGGGGACCACAGCACGT

LDLRex2(27 68 123 30 _190 + 5_dl_f 1513 GACGTGCTGTGATCCCCTTTGGGCA 1514 ACGTG CTGTG ATCCCCTTTG GG C 1515 CGTGCTGTGATCCCCTTTGGG

LDLRex2(27 68 123 30 _190 + 5_dl_r 1516 TG CCCAAAG GG G ATCACAG CACGTC 1517 G CCCAAAG GG GATCACAGCACGT 1518 CCCAAAGGGGATCACAGCACG

LDLRex2(27 68 123 30 _190 + 6_dl_f 1519 ACGTG CTGTG AGCCCCTTTG GG CAT 1520 CGTGCTGTGAGCCCCTTTGGGCA 1521 GTGCTGTGAGCCCCTTTGGGC

LDLRex2(27 68 123 30 _190 + 6_dl_r 1522 ATGCCCAAAGGGGCTCACAGCACGT 1523 TG CCCAAAG GG GCTCACAG CACG 1524 G CCCAAAG GG GCTCACAG CAC

LDLRex2(27 68 123 30 _190 + 7_dl_f 1525 CGTGCTGTGAGTCCCTTTGGGCATG 1526 GTGCTGTGAGTCCCTTTGGGCAT 1527 TGCTGTGAGTCCCTTTGGGCA

LDLRex2(27 68 123 30 _190 + 7_dl_r 1528 CATGCCCAAAGGGACTCACAGCACG 1529 ATGCCCAAAGGGACTCACAGCAC 1530 TGCCCAAAGGGACTCACAGCA

LDLRex2(27 68 123 30 _190 + 8_dl_f 1531 GTGCTGTGAGTCCCTTTGGGCATGA 1532 TGCTGTGAGTCCCTTTGGGCATG 1533 GCTGTGAGTCCCTTTGGGCAT

LDLRex2(27 68 123 30 _190 + 8_dl_r 1534 TCATGCCCAAAGGGACTCACAGCAC 1535 CATGCCCAAAGGGACTCACAGCA 1536 ATGCCCAAAGGGACTCACAGC

LDLRex2(27 68 123 30 _190 + 9_dl_f 1537 TG CTGTG AGTCCCTTTG GG CATG AT 1538 GCTGTGAGTCCCTTTGGGCATGA 1539 CTGTGAGTCCCTTTGGGCATG

LDLRex2(27 68 123 30 _190 + 9_dl_r 1540 ATCATG CCCAAAG GG ACTCACAG CA 1541 TCATGCCCAAAGGGACTCACAGC 1542 CATGCCCAAAGGGACTCACAG

LDLRex2(27 68 123 30) _190_dl_f 1543 CAGGAGACGTGCGTGAGTCCCCTTT 1544 AGGAGACGTGCGTGAGTCCCCTT 1545 GGAGACGTGCGTGAGTCCCCT

LDLRex2(27 68 123 30) _190_dl_r 1546 AAAGGGGACTCACGCACGTCTCCTG 1547 AAGGG G ACTCACG CACGTCTCCT 1548 AG GG G ACTCACG CACGTCTCC

LDLRex2(27 68 123 30) _68 - l_dl_f 1549 TCCTCTCTCTCATGGGCGACAGATG 1550 CCTCTCTCTCATGGGCGACAGAT 1551 CTCTCTCTCATGGGCGACAGA

LDLRex2(27 68 123 30) _68 - l_dl_r 1552 CATCTGTCGCCCATGAGAGAGAGGA 1553 ATCTGTCGCCCATGAGAGAGAGG 1554 TCTGTCGCCCATGAGAGAGAG

LDLRex2(27 68 123 30) _68 - 10_dl_f 1555 TTCTCCTTTTCCCTCTCTCAGTGGG 1556 TCTCCTTTTCCCTCTCT CAGTGG 1557 CTC I 1 1 1 CCCTCTCTCAGTG

LDLRex2(27 68 123 30) _68 - 10_dl_r 1558 CCCACTGAGAGAGGGAAAAGGAGAA 1559 CCACTGAGAGAGGGAAAAGGAGA 1560 CACTGAGAGAGGGAAAAGGAG

LDLRex2(27 68 123 30) _68 - ll_dl_f 1561 TTTCTCCI 1 1 1 1 1 1 1 CAGTGG 1562 TTCTCCI 1 1 I C I C I C I C I CAGTG 1563 TCTCCTTTTCTCTCTCTCAGT

LDLRex2(27 68 123 30) _68 - ll_dl_r 1564 CCACTGAGAGAGAGAAAAGGAGAAA 1565 CACTGAGAGAGAGAAAAGGAGAA 1566 ACTGAGAGAGAGAAAAGGAGA

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _68 - 12_dl_f 1567 CTTTCTCC 1 1 1 1 C 1 C 1 C 1 C 1 CAGTG 1568 TTTCTCCI 1 1 I C I C I C I C I CAGT 1569 TTCTCCI 1 1 l U U U U CAG

LDLRex2(27 68 123 30 _68 - 12_dl_r 1570 CACTGAGAGAGAGAAAAGGAGAAAG 1571 ACTGAGAGAGAGAAAAGGAGAAA 1572 CTGAGAGAGAGAAAAGGAGAA

LDLRex2(27 68 123 30 _68 - 13_dl_f 1573 CCTTTCTCCTTTCCTCTCTCTCAGT 1574 CTTTCTCCTTTCCTCTCTCTCAG 1575 TTTCTCCTTTCCTCTCTCTCA

LDLRex2(27 68 123 30 _68 - 13_dl_r 1576 ACTGAGAGAGAGGAAAGGAGAAAGG 1577 CTGAGAGAGAGGAAAGGAGAAAG 1578 TGAGAGAGAGGAAAGGAGAAA

LDLRex2(27 68 123 30 _68 - 14_dl_f 1579 CCCTTTCTCCTTTCCTCTCTCTCAG 1580 CCTTTCTCCTTTCCTCTCTCTCA 1581 CTTTCTCCTTTCCTCTCTCTC

LDLRex2(27 68 123 30 _68 - 14_dl_r 1582 CTGAGAGAGAGGAAAGGAGAAAGGG 1583 TGAGAGAGAGGAAAGGAGAAAGG 1584 GAGAGAGAGGAAAGGAGAAAG

LDLRex2(27 68 123 30 _68 - 15_dl_f 1585 ACCCTTTCTCCTTTCCTCTCTCTCA 1586 CCCTTTCTCCTTTCCTCTCTCTC 1587 CCTTTCTCCTTTCCTCTCTCT

LDLRex2(27 68 123 30 _68 - 15_dl_r 1588 TGAGAGAGAGGAAAGGAGAAAGGGT 1589 GAGAGAGAGGAAAGGAGAAAGGG 1590 AGAGAGAGGAAAGGAGAAAGG

LDLRex2(27 68 123 30 _68 - 2_dl_f 1591 TTCCTCTCTCTCGTGGGCGACAGAT 1592 TCCTCTCTCTCGTGGGCGACAGA 1593 CCTCTCTCTCGTG GG CG ACAG

LDLRex2(27 68 123 30 _68 - 2_dl_r 1594 ATCTGTCGCCCACGAGAGAGAGGAA 1595 TCTGTCGCCCACGAGAGAGAGGA 1596 CTGTCGCCCACGAGAGAGAGG

LDLRex2(27 68 123 30 _68 - 3_dl_f 1597 TTTCCTCTCTCTAGTGGGCGACAGA 1598 TTCCTCTCTCTAGTG GG CG ACAG 1599 TCCTCTCTCTAGTGGGCGACA

LDLRex2(27 68 123 30 _68 - 3_dl_r 1600 TCTGTCGCCCACTAGAGAGAGGAAA 1601 CTGTCGCCCACTAGAGAGAGGAA 1602 TGTCGCCCACTAGAGAGAGGA

LDLRex2(27 68 123 30 _68 - 4_dl_f 1603 TTTTCCTCTCTCCAGTG GG CG ACAG 1604 TTTCCTCTCTCCAGTGGGCGACA 1605 TTCCTCTCTCCAGTGGGCGAC

LDLRex2(27 68 123 30 _68 - 4_dl_r 1606 CTGTCGCCCACTGGAGAGAGGAAAA 1607 TGTCGCCCACTGGAGAGAGGAAA 1608 GTCGCCCACTGGAGAGAGGAA

LDLRex2(27 68 123 30 _68 - 5_dl_f 1609 CTTTTCCTCTCTTCAGTG GG CG ACA 1610 TTTTCCTCTCTTCAGTG GG CG AC 1611 TTTCCTCTCTTCAGTG GG CG A

LDLRex2(27 68 123 30 _68 - 5_dl_r 1612 TGTCGCCCACTGAAGAGAGGAAAAG 1613 GTCGCCCACTGAAGAGAGGAAAA 1614 TCGCCCACTGAAGAGAGGAAA

LDLRex2(27 68 123 30 _68 - 6_dl_f 1615 CCTTTTCCTCTCCTCAGTGGGCGAC 1616 CTTTTCCTCTCCTCAGTGGGCGA 1617 TTTTCCTCTCCTCAGTG GG CG

LDLRex2(27 68 123 30 _68 - 6_dl_r 1618 GTCGCCCACTGAGGAGAGGAAAAGG 1619 TCGCCCACTGAGGAGAGGAAAAG 1620 CGCCCACTGAGGAGAGGAAAA

LDLRex2(27 68 123 30 _68 - 7_dl_f 1621 TCCTTTTCCTCTTCTCAGTG GG CG A 1622 CCTTTTCCTCTTCTCAGTG GG CG 1623 CTTTTCCTCTTCTCAGTG GG C

LDLRex2(27 68 123 30 _68 - 7_dl_r 1624 TCGCCCACTGAGAAGAGGAAAAGGA 1625 CGCCCACTGAGAAGAGGAAAAGG 1626 GCCCACTGAGAAGAGGAAAAG

LDLRex2(27 68 123 30 _68 - 8_dl_f 1627 CTCCTTTTCCTCCTCTCAGTGGGCG 1628 TCCTTTTCCTCCTCTCAGTGGGC 1629 CCTTTTCCTCCTCTCAGTGGG

LDLRex2(27 68 123 30 _68 - 8_dl_r 1630 CGCCCACTGAGAGGAGGAAAAGGAG 1631 GCCCACTGAGAGGAGGAAAAGGA 1632 CCCACTG AG AG GAG GAAAAG G

LDLRex2(27 68 123 30 _68 - 9_dl_f 1633 TCTCCTTTTCCTTCTCTCAGTG GG C 1634 CTCCTTTTCCTTCTCTCAGTGGG 1635 TCCTTTTCCTTCTCTCAGTG G

LDLRex2(27 68 123 30) _68 - 9_dl_r 1636 GCCCACTGAGAGAAGGAAAAGGAGA 1637 CCCACTGAGAGAAGGAAAAGGAG 1638 CCACTGAGAGAAGGAAAAGGA

LDLRex2(27 68 123 30) _68. .dlj 1639 CCTCTCTCTCAGGGGCGACAGATGC 1640 CTCTCTCTCAGGGGCGACAGATG 1641 TCTCTCTCAGGGGCGACAGAT

LDLRex2(27 68 123 30) _68. .dl_r 1642 GCATCTGTCGCCCCTGAGAGAGAGG 1643 CATCTGTCGCCCCTGAGAGAGAG 1644 ATCTGTCGCCCCTGAGAGAGA

LDLRex2(27 68 123 30) _69. .dlj 1645 CTCTCTCTCAGTGGCGACAGATGCG 1646 TCTCTCTCAGTGGCGACAGATGC 1647 CTCTCTCAGTGGCGACAGATG

LDLRex2(27 68 123 30) _69. .dl_r 1648 CGCATCTGTCGCCACTGAGAGAGAG 1649 GCATCTGTCGCCACTGAGAGAGA 1650 CATCTGTCGCCACTGAGAGAG

LDLRex2(27 68 123 30) _70. .dlj 1651 TCTCTCTCAGTGGCGACAGATGCGA 1652 CTCTCTCAGTGGCGACAGATGCG 1653 TCTCTCAGTGGCGACAGATGC

LDLRex2(27 68 123 30) _70. .dl_r 1654 TCGCATCTGTCGCCACTGAGAGAGA 1655 CGCATCTGTCGCCACTGAGAGAG 1656 GCATCTGTCGCCACTGAGAGA

LDLRex2(27 68 123 30) _71. .dlj 1657 CTCTCTCAGTGGCGACAGATGCGAA 1658 TCTCTCAGTGGCGACAGATGCGA 1659 CTCTCAGTGGCGACAGATGCG

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _71_ _dl_r 1660 TTCGCATCTGTCGCCACTGAGAGAG 1661 TCGCATCTGTCGCCACTGAGAGA 1662 CGCATCTGTCGCCACTGAGAG

LDLRex2(27 68 123 30 _72. .dlj 1663 TCTCTCAGTGGGGACAGATGCGAAA 1664 CTCTCAGTG GG G ACAG ATG CG AA 1665 TCTCAGTGGGGACAGATGCGA

LDLRex2(27 68 123 30 _72. _dl_r 1666 TTTCGCATCTGTCCCCACTGAGAGA 1667 TTCGCATCTGTCCCCACTGAGAG 1668 TCGCATCTGTCCCCACTGAGA

LDLRex2(27 68 123 30 _73. .dlj 1669 CTCTCAGTGGGCACAGATGCGAAAG 1670 TCTCAGTGGGCACAGATGCGAAA 1671 CTCAGTGGGCACAGATGCGAA

LDLRex2(27 68 123 30 _73. _dl_r 1672 CTTTCGCATCTGTGCCCACTGAGAG 1673 TTTCGCATCTGTGCCCACTGAGA 1674 TTCGCATCTGTGCCCACTGAG

LDLRex2(27 68 123 30 _74. .dlj 1675 TCTCAGTGGGCGCAGATGCGAAAGA 1676 CTCAGTGGGCGCAGATGCGAAAG 1677 TCAGTGGGCGCAGATGCGAAA

LDLRex2(27 68 123 30 _74. _dl_r 1678 TCTTTCGCATCTGCGCCCACTGAGA 1679 CTTTCGCATCTGCGCCCACTGAG 1680 TTTCGCATCTGCGCCCACTGA

LDLRex2(27 68 123 30 _75. .dlj 1681 CTCAGTGGGCGAAGATGCGAAAGAA 1682 TCAGTGGGCGAAGATGCGAAAGA 1683 CAGTGGGCGAAGATGCGAAAG

LDLRex2(27 68 123 30 _75. _dl_r 1684 TTCTTTCG CATCTTCG CCCACTG AG 1685 TCTTTCGCATCTTCGCCCACTGA 1686 CTTTCGCATCTTCGCCCACTG

LDLRex2(27 68 123 30 _76. .dlj 1687 TCAGTGGGCGACGATGCGAAAGAAA 1688 CAGTGGGCGACGATGCGAAAGAA 1689 AGTGGGCGACGATGCGAAAGA

LDLRex2(27 68 123 30 _76. _dl_r 1690 TTTCTTTCGCATCGTCGCCCACTGA 1691 TTCTTTCGCATCGTCGCCCACTG 1692 TCTTTCGCATCGTCGCCCACT

LDLRex2(27 68 123 30 _77. .dlj 1693 CAGTG GG CG ACAATG CG AAAG AAAC 1694 AGTGGGCGACAATGCGAAAGAAA 1695 GTGGGCGACAATGCGAAAGAA

LDLRex2(27 68 123 30 _77. _dl_r 1696 GTTTCTTTCGCATTGTCGCCCACTG 1697 TTTCTTTCG CATTGTCG CCCACT 1698 TTCTTTCGCATTGTCGCCCAC

LDLRex2(27 68 123 30 _78. .dlj 1699 AGTGGGCGACAGTGCGAAAGAAACG 1700 GTGGGCGACAGTGCGAAAGAAAC 1701 TG GG CG ACAGTG CG AAAG AAA

LDLRex2(27 68 123 30 _78. .dl_r 1702 CGTTTCTTTCG CACTGTCG CCCACT 1703 GTTTCTTTCGCACTGTCGCCCAC 1704 TTTCTTTCGCACTGTCGCCCA

LDLRex2(27 68 123 30 _79. .dlj 1705 GTGGGCGACAGAGCGAAAGAAACGA 1706 TGGGCGACAGAGCGAAAGAAACG 1707 G GG CG ACAG AG CG AAAG AAAC

LDLRex2(27 68 123 30 _79. .dl_r 1708 TCGTTTCTTTCGCTCTGTCGCCCAC 1709 CGTTTCTTTCGCTCTGTCGCCCA 1710 GTTTCTTTCGCTCTGTCGCCC

LDLRex2(27 68 123 30 _80. .dlj 1711 TGGGCGACAGATCGAAAGAAACGAG 1712 GGGCGACAGATCGAAAGAAACGA 1713 GGCGACAGATCGAAAGAAACG

LDLRex2(27 68 123 30 _80. .dl_r 1714 CTCGTTTCTTTCGATCTGTCGCCCA 1715 TCGTTTCTTTCG ATCTGTCG CCC 1716 CGTTTCTTTCGATCTGTCGCC

LDLRex2(27 68 123 30 _81. .dlj 1717 GGGCGACAGATGGAAAGAAACGAGT 1718 GGCGACAGATGGAAAGAAACGAG 1719 GCGACAGATGGAAAGAAACGA

LDLRex2(27 68 123 30 _81. .dl_r 1720 ACTCGTTTCTTTCCATCTGTCG CCC 1721 CTCGTTTCTTTCCATCTGTCGCC 1722 TCGTTTCTTTCCATCTGTCGC

LDLRex2(27 68 123 30 _82. .dlj 1723 GGCGACAGATGCAAAGAAACGAGTT 1724 GCGACAGATGCAAAGAAACGAGT 1725 CGACAGATGCAAAGAAACGAG

LDLRex2(27 68 123 30 _82. .dl_r 1726 AACTCGTTTCTTTGCATCTGTCGCC 1727 ACTCGTTTCTTTGCATCTGTCGC 1728 CTCGTTTCTTTG CATCTGTCG

LDLRex2(27 68 123 30) _83. .dlj 1729 GCGACAGATGCGAAGAAACGAGTTC 1730 CGACAGATGCGAAGAAACGAGTT 1731 GACAGATGCGAAGAAACGAGT

LDLRex2(27 68 123 30) _83. .dl_r 1732 GAACTCGTTTCTTCGCATCTGTCGC 1733 AACTCGTTTCTTCG CATCTGTCG 1734 ACTCGTTTCTTCGCATCTGTC

LDLRex2(27 68 123 30) _84. .dlj 1735 CGACAGATGCGAAGAAACGAGTTCC 1736 GACAGATGCGAAGAAACGAGTTC 1737 ACAGATGCGAAGAAACGAGTT

LDLRex2(27 68 123 30) _84. .dl_r 1738 GGAACTCGTTTCTTCGCATCTGTCG 1739 GAACTCGTTTCTTCGCATCTGTC 1740 AACTCGTTTCTTCG CATCTGT

LDLRex2(27 68 123 30) _85. .dlj 1741 GACAGATGCGAAGAAACGAGTTCCA 1742 ACAGATGCGAAGAAACGAGTTCC 1743 CAGATGCGAAGAAACGAGTTC

LDLRex2(27 68 123 30) _85. .dl_r 1744 TGGAACTCGTTTCTTCGCATCTGTC 1745 GGAACTCGTTTCTTCGCATCTGT 1746 G AACTCGTTTCTTCG CATCTG

LDLRex2(27 68 123 30) _86. .dlj 1747 ACAGATGCGAAAAAACGAGTTCCAG 1748 CAGATGCGAAAAAACGAGTTCCA 1749 AGATGCGAAAAAACGAGTTCC

LDLRex2(27 68 123 30) _86. .dl_r 1750 CTGGAACTCG 1 1 1 1 1 I CGCATCTGT 1751 TGGAACTCG 1 1 1 1 1 1 CGCATCTG 1752 GGAACTCG 1 1 1 1 1 I CGCATCT

Table 1

SEQ ID SEQ ID SEQ ID

dell NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _87. -dl. j 1753 CAGATGCGAAAGAACGAGTTCCAGT 1754 AGATGCGAAAGAACGAGTTCCAG 1755 GATGCGAAAGAACGAGTTCCA

LDLRex2(27 68 123 30 _87. -dl. 1756 ACTGGAACTCGTTCTTTCGCATCTG 1757 CTGGAACTCGTTCTTTCGCATCT 1758 TGGAACTCGTTCTTTCGCATC

LDLRex2(27 68 123 30 _88. -dl. j 1759 AGATGCGAAAGAACGAGTTCCAGTG 1760 GATGCGAAAGAACGAGTTCCAGT 1761 ATGCGAAAGAACGAGTTCCAG

LDLRex2(27 68 123 30 _88. -dl. 1762 CACTGGAACTCGTTCTTTCGCATCT 1763 ACTGGAACTCGTTCTTTCGCATC 1764 CTGGAACTCGTTCTTTCGCAT

LDLRex2(27 68 123 30 _89. -dl. j 1765 GATGCGAAAGAACGAGTTCCAGTGC 1766 ATG CG AAAG AACG AGTTCCAGTG 1767 TGCGAAAGAACGAGTTCCAGT

LDLRex2(27 68 123 30 _89. -dl. 1768 GCACTGGAACTCGTTCTTTCGCATC 1769 CACTG G AACTCGTTCTTTCG CAT 1770 ACTGGAACTCGTTCTTTCGCA

LDLRex2(27 68 123 30 _90. -dl. j 1771 ATG CG AAAG AAAG AGTTCCAGTG CC 1772 TGCGAAAGAAAGAGTTCCAGTGC 1773 GCGAAAGAAAGAGTTCCAGTG

LDLRex2(27 68 123 30 _90. -dl. 1774 GGCACTG G AACTCTTTCTTTCG CAT 1775 GCACTGGAACTCTTTCTTTCGCA 1776 CACTGGAACTCTTTCTTTCGC

LDLRex2(27 68 123 30 _91. -dl. j Ylll TGCGAAAGAAACAGTTCCAGTGCCA 1778 GCGAAAGAAACAGTTCCAGTGCC 1779 CGAAAGAAACAGTTCCAGTGC

LDLRex2(27 68 123 30 _91. -dl. 1780 TGGCACTGGAACTGTTTCTTTCGCA 1781 GGCACTGGAACTGTTTCTTTCGC 1782 G CACTG G AACTGTTTCTTTCG

LDLRex2(27 68 123 30 _92. -dl. j 1783 G CG AAAG AAACG GTTCCAGTGCCAA 1784 CGAAAGAAACGGTTCCAGTGCCA 1785 GAAAGAAACGGTTCCAGTGCC

LDLRex2(27 68 123 30 _92. -dl. 1786 TTGGCACTGGAACCGTTTCTTTCGC 1787 TG GCACTG G AACCGTTTCTTTCG 1788 GGCACTGGAACCGTTTCTTTC

LDLRex2(27 68 123 30 _93. -dl. j 1789 CGAAAGAAACGATTCCAGTGCCAAG 1790 GAAAGAAACGATTCCAGTGCCAA 1791 AAAGAAACGATTCCAGTGCCA

LDLRex2(27 68 123 30 _93. -dl. 1792 CTTG GCACTG G AATCGTTTCTTTCG 1793 TTGG CACTG G AATCGTTTCTTTC 1794 TGGCACTGGAATCGTTTCTTT

LDLRex2(27 68 123 30 _94. -dl. j 1795 GAAAGAAACGAGTCCAGTGCCAAGA 1796 AAAGAAACGAGTCCAGTGCCAAG 1797 AAGAAACGAGTCCAGTGCCAA

LDLRex2(27 68 123 30 _94. -dl. 1798 TCTTGG CACTG G ACTCGTTTCTTTC 1799 CTTGGCACTGGACTCGTTTCTTT 1800 TTG GCACTG G ACTCGTTTCTT

LDLRex2(27 68 123 30 _95. -dl. j 1801 AAAGAAACGAGTCCAGTGCCAAGAC 1802 AAGAAACGAGTCCAGTGCCAAGA 1803 AGAAACGAGTCCAGTGCCAAG

LDLRex2(27 68 123 30 _95. -dl. _r 1804 GTCTTGGCACTGGACTCGTTTCTTT 1805 TCTTG G CACTG G ACTCGTTTCTT 1806 CTTGGCACTGGACTCGTTTCT

LDLRex2(27 68 123 30 _96. -dl. _f 1807 AAGAAACGAGTTCAGTGCCAAGACG 1808 AGAAACGAGTTCAGTGCCAAGAC 1809 GAAACGAGTTCAGTGCCAAGA

LDLRex2(27 68 123 30 _96. -dl. _r 1810 CGTCTTGGCACTGAACTCGTTTCTT 1811 GTCTTGGCACTGAACTCGTTTCT 1812 TCTTGGCACTGAACTCGTTTC

LDLRex2(27 68 123 30 _97. -dl. _f 1813 AGAAACGAGTTCAGTGCCAAGACGG 1814 GAAACGAGTTCAGTGCCAAGACG 1815 AAACGAGTTCAGTGCCAAGAC

LDLRex2(27 68 123 30 _97. -dl. _r 1816 CCGTCTTGGCACTGAACTCGTTTCT 1817 CGTCTTGGCACTGAACTCGTTTC 1818 GTCTTGGCACTGAACTCGTTT

LDLRex2(27 68 123 30 _98. -dl. _f 1819 GAAACGAGTTCCGTGCCAAGACGGG 1820 AAACGAGTTCCGTGCCAAGACGG 1821 AACG AGTTCCGTG CCAAG ACG

LDLRex2(27 68 123 30) _98. -dl. _r 1822 CCCGTCTTGGCACGGAACTCGTTTC 1823 CCGTCTTGG CACG G AACTCGTTT 1824 CGTCTTGG CACG G AACTCGTT

LDLRex2(27 68 123 30) _99. -dl. j 1825 AAACGAGTTCCATGCCAAGACGGGA 1826 AACG AGTTCCATG CCAAG ACGG G 1827 ACGAGTTCCATGCCAAGACGG

LDLRex2(27 68 123 30) _99. -dl. _r 1828 TCCCGTCTTGG CATG G AACTCGTTT 1829 CCCGTCTTG GCATG G AACTCGTT 1830 CCGTCTTG GCATG G AACTCGT

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30 _100. .d2_r 1831 TTTCCCGTCTTGGCTGGAACTCGTT 1832 TTCCCGTCTTG GCTG G AACTCGT 1833 TCCCGTCTTGGCTGGAACTCG

LDLRex2(27 68 123 30 _101_ .d2_f 1834 ACGAGTTCCAGTCAAGACGGGAAAT 1835 CGAGTTCCAGTCAAGACGGGAAA 1836 GAGTTCCAGTCAAGACGGGAA

LDLRex2(27 68 123 30 _101_ .d2_r 1837 ATTTCCCGTCTTGACTGGAACTCGT 1838 TTTCCCGTCTTGACTGGAACTCG 1839 TTCCCGTCTTG ACTG GAACTC

LDLRex2(27 68 123 30 _102. .d2_f 1840 CGAGTTCCAGTGAAGACGGGAAATG 1841 GAGTTCCAGTGAAGACGGGAAAT 1842 AGTTCCAGTGAAGACGGGAAA

LDLRex2(27 68 123 30 _102. .d2_r 1843 CATTTCCCGTCTTCACTGGAACTCG 1844 ATTTCCCGTCTTCACTG GAACTC 1845 TTTCCCGTCTTCACTGGAACT

LDLRex2(27 68 123 30 _103. .d2_f 1846 GAGTTCCAGTGCAGACGGGAAATGC 1847 AGTTCCAGTGCAGACGGGAAATG 1848 GTTCCAGTGCAGACGGGAAAT

LDLRex2(27 68 123 30 _103. .d2_r 1849 G CATTTCCCGTCTG CACTG GAACTC 1850 CATTTCCCGTCTGCACTGGAACT 1851 ATTTCCCGTCTG CACTG GAAC

LDLRex2(27 68 123 30 _104 .d2_f 1852 AGTTCCAGTGCCGACGGGAAATGCA 1853 GTTCCAGTGCCGACGGGAAATGC 1854 TTCCAGTG CCG ACG G G AAATG

LDLRex2(27 68 123 30 _104 .d2_r 1855 TGCATTTCCCGTCGGCACTGGAACT 1856 G CATTTCCCGTCGG CACTG GAAC 1857 CATTTCCCGTCGGCACTGGAA

LDLRex2(27 68 123 30 _105. .d2_f 1858 GTTCCAGTG CCAACGG G AAATG CAT 1859 TTCCAGTG CCAACGG G AAATG CA 1860 TCCAGTGCCAACGGGAAATGC

LDLRex2(27 68 123 30 _105. .d2_r 1861 ATGCATTTCCCGTTGGCACTGGAAC 1862 TGCATTTCCCGTTGGCACTGGAA 1863 GCATTTCCCGTTGGCACTGGA

LDLRex2(27 68 123 30 _106. .d2_f 1864 TTCCAGTGCCAACGGGAAATGCATC 1865 TCCAGTG CCAACGG G AAATG CAT 1866 CCAGTGCCAACGGGAAATGCA

LDLRex2(27 68 123 30 _106. .d2_r 1867 GATG CATTTCCCGTTG G CACTG G AA 1868 ATGCATTTCCCGTTGGCACTGGA 1869 TGCATTTCCCGTTGGCACTGG

LDLRex2(27 68 123 30 _107. .d2_f 1870 TCCAGTGCCAAGGGGAAATGCATCT 1871 CCAGTGCCAAG GG G AAATG CATC 1872 CAGTGCCAAGGGGAAATGCAT

LDLRex2(27 68 123 30 _107. .d2_r 1873 AGATGCATTTCCCCTTGGCACTGGA 1874 GATG CATTTCCCCTTGG CACTG G 1875 ATG CATTTCCCCTTGG CACTG

LDLRex2(27 68 123 30 _108. .d2_f 1876 CCAGTGCCAAGAGGAAATGCATCTC 1877 CAGTGCCAAGAGGAAATGCATCT 1878 AGTGCCAAGAGGAAATGCATC

LDLRex2(27 68 123 30 _108. .d2_r 1879 GAGATGCATTTCCTCTTGGCACTGG 1880 AGATGCATTTCCTCTTGGCACTG 1881 GATGCATTTCCTCTTGGCACT

LDLRex2(27 68 123 30 _109. .d2_f 1882 CAGTG CCAAG ACG AAATG CATCTCC 1883 AGTGCCAAGACGAAATGCATCTC 1884 GTGCCAAGACGAAATGCATCT

LDLRex2(27 68 123 30 _109. .d2_r 1885 GGAGATGCATTTCGTCTTGGCACTG 1886 GAG ATG CATTTCGTCTTG GCACT 1887 AG ATG CATTTCGTCTTGG CAC

LDLRex2(27 68 123 30 _110. .d2_f 1888 AGTG CCAAG ACG AAATG CATCTCCT 1889 GTG CCAAG ACG AAATG CATCTCC 1890 TG CCAAG ACG AAATG CATCTC

LDLRex2(27 68 123 30 _110. .d2_r 1891 AG G AG ATG CATTTCGTCTTGG CACT 1892 GGAGATGCATTTCGTCTTGGCAC 1893 GAGATGCATTTCGTCTTGGCA

LDLRex2(27 68 123 30 _111_ .d2_f 1894 GTGCCAAGACGGAATGCATCTCCTA 1895 TGCCAAGACGGAATGCATCTCCT 1896 GCCAAGACGGAATGCATCTCC

LDLRex2(27 68 123 30 _111_ .d2_r 1897 TAG GAG ATG CATTCCGTCTTG G CAC 1898 AGGAGATGCATTCCGTCTTGGCA 1899 G GAG ATG CATTCCGTCTTG GC

LDLRex2(27 68 123 30 _112. .d2_f 1900 TGCCAAGACGGGATGCATCTCCTAC 1901 G CCAAG ACGG GATG CATCTCCTA 1902 CCAAGACGGGATGCATCTCCT

LDLRex2(27 68 123 30 _112. .d2_r 1903 GTAGGAGATGCATCCCGTCTTGGCA 1904 TAG GAG ATG CATCCCGTCTTGG C 1905 AGGAGATGCATCCCGTCTTGG

LDLRex2(27 68 123 30 _113. .d2_f 1906 GCCAAGACGGGATGCATCTCCTACA 1907 CCAAGACGGGATGCATCTCCTAC 1908 CAAGACGGGATGCATCTCCTA

LDLRex2(27 68 123 30 _113. .d2_r 1909 TGTAG GAG ATG CATCCCGTCTTGG C 1910 GTAGGAGATGCATCCCGTCTTGG 1911 TAGGAGATGCATCCCGTCTTG

LDLRex2(27 68 123 30 _114. .d2_f 1912 CCAAG ACGG G AAG CATCTCCTACAA 1913 CAAG ACG G G AAG CATCTCCTACA 1914 AAGACGGGAAGCATCTCCTAC

LDLRex2(27 68 123 30 _114. .d2_r 1915 TTGTAG GAG ATG CTTCCCGTCTTGG 1916 TGTAGGAGATGCTTCCCGTCTTG 1917 GTAG GAG ATG CTTCCCGTCTT

LDLRex2(27 68 123 30) _115. .d2_f 1918 CAAGACGGGAAACATCTCCTACAAG 1919 AAG ACG G G AAACATCTCCTACAA 1920 AGACGGGAAACATCTCCTACA

LDLRex2(27 68 123 30) _115. .d2_r 1921 CTTGTAG G AG ATGTTTCCCGTCTTG 1922 TTGTAGGAGATGTTTCCCGTCTT 1923 TGTAGGAGATGTTTCCCGTCT

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _116_ _d2_f 1924 AAGACGGGAAATATCTCCTACAAGT 1925 AGACGGGAAATATCTCCTACAAG 1926 GACGGGAAATATCTCCTACAA

LDLRex2(27 68 123 30) _116_ .d2_r 1927 ACTTGTAGGAGATATTTCCCGTCTT 1928 CTTGTAGGAGATATTTCCCGTCT 1929 TTGTAGGAGATATTTCCCGTC

LDLRex2(27 68 123 30) _117. _d2_f 1930 AGACGGGAAATGTCTCCTACAAGTG 1931 GACGGGAAATGTCTCCTACAAGT 1932 ACGGGAAATGTCTCCTACAAG

LDLRex2(27 68 123 30) _117. .d2_r 1933 CACTTGTAG G AG ACATTTCCCGTCT 1934 ACTTGTAG G AG ACATTTCCCGTC 1935 CTTGTAG G AG ACATTTCCCGT

LDLRex2(27 68 123 30) _118. _d2_f 1936 GACGGGAAATGCCTCCTACAAGTGG 1937 ACGG G AAATG CCTCCTACAAGTG 1938 CGG G AAATG CCTCCTACAAGT

LDLRex2(27 68 123 30) _118. .d2_r 1939 CCACTTGTAG G AGG CATTTCCCGTC 1940 CACTTGTAG G AGG CATTTCCCGT 1941 ACTTGTAGGAGGCATTTCCCG

LDLRex2(27 68 123 30) _119. _d2_f 1942 ACGG G AAATG CATCCTACAAGTGG G 1943 CGGGAAATGCATCCTACAAGTGG 1944 GG G AAATG CATCCTACAAGTG

LDLRex2(27 68 123 30) _119. .d2_r 1945 CCCACTTGTAGGATGCATTTCCCGT 1946 CCACTTGTAGGATGCATTTCCCG 1947 CACTTGTAGGATGCATTTCCC

LDLRex2(27 68 123 30) _120. _d2_f 1948 CGGGAAATGCATCCTACAAGTGGGT 1949 GGGAAATGCATCCTACAAGTGGG 1950 GGAAATGCATCCTACAAGTGG

LDLRex2(27 68 123 30) _120. .d2_r 1951 ACCCACTTGTAGGATGCATTTCCCG 1952 CCCACTTGTAGGATGCATTTCCC 1953 CCACTTGTAGGATGCATTTCC

LDLRex2(27 68 123 30) _121_ _d2_f 1954 GGGAAATGCATCCTACAAGTGGGTC 1955 GGAAATGCATCCTACAAGTGGGT 1956 G AAATG CATCCTACAAGTGG G

LDLRex2(27 68 123 30) _121_ .d2_r 1957 GACCCACTTGTAGGATGCATTTCCC 1958 ACCCACTTGTAG G ATG CATTTCC 1959 CCCACTTGTAG G ATG CATTTC

LDLRex2(27 68 123 30) _122. _d2_f 1960 G G AAATG CATCTTACAAGTGG GTCT 1961 G AAATG CATCTTACAAGTG GGTC 1962 AAATGCATCTTACAAGTGGGT

LDLRex2(27 68 123 30) _122. .d2_r 1963 AGACCCACTTGTAAGATGCATTTCC 1964 GACCCACTTGTAAGATGCATTTC 1965 ACCCACTTGTAAGATGCATTT

LDLRex2(27 68 123 30) _123. _d2_f 1966 GAAATGCATCTCACAAGTGGGTCTG 1967 AAATGCATCTCACAAGTGGGTCT 1968 AATGCATCTCACAAGTGGGTC

LDLRex2(27 68 123 30) _123. .d2_r 1969 CAGACCCACTTGTGAGATGCATTTC 1970 AGACCCACTTGTGAGATGCATTT 1971 G ACCCACTTGTG AG ATG CATT

LDLRex2(27 68 123 30) _124. _d2_f 1972 AAATGCATCTCCCAAGTGGGTCTGC 1973 AATG CATCTCCCAAGTG GGTCTG 1974 ATG CATCTCCCAAGTG GGTCT

LDLRex2(27 68 123 30) _124. .d2_r 1975 G CAG ACCCACTTGG G AG ATG CATTT 1976 CAGACCCACTTGGGAGATGCATT 1977 AGACCCACTTGGGAGATGCAT

LDLRex2(27 68 123 30) _125_ .d2_f 1978 AATG CATCTCCTAAGTG GGTCTG CG 1979 ATG CATCTCCTAAGTGG GTCTG C 1980 TGCATCTCCTAAGTGGGTCTG

LDLRex2(27 68 123 30) _125_ .d2_r 1981 CGCAGACCCACTTAGGAGATGCATT 1982 GCAGACCCACTTAGGAGATGCAT 1983 CAG ACCCACTTAG GAG ATG CA

LDLRex2(27 68 123 30) _126_ .d2_f 1984 ATGCATCTCCTAAGTGGGTCTGCGA 1985 TGCATCTCCTAAGTGGGTCTGCG 1986 G CATCTCCTAAGTG GGTCTG C

LDLRex2(27 68 123 30) _126_ .d2_r 1987 TCGCAG ACCCACTTAG GAG ATG CAT 1988 CGCAGACCCACTTAGGAGATGCA 1989 GCAGACCCACTTAGGAGATGC

LDLRex2(27 68 123 30) _127_ .d2_f 1990 TG CATCTCCTACGTG GGTCTG CG AT 1991 GCATCTCCTACGTGGGTCTGCGA 1992 CATCTCCTACGTG GGTCTG CG

LDLRex2(27 68 123 30) _127. .d2_r 1993 ATCGCAGACCCACGTAGGAGATGCA 1994 TCGCAGACCCACGTAGGAGATGC 1995 CGCAGACCCACGTAGGAGATG

LDLRex2(27 68 123 30) _128. .d2_f 1996 GCATCTCCTACATGGGTCTGCGATG 1997 CATCTCCTACATG G GTCTG CG AT 1998 ATCTCCTACATG GGTCTG CG A

LDLRex2(27 68 123 30) _128. .d2_r 1999 CATCG CAG ACCCATGTAG GAG ATG C 2000 ATCG CAG ACCCATGTAG GAG ATG 2001 TCG CAG ACCCATGTAG GAG AT

LDLRex2(27 68 123 30) _129. .d2_f 2002 CATCTCCTACAAGGGTCTGCGATGG 2003 ATCTCCTACAAGGGTCTGCGATG 2004 TCTCCTACAAGGGTCTGCGAT

LDLRex2(27 68 123 30) _129. .d2_r 2005 CCATCGCAGACCCTTGTAGGAGATG 2006 CATCGCAGACCCTTGTAGGAGAT 2007 ATCGCAGACCCTTGTAGGAGA

LDLRex2(27 68 123 30) _130. .d2_f 2008 ATCTCCTACAAGGGTCTGCGATGGC 2009 TCTCCTACAAGGGTCTGCGATGG 2010 CTCCTACAAGGGTCTGCGATG

LDLRex2(27 68 123 30) _130. .d2_r 2011 GCCATCGCAGACCCTTGTAGGAGAT 2012 CCATCGCAGACCCTTGTAGGAGA 2013 CATCGCAGACCCTTGTAGGAG

LDLRex2(27 68 123 30) _131. .d2_f 2014 TCTCCTACAAGTGTCTGCGATGGCA 2015 CTCCTACAAGTGTCTGCGATGGC 2016 TCCTACAAGTGTCTG CG ATG G

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _131_ .d2_r 2017 TGCCATCGCAGACACTTGTAGGAGA 2018 G CCATCG CAG ACACTTGTAG GAG 2019 CCATCGCAGACACTTGTAGGA

LDLRex2(27 68 123 30) _132_ _d2_f 2020 CTCCTACAAGTGTCTGCGATGGCAG 2021 TCCTACAAGTGTCTG CG ATG GCA 2022 CCTACAAGTGTCTGCGATGGC

LDLRex2(27 68 123 30) _132_ .d2_r 2023 CTGCCATCGCAGACACTTGTAGGAG 2024 TG CCATCG CAG ACACTTGTAG G A 2025 GCCATCGCAGACACTTGTAGG

LDLRex2(27 68 123 30) _133. _d2_f 2026 TCCTACAAGTGGCTGCGATGGCAGC 2027 CCTACAAGTGGCTGCGATGGCAG 2028 CTACAAGTG GCTG CG ATG GCA

LDLRex2(27 68 123 30) _133. .d2_r 2029 GCTGCCATCGCAGCCACTTGTAGGA 2030 CTG CCATCG CAG CCACTTGTAGG 2031 TGCCATCGCAGCCACTTGTAG

LDLRex2(27 68 123 30) _134. _d2_f 2032 CCTACAAGTGGGTGCGATGGCAGCG 2033 CTACAAGTG G GTG CG ATGG CAG C 2034 TACAAGTGGGTGCGATGGCAG

LDLRex2(27 68 123 30) _134. .d2_r 2035 CGCTGCCATCGCACCCACTTGTAGG 2036 GCTGCCATCGCACCCACTTGTAG 2037 CTGCCATCGCACCCACTTGTA

LDLRex2(27 68 123 30) _135. _d2_f 2038 CTACAAGTGGGTGCGATGGCAGCGC 2039 TACAAGTGGGTGCGATGGCAGCG 2040 ACAAGTGGGTGCGATGGCAGC

LDLRex2(27 68 123 30) _135. .d2_r 2041 GCGCTG CCATCG CACCCACTTGTAG 2042 CGCTGCCATCGCACCCACTTGTA 2043 GCTG CCATCG CACCCACTTGT

LDLRex2(27 68 123 30) _136. _d2_f 2044 TACAAGTGGGTCCGATGGCAGCGCT 2045 ACAAGTGGGTCCGATGGCAGCGC 2046 CAAGTGGGTCCGATGGCAGCG

LDLRex2(27 68 123 30) _136. .d2_r 2047 AGCGCTGCCATCGGACCCACTTGTA 2048 GCGCTGCCATCGGACCCACTTGT 2049 CGCTG CCATCG G ACCCACTTG

LDLRex2(27 68 123 30) _137_ _d2_f 2050 ACAAGTGGGTCTGATGGCAGCGCTG 2051 CAAGTGGGTCTGATGGCAGCGCT 2052 AAGTGGGTCTGATGGCAGCGC

LDLRex2(27 68 123 30) _137_ .d2_r 2053 CAGCGCTGCCATCAGACCCACTTGT 2054 AGCGCTGCCATCAGACCCACTTG 2055 GCGCTGCCATCAGACCCACTT

LDLRex2(27 68 123 30) _138. _d2_f 2056 CAAGTGGGTCTGATGGCAGCGCTGA 2057 AAGTGGGTCTGATGGCAGCGCTG 2058 AGTGGGTCTGATGGCAGCGCT

LDLRex2(27 68 123 30) _138. .d2_r 2059 TCAGCGCTGCCATCAGACCCACTTG 2060 CAG CGCTG CCATCAG ACCCACTT 2061 AG CG CTG CCATCAG ACCCACT

LDLRex2(27 68 123 30) _139. _d2_f 2062 AAGTGGGTCTGCTGGCAGCGCTGAG 2063 AGTGGGTCTGCTGGCAGCGCTGA 2064 GTGGGTCTGCTGGCAGCGCTG

LDLRex2(27 68 123 30) _139. .d2_r 2065 CTCAGCGCTGCCAGCAGACCCACTT 2066 TCAG CGCTG CCAG CAG ACCCACT 2067 CAGCGCTGCCAGCAGACCCAC

LDLRex2(27 68 123 30) _140. .d2_f 2068 AGTGGGTCTGCGGGCAGCGCTGAGT 2069 GTGGGTCTGCGGGCAGCGCTGAG 2070 TGGGTCTGCGGGCAGCGCTGA

LDLRex2(27 68 123 30) _140. .d2_r 2071 ACTCAG CG CTG CCCG CAG ACCCACT 2072 CTCAG CGCTG CCCG CAG ACCCAC 2073 TCAG CG CTG CCCG CAG ACCCA

LDLRex2(27 68 123 30) _141. .d2_f 2074 GTGGGTCTGCGAGCAGCGCTGAGTG 2075 TGGGTCTGCGAGCAGCGCTGAGT 2076 GGGTCTGCGAGCAGCGCTGAG

LDLRex2(27 68 123 30) _141. .d2_r 2077 CACTCAGCGCTGCTCGCAGACCCAC 2078 ACTCAGCGCTGCTCGCAGACCCA 2079 CTCAGCGCTGCTCGCAGACCC

LDLRex2(27 68 123 30) _142. .d2_f 2080 TGGGTCTGCGATCAGCGCTGAGTGC 2081 GGGTCTG CG ATCAGCG CTG AGTG 2082 GGTCTGCGATCAGCGCTGAGT

LDLRex2(27 68 123 30) _142. .d2_r 2083 GCACTCAGCGCTGATCGCAGACCCA 2084 CACTCAGCGCTGATCGCAGACCC 2085 ACTCAGCGCTGATCGCAGACC

LDLRex2(27 68 123 30) _143. .d2_f 2086 GGGTCTGCGATGAGCGCTGAGTGCC 2087 GGTCTGCGATGAGCGCTGAGTGC 2088 GTCTGCGATGAGCGCTGAGTG

LDLRex2(27 68 123 30) _143. .d2_r 2089 GGCACTCAGCGCTCATCGCAGACCC 2090 G CACTCAG CG CTCATCGCAG ACC 2091 CACTCAGCGCTCATCGCAGAC

LDLRex2(27 68 123 30) _144. .d2_f 2092 GGTCTGCGATGGGCGCTGAGTGCCA 2093 GTCTGCGATGGGCGCTGAGTGCC 2094 TCTGCGATGGGCGCTGAGTGC

LDLRex2(27 68 123 30) _144. .d2_r 2095 TGGCACTCAGCGCCCATCGCAGACC 2096 GGCACTCAGCGCCCATCGCAGAC 2097 GCACTCAGCGCCCATCGCAGA

LDLRex2(27 68 123 30) _145. .d2_f 2098 GTCTGCGATGGCCGCTGAGTGCCAG 2099 TCTGCGATGGCCGCTGAGTGCCA 2100 CTGCGATGGCCGCTGAGTGCC

LDLRex2(27 68 123 30) _145. .d2_r 2101 CTGGCACTCAGCGGCCATCGCAGAC 2102 TGGCACTCAGCGGCCATCGCAGA 2103 G GCACTCAG CG G CCATCG CAG

LDLRex2(27 68 123 30) _146. .d2_f 2104 TCTGCGATGGCAGCTGAGTGCCAGG 2105 CTGCGATGGCAGCTGAGTGCCAG 2106 TGCGATGGCAGCTGAGTGCCA

LDLRex2(27 68 123 30) _146. .d2_r 2107 CCTG G CACTCAGCTG CCATCG CAG A 2108 CTG GCACTCAG CTG CCATCG CAG 2109 TGGCACTCAGCTGCCATCGCA

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _147_ _d2_f 2110 CTGCGATGGCAGCTGAGTGCCAGGA 2111 TGCGATGGCAGCTGAGTGCCAGG 2112 GCGATGGCAGCTGAGTGCCAG

LDLRex2(27 68 123 30) _147_ .d2_r 2113 TCCTGG CACTCAGCTG CCATCG CAG 2114 CCTGGCACTCAGCTGCCATCGCA 2115 CTGGCACTCAGCTGCCATCGC

LDLRex2(27 68 123 30) _148_ _d2_f 2116 TGCGATGGCAGCTGAGTGCCAGGAT 2117 GCGATGGCAGCTGAGTGCCAGGA 2118 CGATGGCAGCTGAGTGCCAGG

LDLRex2(27 68 123 30) _148_ .d2_r 2119 ATCCTGGCACTCAGCTGCCATCGCA 2120 TCCTGGCACTCAGCTGCCATCGC 2121 CCTGGCACTCAGCTGCCATCG

LDLRex2(27 68 123 30) _149_ _d2_f 2122 GCGATGGCAGCGGAGTGCCAGGATG 2123 CGATGGCAGCGGAGTGCCAGGAT 2124 GATGGCAGCGGAGTGCCAGGA

LDLRex2(27 68 123 30) _149_ .d2_r 2125 CATCCTGGCACTCCGCTGCCATCGC 2126 ATCCTGGCACTCCGCTGCCATCG 2127 TCCTGGCACTCCGCTGCCATC

LDLRex2(27 68 123 30) _150_ _d2_f 2128 CGATGGCAGCGCAGTGCCAGGATGG 2129 GATGGCAGCGCAGTGCCAGGATG 2130 ATGG CAG CG CAGTG CCAG GAT

LDLRex2(27 68 123 30) _150_ .d2_r 2131 CCATCCTGG CACTG CGCTG CCATCG 2132 CATCCTGG CACTG CGCTG CCATC 2133 ATCCTG G CACTG CG CTG CCAT

LDLRex2(27 68 123 30) _151_ _d2_f 2134 GATGGCAGCGCTGTGCCAGGATGGC 2135 ATGGCAGCGCTGTGCCAGGATGG 2136 TGG CAG CGCTGTG CCAG G ATG

LDLRex2(27 68 123 30) _151_ .d2_r 2137 G CCATCCTG GCACAG CGCTG CCATC 2138 CCATCCTGGCACAGCGCTGCCAT 2139 CATCCTGGCACAGCGCTGCCA

LDLRex2(27 68 123 30) _152_ _d2_f 2140 ATGGCAGCGCTGTGCCAGGATGGCT 2141 TGGCAGCGCTGTGCCAGGATGGC 2142 GGCAGCGCTGTGCCAGGATGG

LDLRex2(27 68 123 30) _152_ .d2_r 2143 AGCCATCCTGGCACAGCGCTGCCAT 2144 GCCATCCTG GCACAG CG CTG CCA 2145 CCATCCTG GCACAG CGCTG CC

LDLRex2(27 68 123 30) _153. _d2_f 2146 TGGCAGCGCTGAGCCAGGATGGCTC 2147 GGCAGCGCTGAGCCAGGATGGCT 2148 GCAGCGCTGAGCCAGGATGGC

LDLRex2(27 68 123 30) _153. .d2_r 2149 GAGCCATCCTGGCTCAGCGCTGCCA 2150 AG CCATCCTGG CTCAG CGCTG CC 2151 GCCATCCTGGCTCAGCGCTGC

LDLRex2(27 68 123 30) _154. _d2_f 2152 GGCAGCGCTGAGCCAGGATGGCTCT 2153 GCAGCGCTGAGCCAGGATGGCTC 2154 CAG CG CTG AG CCAG G ATGG CT

LDLRex2(27 68 123 30) _154. .d2_r 2155 AGAGCCATCCTGGCTCAGCGCTGCC 2156 GAGCCATCCTGGCTCAGCGCTGC 2157 AG CCATCCTG GCTCAGCG CTG

LDLRex2(27 68 123 30) _155. _d2_f 2158 G CAG CG CTG AGTCAG G ATG GCTCTG 2159 CAGCGCTGAGTCAGGATGGCTCT 2160 AG CG CTG AGTCAG G ATG GCTC

LDLRex2(27 68 123 30) _155. .d2_r 2161 CAGAGCCATCCTGACTCAGCGCTGC 2162 AGAGCCATCCTGACTCAGCGCTG 2163 GAGCCATCCTGACTCAGCGCT

LDLRex2(27 68 123 30) _156. .d2_f 2164 CAGCGCTGAGTGAGGATGGCTCTGA 2165 AGCGCTGAGTGAGGATGGCTCTG 2166 GCGCTGAGTGAGGATGGCTCT

LDLRex2(27 68 123 30) _156. .d2_r 2167 TCAGAGCCATCCTCACTCAGCGCTG 2168 CAGAGCCATCCTCACTCAGCGCT 2169 AG AG CCATCCTCACTCAG CGC

LDLRex2(27 68 123 30) _157_ .d2_f 2170 AGCGCTGAGTGCGGATGGCTCTGAT 2171 GCGCTGAGTGCGGATGGCTCTGA 2172 CG CTG AGTGCG G ATGG CTCTG

LDLRex2(27 68 123 30) _157_ .d2_r 2173 ATCAG AG CCATCCG CACTCAGCG CT 2174 TCAG AG CCATCCG CACTCAGCG C 2175 CAGAGCCATCCGCACTCAGCG

LDLRex2(27 68 123 30) _158. .d2_f 2176 GCGCTGAGTGCCGATGGCTCTGATG 2177 CGCTGAGTGCCGATGGCTCTGAT 2178 GCTGAGTGCCGATGGCTCTGA

LDLRex2(27 68 123 30) _158. .d2_r 2179 CATCAG AG CCATCG GCACTCAG CGC 2180 ATCAGAGCCATCGGCACTCAGCG 2181 TCAG AG CCATCG GCACTCAG C

LDLRex2(27 68 123 30) _159. .d2_f 2182 CGCTGAGTGCCAATGGCTCTGATGA 2183 GCTGAGTGCCAATGGCTCTGATG 2184 CTGAGTGCCAATGGCTCTGAT

LDLRex2(27 68 123 30) _159. .d2_r 2185 TCATCAGAGCCATTGGCACTCAGCG 2186 CATCAGAGCCATTGGCACTCAGC 2187 ATCAGAGCCATTGGCACTCAG

LDLRex2(27 68 123 30) _160. .d2_f 2188 GCTGAGTGCCAGTGGCTCTGATGAG 2189 CTGAGTGCCAGTGGCTCTGATGA 2190 TGAGTGCCAGTGGCTCTGATG

LDLRex2(27 68 123 30) _160. .d2_r 2191 CTCATCAG AG CCACTG GCACTCAG C 2192 TCATCAGAGCCACTGGCACTCAG 2193 CATCAGAGCCACTGGCACTCA

LDLRex2(27 68 123 30) _161. .d2_f 2194 CTGAGTGCCAGGGGCTCTGATGAGT 2195 TGAGTG CCAG GG GCTCTG ATG AG 2196 GAGTGCCAGGGGCTCTGATGA

LDLRex2(27 68 123 30) _161. .d2_r 2197 ACTCATCAGAGCCCCTGGCACTCAG 2198 CTCATCAGAGCCCCTGGCACTCA 2199 TCATCAGAGCCCCTGGCACTC

LDLRex2(27 68 123 30) _162. .d2_f 2200 TGAGTGCCAGGAGCTCTGATGAGTC 2201 GAGTGCCAGGAGCTCTGATGAGT 2202 AGTG CCAG G AGCTCTG ATG AG

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _162. .d2_r 2203 GACTCATCAGAGCTCCTGGCACTCA 2204 ACTCATCAGAGCTCCTGGCACTC 2205 CTCATCAGAGCTCCTGGCACT

LDLRex2(27 68 123 30) _163_ _d2_f 2206 GAGTGCCAGGATCTCTGATGAGTCC 2207 AGTG CCAG G ATCTCTG ATG AGTC 2208 GTGCCAGGATCTCTGATGAGT

LDLRex2(27 68 123 30) _163_ .d2_r 2209 GGACTCATCAGAGATCCTGGCACTC 2210 GACTCATCAGAGATCCTGGCACT 2211 ACTCATCAGAGATCCTGGCAC

LDLRex2(27 68 123 30) _164_ _d2_f 2212 AGTGCCAGGATGTCTGATGAGTCCC 2213 GTGCCAGGATGTCTGATGAGTCC 2214 TGCCAGGATGTCTGATGAGTC

LDLRex2(27 68 123 30) _164_ .d2_r 2215 GGGACTCATCAGACATCCTGGCACT 2216 G G ACTCATCAG ACATCCTGG CAC 2217 GACTCATCAGACATCCTGGCA

LDLRex2(27 68 123 30) _165_ _d2_f 2218 GTGCCAGGATGGCTGATGAGTCCCA 2219 TGCCAGGATGGCTGATGAGTCCC 2220 GCCAGGATGGCTGATGAGTCC

LDLRex2(27 68 123 30) _165_ .d2_r 2221 TGGGACTCATCAGCCATCCTGGCAC 2222 GGGACTCATCAGCCATCCTGGCA 2223 GGACTCATCAGCCATCCTGGC

LDLRex2(27 68 123 30) _166_ _d2_f 2224 TG CCAG G ATG GCTG ATG AGTCCCAG 2225 GCCAGGATGGCTGATGAGTCCCA 2226 CCAGGATGGCTGATGAGTCCC

LDLRex2(27 68 123 30) _166_ .d2_r 2227 CTGGGACTCATCAGCCATCCTGGCA 2228 TGGGACTCATCAGCCATCCTGGC 2229 GG G ACTCATCAG CCATCCTG G

LDLRex2(27 68 123 30) _167. _d2_f 2230 GCCAGGATGGCTGATGAGTCCCAGG 2231 CCAGGATGGCTGATGAGTCCCAG 2232 CAGGATGGCTGATGAGTCCCA

LDLRex2(27 68 123 30) _167. .d2_r 2233 CCTGGGACTCATCAGCCATCCTGGC 2234 CTGGGACTCATCAGCCATCCTGG 2235 TGG G ACTCATCAG CCATCCTG

LDLRex2(27 68 123 30) _168_ _d2_f 2236 CCAGGATGGCTCATGAGTCCCAGGA 2237 CAG G ATG GCTCATG AGTCCCAG G 2238 AG G ATG GCTCATG AGTCCCAG

LDLRex2(27 68 123 30) _168_ .d2_r 2239 TCCTGGGACTCATGAGCCATCCTGG 2240 CCTGGGACTCATGAGCCATCCTG 2241 CTGGGACTCATGAGCCATCCT

LDLRex2(27 68 123 30) _169_ _d2_f 2242 CAGGATGGCTCTTGAGTCCCAGGAG 2243 AGGATGGCTCTTGAGTCCCAGGA 2244 GGATGGCTCTTGAGTCCCAGG

LDLRex2(27 68 123 30) _169_ .d2_r 2245 CTCCTGGGACTCAAGAGCCATCCTG 2246 TCCTGGGACTCAAGAGCCATCCT 2247 CCTGGGACTCAAGAGCCATCC

LDLRex2(27 68 123 30) _170_ _d2_f 2248 AGGATGGCTCTGGAGTCCCAGGAGA 2249 GGATGGCTCTGGAGTCCCAGGAG 2250 GATGGCTCTGGAGTCCCAGGA

LDLRex2(27 68 123 30) _170_ .d2_r 2251 TCTCCTGGGACTCCAGAGCCATCCT 2252 CTCCTGGGACTCCAGAGCCATCC 2253 TCCTGGGACTCCAGAGCCATC

LDLRex2(27 68 123 30) _171. .d2_f 2254 GGATGGCTCTGAAGTCCCAGGAGAC 2255 GATGGCTCTGAAGTCCCAGGAGA 2256 ATGGCTCTGAAGTCCCAGGAG

LDLRex2(27 68 123 30) _171. .d2_r 2257 GTCTCCTGGGACTTCAGAGCCATCC 2258 TCTCCTGGGACTTCAGAGCCATC 2259 CTCCTGGGACTTCAGAGCCAT

LDLRex2(27 68 123 30) _172. .d2_f 2260 GATGGCTCTGATGTCCCAGGAGACG 2261 ATGGCTCTGATGTCCCAGGAGAC 2262 TGG CTCTG ATGTCCCAG GAGA

LDLRex2(27 68 123 30) _172. .d2_r 2263 CGTCTCCTGGGACATCAGAGCCATC 2264 GTCTCCTGGGACATCAGAGCCAT 2265 TCTCCTGGGACATCAGAGCCA

LDLRex2(27 68 123 30) _173. .d2_f 2266 ATGG CTCTG ATGTCCCAG GAG ACGT 2267 TGGCTCTGATGTCCCAGGAGACG 2268 GGCTCTGATGTCCCAGGAGAC

LDLRex2(27 68 123 30) _173. .d2_r 2269 ACGTCTCCTGGGACATCAGAGCCAT 2270 CGTCTCCTGGGACATCAGAGCCA 2271 GTCTCCTGGGACATCAGAGCC

LDLRex2(27 68 123 30) _174. .d2_f 2272 TGGCTCTGATGACCCAGGAGACGTG 2273 GGCTCTGATGACCCAGGAGACGT 2274 GCTCTGATGACCCAGGAGACG

LDLRex2(27 68 123 30) _174. .d2_r 2275 CACGTCTCCTGGGTCATCAGAGCCA 2276 ACGTCTCCTGGGTCATCAGAGCC 2277 CGTCTCCTGGGTCATCAGAGC

LDLRex2(27 68 123 30) _175. .d2_f 2278 GGCTCTGATGAGCCAGGAGACGTGC 2279 GCTCTGATGAGCCAGGAGACGTG 2280 CTCTGATGAGCCAGGAGACGT

LDLRex2(27 68 123 30) _175. .d2_r 2281 GCACGTCTCCTGGCTCATCAGAGCC 2282 CACGTCTCCTGG CTCATCAG AG C 2283 ACGTCTCCTGGCTCATCAGAG

LDLRex2(27 68 123 30) _176. .d2_f 2284 GCTCTGATGAGTCAGGAGACGTGCT 2285 CTCTGATGAGTCAGGAGACGTGC 2286 TCTGATGAGTCAGGAGACGTG

LDLRex2(27 68 123 30) _176. .d2_r 2287 AG CACGTCTCCTG ACTCATCAG AG C 2288 GCACGTCTCCTGACTCATCAGAG 2289 CACGTCTCCTGACTCATCAGA

LDLRex2(27 68 123 30) _177. .d2_f 2290 CTCTGATGAGTCAGGAGACGTGCTG 2291 TCTGATGAGTCAGGAGACGTGCT 2292 CTGATGAGTCAGGAGACGTGC

LDLRex2(27 68 123 30) _177. .d2_r 2293 CAGCACGTCTCCTGACTCATCAGAG 2294 AGCACGTCTCCTGACTCATCAGA 2295 G CACGTCTCCTG ACTCATCAG

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _178_d2_ .f 2296 TCTGATGAGTCCGGAGACGTGCTGT 2297 CTGATGAGTCCGGAGACGTGCTG 2298 TGATGAGTCCGGAGACGTGCT

LDLRex2(27 68 123 30) _178_d2_ _r 2299 ACAGCACGTCTCCGGACTCATCAGA 2300 CAGCACGTCTCCGGACTCATCAG 2301 AGCACGTCTCCGGACTCATCA

LDLRex2(27 68 123 30) _179_d2_ .f 2302 CTGATGAGTCCCGAGACGTGCTGTG 2303 TGATGAGTCCCGAGACGTGCTGT 2304 GATGAGTCCCGAGACGTGCTG

LDLRex2(27 68 123 30) _179_d2_ _r 2305 CACAG CACGTCTCGG G ACTCATCAG 2306 ACAG CACGTCTCGG GACTCATCA 2307 CAG CACGTCTCGG G ACTCATC

LDLRex2(27 68 123 30) _180_d2_ f 2308 TGATGAGTCCCAAGACGTGCTGTGA 2309 GATGAGTCCCAAGACGTGCTGTG 2310 ATGAGTCCCAAGACGTGCTGT

LDLRex2(27 68 123 30) _180_d2_ _r 2311 TCACAGCACGTCTTGGGACTCATCA 2312 CACAG CACGTCTTGG G ACTCATC 2313 ACAGCACGTCTTGGGACTCAT

LDLRex2(27 68 123 30) _181_d2_ f 2314 GATGAGTCCCAGGACGTGCTGTGAG 2315 ATGAGTCCCAGGACGTGCTGTGA 2316 TG AGTCCCAG G ACGTG CTGTG

LDLRex2(27 68 123 30) _181_d2_ _r 2317 CTCACAG CACGTCCTGG G ACTCATC 2318 TCACAG CACGTCCTGG G ACTCAT 2319 CACAGCACGTCCTGGGACTCA

LDLRex2(27 68 123 30) _182_d2_ f 2320 ATG AGTCCCAG G ACGTG CTGTG AGT 2321 TGAGTCCCAGGACGTGCTGTGAG 2322 GAGTCCCAGGACGTGCTGTGA

LDLRex2(27 68 123 30) _182_d2_ _r 2323 ACTCACAGCACGTCCTGGGACTCAT 2324 CTCACAG CACGTCCTGG GACTCA 2325 TCACAGCACGTCCTGGGACTC

LDLRex2(27 68 123 30) _183_d2_ f 2326 TGAGTCCCAGGACGTGCTGTGAGTC 2327 G AGTCCCAG G ACGTG CTGTG AGT 2328 AGTCCCAG G ACGTG CTGTG AG

LDLRex2(27 68 123 30) _183_d2_ _r 2329 GACTCACAGCACGTCCTGGGACTCA 2330 ACTCACAGCACGTCCTGGGACTC 2331 CTCACAGCACGTCCTGGGACT

LDLRex2(27 68 123 30) _184_d2_ f 2332 GAGTCCCAGGAGGTGCTGTGAGTCC 2333 AGTCCCAG GAG GTG CTGTG AGTC 2334 GTCCCAGGAGGTGCTGTGAGT

LDLRex2(27 68 123 30) _184_d2_ _r 2335 GGACTCACAGCACCTCCTGGGACTC 2336 GACTCACAGCACCTCCTGGGACT 2337 ACTCACAGCACCTCCTGGGAC

LDLRex2(27 68 123 30) _185_d2_ f 2338 AGTCCCAGGAGATGCTGTGAGTCCC 2339 GTCCCAGGAGATGCTGTGAGTCC 2340 TCCCAGGAGATGCTGTGAGTC

LDLRex2(27 68 123 30) _185_d2_ _r 2341 G GG ACTCACAG CATCTCCTG G G ACT 2342 GGACTCACAGCATCTCCTGGGAC 2343 GACTCACAGCATCTCCTGGGA

LDLRex2(27 68 123 30) _186_d2_ f 2344 GTCCCAGGAGACGCTGTGAGTCCCC 2345 TCCCAGGAGACGCTGTGAGTCCC 2346 CCCAGGAGACGCTGTGAGTCC

LDLRex2(27 68 123 30) _186_d2_ _r 2347 GGGGACTCACAGCGTCTCCTGGGAC 2348 GGGACTCACAGCGTCTCCTGGGA 2349 G G ACTCACAG CGTCTCCTG GG

LDLRex2(27 68 123 30) _187_d2_ f 2350 TCCCAGGAGACGCTGTGAGTCCCCT 2351 CCCAGGAGACGCTGTGAGTCCCC 2352 CCAGGAGACGCTGTGAGTCCC

LDLRex2(27 68 123 30) _187_d2_ _r 2353 AGGGGACTCACAGCGTCTCCTGGGA 2354 GGGGACTCACAGCGTCTCCTGGG 2355 GGGACTCACAGCGTCTCCTGG

LDLRex2(27 68 123 30) _188_d2_ f 2356 CCCAGGAGACGTTGTGAGTCCCCTT 2357 CCAGGAGACGTTGTGAGTCCCCT 2358 CAGGAGACGTTGTGAGTCCCC

LDLRex2(27 68 123 30) _188_d2_ r 2359 AAG GG G ACTCACAACGTCTCCTGG G 2360 AG GG G ACTCACAACGTCTCCTG G 2361 G GG G ACTCACAACGTCTCCTG

LDLRex2(27 68 123 30) _189_d2_ f 2362 CCAGGAGACGTGGTGAGTCCCCTTT 2363 CAG G AG ACGTG GTG AGTCCCCTT 2364 AGGAGACGTGGTGAGTCCCCT

LDLRex2(27 68 123 30) _189_d2_ r 2365 AAAGGGGACTCACCACGTCTCCTGG 2366 AAGGGGACTCACCACGTCTCCTG 2367 AGGGGACTCACCACGTCTCCT

LDLRex2(27 68 123 30) _190 + 1_ d2_f 2368 AGGAGACGTGCTGAGTCCCCTTTGG 2369 GGAGACGTGCTGAGTCCCCTTTG 2370 GAGACGTGCTGAGTCCCCTTT

LDLRex2(27 68 123 30) _190 + 1_ d2_r 2371 CCAAAGGGGACTCAGCACGTCTCCT 2372 CAAAG GG G ACTCAG CACGTCTCC 2373 AAAGGG G ACTCAG CACGTCTC

LDLRex2(27 68 123 30) _190 + 10 _d2_f 2374 GCTGTGAGTCCCTTGGGCATGATAT 2375 CTGTGAGTCCCTTGGGCATGATA 2376 TGTGAGTCCCTTGGGCATGAT

LDLRex2(27 68 123 30) _190 + 10 _d2_r 2377 ATATCATGCCCAAGGGACTCACAGC 2378 TATCATGCCCAAGGGACTCACAG 2379 ATCATGCCCAAGGGACTCACA

LDLRex2(27 68 123 30) _190 + 11 _d2_f 2380 CTGTGAGTCCCCTGGGCATGATATG 2381 TGTGAGTCCCCTGGGCATGATAT 2382 GTG AGTCCCCTG GG CATG ATA

LDLRex2(27 68 123 30) _190 + 11 _d2_r 2383 CATATCATGCCCAGGGGACTCACAG 2384 ATATCATGCCCAGGGGACTCACA 2385 TATCATGCCCAGGGGACTCAC

LDLRex2(27 68 123 30) _190 + 12 _d2_f 2386 TGTGAGTCCCCTGGGCATGATATGC 2387 GTGAGTCCCCTGGGCATGATATG 2388 TGAGTCCCCTGGGCATGATAT

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _190 + 12_d2_r 2389 GCATATCATGCCCAGGGGACTCACA 2390 CATATCATG CCCAG GG G ACTCAC 2391 ATATCATGCCCAGGGGACTCA

LDLRex2(27 68 123 30) _190 + 13_d2_f 2392 GTGAGTCCCCTTGGCATGATATGCA 2393 TGAGTCCCCTTGGCATGATATGC 2394 GAGTCCCCTTGGCATGATATG

LDLRex2(27 68 123 30) _190 + 13_d2_r 2395 TGCATATCATGCCAAGGGGACTCAC 2396 G CATATCATGCCAAG GG G ACTCA 2397 CATATCATGCCAAGGGGACTC

LDLRex2(27 68 123 30) _190 + 14_d2_f 2398 TGAGTCCCCTTTGCATGATATGCAT 2399 GAGTCCCCTTTGCATGATATGCA 2400 AGTCCCCTTTG CATG ATATG C

LDLRex2(27 68 123 30) _190 + 14_d2_r 2401 ATGCATATCATGCAAAGGGGACTCA 2402 TG CATATCATGCAAAG GG G ACTC 2403 G CATATCATG CAAAGGGGACT

LDLRex2(27 68 123 30) _190 + 15_d2_f 2404 GAGTCCCCTTTGCATGATATGCATT 2405 AGTCCCCTTTGCATGATATGCAT 2406 GTCCCCTTTGCATGATATGCA

LDLRex2(27 68 123 30) _190 + 15_d2_r 2407 AATGCATATCATG CAAAG GG G ACTC 2408 ATG CATATCATG CAAAGGGGACT 2409 TGCATATCATGCAAAGGGGAC

LDLRex2(27 68 123 30) _190 + 2_d2_f 2410 GGAGACGTGCTGAGTCCCCTTTGGG 2411 GAGACGTGCTGAGTCCCCTTTGG 2412 AGACGTGCTGAGTCCCCTTTG

LDLRex2(27 68 123 30) _190 + 2_d2_r 2413 CCCAAAGGGGACTCAGCACGTCTCC 2414 CCAAAGGGGACTCAGCACGTCTC 2415 CAAAGGGGACTCAGCACGTCT

LDLRex2(27 68 123 30) _190 + 3_d2_f 2416 GAGACGTGCTGTGTCCCCTTTGGGC 2417 AG ACGTG CTGTGTCCCCTTTG GG 2418 GACGTGCTGTGTCCCCTTTGG

LDLRex2(27 68 123 30) _190 + 3_d2_r 2419 G CCCAAAG GG G ACACAGCACGTCTC 2420 CCCAAAG GG GACACAG CACGTCT 2421 CCAAAGGGGACACAGCACGTC

LDLRex2(27 68 123 30) _190 + 4_d2_f 2422 AGACGTGCTGTGTCCCCTTTGGGCA 2423 GACGTGCTGTGTCCCCTTTGGGC 2424 ACGTGCTGTGTCCCCTTTGGG

LDLRex2(27 68 123 30) _190 + 4_d2_r 2425 TG CCCAAAG GG GACACAGCACGTCT 2426 GCCCAAAGGGGACACAGCACGTC 2427 CCCAAAGGGGACACAGCACGT

LDLRex2(27 68 123 30) _190 + 5_d2_f 2428 GACGTGCTGTGACCCCTTTGGGCAT 2429 ACGTGCTGTGACCCCTTTGGGCA 2430 CGTGCTGTGACCCCTTTGGGC

LDLRex2(27 68 123 30) _190 + 5_d2_r 2431 ATGCCCAAAGGGGTCACAGCACGTC 2432 TG CCCAAAGG G GTCACAG CACGT 2433 G CCCAAAG G GGTCACAGCACG

LDLRex2(27 68 123 30) _190 + 6_d2_f 2434 ACGTGCTGTGAGCCCTTTGGGCATG 2435 CGTGCTGTGAGCCCTTTGGGCAT 2436 GTGCTGTGAGCCCTTTGGGCA

LDLRex2(27 68 123 30) _190 + 6_d2_r 2437 CATGCCCAAAGGGCTCACAGCACGT 2438 ATGCCCAAAGGGCTCACAGCACG 2439 TGCCCAAAGGGCTCACAGCAC

LDLRex2(27 68 123 30) _190 + 7_d2_f 2440 CGTGCTGTGAGTCCTTTGGGCATGA 2441 GTGCTGTGAGTCCTTTGGGCATG 2442 TGCTGTGAGTCCTTTGGGCAT

LDLRex2(27 68 123 30) _190 + 7_d2_r 2443 TCATGCCCAAAGGACTCACAGCACG 2444 CATG CCCAAAG G ACTCACAG CAC 2445 ATG CCCAAAG GACTCACAGCA

LDLRex2(27 68 123 30) _190 + 8_d2_f 2446 GTGCTGTGAGTCCTTTGGGCATGAT 2447 TGCTGTGAGTCCTTTGGGCATGA 2448 GCTGTGAGTCCTTTGGGCATG

LDLRex2(27 68 123 30) _190 + 8_d2_r 2449 ATCATG CCCAAAG G ACTCACAGCAC 2450 TCATG CCCAAAG G ACTCACAG CA 2451 CATGCCCAAAGGACTCACAGC

LDLRex2(27 68 123 30) _190 + 9_d2_f 2452 TG CTGTG AGTCCTTTG GG CATG ATA 2453 GCTGTGAGTCCTTTGGGCATGAT 2454 CTGTGAGTCCTTTGGGCATGA

LDLRex2(27 68 123 30) _190 + 9_d2_r 2455 TATCATG CCCAAAG GACTCACAGCA 2456 ATCATGCCCAAAGGACTCACAGC 2457 TCATG CCCAAAG G ACTCACAG

LDLRex2(27 68 123 30) _190_d2_f 2458 CAGGAGACGTGCTGAGTCCCCTTTG 2459 AG GAG ACGTG CTG AGTCCCCTTT 2460 GGAGACGTGCTGAGTCCCCTT

LDLRex2(27 68 123 30) _190_d2_r 2461 CAAAGGGGACTCAGCACGTCTCCTG 2462 AAAG GG G ACTCAG CACGTCTCCT 2463 AAGGGGACTCAGCACGTCTCC

LDLRex2(27 68 123 30) _68 - l_d2_f 2464 TCCTCTCTCTCAGGGCGACAGATGC 2465 CCTCTCTCTCAGGGCGACAGATG 2466 CTCTCTCTCAGGGCGACAGAT

LDLRex2(27 68 123 30) _68 - l_d2_r 2467 GCATCTGTCGCCCTGAGAGAGAGGA 2468 CATCTGTCGCCCTGAGAGAGAGG 2469 ATCTGTCGCCCTGAGAGAGAG

LDLRex2(27 68 123 30) _68 - 10_d2_f 2470 TTCTCCTTTTCCTCTCTCAGTGGGC 2471 TCTC I 1 1 I CCTCTCTCAGTGGG 2472 CTCCTTTTCCTCTCTCAGTG G

LDLRex2(27 68 123 30) _68 - 10_d2_r 2473 GCCCACTGAGAGAGGAAAAGGAGAA 2474 CCCACTGAGAGAGGAAAAGGAGA 2475 CCACTGAGAGAGGAAAAGGAG

LDLRex2(27 68 123 30) _68 - ll_d2_f 2476 TTTCTCCTTTTCCTCTCTCAGTGGG 2477 TTCTCCTTTTCCTCTCTCAGTGG 2478 TCTCCTTTTCCTCTCTCAGTG

LDLRex2(27 68 123 30) _68 - ll_d2_r 2479 CCCACTGAGAGAGGAAAAGGAGAAA 2480 CCACTGAGAGAGGAAAAGGAGAA 2481 CACTGAGAGAGGAAAAGGAGA

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _68 - 12_d2_f 2482 CTTTCTCCTTTTTCTCTCTCAGTGG 2483 TTTCTCC I 1 1 1 l U U U CAGTG 2484 TTCTCC I 1 1 1 I C I C I C I CAGT

LDLRex2(27 68 123 30) _68 - 12_d2_r 2485 CCACTGAGAGAGAAAAAGGAGAAAG 2486 CACTGAGAGAGAAAAAGGAGAAA 2487 ACTGAGAGAGAAAAAGGAGAA

LDLRex2(27 68 123 30) _68 - 13_d2_f 2488 CCTTTCTCCTTTCTCTCTCTCAGTG 2489 CTTTCTCCTTTCTCTCTCTCAGT 2490 TTTCTCCTTTCTCTCTCTCAG

LDLRex2(27 68 123 30) _68 - 13_d2_r 2491 CACTGAGAGAGAGAAAGGAGAAAGG 2492 ACTGAGAGAGAGAAAGGAGAAAG 2493 CTGAGAGAGAGAAAGGAGAAA

LDLRex2(27 68 123 30) _68 - 14_d2_f 2494 CCCTTTCTCCTTCCTCTCTCTCAGT 2495 CCTTTCTCCTTCCTCTCTCTCAG 2496 CTTTCTCCTTCCTCTCTCTCA

LDLRex2(27 68 123 30) _68 - 14_d2_r 2497 ACTGAGAGAGAGGAAGGAGAAAGGG 2498 CTGAGAGAGAGGAAGGAGAAAGG 2499 TGAGAGAGAGGAAGGAGAAAG

LDLRex2(27 68 123 30) _68 - 15_d2_f 2500 ACCCTTTCTCCTTCCTCTCTCTCAG 2501 CCCTTTCTCCTTCCTCTCTCTCA 2502 CCTTTCTCCTTCCTCTCTCTC

LDLRex2(27 68 123 30) _68 - 15_d2_r 2503 CTGAGAGAGAGGAAGGAGAAAGGGT 2504 TGAGAGAGAGGAAGGAGAAAGGG 2505 GAGAGAGAGGAAGGAGAAAGG

LDLRex2(27 68 123 30) _68 - 2_d2_f 2506 TTCCTCTCTCTCTGGGCGACAGATG 2507 TCCTCTCTCTCTG GG CG ACAG AT 2508 CCTCTCTCTCTGGGCGACAGA

LDLRex2(27 68 123 30) _68 - 2_d2_r 2509 CATCTGTCGCCCAGAGAGAGAGGAA 2510 ATCTGTCGCCCAGAGAGAGAGGA 2511 TCTGTCGCCCAGAGAGAGAGG

LDLRex2(27 68 123 30) _68 - 3_d2_f 2512 TTTCCTCTCTCTGTGGGCGACAGAT 2513 TTCCTCTCTCTGTGGGCGACAGA 2514 TCCTCTCTCTGTGGGCGACAG

LDLRex2(27 68 123 30) _68 - 3_d2_r 2515 ATCTGTCGCCCACAGAGAGAGGAAA 2516 TCTGTCGCCCACAGAGAGAGGAA 2517 CTGTCGCCCACAGAGAGAGGA

LDLRex2(27 68 123 30) _68 - 4_d2_f 2518 TTTTCCTCTCTCAGTGGGCGACAGA 2519 TTTCCTCTCTCAGTGGGCGACAG 2520 TTCCTCTCTCAGTG GG CG ACA

LDLRex2(27 68 123 30) _68 - 4_d2_r 2521 TCTGTCGCCCACTGAGAGAGGAAAA 2522 CTGTCGCCCACTGAGAGAGGAAA 2523 TGTCGCCCACTGAGAGAGGAA

LDLRex2(27 68 123 30) _68 - 5_d2_f 2524 CTTTTCCTCTCTCAGTGGGCGACAG 2525 TTTTCCTCTCTCAGTGGGCGACA 2526 TTTCCTCTCTCAGTG GG CG AC

LDLRex2(27 68 123 30) _68 - 5_d2_r 2527 CTGTCGCCCACTGAGAGAGGAAAAG 2528 TGTCGCCCACTGAGAGAGGAAAA 2529 GTCGCCCACTGAGAGAGGAAA

LDLRex2(27 68 123 30) _68 - 6_d2_f 2530 CCTTTTCCTCTCTCAGTGGGCGACA 2531 CTTTTCCTCTCTCAGTGGGCGAC 2532 TTTTCCTCTCTCAGTG GGCGA

LDLRex2(27 68 123 30) _68 - 6_d2_r 2533 TGTCGCCCACTGAGAGAGGAAAAGG 2534 GTCGCCCACTGAGAGAGGAAAAG 2535 TCGCCCACTGAGAGAGGAAAA

LDLRex2(27 68 123 30) _68 - 7_d2_f 2536 TCCTTTTCCTCTCTCAGTGGGCGAC 2537 CC I 1 1 I CCTCTCTCAGTGGGCGA 2538 CTTTTCCTCTCTCAGTG GG CG

LDLRex2(27 68 123 30) _68 - 7_d2_r 2539 GTCGCCCACTGAGAGAGGAAAAGGA 2540 TCGCCCACTGAGAGAGGAAAAGG 2541 CGCCCACTGAGAGAGGAAAAG

LDLRex2(27 68 123 30) _68 - 8_d2_f 2542 CTCCTTTTCCTCTCTCAGTGGGCGA 2543 TCCTTTTCCTCTCTCAGTGGGCG 2544 CCTTTTCCTCTCTCAGTG GG C

LDLRex2(27 68 123 30) _68 - 8_d2_r 2545 TCGCCCACTGAGAGAGGAAAAGGAG 2546 CGCCCACTGAGAGAGGAAAAGGA 2547 GCCCACTGAGAGAGGAAAAGG

LDLRex2(27 68 123 30) _68 - 9_d2_f 2548 TCTCCTTTTCCTCTCTCAGTGGGCG 2549 CTC I 1 1 I CCTCTCTCAGTGGGC 2550 TCCTTTTCCTCTCTCAGTGGG

LDLRex2(27 68 123 30) _68 - 9_d2_r 2551 CGCCCACTGAGAGAGGAAAAGGAGA 2552 GCCCACTGAGAGAGGAAAAGGAG 2553 CCCACTGAGAGAGGAAAAGGA

LDLRex2(27 68 123 30) _68. .d2_f 2554 CCTCTCTCTCAGGGCGACAGATGCG 2555 CTCTCTCTCAGGGCGACAGATGC 2556 TCTCTCTCAGGGCGACAGATG

LDLRex2(27 68 123 30) _68. .d2_r 2557 CGCATCTGTCGCCCTGAGAGAGAGG 2558 GCATCTGTCGCCCTGAGAGAGAG 2559 CATCTGTCGCCCTGAGAGAGA

LDLRex2(27 68 123 30) _69. .d2_f 2560 CTCTCTCTCAGTG CG ACAG ATG CG A 2561 TCTCTCTCAGTGCGACAGATGCG 2562 CTCTCTCAGTGCGACAGATGC

LDLRex2(27 68 123 30) _69. .d2_r 2563 TCGCATCTGTCGCACTGAGAGAGAG 2564 CGCATCTGTCGCACTGAGAGAGA 2565 GCATCTGTCGCACTGAGAGAG

LDLRex2(27 68 123 30) _70. .d2_f 2566 TCTCTCTCAGTG CG ACAG ATG CG AA 2567 CTCTCTCAGTGCGACAGATGCGA 2568 TCTCTCAGTGCGACAGATGCG

LDLRex2(27 68 123 30) _70. .d2_r 2569 TTCGCATCTGTCGCACTGAGAGAGA 2570 TCGCATCTGTCGCACTGAGAGAG 2571 CGCATCTGTCGCACTGAGAGA

LDLRex2(27 68 123 30) _71. .d2_f 2572 CTCTCTCAGTGGGACAGATGCGAAA 2573 TCTCTCAGTGGGACAGATGCGAA 2574 CTCTCAGTGGGACAGATGCGA

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _71. .d2_r 2575 TTTCGCATCTGTCCCACTGAGAGAG 2576 TTCGCATCTGTCCCACTGAGAGA 2577 TCGCATCTGTCCCACTGAGAG

LDLRex2(27 68 123 30) _72. _d2_f 2578 TCTCTCAGTGGGACAGATGCGAAAG 2579 CTCTCAGTG G GACAGATG CG AAA 2580 TCTCAGTGGGACAGATGCGAA

LDLRex2(27 68 123 30) _72. .d2_r 2581 CTTTCGCATCTGTCCCACTGAGAGA 2582 TTTCGCATCTGTCCCACTGAGAG 2583 TTCGCATCTGTCCCACTGAGA

LDLRex2(27 68 123 30) _73. _d2_f 2584 CTCTCAGTGGGCCAGATGCGAAAGA 2585 TCTCAGTGGGCCAGATGCGAAAG 2586 CTCAGTG GG CCAG ATG CG AAA

LDLRex2(27 68 123 30) _73. .d2_r 2587 TCTTTCGCATCTGGCCCACTGAGAG 2588 CTTTCGCATCTGGCCCACTGAGA 2589 TTTCG CATCTG GCCCACTG AG

LDLRex2(27 68 123 30) _74. _d2_f 2590 TCTCAGTGGGCGAGATGCGAAAGAA 2591 CTCAGTG GG CG AG ATG CG AAAG A 2592 TCAGTGGGCGAGATGCGAAAG

LDLRex2(27 68 123 30) _74. .d2_r 2593 TTCTTTCGCATCTCGCCCACTGAGA 2594 TCTTTCGCATCTCGCCCACTGAG 2595 CTTTCG CATCTCG CCCACTG A

LDLRex2(27 68 123 30) _75. _d2_f 2596 CTCAGTGGGCGAGATGCGAAAGAAA 2597 TCAGTG GG CG AG ATG CG AAAG AA 2598 CAGTGGGCGAGATGCGAAAGA

LDLRex2(27 68 123 30) _75. .d2_r 2599 TTTCTTTCG CATCTCG CCCACTG AG 2600 TTCTTTCGCATCTCGCCCACTGA 2601 TCTTTCG CATCTCG CCCACTG

LDLRex2(27 68 123 30) _76. _d2_f 2602 TCAGTGGGCGACATGCGAAAGAAAC 2603 CAGTG GG CG ACATG CG AAAG AAA 2604 AGTGGGCGACATGCGAAAGAA

LDLRex2(27 68 123 30) _76. .d2_r 2605 GTTTCTTTCGCATGTCGCCCACTGA 2606 TTTCTTTCGCATGTCGCCCACTG 2607 TTCTTTCG CATGTCG CCCACT

LDLRex2(27 68 123 30) _77. _d2_f 2608 CAGTGGGCGACATGCGAAAGAAACG 2609 AGTG GG CG ACATG CG AAAG AAAC 2610 GTGGGCGACATGCGAAAGAAA

LDLRex2(27 68 123 30) _77. .d2_r 2611 CGTTTCTTTCG CATGTCG CCCACTG 2612 GTTTCTTTCG CATGTCG CCCACT 2613 TTTCTTTCG CATGTCG CCCAC

LDLRex2(27 68 123 30) _78. _d2_f 2614 AGTGGGCGACAGGCGAAAGAAACGA 2615 GTGGGCGACAGGCGAAAGAAACG 2616 TGGGCGACAGGCGAAAGAAAC

LDLRex2(27 68 123 30) _78. .d2_r 2617 TCGTTTCTTTCGCCTGTCGCCCACT 2618 CGTTTCTTTCG CCTGTCG CCCAC 2619 GTTTCTTTCGCCTGTCGCCCA

LDLRex2(27 68 123 30) _79. _d2_f 2620 GTGGGCGACAGACGAAAGAAACGAG 2621 TGGGCGACAGACGAAAGAAACGA 2622 GGGCGACAGACGAAAGAAACG

LDLRex2(27 68 123 30) _79. .d2_r 2623 CTCGTTTCTTTCGTCTGTCGCCCAC 2624 TCGTTTCTTTCGTCTGTCGCCCA 2625 CGTTTCTTTCGTCTGTCG CCC

LDLRex2(27 68 123 30) _80. _d2_f 2626 TGGGCGACAGATGAAAGAAACGAGT 2627 GGGCGACAGATGAAAGAAACGAG 2628 GGCGACAGATGAAAGAAACGA

LDLRex2(27 68 123 30) _80. .d2_r 2629 ACTCGTTTCTTTCATCTGTCG CCCA 2630 CTCGTTTCTTTCATCTGTCGCCC 2631 TCGTTTCTTTCATCTGTCG CC

LDLRex2(27 68 123 30) _81. .d2_f 2632 GGGCGACAGATGAAAGAAACGAGTT 2633 GGCGACAGATGAAAGAAACGAGT 2634 GCGACAGATGAAAGAAACGAG

LDLRex2(27 68 123 30) _81. .d2_r 2635 AACTCGTTTCTTTCATCTGTCGCCC 2636 ACTCGTTTCTTTCATCTGTCG CC 2637 CTCGTTTCTTTCATCTGTCG C

LDLRex2(27 68 123 30) _82. .d2_f 2638 GGCGACAGATGCAAGAAACGAGTTC 2639 GCGACAGATGCAAGAAACGAGTT 2640 CGACAGATGCAAGAAACGAGT

LDLRex2(27 68 123 30) _82. .d2_r 2641 GAACTCGTTTCTTGCATCTGTCGCC 2642 AACTCGTTTCTTGCATCTGTCGC 2643 ACTCGTTTCTTG CATCTGTCG

LDLRex2(27 68 123 30) _83. .d2_f 2644 GCGACAGATGCGAGAAACGAGTTCC 2645 CGACAGATGCGAGAAACGAGTTC 2646 GACAGATGCGAGAAACGAGTT

LDLRex2(27 68 123 30) _83. .d2_r 2647 GGAACTCGTTTCTCGCATCTGTCGC 2648 GAACTCGTTTCTCGCATCTGTCG 2649 AACTCGTTTCTCG CATCTGTC

LDLRex2(27 68 123 30) _84. .d2_f 2650 CGACAGATGCGAGAAACGAGTTCCA 2651 GACAGATGCGAGAAACGAGTTCC 2652 ACAGATGCGAGAAACGAGTTC

LDLRex2(27 68 123 30) _84. .d2_r 2653 TGGAACTCGTTTCTCGCATCTGTCG 2654 GGAACTCGTTTCTCGCATCTGTC 2655 GAACTCGTTTCTCGCATCTGT

LDLRex2(27 68 123 30) _85. .d2_f 2656 GACAGATGCGAAAAACGAGTTCCAG 2657 ACAGATGCGAAAAACGAGTTCCA 2658 CAGATGCGAAAAACGAGTTCC

LDLRex2(27 68 123 30) _85. .d2_r 2659 CTGGAACTCG I 1 1 1 I CGCATCTGTC 2660 TGGAACTCG I 1 1 1 1 CGCATCTGT 2661 GGAACTCG 1 1 1 1 1 CGCATCTG

LDLRex2(27 68 123 30) _86. .d2_f 2662 ACAGATGCGAAAAACGAGTTCCAGT 2663 CAGATGCGAAAAACGAGTTCCAG 2664 AGATGCGAAAAACGAGTTCCA

LDLRex2(27 68 123 30) _86. .d2_r 2665 ACTGGAACTCG 1 1 1 1 1 CGCATCTGT 2666 CTGGAACTCG 1 1 1 1 1 CGCATCTG 2667 TGGAACTCG 1 1 1 1 I CGCATCT

Table 1

SEQ ID SEQ ID SEQ ID

del2 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _87. .d2_ j 2668 CAG ATG CG AAAG ACG AGTTCCAGTG 2669 AGATGCGAAAGACGAGTTCCAGT 2670 G ATG CG AAAG ACG AGTTCCAG

LDLRex2(27 68 123 30) _87. _d2. 2671 CACTGGAACTCGTCTTTCGCATCTG 2672 ACTGGAACTCGTCTTTCGCATCT 2673 CTGGAACTCGTCTTTCGCATC

LDLRex2(27 68 123 30) _88. _d2. j 2674 AG ATG CG AAAG ACG AGTTCCAGTG C 2675 GATGCGAAAGACGAGTTCCAGTG 2676 ATGCGAAAGACGAGTTCCAGT

LDLRex2(27 68 123 30) _88. _d2. 2677 G CACTG G AACTCGTCTTTCGCATCT 2678 CACTGGAACTCGTCTTTCGCATC 2679 ACTGGAACTCGTCTTTCGCAT

LDLRex2(27 68 123 30) _89. _d2. j 2680 GATGCGAAAGAAGAGTTCCAGTGCC 2681 ATGCGAAAGAAGAGTTCCAGTGC 2682 TGCGAAAGAAGAGTTCCAGTG

LDLRex2(27 68 123 30) _89. -d2_ 2683 GGCACTGGAACTCTTCTTTCGCATC 2684 G CACTG G AACTCTTCTTTCG CAT 2685 CACTG G AACTCTTCTTTCG CA

LDLRex2(27 68 123 30) _90. _d2. j 2686 ATGCGAAAGAAAAGTTCCAGTGCCA 2687 TGCGAAAGAAAAGTTCCAGTGCC 2688 GCGAAAGAAAAGTTCCAGTGC

LDLRex2(27 68 123 30) _90. _d2. 2689 TGGCACTG G AACTTTTCTTTCG CAT 2690 GGCACTGGAACTTTTCTTTCGCA 2691 GCACTGGAACTTTTCTTTCGC

LDLRex2(27 68 123 30) _91. _d2. j 2692 TG CG AAAG AAACGTTCCAGTG CCAA 2693 GCGAAAGAAACGTTCCAGTGCCA 2694 CGAAAGAAACGTTCCAGTGCC

LDLRex2(27 68 123 30) _91. _d2. 2695 TTGGCACTGGAACGTTTCTTTCGCA 2696 TGGCACTGGAACGTTTCTTTCGC 2697 GG CACTG G AACGTTTCTTTCG

LDLRex2(27 68 123 30) _92. _d2. j 2698 GCGAAAGAAACGTTCCAGTGCCAAG 2699 CGAAAGAAACGTTCCAGTGCCAA 2700 G AAAG AAACGTTCCAGTG CCA

LDLRex2(27 68 123 30) _92. _d2. 2701 CTTGGCACTGGAACGTTTCTTTCGC 2702 TTGGCACTGGAACGTTTCTTTCG 2703 TGG CACTG G AACGTTTCTTTC

LDLRex2(27 68 123 30) _93. _d2. j 2704 CGAAAGAAACGATCCAGTGCCAAGA 2705 GAAAGAAACGATCCAGTGCCAAG 2706 AAAGAAACGATCCAGTGCCAA

LDLRex2(27 68 123 30) _93. _d2. 2707 TCTTGG CACTG G ATCGTTTCTTTCG 2708 CTTGGCACTGGATCGTTTCTTTC 2709 TTGGCACTGGATCGTTTCTTT

LDLRex2(27 68 123 30) _94. _d2. j 2710 GAAAGAAACGAGCCAGTGCCAAGAC 2711 AAAGAAACGAGCCAGTGCCAAGA 2712 AAGAAACGAGCCAGTGCCAAG

LDLRex2(27 68 123 30) _94. -d2_ 2713 GTCTTGGCACTGGCTCGTTTCTTTC 2714 TCTTGGCACTGGCTCGTTTCTTT 2715 CTTGGCACTGGCTCGTTTCTT

LDLRex2(27 68 123 30) _95. _d2. j 2716 AAAGAAACGAGTCAGTGCCAAGACG 2717 AAGAAACGAGTCAGTGCCAAGAC 2718 AGAAACGAGTCAGTGCCAAGA

LDLRex2(27 68 123 30) _95. _d2. 2719 CGTCTTGGCACTGACTCGTTTCTTT 2720 GTCTTGGCACTGACTCGTTTCTT 2721 TCTTGGCACTGACTCGTTTCT

LDLRex2(27 68 123 30) _96. _d2. j 2722 AAGAAACGAGTTAGTGCCAAGACGG 2723 AGAAACGAGTTAGTGCCAAGACG 2724 GAAACGAGTTAGTGCCAAGAC

LDLRex2(27 68 123 30) _96. _d2. 2725 CCGTCTTGGCACTAACTCGTTTCTT 2726 CGTCTTGGCACTAACTCGTTTCT 2727 GTCTTGGCACT AACTCGTTTC

LDLRex2(27 68 123 30) _97. .d2. j 2728 AGAAACGAGTTCGTGCCAAGACGGG 2729 GAAACGAGTTCGTGCCAAGACGG 2730 AAACGAGTTCGTGCCAAGACG

LDLRex2(27 68 123 30) _97. .d2. 2731 CCCGTCTTG G CACG AACTCGTTTCT 2732 CCGTCTTGGCACGAACTCGTTTC 2733 CGTCTTGGCACGAACTCGTTT

LDLRex2(27 68 123 30) _98. .d2. j 2734 GAAACGAGTTCCTGCCAAGACGGGA 2735 AAACGAGTTCCTGCCAAGACGGG 2736 AACGAGTTCCTGCCAAGACGG

LDLRex2(27 68 123 30) _98. .d2. _r 2737 TCCCGTCTTGG CAG G AACTCGTTTC 2738 CCCGTCTTGGCAGGAACTCGTTT 2739 CCGTCTTGGCAGGAACTCGTT

LDLRex2(27 68 123 30) _99. .d2. j 2740 AAACGAGTTCCAGCCAAGACGGGAA 2741 AACGAGTTCCAGCCAAGACGGGA 2742 ACGAGTTCCAGCCAAGACGGG

LDLRex2(27 68 123 30) _99. .d2_ _r 2743 TTCCCGTCTTGGCTGGAACTCGTTT 2744 TCCCGTCTTG GCTG G AACTCGTT 2745 CCCGTCTTGGCTGGAACTCGT

Table 1

SEQ ID SEQ I SEQ ID

del3 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _100. _d3_r 2746 ATTTCCCGTCTTGCTGGAACTCGTT 2747 TTTCCCGTCTTGCTGGAACTCGT 2748 TTCCCGTCTTGCTGGAACTCG

LDLRex2(27 68 123 30) _101_ _d3_f 2749 ACGAGTTCCAGTAAGACGGGAAATG 2750 CGAGTTCCAGTAAGACGGGAAAT 2751 GAGTTCCAGTAAGACGGGAAA

LDLRex2(27 68 123 30) _101_ _d3_r 2752 CATTTCCCGTCTTACTGGAACTCGT 2753 ATTTCCCGTCTTACTGGAACTCG 2754 TTTCCCGTCTTACTGGAACTC

LDLRex2(27 68 123 30) _102. _d3_f 2755 CGAGTTCCAGTGAGACGGGAAATGC 2756 GAGTTCCAGTGAGACGGGAAATG 2757 AGTTCCAGTGAGACGGGAAAT

LDLRex2(27 68 123 30) _102. _d3_r 2758 GCATTTCCCGTCTCACTGGAACTCG 2759 CATTTCCCGTCTCACTG GAACTC 2760 ATTTCCCGTCTCACTGGAACT

LDLRex2(27 68 123 30) _103. _d3_f 2761 G AGTTCCAGTG CG ACGG G AAATG CA 2762 AGTTCCAGTGCGACGGGAAATGC 2763 GTTCCAGTGCGACGGGAAATG

LDLRex2(27 68 123 30) _103. _d3_r 2764 TGCATTTCCCGTCG CACTG GAACTC 2765 G CATTTCCCGTCG CACTG G AACT 2766 CATTTCCCGTCGCACTGGAAC

LDLRex2(27 68 123 30) _104. _d3_f 2767 AGTTCCAGTGCCACGGGAAATGCAT 2768 GTTCCAGTG CCACG GG AAATG CA 2769 TTCCAGTG CCACGG G AAATG C

LDLRex2(27 68 123 30) _104. _d3_r 2770 ATGCATTTCCCGTGGCACTGGAACT 2771 TGCATTTCCCGTGGCACTGGAAC 2772 GCATTTCCCGTGGCACTGGAA

LDLRex2(27 68 123 30) _105. _d3_f 2773 GTTCCAGTGCCACGGGAAATGCATC 2774 TTCCAGTGCCACGGGAAATGCAT 2775 TCCAGTGCCACGGGAAATGCA

LDLRex2(27 68 123 30) _105. _d3_r 2776 GATGCATTTCCCGTGGCACTGGAAC 2777 ATGCATTTCCCGTGGCACTGGAA 2778 TGCATTTCCCGTGGCACTGGA

LDLRex2(27 68 123 30) _106. _d3_f 2779 TTCCAGTGCCAAGGGAAATGCATCT 2780 TCCAGTG CCAAGG G AAATG CATC 2781 CCAGTGCCAAGGGAAATGCAT

LDLRex2(27 68 123 30) _106. _d3_r 2782 AG ATG CATTTCCCTTGG CACTG G AA 2783 GATGCATTTCCCTTGGCACTGGA 2784 ATGCATTTCCCTTGGCACTGG

LDLRex2(27 68 123 30) _107. _d3_f 2785 TCCAGTGCCAAGGGAAATGCATCTC 2786 CCAGTG CCAAGG G AAATG CATCT 2787 CAGTGCCAAGGGAAATGCATC

LDLRex2(27 68 123 30) _107. _d3_r 2788 GAGATGCATTTCCCTTGGCACTGGA 2789 AG ATG CATTTCCCTTGG CACTG G 2790 GATGCATTTCCCTTGGCACTG

LDLRex2(27 68 123 30) _108. _d3_f 2791 CCAGTG CCAAG AG AAATG CATCTCC 2792 CAGTG CCAAG AG AAATG CATCTC 2793 AGTGCCAAGAGAAATGCATCT

LDLRex2(27 68 123 30) _108. _d3_r 2794 GGAGATGCATTTCTCTTGGCACTGG 2795 GAGATGCATTTCTCTTGGCACTG 2796 AG ATG C ATTTCTCTTG G C ACT

LDLRex2(27 68 123 30) _109. _d3_f 2797 CAGTGCCAAGACAAATGCATCTCCT 2798 AGTGCCAAGACAAATGCATCTCC 2799 GTGCCAAGACAAATGCATCTC

LDLRex2(27 68 123 30) _109. _d3_r 2800 AGGAGATGCATTTGTCTTGGCACTG 2801 G GAG ATG CATTTGTCTTGG CACT 2802 GAGATGCATTTGTCTTGGCAC

LDLRex2(27 68 123 30) _110. _d3_f 2803 AGTGCCAAGACGAATGCATCTCCTA 2804 GTGCCAAGACGAATGCATCTCCT 2805 TGCCAAGACGAATGCATCTCC

LDLRex2(27 68 123 30) _110. _d3_r 2806 TAGGAGATGCATTCGTCTTGGCACT 2807 AGGAGATGCATTCGTCTTGGCAC 2808 GGAGATGCATTCGTCTTGGCA

LDLRex2(27 68 123 30) _111_ _d3_f 2809 GTGCCAAGACGGATGCATCTCCTAC 2810 TGCCAAGACGGATGCATCTCCTA 2811 GCCAAGACGGATGCATCTCCT

LDLRex2(27 68 123 30) _111_ _d3_r 2812 GTAG GAG ATG CATCCGTCTTG GCAC 2813 TAGGAGATGCATCCGTCTTGGCA 2814 AGGAGATGCATCCGTCTTGGC

LDLRex2(27 68 123 30) _112. _d3_f 2815 TGCCAAGACGGGTGCATCTCCTACA 2816 G CCAAG ACG G GTG CATCTCCTAC 2817 CCAAGACGGGTGCATCTCCTA

LDLRex2(27 68 123 30) _112. _d3_r 2818 TGTAGGAGATGCACCCGTCTTGGCA 2819 GTAG GAG ATG CACCCGTCTTGG C 2820 TAG GAG ATG CACCCGTCTTGG

LDLRex2(27 68 123 30) _113. _d3_f 2821 GCCAAGACGGGAGCATCTCCTACAA 2822 CCAAGACGGGAGCATCTCCTACA 2823 CAAGACGGGAGCATCTCCTAC

LDLRex2(27 68 123 30) _113. _d3_r 2824 TTGTAGGAGATGCTCCCGTCTTGGC 2825 TGTAGGAGATGCTCCCGTCTTGG 2826 GTAGGAGATGCTCCCGTCTTG

LDLRex2(27 68 123 30) _114. _d3_f 2827 CCAAGACGGGAACATCTCCTACAAG 2828 CAAGACGGGAACATCTCCTACAA 2829 AAG ACG G G AACATCTCCTACA

LDLRex2(27 68 123 30) _114. _d3_r 2830 CTTGTAGGAGATGTTCCCGTCTTGG 2831 TTGTAGGAGATGTTCCCGTCTTG 2832 TGTAGGAGATGTTCCCGTCTT

LDLRex2(27 68 123 30) _115. _d3_f 2833 CAAGACGGGAAAATCTCCTACAAGT 2834 AAGACGGGAAAATCTCCTACAAG 2835 AGACGGGAAAATCTCCTACAA

LDLRex2(27;68;123 30) _115. _d3_r 2836 ACTTGTAG G AG ATTTTCCCGTCTTG 2837 CTTGTAGGAGATTTTCCCGTCTT 2838 TTGTAGGAGATTTTCCCGTCT

Table 1

SEQ ID SEQ ID

del3 NO: 25 nt NO: 21 nt

LDLRex2(27 68 123 30) _116_ _d3_f 2839 AAGACGGGAAATTCTCCTACAAGTG 2840 GACGGGAAATTCTCCTACAAG

LDLRex2(27 68 123 30) _116_ _d3_r 2842 CACTTGTAGGAGAATTTCCCGTCTT 2843 CTTGTAG G AG AATTTCCCGTC

LDLRex2(27 68 123 30) _117. _d3_f 2845 AG ACGG G AAATG CTCCTACAAGTG G 2846 ACGGGAAATGCTCCTACAAGT

LDLRex2(27 68 123 30) _117. _d3_r 2848 CCACTTGTAGGAGCATTTCCCGTCT 2849 ACTTGTAGGAGCATTTCCCGT

LDLRex2(27 68 123 30) _118. _d3_f 2851 GACGGGAAATGCTCCTACAAGTGGG 2852 CGG G AAATG CTCCTACAAGTG

LDLRex2(27 68 123 30) _118. _d3_r 2854 CCCACTTGTAGGAGCATTTCCCGTC 2855 CACTTGTAGGAGCATTTCCCG

LDLRex2(27 68 123 30) _119. _d3_f 2857 ACGG G AAATG CACCTACAAGTGG GT 2858 GG G AAATG CACCTACAAGTG G

LDLRex2(27 68 123 30) _119. _d3_r 2860 ACCCACTTGTAGGTGCATTTCCCGT 2861 CCACTTGTAGGTGCATTTCCC

LDLRex2(27 68 123 30) _120. _d3_f 2863 CGGGAAATGCATCTACAAGTGGGTC 2864 GGAAATGCATCTACAAGTGGG

LDLRex2(27 68 123 30) _120. _d3_r 2866 GACCCACTTGTAGATGCATTTCCCG 2867 CCCACTTGTAGATGCATTTCC

LDLRex2(27 68 123 30) _121_ _d3_f 2869 GGGAAATGCATCTACAAGTGGGTCT 2870 G AAATG CATCTACAAGTGG GT

LDLRex2(27 68 123 30) _121_ _d3_r 2872 AG ACCCACTTGTAG ATG CATTTCCC 2873 ACCCACTTGTAG ATG CATTTC

LDLRex2(27 68 123 30) _122. _d3_f 2875 G G AAATG CATCTACAAGTGG GTCTG 2876 AAATG CATCTACAAGTG GGTC

LDLRex2(27 68 123 30) _122. _d3_r 2878 CAGACCCACTTGTAGATGCATTTCC 2879 GACCCACTTGTAGATGCATTT

LDLRex2(27 68 123 30) _123. _d3_f 2881 GAAATGCATCTCCAAGTGGGTCTGC 2882 AATGCATCTCCAAGTGGGTCT

LDLRex2(27 68 123 30) _123. _d3_r 2884 GCAGACCCACTTGGAGATGCATTTC 2885 AGACCCACTTGGAGATGCATT

LDLRex2(27 68 123 30) _124. _d3_f 2887 AAATGCATCTCCAAGTGGGTCTGCG 2888 ATG CATCTCCAAGTG GGTCTG

LDLRex2(27 68 123 30) _124. _d3_r 2890 CGCAGACCCACTTGGAGATGCATTT 2891 CAGACCCACTTGGAGATGCAT

LDLRex2(27 68 123 30) _125_ _d3_f 2893 AATGCATCTCCTAGTGGGTCTGCGA 2894 TGCATCTCCTAGTGGGTCTGC

LDLRex2(27 68 123 30) _125_ _d3_r 2896 TCG CAG ACCCACTAG GAG ATG CATT 2897 GCAGACCCACTAGGAGATGCA

LDLRex2(27 68 123 30) _126_ _d3_f 2899 ATGCATCTCCTAGTGGGTCTGCGAT 2900 GCATCTCCTAGTGGGTCTGCG

LDLRex2(27 68 123 30) _126_ _d3_r 2902 ATCGCAGACCCACTAGGAGATGCAT 2903 CG CAG ACCCACTAG GAG ATG C

LDLRex2(27 68 123 30) _127. _d3_f 2905 TG C ATCTCCT ACTG G GTCTG CG ATG 2906 CATCTCCTACTGGGTCTGCGA

LDLRex2(27 68 123 30) _127_ _d3_r 2908 CATCGCAG ACCCAGTAG GAG ATG CA 2909 TCG CAG ACCCAGTAG GAG ATG

LDLRex2(27 68 123 30) _128. _d3_f 2911 G CATCTCCTACAG GGTCTG CG ATGG 2912 ATCTCCTACAGGGTCTGCGAT

LDLRex2(27 68 123 30) _128. _d3_r 2914 CCATCGCAGACCCTGTAGGAGATGC 2915 ATCG CAG ACCCTGTAG GAG AT

LDLRex2(27 68 123 30) _129. _d3_f 2917 CATCTCCTACAAGGTCTGCGATGGC 2918 TCTCCTACAAGGTCTGCGATG

LDLRex2(27 68 123 30) _129. _d3_r 2920 GCCATCGCAGACCTTGTAGGAGATG 2921 CATCGCAGACCTTGTAGGAGA

LDLRex2(27 68 123 30) _130. _d3_f 2923 ATCTCCTACAAGGTCTGCGATGGCA 2924 CTCCTACAAG GTCTG CG ATG G

LDLRex2(27 68 123 30) _130. _d3_r 2926 TGCCATCGCAGACCTTGTAGGAGAT 2927 CCATCGCAGACCTTGTAGGAG

LDLRex2(27;68;123 30) _131. _d3_f 2929 TCTCCTACAAGTTCTGCGATGGCAG 2930 TCCTACAAGTTCTGCGATGGC

Table 1

SEQ ID SEQ ID

del3 NO: 25 nt NO: 21 nt

LDLRex2(27 68 123 30) _131_ _d3_r 2932 CTGCCATCGCAGAACTTGTAGGAGA 2933 GCCATCGCAGAACTTGTAGGA

LDLRex2(27 68 123 30) _132_ _d3_f 2935 CTCCTACAAGTGCTGCGATGGCAGC 2936 CCTACAAGTGCTGCGATGGCA

LDLRex2(27 68 123 30) _132_ _d3_r 2938 GCTGCCATCGCAGCACTTGTAGGAG 2939 TGCCATCGCAGCACTTGTAGG

LDLRex2(27 68 123 30) _133. _d3_f 2941 TCCTACAAGTGGTG CG ATGG CAG CG 2942 CTACAAGTG GTG CG ATG GCAG

LDLRex2(27 68 123 30) _133. _d3_r 2944 CGCTGCCATCGCACCACTTGTAGGA 2945 CTGCCATCGCACCACTTGTAG

LDLRex2(27 68 123 30) _134. _d3_f 2947 CCTACAAGTGGGGCGATGGCAGCGC 2948 TACAAGTGGGGCGATGGCAGC

LDLRex2(27 68 123 30) _134. _d3_r 2950 GCGCTG CCATCG CCCCACTTGTAGG 2951 GCTG CCATCG CCCCACTTGTA

LDLRex2(27 68 123 30) _135. _d3_f 2953 CTACAAGTGGGTCGATGGCAGCGCT 2954 ACAAGTGG GTCG ATGG CAG CG

LDLRex2(27 68 123 30) _135. _d3_r 2956 AGCGCTGCCATCGACCCACTTGTAG 2957 CG CTG CCATCG ACCCACTTGT

LDLRex2(27 68 123 30) _136. _d3_f 2959 TACAAGTGGGTCGATGGCAGCGCTG 2960 CAAGTGGGTCGATGGCAGCGC

LDLRex2(27 68 123 30) _136. _d3_r 2962 CAGCGCTGCCATCGACCCACTTGTA 2963 GCGCTGCCATCGACCCACTTG

LDLRex2(27 68 123 30) _137_ _d3_f 2965 ACAAGTGGGTCTATGGCAGCGCTGA 2966 AAGTGGGTCTATGGCAGCGCT

LDLRex2(27 68 123 30) _137_ _d3_r 2968 TCAGCGCTGCCATAGACCCACTTGT 2969 AG CGCTG CCATAG ACCCACTT

LDLRex2(27 68 123 30) _138. _d3_f 2971 CAAGTGGGTCTGTGGCAGCGCTGAG 2972 AGTGGGTCTGTGGCAGCGCTG

LDLRex2(27 68 123 30) _138. _d3_r 2974 CTCAGCGCTGCCACAGACCCACTTG 2975 CAG CG CTG CCACAG ACCCACT

LDLRex2(27 68 123 30) _139. _d3_f 2977 AAGTGGGTCTGCGGCAGCGCTGAGT 2978 GTGGGTCTGCGGCAGCGCTGA

LDLRex2(27 68 123 30) _139. _d3_r 2980 ACTCAGCGCTGCCGCAGACCCACTT 2981 TCAGCGCTGCCGCAGACCCAC

LDLRex2(27 68 123 30) _140. _d3_f 2983 AGTGGGTCTGCGGCAGCGCTGAGTG 2984 TGGGTCTGCGGCAGCGCTGAG

LDLRex2(27 68 123 30) _140. _d3_r 2986 CACTCAGCGCTGCCGCAGACCCACT 2987 CTCAG CG CTG CCG CAG ACCCA

LDLRex2(27 68 123 30) _141_ _d3_f 2989 GTGGGTCTGCGACAGCGCTGAGTGC 2990 GGGTCTGCGACAGCGCTGAGT

LDLRex2(27 68 123 30) _141_ _d3_r 2992 G CACTCAGCG CTGTCG CAG ACCCAC 2993 ACTCAGCGCTGTCGCAGACCC

LDLRex2(27 68 123 30) _142. _d3_f 2995 TGGGTCTGCGATAGCGCTGAGTGCC 2996 GGTCTGCGATAGCGCTGAGTG

LDLRex2(27 68 123 30) _142. _d3_r 2998 GGCACTCAGCGCTATCGCAGACCCA 2999 CACTCAGCGCTATCGCAGACC

LDLRex2(27 68 123 30) _143. _d3_f 3001 GGGTCTGCGATGGCGCTGAGTGCCA 3002 GTCTGCGATGGCGCTGAGTGC

LDLRex2(27 68 123 30) _143. _d3_r 3004 TGGCACTCAGCGCCATCGCAGACCC 3005 GCACTCAGCGCCATCGCAGAC

LDLRex2(27 68 123 30) _144. _d3_f 3007 G GTCTG CG ATG GCG CTG AGTG CCAG 3008 TCTGCGATGGCGCTGAGTGCC

LDLRex2(27 68 123 30) _144. _d3_r 3010 CTGGCACTCAGCGCCATCGCAGACC 3011 GGCACTCAGCGCCATCGCAGA

LDLRex2(27 68 123 30) _145. _d3_f 3013 GTCTGCGATGGCGCTGAGTGCCAGG 3014 CTG CG ATG GCG CTG AGTG CCA

LDLRex2(27 68 123 30) _145. _d3_r 3016 CCTGGCACTCAGCGCCATCGCAGAC 3017 TGG CACTCAGCG CCATCG CAG

LDLRex2(27 68 123 30) _146. _d3_f 3019 TCTG CG ATG GCACTG AGTG CCAG G A 3020 TGCGATGGCACTGAGTGCCAG

LDLRex2(27;68;123 30) _146. _d3_r 3022 TCCTG GCACTCAGTG CCATCG CAG A 3023 CTG GCACTCAGTG CCATCG CA

Table 1

SEQ ID SEQ ID SEQ ID

del3 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _147_ _d3_f 3025 CTG CG ATG GCAGTG AGTG CCAG GAT 3026 TG CG ATG GCAGTG AGTG CCAG G A 3027 GCGATGGCAGTGAGTGCCAGG

LDLRex2(27 68 123 30) _147_ _d3_r 3028 ATCCTG GCACTCACTG CCATCG CAG 3029 TCCTGGCACTCACTGCCATCGCA 3030 CCTGGCACTCACTGCCATCGC

LDLRex2(27 68 123 30) _148_ _d3_f 3031 TGCGATGGCAGCGAGTGCCAGGATG 3032 GCGATGGCAGCGAGTGCCAGGAT 3033 CGATGGCAGCGAGTGCCAGGA

LDLRex2(27 68 123 30) _148_ _d3_r 3034 CATCCTG GCACTCGCTG CCATCG CA 3035 ATCCTG GCACTCGCTG CCATCG C 3036 TCCTGGCACTCGCTGCCATCG

LDLRex2(27 68 123 30) _149_ _d3_f 3037 GCGATGGCAGCGAGTGCCAGGATGG 3038 CGATGGCAGCGAGTGCCAGGATG 3039 GATGGCAGCGAGTGCCAGGAT

LDLRex2(27 68 123 30) _149_ _d3_r 3040 CCATCCTGG CACTCG CTG CCATCGC 3041 CATCCTGG CACTCG CTG CCATCG 3042 ATCCTGGCACTCGCTGCCATC

LDLRex2(27 68 123 30) _150_ _d3_f 3043 CGATGGCAGCGCGTGCCAGGATGGC 3044 GATGGCAGCGCGTGCCAGGATGG 3045 ATGGCAGCGCGTGCCAGGATG

LDLRex2(27 68 123 30) _150_ _d3_r 3046 GCCATCCTGGCACGCGCTGCCATCG 3047 CCATCCTGG CACG CGCTG CCATC 3048 CATCCTGGCACGCGCTGCCAT

LDLRex2(27 68 123 30) _151_ _d3_f 3049 GATGGCAGCGCTTGCCAGGATGGCT 3050 ATGGCAGCGCTTGCCAGGATGGC 3051 TGGCAGCGCTTGCCAGGATGG

LDLRex2(27 68 123 30) _151_ _d3_r 3052 AGCCATCCTGG CAAG CG CTG CCATC 3053 G CCATCCTG GCAAG CGCTG CCAT 3054 CCATCCTG GCAAG CGCTG CCA

LDLRex2(27 68 123 30) _152_ _d3_f 3055 ATGGCAGCGCTGGCCAGGATGGCTC 3056 TGGCAGCGCTGGCCAGGATGGCT 3057 GGCAGCGCTGGCCAGGATGGC

LDLRex2(27 68 123 30) _152_ _d3_r 3058 GAGCCATCCTGGCCAGCGCTGCCAT 3059 AGCCATCCTGGCCAGCGCTGCCA 3060 GCCATCCTGGCCAGCGCTGCC

LDLRex2(27 68 123 30) _153. _d3_f 3061 TGGCAGCGCTGACCAGGATGGCTCT 3062 GGCAGCGCTGACCAGGATGGCTC 3063 GCAGCGCTGACCAGGATGGCT

LDLRex2(27 68 123 30) _153. _d3_r 3064 AGAGCCATCCTGGTCAGCGCTGCCA 3065 GAG CCATCCTG GTCAG CG CTG CC 3066 AG CCATCCTG GTCAGCG CTGC

LDLRex2(27 68 123 30) _154. _d3_f 3067 GGCAGCGCTGAGCAGGATGGCTCTG 3068 GCAGCGCTGAGCAGGATGGCTCT 3069 CAGCGCTGAGCAGGATGGCTC

LDLRex2(27 68 123 30) _154. _d3_r 3070 CAGAGCCATCCTGCTCAGCGCTGCC 3071 AGAGCCATCCTGCTCAGCGCTGC 3072 GAGCCATCCTGCTCAGCGCTG

LDLRex2(27 68 123 30) _155. _d3_f 3073 GCAGCGCTGAGTAGGATGGCTCTGA 3074 CAGCG CTG AGTAG GATGG CTCTG 3075 AGCGCTGAGTAGGATGGCTCT

LDLRex2(27 68 123 30) _155. _d3_r 3076 TCAG AG CCATCCTACTCAG CGCTGC 3077 CAGAGCCATCCTACTCAGCGCTG 3078 AGAGCCATCCTACTCAGCGCT

LDLRex2(27 68 123 30) _156. _d3_f 3079 CAGCGCTGAGTGGGATGGCTCTGAT 3080 AGCGCTGAGTGGGATGGCTCTGA 3081 GCGCTGAGTGGGATGGCTCTG

LDLRex2(27 68 123 30) _156. _d3_r 3082 ATCAGAGCCATCCCACTCAGCGCTG 3083 TCAGAGCCATCCCACTCAGCGCT 3084 CAG AG CCATCCCACTCAGCG C

LDLRex2(27 68 123 30) _157_ _d3_f 3085 AGCGCTGAGTGCGATGGCTCTGATG 3086 GCGCTGAGTGCGATGGCTCTGAT 3087 CGCTGAGTGCGATGGCTCTGA

LDLRex2(27 68 123 30) _157_ _d3_r 3088 CATCAG AG CCATCG CACTCAGCG CT 3089 ATCAG AG CCATCG CACTCAGCG C 3090 TCAGAGCCATCGCACTCAGCG

LDLRex2(27 68 123 30) _158. _d3_f 3091 GCGCTGAGTGCCATGGCTCTGATGA 3092 CGCTGAGTGCCATGGCTCTGATG 3093 GCTGAGTGCCATGGCTCTGAT

LDLRex2(27 68 123 30) _158. _d3_r 3094 TCATCAGAGCCATGGCACTCAGCGC 3095 CATCAG AG CCATG GCACTCAG CG 3096 ATCAGAGCCATGGCACTCAGC

LDLRex2(27 68 123 30) _159. _d3_f 3097 CG CTG AGTG CCATGG CTCTG ATG AG 3098 G CTG AGTG CCATGG CTCTG ATG A 3099 CTGAGTGCCATGGCTCTGATG

LDLRex2(27 68 123 30) _159. _d3_r 3100 CTCATCAG AG CCATG G CACTCAGCG 3101 TCATCAGAGCCATGGCACTCAGC 3102 CATCAGAGCCATGGCACTCAG

LDLRex2(27 68 123 30) _160. _d3_f 3103 GCTGAGTGCCAGGGCTCTGATGAGT 3104 CTGAGTGCCAGGGCTCTGATGAG 3105 TGAGTGCCAGGGCTCTGATGA

LDLRex2(27 68 123 30) _160. _d3_r 3106 ACTCATCAG AG CCCTG GCACTCAG C 3107 CTCATCAGAGCCCTGGCACTCAG 3108 TCATCAGAGCCCTGGCACTCA

LDLRex2(27 68 123 30) _161_ _d3_f 3109 CTGAGTGCCAGGGCTCTGATGAGTC 3110 TGAGTGCCAGGGCTCTGATGAGT 3111 GAGTGCCAGGGCTCTGATGAG

LDLRex2(27 68 123 30) _161. _d3_r 3112 GACTCATCAGAGCCCTGGCACTCAG 3113 ACTCATCAGAGCCCTGGCACTCA 3114 CTCATCAGAGCCCTGGCACTC

LDLRex2(27;68;123 30) _162. _d3_f 3115 TGAGTGCCAGGACTCTGATGAGTCC 3116 GAGTGCCAGGACTCTGATGAGTC 3117 AGTGCCAGGACTCTGATGAGT

Table 1

SEQ ID SEQ ID

del3 NO: 25 nt NO: 21 nt

LDLRex2(27 68 123 30) _162. _d3_r 3118 GGACTCATCAGAGTCCTGGCACTCA 3119 ACTCATCAGAGTCCTGGCACT

LDLRex2(27 68 123 30) _163_ _d3_f 3121 GAGTGCCAGGATTCTGATGAGTCCC 3122 GTG CCAG G ATTCTG ATG AGTC

LDLRex2(27 68 123 30) _163_ _d3_r 3124 GGGACTCATCAGAATCCTGGCACTC 3125 GACTCATCAGAATCCTGGCAC

LDLRex2(27 68 123 30) _164_ _d3_f 3127 AGTGCCAGGATGCTGATGAGTCCCA 3128 TGCCAGGATGCTGATGAGTCC

LDLRex2(27 68 123 30) _164_ _d3_r 3130 TGGGACTCATCAGCATCCTGGCACT 3131 GGACTCATCAGCATCCTGGCA

LDLRex2(27 68 123 30) _165_ _d3_f 3133 GTGCCAGGATGGTGATGAGTCCCAG 3134 GCCAGGATGGTGATGAGTCCC

LDLRex2(27 68 123 30) _165_ _d3_r 3136 CTGGGACTCATCACCATCCTGGCAC 3137 GGGACTCATCACCATCCTGGC

LDLRex2(27 68 123 30) _166_ _d3_f 3139 TGCCAGGATGGCGATGAGTCCCAGG 3140 CCAGGATGGCGATGAGTCCCA

LDLRex2(27 68 123 30) _166_ _d3_r 3142 CCTGGGACTCATCGCCATCCTGGCA 3143 TGGGACTCATCGCCATCCTGG

LDLRex2(27 68 123 30) _167. _d3_f 3145 GCCAGGATGGCTATGAGTCCCAGGA 3146 CAG G ATGG CTATG AGTCCCAG

LDLRex2(27 68 123 30) _167. _d3_r 3148 TCCTGGGACTCATAGCCATCCTGGC 3149 CTGG G ACTCATAG CCATCCTG

LDLRex2(27 68 123 30) _168_ _d3_f 3151 CCAGGATGGCTCTGAGTCCCAGGAG 3152 AG G ATGG CTCTG AGTCCCAG G

LDLRex2(27 68 123 30) _168_ _d3_r 3154 CTCCTGGGACTCAGAGCCATCCTGG 3155 CCTGGGACTCAGAGCCATCCT

LDLRex2(27 68 123 30) _169_ _d3_f 3157 CAGGATGGCTCTGAGTCCCAGGAGA 3158 GGATGGCTCTGAGTCCCAGGA

LDLRex2(27 68 123 30) _169_ _d3_r 3160 TCTCCTG G G ACTCAG AG CCATCCTG 3161 TCCTGGGACTCAGAGCCATCC

LDLRex2(27 68 123 30) _170_ _d3_f 3163 AGGATGGCTCTGAGTCCCAGGAGAC 3164 GATGGCTCTGAGTCCCAGGAG

LDLRex2(27 68 123 30) _170_ _d3_r 3166 GTCTCCTGGGACTCAGAGCCATCCT 3167 CTCCTGGGACTCAGAGCCATC

LDLRex2(27 68 123 30) _171_ _d3_f 3169 G G ATG GCTCTG AGTCCCAG GAG ACG 3170 ATGGCTCTGAGTCCCAGGAGA

LDLRex2(27 68 123 30) _171_ _d3_r 3172 CGTCTCCTGGGACTCAGAGCCATCC 3173 TCTCCTGGGACTCAGAGCCAT

LDLRex2(27 68 123 30) _172. _d3_f 3175 GATGGCTCTGATTCCCAGGAGACGT 3176 TGGCTCTGATTCCCAGGAGAC

LDLRex2(27 68 123 30) _172. _d3_r 3178 ACGTCTCCTGGGAATCAGAGCCATC 3179 GTCTCCTGGGAATCAGAGCCA

LDLRex2(27 68 123 30) _173. _d3_f 3181 ATGG CTCTG ATG CCCAG GAG ACGTG 3182 GGCTCTGATGCCCAGGAGACG

LDLRex2(27 68 123 30) _173. _d3_r 3184 CACGTCTCCTG GG CATCAG AG CCAT 3185 CGTCTCCTGGGCATCAGAGCC

LDLRex2(27 68 123 30) _174. _d3_f 3187 TGGCTCTGATGACCAGGAGACGTGC 3188 GCTCTGATGACCAGGAGACGT

LDLRex2(27 68 123 30) _174. _d3_r 3190 GCACGTCTCCTGGTCATCAGAGCCA 3191 ACGTCTCCTGGTCATCAGAGC

LDLRex2(27 68 123 30) _175. _d3_f 3193 GGCTCTGATGAGCAGGAGACGTGCT 3194 CTCTGATGAGCAGGAGACGTG

LDLRex2(27 68 123 30) _175. _d3_r 3196 AGCACGTCTCCTGCTCATCAGAGCC 3197 CACGTCTCCTGCTCATCAGAG

LDLRex2(27 68 123 30) _176. _d3_f 3199 GCTCTGATGAGTAGGAGACGTGCTG 3200 TCTGATGAGTAGGAGACGTGC

LDLRex2(27 68 123 30) _176_ _d3_r 3202 CAGCACGTCTCCTACTCATCAGAGC 3203 G CACGTCTCCTACTCATCAG A

LDLRex2(27 68 123 30) _177. _d3_f 3205 CTCTGATGAGTCGGAGACGTGCTGT 3206 CTGATGAGTCGGAGACGTGCT

LDLRex2(27;68;123 30) _177. _d3_r 3208 ACAG CACGTCTCCG ACTCATCAG AG 3209 AGCACGTCTCCGACT CATCAG

Table 1

SEQ ID SEQ ID

del3 NO: 25 nt NO: 21 nt

LDLRex2(27 68 123 30) _178_d3_ _f 3211 TCTG ATG AGTCCG AG ACGTG CTGTG 3212 TGATGAGTCCGAGACGTGCTG

LDLRex2(27 68 123 30) _178_d3_ _r 3214 CACAGCACGTCTCGGACTCATCAGA 3215 CAGCACGTCTCGGACTCATCA

LDLRex2(27 68 123 30) _179_d3_ .f 3217 CTGATGAGTCCCAGACGTGCTGTGA 3218 GATGAGTCCCAGACGTGCTGT

LDLRex2(27 68 123 30) _179_d3_ _r 3220 TCACAGCACGTCTGGGACTCATCAG 3221 ACAGCACGTCTGGGACTCATC

LDLRex2(27 68 123 30) _180_d3_ .f 3223 TGATGAGTCCCAGACGTGCTGTGAG 3224 ATGAGTCCCAGACGTGCTGTG

LDLRex2(27 68 123 30) _180_d3_ _r 3226 CTCACAGCACGTCTGGGACTCATCA 3227 CACAGCACGTCTGGGACTCAT

LDLRex2(27 68 123 30) _181_d3_ .f 3229 GATGAGTCCCAGACGTGCTGTGAGT 3230 TGAGTCCCAGACGTGCTGTGA

LDLRex2(27 68 123 30) _181_d3_ _r 3232 ACTCACAGCACGTCTGGGACTCATC 3233 TCACAGCACGTCTGGGACTCA

LDLRex2(27 68 123 30) _182_d3_ .f 3235 ATGAGTCCCAGGCGTGCTGTGAGTC 3236 GAGTCCCAGGCGTGCTGTGAG

LDLRex2(27 68 123 30) _182_d3_ _r 3238 G ACTCACAG CACG CCTGG G ACTCAT 3239 CTCACAGCACGCCTGGGACTC

LDLRex2(27 68 123 30) _183_d3_ f 3241 TGAGTCCCAGGAGTGCTGTGAGTCC 3242 AGTCCCAG GAGTG CTGTG AGT

LDLRex2(27 68 123 30) _183_d3_ _r 3244 GGACTCACAGCACTCCTGGGACTCA 3245 ACTCACAGCACTCCTGGGACT

LDLRex2(27 68 123 30) _184_d3_ f 3247 GAGTCCCAGGAGTGCTGTGAGTCCC 3248 GTCCCAGGAGTGCTGTGAGTC

LDLRex2(27 68 123 30) _184_d3_ _r 3250 GGGACTCACAGCACTCCTGGGACTC 3251 GACTCACAGCACTCCTGGGAC

LDLRex2(27 68 123 30) _185_d3_ f 3253 AGTCCCAGGAGAGCTGTGAGTCCCC 3254 TCCCAGGAGAGCTGTGAGTCC

LDLRex2(27 68 123 30) _185_d3_ _r 3256 GGGGACTCACAGCTCTCCTGGGACT 3257 GGACTCACAGCTCTCCTGGGA

LDLRex2(27 68 123 30) _186_d3_ f 3259 GTCCCAGGAGACCTGTGAGTCCCCT 3260 CCCAGGAGACCTGTGAGTCCC

LDLRex2(27 68 123 30) _186_d3_ _r 3262 AGGGGACTCACAGGTCTCCTGGGAC 3263 G G G ACTCACAGGTCTCCTGG G

LDLRex2(27 68 123 30) _187_d3_ f 3265 TCCCAGGAGACGTGTGAGTCCCCTT 3266 CCAGGAGACGTGTGAGTCCCC

LDLRex2(27 68 123 30) _187_d3_ _r 3268 AAG GG G ACTCACACGTCTCCTGG G A 3269 GGGGACTCACACGTCTCCTGG

LDLRex2(27 68 123 30) _188_d3_ f 3271 CCCAGGAGACGTGTGAGTCCCCTTT 3272 CAGGAGACGTGTGAGTCCCCT

LDLRex2(27 68 123 30) _188_d3_ _r 3274 AAAGGGGACTCACACGTCTCCTGGG 3275 AGG G G ACTCACACGTCTCCTG

LDLRex2(27 68 123 30) _189_d3_ f 3277 CCAGGAGACGTGTGAGTCCCCTTTG 3278 AGGAGACGTGTGAGTCCCCTT

LDLRex2(27 68 123 30) _189_d3_ _r 3280 CAAAGGGGACTCACACGTCTCCTGG 3281 AAGGGGACTCACACGTCTCCT

LDLRex2(27 68 123 30) _190 + 1_ d3_f 3283 AGGAGACGTGCTAGTCCCCTTTGGG 3284 GAGACGTGCTAGTCCCCTTTG

LDLRex2(27 68 123 30) _190 + 1_ d3_r 3286 CCCAAAGGGGACTAGCACGTCTCCT 3287 CAAAG GG G ACTAG CACGTCTC

LDLRex2(27 68 123 30) _190 + 10 _d3_ 1 3289 G CTGTG AGTCCCTG GG CATGATATG 3290 TGTGAGTCCCTGGGCATGATA

LDLRex2(27 68 123 30) _190 + 10 _d3_ 1 3292 CATATCATGCCCAGGGACTCACAGC 3293 TATCATGCCCAGGGACTCACA

LDLRex2(27 68 123 30) _190 + 11 _d3_ 1 3295 CTGTGAGTCCCCGGGCATGATATGC 3296 GTGAGTCCCCGGGCATGATAT

LDLRex2(27 68 123 30) _190 + 11 _d3_ 1 3298 G CATATCATG CCCG GG G ACTCACAG 3299 ATATCATGCCCGGGGACTCAC

LDLRex2(27;68;123;30) _190 + 12 _d3_ 1 3301 TGTGAGTCCCCTGGCATGATATGCA 3302 TGAGTCCCCTGGCATGATATG

Table 1

SEQ ID SEQ ID SEQ ID

del3 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _190 + 12_d3_ 1 3304 TGCATATCATG CCAG GG G ACTCACA 3305 GCATATCATGCCAGGGGACTCAC 3306 CATATCATGCCAGGGGACTCA

LDLRex2(27 68 123 30) _190 + 13_d3_ 1 3307 GTGAGTCCCCTTGCATGATATGCAT 3308 TGAGTCCCCTTGCATGATATGCA 3309 GAGTCCCCTTGCATGATATGC

LDLRex2(27 68 123 30) _190 + 13_d3_ 1 3310 ATG CATATCATGCAAG GG G ACTCAC 3311 TG CAT ATC ATG CAAGGGGACTCA 3312 GCATATCATGCAAGGGGACTC

LDLRex2(27 68 123 30) _190 + 14_d3_ 1 3313 TGAGTCCCCTTTCATGATATGCATT 3314 GAGTCCCCTTTCATGATATGCAT 3315 AGTCCCCTTTCATGATATGCA

LDLRex2(27 68 123 30) _190 + 14_d3_ 1 3316 A ATG C ATATC ATG AAAGGGGACTCA 3317 ATG CATATCATG AAAGG G G ACTC 3318 TG CATATCATG A AAG G G G ACT

LDLRex2(27 68 123 30) _190 + 15_d3_ 1 3319 GAGTCCCCTTTGATGATATGCATTT 3320 AGTCCCCTTTGATGATATGCATT 3321 GTCCCCTTTGATGATATGCAT

LDLRex2(27 68 123 30) _190 + 15_d3_ 1 3322 A A ATG C AT ATC ATC AA AG G G G ACTC 3323 AATGCATATCATCAAAGGGGACT 3324 ATG CAT ATC ATC A AAG G G G AC

LDLRex2(27 68 123 30) _190 + 2_d3_f 3325 GGAGACGTGCTGGTCCCCTTTGGGC 3326 GAGACGTGCTGGTCCCCTTTGGG 3327 AGACGTGCTGGTCCCCTTTGG

LDLRex2(27 68 123 30) _190 + 2_d3_r 3328 G CCCAAAG GG GACCAG CACGTCTCC 3329 CCCAAAGGGGACCAGCACGTCTC 3330 CCAAAG GG GACCAG CACGTCT

LDLRex2(27 68 123 30) _190 + 3_d3_f 3331 GAGACGTGCTGTTCCCCTTTGGGCA 3332 AGACGTGCTGTTCCCCTTTGGGC 3333 G ACGTG CTGTTCCCCTTTG GG

LDLRex2(27 68 123 30) _190 + 3_d3_r 3334 TGCCCAAAGGGGAACAGCACGTCTC 3335 G CCCAAAG GG GAACAGCACGTCT 3336 CCCAAAGGGGAACAGCACGTC

LDLRex2(27 68 123 30) _190 + 4_d3_f 3337 AGACGTGCTGTGCCCCTTTGGGCAT 3338 GACGTGCTGTGCCCCTTTGGGCA 3339 ACGTGCTGTGCCCCTTTGGGC

LDLRex2(27 68 123 30) _190 + 4_d3_r 3340 ATG CCCAAAG GG GCACAG CACGTCT 3341 TG CCCAAAG GG GCACAG CACGTC 3342 GCCCAAAGGGGCACAGCACGT

LDLRex2(27 68 123 30) _190 + 5_d3_f 3343 GACGTGCTGTGACCCTTTGGGCATG 3344 ACGTG CTGTG ACCCTTTG GG CAT 3345 CGTGCTGTGACCCTTTGGGCA

LDLRex2(27 68 123 30) _190 + 5_d3_r 3346 CATGCCCAAAGGGTCACAGCACGTC 3347 ATGCCCAAAGGGTCACAGCACGT 3348 TGCCCAAAGGGTCACAGCACG

LDLRex2(27 68 123 30) _190 + 6_d3_f 3349 ACGTGCTGTGAGCCTTTGGGCATGA 3350 CGTGCTGTGAGCCTTTGGGCATG 3351 GTGCTGTGAGCCTTTGGGCAT

LDLRex2(27 68 123 30) _190 + 6_d3_r 3352 TCATG CCCAAAG GCTCACAG CACGT 3353 CATGCCCAAAGGCTCACAGCACG 3354 ATG CCCAAAG GCTCACAG CAC

LDLRex2(27 68 123 30) _190 + 7_d3_f 3355 CGTGCTGTGAGTCTTTGGGCATGAT 3356 GTGCTGTGAGTCTTTGGGCATGA 3357 TGCTGTGAGTCTTTGGGCATG

LDLRex2(27 68 123 30) _190 + 7_d3_r 3358 ATCATGCCCAAAGACTCACAGCACG 3359 TCATG CCCAAAG ACTCACAGCAC 3360 CATG CCCAAAG ACTCACAG CA

LDLRex2(27 68 123 30) _190 + 8_d3_f 3361 GTGCTGTGAGTCTTTGGGCATGATA 3362 TGCTGTGAGTCTTTGGGCATGAT 3363 GCTGTGAGTCTTTGGGCATGA

LDLRex2(27 68 123 30) _190 + 8_d3_r 3364 TATCATGCCCAAAGACTCACAGCAC 3365 ATCATGCCCAAAGACTCACAGCA 3366 TCATG CCCAAAG ACTCACAG C

LDLRex2(27 68 123 30) _190 + 9_d3_f 3367 TGCTGTGAGTCCTTGGGCATGATAT 3368 G CTGTG AGTCCTTG GG CATG ATA 3369 CTGTGAGTCCTTGGGCATGAT

LDLRex2(27 68 123 30) _190 + 9_d3_r 3370 ATATCATGCCCAAGGACTCACAGCA 3371 TATCATGCCCAAGGACTCACAGC 3372 ATCATGCCCAAGGACTCACAG

LDLRex2(27 68 123 30) _190_d3_f 3373 CAGGAGACGTGCGAGTCCCCTTTGG 3374 AGGAGACGTGCGAGTCCCCTTTG 3375 GGAGACGTGCGAGTCCCCTTT

LDLRex2(27 68 123 30) _190_d3_r 3376 CCAAAGGGGACTCGCACGTCTCCTG 3377 CAAAGGGGACTCGCACGTCTCCT 3378 AAAGGGGACTCGCACGTCTCC

LDLRex2(27 68 123 30) _68 - l_d3_f 3379 TCCTCTCTCTCAGGCGACAGATGCG 3380 CCTCTCTCTCAGGCGACAGATGC 3381 CTCTCTCTCAGGCGACAGATG

LDLRex2(27 68 123 30) _68 - l_d3_r 3382 CGCATCTGTCGCCTGAGAGAGAGGA 3383 GCATCTGTCGCCTGAGAGAGAGG 3384 CATCTGTCGCCTGAGAGAGAG

LDLRex2(27 68 123 30) _68 - 10_d3_f 3385 TTCTCCTTTTCCCTCTCAGTG GG CG 3386 TCTCCTTTTCCCTCTCAGTG GG C 3387 CTCCTTTTCCCTCTCAGTGGG

LDLRex2(27 68 123 30) _68 - 10_d3_r 3388 CGCCCACTGAGAGGGAAAAGGAGAA 3389 GCCCACTGAGAGGGAAAAGGAGA 3390 CCCACTGAGAGGGAAAAGGAG

LDLRex2(27 68 123 30) _68 - ll_d3_f 3391 TTTCTCCTTTTCTCTCTCAGTGGGC 3392 TTCTCCTTTTCTCTCTCAGTGGG 3393 TCTCCTTTTCTCTCTCAGTGG

LDLRex2(27;68;123 30) _68 - ll_d3_r 3394 GCCCACTGAGAGAGAAAAGGAGAAA 3395 CCCACTGAGAGAGAAAAGGAGAA 3396 CCACTGAGAGAGAAAAGGAGA

Table

SEQ ID SEQ ID

del3 NO: 25 nt NO: 21 nt

LDLRex2(27 68 123 30) _68 - 12_d3_f 3397 CTTTCTCCTTTTCTCTCTCAGTGGG 3398 TTCTCCTTTTCTCTCTCAGTG

LDLRex2(27 68 123 30) _68 - 12_d3_r 3400 CCCACTGAGAGAGAAAAGGAGAAAG 3401 CACTGAGAGAGAAAAGGAGAA

LDLRex2(27 68 123 30) _68 - 13_d3_f 3403 CCTTTCTCCTTTTCTCTCTCAGTGG 3404 TTTCTCCTTTTCTCTCTCAGT

LDLRex2(27 68 123 30) _68 - 13_d3_r 3406 CCACTGAGAGAGAAAAGGAGAAAGG 3407 ACTGAGAGAGAAAAGGAGAAA

LDLRex2(27 68 123 30) _68 - 14_d3_f 3409 CCCTTTCTCCTTCTCTCTCTCAGTG 3410 CTTTCTCCTTCTCTCTCTCAG

LDLRex2(27 68 123 30) _68 - 14_d3_r 3412 CACTGAGAGAGAGAAGGAGAAAGGG 3413 CTGAGAGAGAGAAGGAGAAAG

LDLRex2(27 68 123 30) _68 - 15_d3_f 3415 ACCCTTTCTCCTCCTCTCTCTCAGT 3416 CCTTTCTCCTCCTCTCTCTCA

LDLRex2(27 68 123 30) _68 - 15_d3_r 3418 ACTGAGAGAGAGGAGGAGAAAGGGT 3419 TGAGAGAGAGGAGGAGAAAGG

LDLRex2(27 68 123 30) _68 - 2_d3_f 3421 TTCCTCTCTCTCGGGCGACAGATGC 3422 CCTCTCTCTCGGGCGACAGAT

LDLRex2(27 68 123 30) _68 - 2_d3_r 3424 GCATCTGTCGCCCGAGAGAGAGGAA 3425 ATCTGTCGCCCGAGAGAGAGG

LDLRex2(27 68 123 30) _68 - 3_d3_f 3427 TTTCCTCTCTCTTGGGCGACAGATG 3428 TCCTCTCTCTTGGGCGACAGA

LDLRex2(27 68 123 30) _68 - 3_d3_r 3430 CATCTGTCGCCCAAGAGAGAGGAAA 3431 TCTGTCG CCCAAG AG AG AG G A

LDLRex2(27 68 123 30) _68 - 4_d3_f 3433 TTTTCCTCTCTCGTGGGCGACAGAT 3434 TTCCTCTCTCGTGGGCGACAG

LDLRex2(27 68 123 30) _68 - 4_d3_r 3436 ATCTGTCGCCCACGAGAGAGGAAAA 3437 CTGTCGCCCACGAGAGAGGAA

LDLRex2(27 68 123 30) _68 - 5_d3_f 3439 CTTTTCCTCTCTAGTGGGCGACAGA 3440 TTTCCTCTCTAGTG G GCG ACA

LDLRex2(27 68 123 30) _68 - 5_d3_r 3442 TCTGTCGCCCACTAGAGAGGAAAAG 3443 TGTCGCCCACTAGAGAGGAAA

LDLRex2(27 68 123 30) _68 - 6_d3_f 3445 CCTTTTCCTCTCCAGTGGGCGACAG 3446 TTTTCCTCTCCAGTG GG CG AC

LDLRex2(27 68 123 30) _68 - 6_d3_r 3448 CTGTCGCCCACTGGAGAGGAAAAGG 3449 GTCGCCCACTGGAGAGGAAAA

LDLRex2(27 68 123 30) _68 - 7_d3_f 3451 TCCTTTTCCTCTTCAGTG GG CG ACA 3452 CTTTTCCTCTTCAGTG G GCG A

LDLRex2(27 68 123 30) _68 - 7_d3_r 3454 TGTCGCCCACTGAAGAGGAAAAGGA 3455 TCGCCCACTGAAGAGGAAAAG

LDLRex2(27 68 123 30) _68 - 8_d3_f 3457 CTCCTTTTCCTCCTCAGTGGGCGAC 3458 CCTTTTCCTCCTCAGTG GG CG

LDLRex2(27 68 123 30) _68 - 8_d3_r 3460 GTCGCCCACTGAGGAGGAAAAGGAG 3461 CGCCCACTGAGGAGGAAAAGG

LDLRex2(27 68 123 30) _68 - 9_d3_f 3463 TCTCCTTTTCCTTCTCAGTG GG CG A 3464 TCCTTTTCCTTCTCAGTGGGC

LDLRex2(27 68 123 30) _68 - 9_d3_r 3466 TCGCCCACTGAGAAGGAAAAGGAGA 3467 G CCCACTG AG AAG GAAAAG G A

LDLRex2(27 68 123 30) _68. _d3_f 3469 CCTCTCTCTCAGGCGACAGATGCGA 3470 TCTCTCTCAGGCGACAGATGC

LDLRex2(27 68 123 30) _68. _d3_r 3472 TCGCATCTGTCGCCTGAGAGAGAGG 3473 GCATCTGTCGCCTGAGAGAGA

LDLRex2(27 68 123 30) _69. _d3_f 3475 CTCTCTCTCAGTCGACAGATGCGAA 3476 CTCTCTCAGTCGACAGATGCG

LDLRex2(27 68 123 30) _69. _d3_r 3478 TTCGCATCTGTCGACTGAGAGAGAG 3479 CGCATCTGTCGACTGAGAGAG

LDLRex2(27 68 123 30) _70. _d3_f 3481 TCTCTCTCAGTGGACAGATGCGAAA 3482 TCTCTCAGTGGACAGATGCGA

LDLRex2(27 68 123 30) _70. _d3_r 3484 TTTCGCATCTGTCCACTGAGAGAGA 3485 TCGCATCTGTCCACTGAGAGA

LDLRex2(27;68;123 30) _71 _d3_f 3487 CTCTCTCAGTGGACAGATGCGAAAG 3488 CTCTCAGTGGACAGATGCGAA

Table 1

SEQ ID SEQ ID SEQ ID

del3 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _71. _d3_r 3490 CTTTCG C ATCTGTCC ACTG AG AG AG 3491 TTTCGCATCTGTCCACTGAGAGA 3492 TTCGCATCTGTCCACTGAGAG

LDLRex2(27 68 123 30) _72. _d3_f 3493 TCTCTCAGTGGGCAGATGCGAAAGA 3494 CTCTCAGTGGGCAGATGCGAAAG 3495 TCTCAGTGGGCAGATGCGAAA

LDLRex2(27 68 123 30) _72. _d3_r 3496 TCTTTCGCATCTGCCCACTGAGAGA 3497 CTTTCGCATCTGCCCACTGAGAG 3498 TTTCGCATCTGCCCACTGAGA

LDLRex2(27 68 123 30) _73. _d3_f 3499 CTCTCAGTGGGCAGATGCGAAAGAA 3500 TCTCAGTGGGCAGATGCGAAAGA 3501 CTCAGTGGGCAGATGCGAAAG

LDLRex2(27 68 123 30) _73. _d3_r 3502 TTCTTTCGCATCTGCCCACTGAGAG 3503 TCTTTCGCATCTGCCCACTGAGA 3504 CTTTCGCATCTGCCCACTGAG

LDLRex2(27 68 123 30) _74. _d3_f 3505 TCTCAGTGGGCGGATGCGAAAGAAA 3506 CTCAGTGGGCGGATGCGAAAGAA 3507 TCAGTGG G CG GATG CG AAAG A

LDLRex2(27 68 123 30) _74. _d3_r 3508 TTTCTTTCGCATCCGCCCACTGAGA 3509 TTCTTTCGCATCCGCCCACTGAG 3510 TCTTTCG CATCCG CCCACTG A

LDLRex2(27 68 123 30) _75. _d3_f 3511 CTCAGTGGGCGAATGCGAAAGAAAC 3512 TCAGTGGGCGAATGCGAAAGAAA 3513 CAGTGGGCGAATGCGAAAGAA

LDLRex2(27 68 123 30) _75. _d3_r 3514 GTTTCTTTCGCATTCGCCCACTGAG 3515 TTTCTTTCG CATTCG CCCACTG A 3516 TTCTTTCGCATTCGCCCACTG

LDLRex2(27 68 123 30) _76. _d3_f 3517 TCAGTGGGCGACTGCGAAAGAAACG 3518 CAGTG GG CG ACTG CGAAAGAAAC 3519 AGTGGGCGACTGCGAAAGAAA

LDLRex2(27 68 123 30) _76. _d3_r 3520 CGTTTCTTTCGCAGTCGCCCACTGA 3521 GTTTCTTTCGCAGTCGCCCACTG 3522 TTTCTTTCG CAGTCG CCCACT

LDLRex2(27 68 123 30) _77. _d3_f 3523 CAGTGGGCGACAGCGAAAGAAACGA 3524 AGTGGGCGACAGCGAAAGAAACG 3525 GTG GG CG ACAG CGAAAGAAAC

LDLRex2(27 68 123 30) _77. _d3_r 3526 TCGTTTCTTTCGCTGTCGCCCACTG 3527 CGTTTCTTTCGCTGTCGCCCACT 3528 GTTTCTTTCGCTGTCGCCCAC

LDLRex2(27 68 123 30) _78. _d3_f 3529 AGTGGGCGACAGCGAAAGAAACGAG 3530 GTGGGCGACAGCGAAAGAAACGA 3531 TGGGCGACAGCGAAAGAAACG

LDLRex2(27 68 123 30) _78. _d3_r 3532 CTCGTTTCTTTCGCTGTCGCCCACT 3533 TCGTTTCTTTCGCTGTCGCCCAC 3534 CGTTTCTTTCGCTGTCGCCCA

LDLRex2(27 68 123 30) _79. _d3_f 3535 GTGGGCGACAGAGAAAGAAACGAGT 3536 TGGGCGACAGAGAAAGAAACGAG 3537 GGGCGACAGAGAAAGAAACGA

LDLRex2(27 68 123 30) _79. _d3_r 3538 ACTCGTTTCTTTCTCTGTCG CCCAC 3539 CTCGTTTCTTTCTCTGTCG CCCA 3540 TCGTTTCTTTCTCTGTCGCCC

LDLRex2(27 68 123 30) _80. _d3_f 3541 TGGGCGACAGATAAAGAAACGAGTT 3542 GGGCGACAGATAAAGAAACGAGT 3543 GGCGACAGATAAAGAAACGAG

LDLRex2(27 68 123 30) _80. _d3_r 3544 AACTCGTTTCTTTATCTGTCG CCCA 3545 ACTCGTTTCTTTATCTGTCGCCC 3546 CTCGTTTCTTTATCTGTCG CC

LDLRex2(27 68 123 30) _81. _d3_f 3547 GGGCGACAGATGAAGAAACGAGTTC 3548 GGCGACAGATGAAGAAACGAGTT 3549 GCGACAGATGAAGAAACGAGT

LDLRex2(27 68 123 30) _81. _d3_r 3550 GAACTCGTTTCTTCATCTGTCGCCC 3551 AACTCGTTTCTTCATCTGTCGCC 3552 ACTCGTTTCTTCATCTGTCGC

LDLRex2(27 68 123 30) _82. _d3_f 3553 GGCGACAGATGCAGAAACGAGTTCC 3554 GCGACAGATGCAGAAACGAGTTC 3555 CGACAGATGCAGAAACGAGTT

LDLRex2(27 68 123 30) _82. _d3_r 3556 G G AACTCGTTTCTG CATCTGTCG CC 3557 GAACTCGTTTCTGCATCTGTCGC 3558 AACTCGTTTCTGCATCTGTCG

LDLRex2(27 68 123 30) _83. _d3_f 3559 GCGACAGATGCGGAAACGAGTTCCA 3560 CGACAGATGCGGAAACGAGTTCC 3561 GACAGATGCGGAAACGAGTTC

LDLRex2(27 68 123 30) _83. _d3_r 3562 TG G AACTCGTTTCCG CATCTGTCG C 3563 G G AACTCGTTTCCG CATCTGTCG 3564 GAACTCGTTTCCGCATCTGTC

LDLRex2(27 68 123 30) _84. _d3_f 3565 CGACAGATGCGAAAACGAGTTCCAG 3566 GACAGATGCGAAAACGAGTTCCA 3567 ACAGATGCGAAAACGAGTTCC

LDLRex2(27 68 123 30) _84. _d3_r 3568 CTG G AACTCGTTTTCG CATCTGTCG 3569 TG G AACTCGTTTTCG CATCTGTC 3570 GGAACTCGTTTTCGCATCTGT

LDLRex2(27 68 123 30) _85. _d3_f 3571 GACAGATGCGAAAACGAGTTCCAGT 3572 ACAGATGCGAAAACGAGTTCCAG 3573 CAGATGCGAAAACGAGTTCCA

LDLRex2(27 68 123 30) _85. _d3_r 3574 ACTGGAACTCGTTTTCGCATCTGTC 3575 CTG G AACTCGTTTTCG CATCTGT 3576 TGGAACTCGTTTTCGCATCTG

LDLRex2(27 68 123 30) _86. _d3_f 3577 ACAGATGCGAAAACGAGTTCCAGTG 3578 CAGATGCGAAAACGAGTTCCAGT 3579 AGATGCGAAAACGAGTTCCAG

LDLRex2(27;68;123 30) _86. _d3_r 3580 CACTGGAACTCGTTTTCGCATCTGT 3581 ACTGGAACTCGTTTTCGCATCTG 3582 CTGGAACTCGTTTTCGCATCT

Table 1

SEQ ID SEQ ID SEQ ID

del3 NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _87. _d3_f 3583 CAGATGCGAAAGCGAGTTCCAGTGC 3584 AGATGCGAAAGCGAGTTCCAGTG 3585 GATGCGAAAGCGAGTTCCAGT

LDLRex2(27 68 123 30) _87. _d3_r 3586 GCACTGGAACTCGCTTTCGCATCTG 3587 CACTGGAACTCGCTTTCGCATCT 3588 ACTG GAACTCG CTTTCG CATC

LDLRex2(27 68 123 30) _88. _d3_f 3589 AGATGCGAAAGAGAGTTCCAGTGCC 3590 GATGCGAAAGAGAGTTCCAGTGC 3591 ATGCGAAAGAGAGTTCCAGTG

LDLRex2(27 68 123 30) _88. _d3_r 3592 GGCACTGGAACTCTCTTTCGCATCT 3593 G CACTG G AACTCTCTTTCG CATC 3594 CACTGGAACTCTCTTTCGCAT

LDLRex2(27 68 123 30) _89. _d3_f 3595 GATGCGAAAGAAAGTTCCAGTGCCA 3596 ATGCGAAAGAAAGTTCCAGTGCC 3597 TGCGAAAGAAAGTTCCAGTGC

LDLRex2(27 68 123 30) _89. _d3_r 3598 TGGCACTG G AACTTTCTTTCG CATC 3599 GGCACTGGAACTTTCTTTCGCAT 3600 GCACTGGAACTTTCTTTCGCA

LDLRex2(27 68 123 30) _90. _d3_f 3601 ATG CG AAAG AAAGTTCCAGTG CCAA 3602 TG CG AAAG AAAGTTCCAGTG CCA 3603 GCGAAAGAAAGTTCCAGTGCC

LDLRex2(27 68 123 30) _90. _d3_r 3604 TTGG CACTG G AACTTTCTTTCG CAT 3605 TGGCACTG G AACTTTCTTTCG CA 3606 GG CACTG G AACTTTCTTTCG C

LDLRex2(27 68 123 30) _91. _d3_f 3607 TGCGAAAGAAACTTCCAGTGCCAAG 3608 GCGAAAGAAACTTCCAGTGCCAA 3609 CGAAAGAAACTTCCAGTGCCA

LDLRex2(27 68 123 30) _91. _d3_r 3610 CTTGGCACTGGAAGTTTCTTTCGCA 3611 TTGGCACTGGAAGTTTCTTTCGC 3612 TGG CACTG GAAGTTT CTTTCG

LDLRex2(27 68 123 30) _92. _d3_f 3613 GCGAAAGAAACGTCCAGTGCCAAGA 3614 CGAAAGAAACGTCCAGTGCCAAG 3615 GAAAGAAACGTCCAGTGCCAA

LDLRex2(27 68 123 30) _92. _d3_r 3616 TCTTGG CACTG G ACGTTTCTTTCG C 3617 CTTG G CACTG G ACGTTTCTTTCG 3618 TTGGCACTGGACGTTTCTTTC

LDLRex2(27 68 123 30) _93. _d3_f 3619 CGAAAGAAACGACCAGTGCCAAGAC 3620 GAAAGAAACGACCAGTGCCAAGA 3621 AAAGAAACGACCAGTGCCAAG

LDLRex2(27 68 123 30) _93. _d3_r 3622 GTCTTGGCACTGGTCGTTTCTTTCG 3623 TCTTGG CACTG GTCGTTTCTTTC 3624 CTTGG CACTG GTCGTTTCTTT

LDLRex2(27 68 123 30) _94. _d3_f 3625 GAAAGAAACGAGCAGTGCCAAGACG 3626 AAAGAAACGAGCAGTGCCAAGAC 3627 AAGAAACGAGCAGTGCCAAGA

LDLRex2(27 68 123 30) _94. _d3_r 3628 CGTCTTGGCACTGCTCGTTTCTTTC 3629 GTCTTGGCACTGCTCGTTTCTTT 3630 TCTTGGCACTGCTCGTTTCTT

LDLRex2(27 68 123 30) _95. _d3_f 3631 AAAGAAACGAGTAGTGCCAAGACGG 3632 AAGAAACGAGTAGTGCCAAGACG 3633 AGAAACGAGTAGTGCCAAGAC

LDLRex2(27 68 123 30) _95. _d3_r 3634 CCGTCTTGGCACTACTCGTTTCTTT 3635 CGTCTTGGCACTACTCGTTTCTT 3636 GTCTTGGCACTACTCGTTTCT

LDLRex2(27 68 123 30) _96. _d3_f 3637 AAGAAACGAGTTGTGCCAAGACGGG 3638 AGAAACGAGTTGTGCCAAGACGG 3639 GAAACGAGTTGTGCCAAGACG

LDLRex2(27 68 123 30) _96. _d3_r 3640 CCCGTCTTGGCACAACTCGTTTCTT 3641 CCGTCTTGGCACAACTCGTTTCT 3642 CGTCTTGGCACAACTCGTTTC

LDLRex2(27 68 123 30) _97. _d3_f 3643 AGAAACGAGTTCTGCCAAGACGGGA 3644 GAAACGAGTTCTGCCAAGACGGG 3645 AAACGAGTTCTGCCAAGACGG

LDLRex2(27 68 123 30) _97. _d3_r 3646 TCCCGTCTTGGCAGAACTCGTTTCT 3647 CCCGTCTTGGCAGAACTCGTTTC 3648 CCGTCTTGGCAGAACTCGTTT

LDLRex2(27 68 123 30) _98. _d3_f 3649 GAAACGAGTTCCGCCAAGACGGGAA 3650 AAACGAGTTCCGCCAAGACGGGA 3651 AACGAGTTCCGCCAAGACGGG

LDLRex2(27 68 123 30) _98. _d3_r 3652 TTCCCGTCTTG GCG G AACTCGTTTC 3653 TCCCGTCTTGGCGGAACTCGTTT 3654 CCCGTCTTG GCG G AACTCGTT

LDLRex2(27 68 123 30) _99. _d3_f 3655 AAACGAGTTCCACCAAGACGGGAAA 3656 AACGAGTTCCACCAAGACGGGAA 3657 ACGAGTTCCACCAAGACGGGA

LDLRex2(27;68;123 30) _99. _d3_r 3658 TTTCCCGTCTTGGTGGAACTCGTTT 3659 TTCCCGTCTTG GTG G AACTCGTT 3660 TCCCGTCTTG GTG G AACTCGT

Table 1

SEQ ID SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _100_ l_r 3661 CCCGTCTTGGCAACTGGAACTCGTT 3662 CCGTCTTGGCAACTGGAACTCGT 3663 CGTCTTGG CAACTG GAACTCG

LDLRex2(27 68 123 30) _101_ IJ 3664 ACGAGTTCCAGTGGCCAAGACGGGA 3665 CGAGTTCCAGTGGCCAAGACGGG 3666 GAGTTCCAGTGGCCAAGACGG

LDLRex2(27 68 123 30) _101_ l_r 3667 TCCCGTCTTGG CCACTG G AACTCGT 3668 CCCGTCTTGG CCACTG GAACTCG 3669 CCGTCTTGG CCACTG GAACTC

LDLRex2(27 68 123 30) _102_ IJ 3670 CGAGTTCCAGTGCCCAAGACGGGAA 3671 GAGTTCCAGTGCCCAAGACGGGA 3672 AGTTCCAGTGCCCAAGACGGG

LDLRex2(27 68 123 30) _102_ l_r 3673 TTCCCGTCTTGGGCACTGGAACTCG 3674 TCCCGTCTTGGGCACTGGAACTC 3675 CCCGTCTTGGGCACTGGAACT

LDLRex2(27 68 123 30) _103_ IJ 3676 GAGTTCCAGTGCCCAAGACGGGAAA 3677 AGTTCCAGTGCCCAAGACGGGAA 3678 GTTCCAGTGCCCAAGACGGGA

LDLRex2(27 68 123 30) _103_ l_r 3679 TTTCCCGTCTTGGGCACTGGAACTC 3680 TTCCCGTCTTGGGCACTGGAACT 3681 TCCCGTCTTGGGCACTGGAAC

LDLRex2(27 68 123 30) _104_ IJ 3682 AGTTCCAGTGCCAAAGACGGGAAAT 3683 GTTCCAGTGCCAAAGACGGGAAA 3684 TTCCAGTGCCAAAGACGGGAA

LDLRex2(27 68 123 30) _104_ l_r 3685 ATTTCCCGTCTTTG G CACTG G AACT 3686 TTTCCCGTCTTTGGCACTGGAAC 3687 TTCCCGTCTTTGGCACTGGAA

LDLRex2(27 68 123 30) _105_ IJ 3688 GTTCCAGTG CCAAAG ACGG G AAATG 3689 TTCCAGTGCCAAAGACGGGAAAT 3690 TCCAGTGCCAAAGACGGGAAA

LDLRex2(27 68 123 30) _105_ l_r 3691 CATTTCCCGTCTTTGGCACTGGAAC 3692 ATTTCCCGTCTTTGG CACTG G AA 3693 TTTCCCGTCTTTGGCACTGGA

LDLRex2(27 68 123 30) _106_ IJ 3694 TTCCAGTGCCAAG G ACGG G AAATG C 3695 TCCAGTGCCAAGGACGGGAAATG 3696 CCAGTGCCAAGGACGGGAAAT

LDLRex2(27 68 123 30) _106_ l_r 3697 G CATTTCCCGTCCTTGG CACTG G AA 3698 CATTTCCCGTCCTTGGCACTGGA 3699 ATTTCCCGTCCTTGG CACTG G

LDLRex2(27 68 123 30) _107_ IJ 3700 TCCAGTGCCAAGAACGGGAAATGCA 3701 CCAGTGCCAAGAACGGGAAATGC 3702 CAGTGCCAAGAACGGGAAATG

LDLRex2(27 68 123 30) _107_ l_r 3703 TGCATTTCCCGTTCTTGGCACTGGA 3704 GCATTTCCCGTTCTTGGCACTGG 3705 CATTTCCCGTTCTTGGCACTG

LDLRex2(27 68 123 30) _108_ IJ 3706 CCAGTGCCAAGACCGGGAAATGCAT 3707 CAGTGCCAAGACCGGGAAATGCA 3708 AGTGCCAAGACCGGGAAATGC

LDLRex2(27 68 123 30) _108_ l_r 3709 ATG CATTTCCCG GTCTTGG CACTGG 3710 TGCATTTCCCGGTCTTGGCACTG 3711 GCATTTCCCGGTCTTGGCACT

LDLRex2(27 68 123 30) _109_ IJ 3712 CAGTGCCAAGACGGGGAAATGCATC 3713 AGTGCCAAGACGGGGAAATGCAT 3714 GTGCCAAGACGGGGAAATGCA

LDLRex2(27 68 123 30) _109_ l_r 3715 GATGCATTTCCCCGTCTTGGCACTG 3716 ATG CATTTCCCCGTCTTG G CACT 3717 TGCATTTCCCCGTCTTGGCAC

LDLRex2(27 68 123 30) _110_ IJ 3718 AGTGCCAAGACGGGGAAATGCATCT 3719 GTGCCAAGACGGGGAAATGCATC 3720 TGCCAAGACGGGGAAATGCAT

LDLRex2(27 68 123 30) _110_ l_r 3721 AG ATG CATTTCCCCGTCTTG GCACT 3722 GATGCATTTCCCCGTCTTGGCAC 3723 ATG CATTTCCCCGTCTTGG CA

LDLRex2(27 68 123 30) _111_ IJ 3724 GTGCCAAGACGGGGAAATGCATCTC 3725 TGCCAAGACGGGGAAATGCATCT 3726 GCCAAGACGGGGAAATGCATC

LDLRex2(27 68 123 30) _111_ l_r 3727 GAGATGCATTTCCCCGTCTTGGCAC 3728 AG ATG CATTTCCCCGTCTTG G CA 3729 GATGCATTTCCCCGTCTTGGC

LDLRex2(27 68 123 30) _112_ IJ 3730 TG CCAAG ACGG G AAAATG CATCTCC 3731 GCCAAGACGGGAAAATGCATCTC 3732 CCAAGACGGGAAAATGCATCT

LDLRex2(27 68 123 30) _112_ l_r 3733 G GAG ATG CATTTTCCCGTCTTGG CA 3734 GAGATGCATTTTCCCGTCTTGGC 3735 AGATGCATTTTCCCGTCTTGG

LDLRex2(27 68 123 30) _113_ IJ 3736 GCCAAGACGGGAAAATGCATCTCCT 3737 CCAAGACGGGAAAATGCATCTCC 3738 CAAGACGGGAAAATGCATCTC

LDLRex2(27 68 123 30) _113_ l_r 3739 AGGAGATGCATTTTCCCGTCTTGGC 3740 GGAGATGCATTTTCCCGTCTTGG 3741 GAG ATG CATTTTCCCGTCTTG

LDLRex2(27 68 123 30) _114_ IJ 3742 CCAAGACGGGAAAATGCATCTCCTA 3743 CAAGACGGGAAAATGCATCTCCT 3744 AAGACGGGAAAATGCATCTCC

LDLRex2(27 68 123 30) _114_ l_r 3745 TAG G AG ATGCATTTTCCCGTCTTG G 3746 AGGAGATGCATTTTCCCGTCTTG 3747 GGAGATGCATTTTCCCGTCTT

LDLRex2(27 68 123 30) _115_ IJ 3748 CAAGACGGGAAATTGCATCTCCTAC 3749 AAG ACGG G AAATTG CATCTCCTA 3750 AGACGGGAAATTGCATCTCCT

LDLRex2(27;68;123 30) _115_ l_r 3751 GTAGGAGATGCAATTTCCCGTCTTG 3752 TAG GAG ATG CAATTTCCCGTCTT 3753 AG GAG ATG CAATTTCCCGTCT

Table 1

SEQ ID SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _116_ IJ 3754 AAGACGGGAAATGGCATCTCCTACA 3755 AGACGGGAAATGGCATCTCCTAC 3756 GACGGGAAATGGCATCTCCTA

LDLRex2(27 68 123 30) _116_ l_r 3757 TGTAG GAG ATG CCATTTCCCGTCTT 3758 GTAG GAG ATG CCATTTCCCGTCT 3759 TAGGAGATGCCATTTCCCGTC

LDLRex2(27 68 123 30) _117_ IJ 3760 AGACGGGAAATGCCATCTCCTACAA 3761 G ACGG G AAATG CCATCTCCTACA 3762 ACGGGAAATGCCATCTCCTAC

LDLRex2(27 68 123 30) _117_ l_r 3763 TTGTAG G AG ATG GCATTTCCCGTCT 3764 TGTAG G AG ATG GCATTTCCCGTC 3765 GTAG G AG ATG GCATTTCCCGT

LDLRex2(27 68 123 30) _118_ IJ 3766 G ACGG G AAATG CAATCTCCTACAAG 3767 ACGGGAAATGCAATCTCCTACAA 3768 CGG G AAATG CAATCTCCTACA

LDLRex2(27 68 123 30) _118_ l_r 3769 CTTGTAG G AG ATTG CATTTCCCGTC 3770 TTGTAGGAGATTGCATTTCCCGT 3771 TGTAGGAGATTGCATTTCCCG

LDLRex2(27 68 123 30) _119_ IJ 3772 ACGGGAAATGCATTCTCCTACAAGT 3773 CGG G AAATG CATTCTCCTACAAG 3774 G G G AAATG C ATTCTCCTAC A A

LDLRex2(27 68 123 30) _119_ l_r 3775 ACTTGTAGGAGAATGCATTTCCCGT 3776 CTTGTAGGAGAATGCATTTCCCG 3777 TTGTAGGAGAATGCATTTCCC

LDLRex2(27 68 123 30) _120_ IJ 3778 CGG G AAATG CATCCTCCTACAAGTG 3779 GG G AAATG CATCCTCCTACAAGT 3780 GGAAATGCATCCTCCTACAAG

LDLRex2(27 68 123 30) _120_ l_r 3781 CACTTGTAGGAGGATGCATTTCCCG 3782 ACTTGTAGGAGGATGCATTTCCC 3783 CTTGTAGGAGGATGCATTTCC

LDLRex2(27 68 123 30) _121_ IJ 3784 GGGAAATGCATCTTCCTACAAGTGG 3785 GGAAATGCATCTTCCTACAAGTG 3786 G AAATG CATCTTCCTACAAGT

LDLRex2(27 68 123 30) _121_ l_r 3787 CCACTTGTAGGAAGATGCATTTCCC 3788 CACTTGTAGGAAGATGCATTTCC 3789 ACTTGTAGGAAGATGCATTTC

LDLRex2(27 68 123 30) _122_ IJ 3790 GGAAATGCATCTCCCTACAAGTGGG 3791 GAAATGCATCTCCCTACAAGTGG 3792 AAATGCATCTCCCTACAAGTG

LDLRex2(27 68 123 30) _122_ l_r 3793 CCCACTTGTAGGGAGATGCATTTCC 3794 CCACTTGTAGG G AG ATG CATTTC 3795 C ACTTGTAG G G AG ATG CATTT

LDLRex2(27 68 123 30) _123_ IJ 3796 G AAATG CATCTCCCTACAAGTGG GT 3797 AAATGCATCTCCCTACAAGTGGG 3798 AATGCATCTCCCTACAAGTGG

LDLRex2(27 68 123 30) _123_ l_r 3799 ACCCACTTGTAGGGAGATGCATTTC 3800 CCCACTTGTAGG G AG ATG CATTT 3801 CCACTTGTAGGGAGATGCATT

LDLRex2(27 68 123 30) _124_ IJ 3802 AAATGCATCTCCTTACAAGTGGGTC 3803 AATG CATCTCCTTACAAGTGG GT 3804 ATGCATCTCCTTACAAGTGGG

LDLRex2(27 68 123 30) _124_ l_r 3805 G ACCCACTTGTAAG GAG ATG CATTT 3806 ACCCACTTGTAAGGAGATGCATT 3807 CCCACTTGTAAG GAG ATG CAT

LDLRex2(27 68 123 30) _125_ IJ 3808 AATGCATCTCCTAACAAGTGGGTCT 3809 ATGCATCTCCTAACAAGTGGGTC 3810 TG CATCTCCTAACAAGTG GGT

LDLRex2(27 68 123 30) _125_ l_r 3811 AG ACCCACTTGTTAG GAG ATG CATT 3812 GACCCACTTGTTAGGAGATGCAT 3813 ACCCACTTGTTAG GAG ATG CA

LDLRex2(27 68 123 30) _126_ IJ 3814 ATG CATCTCCTACCAAGTGG GTCTG 3815 TGCATCTCCTACCAAGTGGGTCT 3816 GCATCTCCTACCAAGTGGGTC

LDLRex2(27 68 123 30) _126_ l_r 3817 CAGACCCACTTGGTAGGAGATGCAT 3818 AGACCCACTTGGTAGGAGATGCA 3819 G ACCCACTTG GTAG GAG ATG C

LDLRex2(27 68 123 30) _127_ IJ 3820 TGCATCTCCTACAAAGTGGGTCTGC 3821 GCATCTCCTACAAAGTGGGTCTG 3822 CATCTCCTACAAAGTG G GTCT

LDLRex2(27 68 123 30) _127_ l_r 3823 GCAGACCCACTTTGTAGGAGATGCA 3824 CAG ACCCACTTTGTAG GAG ATG C 3825 AGACCCACTTTGTAGGAGATG

LDLRex2(27 68 123 30) _128_ IJ 3826 GCATCTCCTACAAAGTGGGTCTGCG 3827 CATCTCCTACAAAGTG GGTCTG C 3828 ATCTCCTACAAAGTGGGTCTG

LDLRex2(27 68 123 30) _128_ l_r 3829 CGCAGACCCACTTTGTAGGAGATGC 3830 GCAGACCCACTTTGTAGGAGATG 3831 CAGACCCACTTTGTAGGAGAT

LDLRex2(27 68 123 30) _129_ IJ 3832 CATCTCCTACAAGGTGGGTCTGCGA 3833 ATCTCCTACAAG GTG GGTCTG CG 3834 TCTCCTACAAGGTGGGTCTGC

LDLRex2(27 68 123 30) _129_ l_r 3835 TCGCAGACCCACCTTGTAGGAGATG 3836 CGCAGACCCACCTTGTAGGAGAT 3837 GCAGACCCACCTTGTAGGAGA

LDLRex2(27 68 123 30) _130_ IJ 3838 ATCTCCTACAAGTTGGGTCTGCGAT 3839 TCTCCTACAAGTTG GGTCTG CG A 3840 CTCCTACAAGTTG GGTCTG CG

LDLRex2(27 68 123 30) _130_ l_r 3841 ATCGCAGACCCAACTTGTAGGAGAT 3842 TCGCAGACCCAACTTGTAGGAGA 3843 CGCAGACCCAACTTGTAGGAG

LDLRex2(27;68;123 30) _131_ IJ 3844 TCTCCTACAAGTGG G GTCTG CG ATG 3845 CTCCTACAAGTG GG GTCTG CG AT 3846 TCCTACAAGTGGGGTCTGCGA

Table 1

SEQ ID SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _131_ l_r 3847 CATCG CAG ACCCCACTTGTAG GAGA 3848 ATCGCAGACCCCACTTGTAGGAG 3849 TCGCAGACCCCACTTGTAGGA

LDLRex2(27 68 123 30) _132_ IJ 3850 CTCCTACAAGTG GG GTCTG CG ATG G 3851 TCCTACAAGTGGGGTCTGCGATG 3852 CCTACAAGTGGGGTCTGCGAT

LDLRex2(27 68 123 30) _132_ l_r 3853 CCATCGCAGACCCCACTTGTAGGAG 3854 CATCG CAG ACCCCACTTGTAG G A 3855 ATCGCAGACCCCACTTGTAGG

LDLRex2(27 68 123 30) _133_ IJ 3856 TCCTACAAGTG GG GTCTG CG ATG GC 3857 CCTACAAGTG GG GTCTGCG ATG G 3858 CTACAAGTGGGGTCTGCGATG

LDLRex2(27 68 123 30) _133_ l_r 3859 GCCATCGCAGACCCCACTTGTAGGA 3860 CCATCG CAG ACCCCACTTGTAG G 3861 CATCGCAGACCCCACTTGTAG

LDLRex2(27 68 123 30) _134_ IJ 3862 CCTACAAGTGGGTTCTGCGATGGCA 3863 CTACAAGTG GGTTCTG CG ATGG C 3864 TACAAGTG GGTTCTG CG ATG G

LDLRex2(27 68 123 30) _134_ l_r 3865 TGCCATCGCAGAACCCACTTGTAGG 3866 GCCATCGCAGAACCCACTTGTAG 3867 CCATCGCAGAACCCACTTGTA

LDLRex2(27 68 123 30) _135_ IJ 3868 CTACAAGTGGGTCCTGCGATGGCAG 3869 TACAAGTGGGTCCTGCGATGGCA 3870 ACAAGTGGGTCCTGCGATGGC

LDLRex2(27 68 123 30) _135_ l_r 3871 CTGCCATCGCAGGACCCACTTGTAG 3872 TGCCATCGCAGGACCCACTTGTA 3873 GCCATCGCAGGACCCACTTGT

LDLRex2(27 68 123 30) _136_ IJ 3874 TACAAGTGGGTCTTGCGATGGCAGC 3875 AC A AGTG G GTCTTG CGATGGCAG 3876 CAAGTGGGTCTTGCGATGGCA

LDLRex2(27 68 123 30) _136_ l_r 3877 G CTG CCATCG CAAG ACCCACTTGTA 3878 CTGCCATCGCAAGACCCACTTGT 3879 TGCCATCGCAAGACCCACTTG

LDLRex2(27 68 123 30) _137_ IJ 3880 ACAAGTGGGTCTGGCGATGGCAGCG 3881 CAAGTGGGTCTGGCGATGGCAGC 3882 AAGTGGGTCTGGCGATGGCAG

LDLRex2(27 68 123 30) _137_ l_r 3883 CGCTGCCATCGCCAGACCCACTTGT 3884 GCTGCCATCGCCAGACCCACTTG 3885 CTGCCATCGCCAGACCCACTT

LDLRex2(27 68 123 30) _138_ IJ 3886 CAAGTGGGTCTGCCGATGGCAGCGC 3887 AAGTGG GTCTG CCG ATGG CAG CG 3888 AGTGGGTCTGCCGATGGCAGC

LDLRex2(27 68 123 30) _138_ l_r 3889 GCGCTGCCATCGGCAGACCCACTTG 3890 CGCTGCCATCGGCAGACCCACTT 3891 GCTGCCATCGGCAGACCCACT

LDLRex2(27 68 123 30) _139_ IJ 3892 AAGTGGGTCTGCGGATGGCAGCGCT 3893 AGTGGGTCTGCGGATGGCAGCGC 3894 GTGGGTCTGCGGATGGCAGCG

LDLRex2(27 68 123 30) _139_ l_r 3895 AGCGCTGCCATCCGCAGACCCACTT 3896 GCGCTGCCATCCGCAGACCCACT 3897 CGCTGCCATCCGCAGACCCAC

LDLRex2(27 68 123 30) _140_ IJ 3898 AGTGGGTCTGCGAATGGCAGCGCTG 3899 GTGGGTCTGCGAATGGCAGCGCT 3900 TGGGTCTGCGAATGGCAGCGC

LDLRex2(27 68 123 30) _140_ l_r 3901 CAGCGCTGCCATTCGCAGACCCACT 3902 AG CGCTG CCATTCG CAG ACCCAC 3903 GCGCTGCCATTCGCAGACCCA

LDLRex2(27 68 123 30) _141_ IJ 3904 GTGGGTCTGCGATTGGCAGCGCTGA 3905 TGGGTCTGCGATTGGCAGCGCTG 3906 GGGTCTGCGATTGGCAGCGCT

LDLRex2(27 68 123 30) _141_ l_r 3907 TCAGCGCTGCCAATCGCAGACCCAC 3908 CAGCGCTGCCAATCGCAGACCCA 3909 AGCGCTGCCAATCGCAGACCC

LDLRex2(27 68 123 30) _142_ IJ 3910 TG G GTCTG CG ATG GG CAG CG CTG AG 3911 GGGTCTGCGATGGGCAGCGCTGA 3912 GGTCTGCGATGGGCAGCGCTG

LDLRex2(27 68 123 30) _142_ l_r 3913 CTCAGCGCTGCCCATCGCAGACCCA 3914 TCAG CGCTG CCCATCG CAG ACCC 3915 CAG CG CTG CCCATCG CAG ACC

LDLRex2(27 68 123 30) _143_ IJ 3916 GGGTCTGCGATGGGCAGCGCTGAGT 3917 GGTCTGCGATGGGCAGCGCTGAG 3918 GTCTGCGATGGGCAGCGCTGA

LDLRex2(27 68 123 30) _143_ l_r 3919 ACTCAG CGCTG CCCATCG CAG ACCC 3920 CTCAG CG CTG CCCATCGCAG ACC 3921 TCAG CGCTG CCCATCG CAG AC

LDLRex2(27 68 123 30) _144_ IJ 3922 GGTCTGCGATGGCCAGCGCTGAGTG 3923 GTCTGCGATGGCCAGCGCTGAGT 3924 TCTGCGATGGCCAGCGCTGAG

LDLRex2(27 68 123 30) _144_ l_r 3925 CACTCAGCGCTGGCCATCGCAGACC 3926 ACTCAGCGCTGGCCATCGCAGAC 3927 CTCAGCGCTGGCCATCGCAGA

LDLRex2(27 68 123 30) _145_ IJ 3928 GTCTGCGATGGCAAGCGCTGAGTGC 3929 TCTGCGATGGCAAGCGCTGAGTG 3930 CTGCGATGGCAAGCGCTGAGT

LDLRex2(27 68 123 30) _145_ l_r 3931 GCACTCAGCGCTTGCCATCGCAGAC 3932 CACTCAGCGCTTGCCATCGCAGA 3933 ACTCAGCGCTTGCCATCGCAG

LDLRex2(27 68 123 30) _146_ IJ 3934 TCTGCGATGGCAGGCGCTGAGTGCC 3935 CTGCGATGGCAGGCGCTGAGTGC 3936 TGCGATGGCAGGCGCTGAGTG

LDLRex2(27;68 123 30) _146_ l_r 3937 GGCACTCAGCGCCTGCCATCGCAGA 3938 GCACTCAGCGCCTGCCATCGCAG 3939 CACTCAG CGCCTG CCATCG CA

Table 1

SEQ ID SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _147_ IJ 3940 CTGCGATGGCAGCCGCTGAGTGCCA 3941 TGCGATGGCAGCCGCTGAGTGCC 3942 GCGATGGCAGCCGCTGAGTGC

LDLRex2(27 68 123 30) _147_ l_r 3943 TGGCACTCAGCGGCTGCCATCGCAG 3944 GGCACTCAGCGGCTGCCATCGCA 3945 GCACTCAGCGGCTGCCATCGC

LDLRex2(27 68 123 30) _148_ IJ 3946 TGCGATGGCAGCGGCTGAGTGCCAG 3947 GCGATGGCAGCGGCTGAGTGCCA 3948 CGATGGCAGCGGCTGAGTGCC

LDLRex2(27 68 123 30) _148_ l_r 3949 CTGGCACTCAGCCGCTGCCATCGCA 3950 TG GCACTCAG CCG CTG CCATCG C 3951 GG CACTCAG CCG CTGCCATCG

LDLRex2(27 68 123 30) _149_ IJ 3952 GCGATGGCAGCGCCTGAGTGCCAGG 3953 CGATGGCAGCGCCTGAGTGCCAG 3954 GATGGCAGCGCCTGAGTGCCA

LDLRex2(27 68 123 30) _149_ l_r 3955 CCTGGCACTCAGGCGCTGCCATCGC 3956 CTGGCACTCAGGCGCTGCCATCG 3957 TGGCACTCAGGCGCTGCCATC

LDLRex2(27 68 123 30) _150_ IJ 3958 CGATGGCAGCGCTTGAGTGCCAGGA 3959 GATGGCAGCGCTTGAGTGCCAGG 3960 ATGGCAGCGCTTGAGTGCCAG

LDLRex2(27 68 123 30) _150_ l_r 3961 TCCTGG CACTCAAG CGCTG CCATCG 3962 CCTGG CACTCAAG CGCTG CCATC 3963 CTGGCACTCAAGCGCTGCCAT

LDLRex2(27 68 123 30) _151_ IJ 3964 GATGGCAGCGCTGGAGTGCCAGGAT 3965 ATG G CAG CG CTG GAGTG CCAG G A 3966 TGGCAGCGCTGGAGTGCCAGG

LDLRex2(27 68 123 30) _151_ l_r 3967 ATCCTG GCACTCCAG CGCTG CCATC 3968 TCCTGGCACTCCAGCGCTGCCAT 3969 CCTGGCACTCCAGCGCTGCCA

LDLRex2(27 68 123 30) _152_ IJ 3970 ATG GCAGCG CTG AAGTG CCAG G ATG 3971 TGGCAGCGCTGAAGTGCCAGGAT 3972 GGCAGCGCTGAAGTGCCAGGA

LDLRex2(27 68 123 30) _152_ l_r 3973 CATCCTG GCACTTCAG CGCTG CCAT 3974 ATCCTGGCACTTCAGCGCTGCCA 3975 TCCTGG CACTTCAG CGCTG CC

LDLRex2(27 68 123 30) _153_ IJ 3976 TGGCAGCGCTGAGGTGCCAGGATGG 3977 GGCAGCGCTGAGGTGCCAGGATG 3978 GCAGCGCTGAGGTGCCAGGAT

LDLRex2(27 68 123 30) _153_ l_r 3979 CCATCCTG GCACCTCAGCG CTG CCA 3980 CATCCTG GCACCTCAG CGCTG CC 3981 ATCCTG G CACCTCAG CGCTG C

LDLRex2(27 68 123 30) _154_ IJ 3982 GGCAGCGCTGAGTTGCCAGGATGGC 3983 GCAGCGCTGAGTTGCCAGGATGG 3984 CAGCGCTGAGTTGCCAGGATG

LDLRex2(27 68 123 30) _154_ l_r 3985 G CCATCCTG G CAACTCAG CGCTG CC 3986 CCATCCTGGCAACTCAGCGCTGC 3987 CATCCTG GCAACTCAG CG CTG

LDLRex2(27 68 123 30) _155_ IJ 3988 GCAGCGCTGAGTGGCCAGGATGGCT 3989 CAGCGCTGAGTGGCCAGGATGGC 3990 AGCGCTGAGTGGCCAGGATGG

LDLRex2(27 68 123 30) _155_ l_r 3991 AGCCATCCTGGCCACTCAGCGCTGC 3992 GCCATCCTGGCCACTCAGCGCTG 3993 CCATCCTGGCCACTCAGCGCT

LDLRex2(27 68 123 30) _156_ IJ 3994 CAGCGCTGAGTGCCCAGGATGGCTC 3995 AGCGCTGAGTGCCCAGGATGGCT 3996 GCGCTGAGTGCCCAGGATGGC

LDLRex2(27 68 123 30) _156_ l_r 3997 GAG CCATCCTG G GCACTCAG CG CTG 3998 AG CCATCCTG GG CACTCAGCG CT 3999 GCCATCCTGGGCACTCAGCGC

LDLRex2(27 68 123 30) _157_ IJ 4000 AGCGCTGAGTGCCCAGGATGGCTCT 4001 G CGCTG AGTG CCCAG GATGGCTC 4002 CGCTGAGTGCCCAGGATGGCT

LDLRex2(27 68 123 30) _157_ l_r 4003 AGAGCCATCCTGGGCACTCAGCGCT 4004 GAGCCATCCTGGGCACTCAGCGC 4005 AG CCATCCTG GG CACTCAGCG

LDLRex2(27 68 123 30) _158_ IJ 4006 GCGCTGAGTGCCAAGGATGGCTCTG 4007 CGCTGAGTGCCAAGGATGGCTCT 4008 GCTGAGTGCCAAGGATGGCTC

LDLRex2(27 68 123 30) _158_ l_r 4009 CAGAGCCATCCTTGGCACTCAGCGC 4010 AG AG CCATCCTTG GCACTCAG CG 4011 GAGCCATCCTTGGCACTCAGC

LDLRex2(27 68 123 30) _159_ IJ 4012 CGCTGAGTGCCAGGGATGGCTCTGA 4013 GCTGAGTGCCAGGGATGGCTCTG 4014 CTGAGTGCCAGGGATGGCTCT

LDLRex2(27 68 123 30) _159_ l_r 4015 TCAGAGCCATCCCTGGCACTCAGCG 4016 CAG AG CCATCCCTGG CACTCAG C 4017 AGAGCCATCCCTGGCACTCAG

LDLRex2(27 68 123 30) _160_ IJ 4018 GCTGAGTGCCAGGGATGGCTCTGAT 4019 CTGAGTGCCAGGGATGGCTCTGA 4020 TGAGTGCCAGGGATGGCTCTG

LDLRex2(27 68 123 30) _160_ l_r 4021 ATCAG AG CCATCCCTG G CACTCAGC 4022 TCAGAGCCATCCCTGGCACTCAG 4023 CAG AG CCATCCCTG GCACTCA

LDLRex2(27 68 123 30) _161_ IJ 4024 CTGAGTGCCAGGAATGGCTCTGATG 4025 TG AGTG CCAG GAATGG CTCTG AT 4026 GAGTGCCAGGAATGGCTCTGA

LDLRex2(27 68 123 30) _161_ l_r 4027 CATCAGAGCCATTCCTGGCACTCAG 4028 ATCAGAGCCATTCCTGGCACTCA 4029 TCAGAGCCATTCCTGGCACTC

LDLRex2(27;68 123 30) _162_ IJ 4030 TGAGTGCCAGG ATTG G CTCTG ATG A 4031 GAGTGCCAGGATTGGCTCTGATG 4032 AGTGCCAGGATTGGCTCTGAT

Table 1

SEQ ID SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _162_ l_r 4033 TCATCAG AG CCAATCCTGG CACTCA 4034 CATCAGAGCCAATCCTGGCACTC 4035 ATCAGAGCCAATCCTGGCACT

LDLRex2(27 68 123 30) _163_ IJ 4036 G AGTG CCAG G ATG GG CTCTG ATG AG 4037 AGTG CCAG G ATGG GCTCTG ATG A 4038 GTGCCAGGATGGGCTCTGATG

LDLRex2(27 68 123 30) _163_ l_r 4039 CTCATCAG AG CCCATCCTGG CACTC 4040 TCATCAGAGCCCATCCTGGCACT 4041 CATCAGAGCCCATCCTGGCAC

LDLRex2(27 68 123 30) _164_ IJ 4042 AGTGCCAGGATGGGCTCTGATGAGT 4043 GTGCCAGGATGGGCTCTGATGAG 4044 TG CCAG G ATGG GCTCTG ATG A

LDLRex2(27 68 123 30) _164_ l_r 4045 ACTCATCAGAGCCCATCCTGGCACT 4046 CTCATCAGAGCCCATCCTGGCAC 4047 TCATCAGAGCCCATCCTGGCA

LDLRex2(27 68 123 30) _165_ IJ 4048 GTGCCAGGATGGCCTCTGATGAGTC 4049 TGCCAGGATGGCCTCTGATGAGT 4050 GCCAGGATGGCCTCTGATGAG

LDLRex2(27 68 123 30) _165_ l_r 4051 GACTCATCAGAGGCCATCCTGGCAC 4052 ACTCATCAGAGGCCATCCTGGCA 4053 CTCATCAGAGGCCATCCTGGC

LDLRex2(27 68 123 30) _166_ IJ 4054 TGCCAGGATGGCTTCTGATGAGTCC 4055 GCCAGGATGGCTTCTGATGAGTC 4056 CCAGGATGGCTTCTGATGAGT

LDLRex2(27 68 123 30) _166_ l_r 4057 GGACTCATCAGAAGCCATCCTGGCA 4058 GACTCATCAGAAGCCATCCTGGC 4059 ACTCATCAG AAG CCATCCTG G

LDLRex2(27 68 123 30) _167_ IJ 4060 G CCAG G ATG GCTCCTG ATG AGTCCC 4061 CCAGGATGGCTCCTGATGAGTCC 4062 CAGGATGGCTCCTGATGAGTC

LDLRex2(27 68 123 30) _167_ l_r 4063 GGGACTCATCAGGAGCCATCCTGGC 4064 GGACTCATCAGGAGCCATCCTGG 4065 GACTCATCAGGAGCCATCCTG

LDLRex2(27 68 123 30) _168_ IJ 4066 CCAGGATGGCTCTTGATGAGTCCCA 4067 CAGGATGGCTCTTGATGAGTCCC 4068 AG G ATG GCTCTTG ATG AGTCC

LDLRex2(27 68 123 30) _168_ l_r 4069 TGGGACTCATCAAGAGCCATCCTGG 4070 GGGACTCATCAAGAGCCATCCTG 4071 GGACTCATCAAGAGCCATCCT

LDLRex2(27 68 123 30) _169_ IJ 4072 CAGGATGGCTCTGGATGAGTCCCAG 4073 AG G ATG GCTCTG G ATG AGTCCCA 4074 GGATGGCTCTGGATGAGTCCC

LDLRex2(27 68 123 30) _169_ l_r 4075 CTG G G ACTCATCCAG AGCCATCCTG 4076 TGGGACTCATCCAGAGCCATCCT 4077 GGGACTCATCCAGAGCCATCC

LDLRex2(27 68 123 30) _170_ IJ 4078 AGGATGGCTCTGAATGAGTCCCAGG 4079 GGATGGCTCTGAATGAGTCCCAG 4080 GATGGCTCTGAATGAGTCCCA

LDLRex2(27 68 123 30) _170_ l_r 4081 CCTGGGACTCATTCAGAGCCATCCT 4082 CTGGGACTCATTCAGAGCCATCC 4083 TGGGACTCATTCAGAGCCATC

LDLRex2(27 68 123 30) _171_ IJ 4084 GGATGGCTCTGATTGAGTCCCAGGA 4085 GATGGCTCTGATTGAGTCCCAGG 4086 ATGGCTCTGATTGAGTCCCAG

LDLRex2(27 68 123 30) _171_ l_r 4087 TCCTGGGACTCAATCAGAGCCATCC 4088 CCTGGGACTCAATCAGAGCCATC 4089 CTGGGACTCAATCAGAGCCAT

LDLRex2(27 68 123 30) _172_ IJ 4090 GATGGCTCTGATGGAGTCCCAGGAG 4091 ATGGCTCTGATGGAGTCCCAGGA 4092 TGGCTCTGATGGAGTCCCAGG

LDLRex2(27 68 123 30) _172_ l_r 4093 CTCCTGGGACTCCATCAGAGCCATC 4094 TCCTGG G ACTCCATCAG AG CCAT 4095 CCTGGGACTCCATCAGAGCCA

LDLRex2(27 68 123 30) _173_ IJ 4096 ATGGCTCTGATGAAGTCCCAGGAGA 4097 TGGCTCTGATGAAGTCCCAGGAG 4098 GGCTCTGATGAAGTCCCAGGA

LDLRex2(27 68 123 30) _173_ l_r 4099 TCTCCTGGGACTTCATCAGAGCCAT 4100 CTCCTGGGACTTCATCAGAGCCA 4101 TCCTGGGACTTCATCAGAGCC

LDLRex2(27 68 123 30) _174_ IJ 4102 TGGCTCTGATGAGGTCCCAGGAGAC 4103 GGCTCTGATGAGGTCCCAGGAGA 4104 GCTCTGATGAGGTCCCAGGAG

LDLRex2(27 68 123 30) _174_ l_r 4105 GTCTCCTGGGACCTCATCAGAGCCA 4106 TCTCCTGGGACCTCATCAGAGCC 4107 CTCCTGGGACCTCATCAGAGC

LDLRex2(27 68 123 30) _175_ IJ 4108 GGCTCTGATGAGTTCCCAGGAGACG 4109 GCTCTGATGAGTTCCCAGGAGAC 4110 CTCTGATGAGTTCCCAGGAGA

LDLRex2(27 68 123 30) _175_ l_r 4111 CGTCTCCTGGGAACTCATCAGAGCC 4112 GTCTCCTGGGAACTCATCAGAGC 4113 TCTCCTGGGAACTCATCAGAG

LDLRex2(27 68 123 30) _176_ IJ 4114 G CTCTG ATG AGTCCCCAG G AG ACGT 4115 CTCTGATGAGTCCCCAGGAGACG 4116 TCTGATGAGTCCCCAGGAGAC

LDLRex2(27 68 123 30) _176_ l_r 4117 ACGTCTCCTGGGGACTCATCAGAGC 4118 CGTCTCCTGGGGACTCATCAGAG 4119 GTCTCCTGGGGACTCATCAGA

LDLRex2(27 68 123 30) _177_ IJ 4120 CTCTGATGAGTCCCCAGGAGACGTG 4121 TCTGATGAGTCCCCAGGAGACGT 4122 CTGATGAGTCCCCAGGAGACG

LDLRex2(27;68 123 30) _177_ l_r 4123 CACGTCTCCTGGGGACTCATCAGAG 4124 ACGTCTCCTGGGGACTCATCAGA 4125 CGTCTCCTG GG G ACTCATCAG

Table 1

SEQ ID SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _178_ IJ 4126 TCTGATGAGTCCCCAGGAGACGTGC 4127 CTGATGAGTCCCCAGGAGACGTG 4128 TGATGAGTCCCCAGGAGACGT

LDLRex2(27 68 123 30) _178_ l_r 4129 GCACGTCTCCTGGGGACTCATCAGA 4130 CACGTCTCCTG GG GACTCATCAG 4131 ACGTCTCCTG GG G ACTCATCA

LDLRex2(27 68 123 30) _179_ IJ 4132 CTGATGAGTCCCAAGGAGACGTGCT 4133 TGATGAGTCCCAAGGAGACGTGC 4134 GATGAGTCCCAAGGAGACGTG

LDLRex2(27 68 123 30) _179_ l_r 4135 AGCACGTCTCCTTGGGACTCATCAG 4136 GCACGTCTCCTTGGGACTCATCA 4137 CACGTCTCCTTGGGACTCATC

LDLRex2(27 68 123 30) _180_ IJ 4138 TGATGAGTCCCAGGGAGACGTGCTG 4139 GATGAGTCCCAGGGAGACGTGCT 4140 ATGAGTCCCAGGGAGACGTGC

LDLRex2(27 68 123 30) _180_ l_r 4141 CAG CACGTCTCCCTGG G ACTCATCA 4142 AGCACGTCTCCCTGGGACTCATC 4143 GCACGTCTCCCTGGGACTCAT

LDLRex2(27 68 123 30) _181_ IJ 4144 GATGAGTCCCAGGGAGACGTGCTGT 4145 ATGAGTCCCAGGGAGACGTGCTG 4146 TGAGTCCCAGGGAGACGTGCT

LDLRex2(27 68 123 30) _181_ l_r 4147 ACAGCACGTCTCCCTGGGACTCATC 4148 CAG CACGTCTCCCTGG G ACTCAT 4149 AGCACGTCTCCCTGGGACTCA

LDLRex2(27 68 123 30) _182_ IJ 4150 ATG AGTCCCAG G AAG ACGTG CTGTG 4151 TGAGTCCCAGGAAGACGTGCTGT 4152 GAGTCCCAGGAAGACGTGCTG

LDLRex2(27 68 123 30) _182_ l_r 4153 CACAGCACGTCTTCCTGGGACTCAT 4154 ACAGCACGTCTTCCTGGGACTCA 4155 CAGCACGTCTTCCTGGGACTC

LDLRex2(27 68 123 30) _183_ IJ 4156 TGAGTCCCAGGAGGACGTGCTGTGA 4157 GAGTCCCAGGAGGACGTGCTGTG 4158 AGTCCCAGGAGGACGTGCTGT

LDLRex2(27 68 123 30) _183_ l_r 4159 TCACAGCACGTCCTCCTGGGACTCA 4160 CACAGCACGTCCTCCTGGGACTC 4161 ACAGCACGTCCTCCTGGGACT

LDLRex2(27 68 123 30) _184_ IJ 4162 GAGTCCCAGGAGAACGTGCTGTGAG 4163 AGTCCCAG G AG AACGTG CTGTG A 4164 GTCCCAGGAGAACGTGCTGTG

LDLRex2(27 68 123 30) _184_ l_r 4165 CTCACAGCACGTTCTCCTGGGACTC 4166 TCACAGCACGTTCTCCTGGGACT 4167 CACAGCACGTTCTCCTGGGAC

LDLRex2(27 68 123 30) _185_ IJ 4168 AGTCCCAGGAGACCGTGCTGTGAGT 4169 GTCCCAGGAGACCGTGCTGTGAG 4170 TCCCAG G AG ACCGTG CTGTG A

LDLRex2(27 68 123 30) _185_ l_r 4171 ACTCACAGCACGGTCTCCTGGGACT 4172 CTCACAGCACGGTCTCCTGGGAC 4173 TCACAGCACGGTCTCCTGGGA

LDLRex2(27 68 123 30) _186_ IJ 4174 GTCCCAGGAGACGGTGCTGTGAGTC 4175 TCCCAGGAGACGGTGCTGTGAGT 4176 CCCAGGAGACGGTGCTGTGAG

LDLRex2(27 68 123 30) _186_ l_r 4177 GACTCACAGCACCGTCTCCTGGGAC 4178 ACTCACAG CACCGTCTCCTGG G A 4179 CTCACAGCACCGTCTCCTGGG

LDLRex2(27 68 123 30) _187_ IJ 4180 TCCCAGGAGACGTTGCTGTGAGTCC 4181 CCCAGGAGACGTTGCTGTGAGTC 4182 CCAGGAGACGTTGCTGTGAGT

LDLRex2(27 68 123 30) _187_ l_r 4183 GGACTCACAGCAACGTCTCCTGGGA 4184 GACTCACAGCAACGTCTCCTGGG 4185 ACTCACAG CAACGTCTCCTG G

LDLRex2(27 68 123 30) _188_ IJ 4186 CCCAGGAGACGTGGCTGTGAGTCCC 4187 CCAGGAGACGTGGCTGTGAGTCC 4188 CAGGAGACGTGGCTGTGAGTC

LDLRex2(27 68 123 30) _188_ l_r 4189 GGGACTCACAGCCACGTCTCCTGGG 4190 GGACTCACAGCCACGTCTCCTGG 4191 GACTCACAGCCACGTCTCCTG

LDLRex2(27 68 123 30) _189_ IJ 4192 CCAGGAGACGTGCCTGTGAGTCCCC 4193 CAGGAGACGTGCCTGTGAGTCCC 4194 AG GAG ACGTG CCTGTG AGTCC

LDLRex2(27 68 123 30) _189_ l_r 4195 G GG G ACTCACAGG CACGTCTCCTG G 4196 G G G ACTCACAGG CACGTCTCCTG 4197 GGACTCACAGGCACGTCTCCT

LDLRex2(27 68 123 30) _190 + l_il_f 4198 AGGAGACGTGCTGGTGAGTCCCCTT 4199 GGAGACGTGCTGGTGAGTCCCCT 4200 GAGACGTGCTGGTGAGTCCCC

LDLRex2(27 68 123 30) _190 + l_il_r 4201 AAG GG G ACTCACCAG CACGTCTCCT 4202 AGGGGACTCACCAGCACGTCTCC 4203 GGGGACTCACCAGCACGTCTC

LDLRex2(27 68 123 30) _190 + 10_ il_ f 4204 GCTGTGAGTCCCCCTTTGGGCATGA 4205 CTGTGAGTCCCCCTTTGGGCATG 4206 TGTGAGTCCCCCTTTGGGCAT

LDLRex2(27 68 123 30) _190 + 10_ il_ r 4207 TCATGCCCAAAGGGGGACTCACAGC 4208 CATGCCCAAAGGGGGACTCACAG 4209 ATGCCCAAAGGGGGACTCACA

LDLRex2(27 68 123 30) _190 + 11_ il_ f 4210 CTGTGAGTCCCCTTTTGGGCATGAT 4211 TGTGAGTCCCCTTTTGGGCATGA 4212 GTGAGTCCCCTTTTGGGCATG

LDLRex2(27 68 123 30) _190 + 11_ il_ r 4213 ATCATGCCCAAAAGGGGACTCACAG 4214 TCATGCCCAAAAGGGGACTCACA 4215 CATGCCCAAAAGGGGACTCAC

LDLRex2(27;68;123;30) _190 + 12_ il_ f 4216 TGTGAGTCCCCTTTTGGGCATGATA 4217 GTGAGTCCCCTTTTGGGCATGAT 4218 TGAGTCCCCTTTTGGGCATGA

Table 1

SEQ I SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

190 + 12_il_ r 4219 TATCATGCCCAAAAGGGGACTCACA 4220 ATCATGCCCAAAAGGGGACTCAC 4221 TCATGCCCAAAAGGGGACTCA

190 + 13_il_ f 4222 GTGAGTCCCCTTTTGGGCATGATAT 4223 TGAGTCCCCTTTTGGGCATGATA 4224 GAGTCCC I 1 1 I GGGCATGAT

190 + 13_il_ r 4225 ATATCATGCCCAAAAGGGGACTCAC 4226 TATCATGCCCAAAAGGGGACTCA 4227 ATCATG CCCAAAAG GG G ACTC

190 + 14_il_ f 4228 TGAGTCCCCTTTGGGGCATGATATG 4229 GAGTCCCCTTTGGGGCATGATAT 4230 AGTCCCCTTTGGGGCATGATA

190 + 14_il_ r 4231 CATATCATGCCCCAAAGGGGACTCA 4232 ATATCATG CCCCAAAGG G G ACTC 4233 TATCATGCCCCAAAGGGGACT

190 + 15_il_ f 4234 GAGTCCCCTTTGGGGCATGATATGC 4235 AGTCCCCTTTGGGGCATGATATG 4236 GTCCCCTTTGGGGCATGATAT

190 + 15_il_ r 4237 GCATATCATG CCCCAAAG GG G ACTC 4238 CATATCATGCCCCAAAGGGGACT 4239 ATATCATG CCCCAAAG GG G AC

190 + 2_il_f 4240 GGAGACGTGCTGTTGAGTCCCCTTT 4241 GAGACGTGCTGTTGAGTCCCCTT 4242 AG ACGTG CTGTTG AGTCCCCT

190 + 2_il_r 4243 AAAGGGGACTCAACAGCACGTCTCC 4244 AAG GG G ACTCAACAG CACGTCTC 4245 AGGGGACTCAACAGCACGTCT

190 + 3_il_f 4246 GAGACGTGCTGTGGAGTCCCCTTTG 4247 AG ACGTG CTGTG G AGTCCCCTTT 4248 GACGTGCTGTGGAGTCCCCTT

190 + 3_il_r 4249 CAAAGGGGACTCCACAGCACGTCTC 4250 AAAGGGGACTCCACAGCACGTCT 4251 AAGGGGACTCCACAGCACGTC

190 + 4_il_f 4252 AGACGTGCTGTGAAGTCCCCTTTGG 4253 GACGTGCTGTGAAGTCCCCTTTG 4254 ACGTGCTGTGAAGTCCCCTTT

190 + 4_il_r 4255 CCAAAG GG G ACTTCACAG CACGTCT 4256 CAAAG GG G ACTTCACAG CACGTC 4257 AAAGGGGACTTCACAGCACGT

190 + 5_il_f 4258 GACGTGCTGTGAGGTCCCCTTTGGG 4259 ACGTGCTGTGAGGTCCCCTTTGG 4260 CGTGCTGTGAGGTCCCCTTTG

190 + 5_il_r 4261 CCCAAAGGGGACCTCACAGCACGTC 4262 CCAAAGGGGACCTCACAGCACGT 4263 CAAAGGGGACCTCACAGCACG

190 + 6_il_f 4264 ACGTGCTGTGAGTTCCCCTTTGGGC 4265 CGTG CTGTG AGTTCCCCTTTGG G 4266 GTGCTGTGAGTTCCCCTTTGG

190 + 6_il_r 4267 GCCCAAAGGGGAACTCACAGCACGT 4268 CCCAAAGGGGAACTCACAGCACG 4269 CCAAAGGGGAACTCACAGCAC

190 + 7_il_f 4270 CGTG CTGTG AGTCCCCCTTTG GG CA 4271 GTGCTGTGAGTCCCCCTTTGGGC 4272 TGCTGTGAGTCCCCCTTTGGG

190 + 7_il_r 4273 TGCCCAAAGGGGGACTCACAGCACG 4274 GCCCAAAGGGGGACTCACAGCAC 4275 CCCAAAGGGGGACTCACAGCA

190 + 8_il_f 4276 GTG CTGTG AGTCCCCCTTTG GG CAT 4277 TGCTGTGAGTCCCCCTTTGGGCA 4278 GCTGTGAGTCCCCCTTTGGGC

190 + 8_il_r 4279 ATGCCCAAAGGGGGACTCACAGCAC 4280 TGCCCAAAGGGGGACTCACAGCA 4281 GCCCAAAGGGGGACTCACAGC

190 + 9_il_f 4282 TGCTGTGAGTCCCCCTTTGGGCATG 4283 GCTGTGAGTCCCCCTTTGGGCAT 4284 CTGTG AGTCCCCCTTTG GG CA

190 + 9_il_r 4285 CATGCCCAAAGGGGGACTCACAGCA 4286 ATG CCCAAAG GG G G ACTCACAGC 4287 TGCCCAAAGGGGGACTCACAG

190_il_f 4288 CAGGAGACGTGCTTGTGAGTCCCCT 4289 AGGAGACGTGCTTGTGAGTCCCC 4290 GGAGACGTGCTTGTGAGTCCC

190_il_r 4291 AG GG G ACTCACAAG CACGTCTCCTG 4292 GGGGACTCACAAGCACGTCTCCT 4293 GGGACTCACAAGCACGTCTCC

.68 - l_il_f 4294 TCCTCTCTCTCAGGTGGGCGACAGA 4295 CCTCTCTCTCAGGTGGGCGACAG 4296 CTCTCTCTCAGGTGGGCGACA

.68 - l_il_r 4297 TCTGTCGCCCACCTGAGAGAGAGGA 4298 CTGTCGCCCACCTGAGAGAGAGG 4299 TGTCGCCCACCTGAGAGAGAG

.68 - 10_il_f 4300 TTCTCCTTTTCCTTCTCTCTCAGTG 4301 TCTCCTTTTCCTTCTCTCTCAGT 4302 CTCCTTTTCCTTCTCTCTCAG

.68 - 10_il_r 4303 CACTGAGAGAGAAGGAAAAGGAGAA 4304 ACTGAGAGAGAAGGAAAAGGAGA 4305 CTGAGAGAGAAGGAAAAGGAG

.68 - ll_il_f 4306 TTTCTCCTTTTCCCTCTCTCTCAGT 4307 TTCTCCTTTTCCCTCTCTCTCAG 4308 TCTCCTTTTCCCTCTCTCTCA

68 - 11 il r 4309 ACTGAGAGAGAGGGAAAAGGAGAAA 4310 CTGAGAGAGAGGGAAAAGGAGAA 4311 TGAGAGAGAGGGAAAAGGAGA

Table 1

SEQ ID SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _68 - 12_il_f 4312 CTTTCTCCTTTTCCCTCTCTCTCAG 4313 TTTCTCCTTTTCCCTCTCTCTCA 4314 TTCTCCTTTTCCCTCTCTCTC

LDLRex2(27 68 123 30) _68 - 12_il_r 4315 CTGAGAGAGAGGGAAAAGGAGAAAG 4316 TGAGAGAGAGGGAAAAGGAGAAA 4317 GAGAGAGAGGGAAAAGGAGAA

LDLRex2(27 68 123 30) _68 - 13_il_f 4318 CCTTTCTCCI 1 1 1 I CCTCTCTCTCA 4319 CTTTCTCCI 1 1 1 I CCTCTCTCTC 4320 TTTCTCU 1 1 1 I CCTCTCTCT

LDLRex2(27 68 123 30) _68 - 13_il_r 4321 TG AG AG AG AG G AAAAAG GAG AAAG G 4322 GAGAGAGAGGAAAAAGGAGAAAG 4323 AGAGAGAGGAAAAAGGAGAAA

LDLRex2(27 68 123 30) _68 - 14_il_f 4324 CCCTTTCTCCI 1 1 1 I CCTCTCTCTC 4325 CCTTTCTCC I 1 1 1 I CCTCTCTCT 4326 CTTTCTCC I 1 1 1 I CCTCTCTC

LDLRex2(27 68 123 30) _68 - 14_il_r 4327 GAGAGAGAGGAAAAAGGAGAAAGGG 4328 AGAGAGAGGAAAAAGGAGAAAGG 4329 GAGAGAGGAAAAAGGAGAAAG

LDLRex2(27 68 123 30) _68 - 15_il_f 4330 ACCCTTTCTCU 1 1 1 I CCTCTCTCT 4331 CCCTTTCTCC I 1 1 1 I CCTCTCTC 4332 CCTTTCTCC I 1 1 1 I CCTCTCT

LDLRex2(27 68 123 30) _68 - 15_il_r 4333 AGAGAGAGGAAAAAGGAGAAAGGGT 4334 GAGAGAGGAAAAAGGAGAAAGGG 4335 AGAGAGGAAAAAGGAGAAAGG

LDLRex2(27 68 123 30) _68 - 2_il_f 4336 TTCCTCTCTCTCAAGTG GG CG ACAG 4337 TCCTCTCTCTCAAGTG GG CG ACA 4338 CCTCTCTCTCAAGTGGGCGAC

LDLRex2(27 68 123 30) _68 - 2_il_r 4339 CTGTCGCCCACTTGAGAGAGAGGAA 4340 TGTCGCCCACTTGAGAGAGAGGA 4341 GTCGCCCACTTGAGAGAGAGG

LDLRex2(27 68 123 30) _68 - 3_il_f 4342 TTTCCTCTCTCTCCAGTGGGCGACA 4343 TTCCTCTCTCTCCAGTGGGCGAC 4344 TCCTCTCTCTCCAGTGGGCGA

LDLRex2(27 68 123 30) _68 - 3_il_r 4345 TGTCGCCCACTGGAGAGAGAGGAAA 4346 GTCGCCCACTGGAGAGAGAGGAA 4347 TCGCCCACTGGAGAGAGAGGA

LDLRex2(27 68 123 30) _68 - 4_il_f 4348 TTTTCCTCTCTCTTCAGTGGGCGAC 4349 TTTCCTCTCTCTTCAGTG GG CG A 4350 TTCCTCTCTCTTCAGTG GG CG

LDLRex2(27 68 123 30) _68 - 4_il_r 4351 GTCGCCCACTGAAGAGAGAGGAAAA 4352 TCGCCCACTGAAGAGAGAGGAAA 4353 CGCCCACTGAAGAGAGAGGAA

LDLRex2(27 68 123 30) _68 - 5_il_f 4354 CTTTTCCTCTCTCCTCAGTGGGCGA 4355 TTTTCCTCTCTCCTCAGTG GG CG 4356 TTTCCTCTCTCCTCAGTGGGC

LDLRex2(27 68 123 30) _68 - 5_il_r 4357 TCGCCCACTGAGGAGAGAGGAAAAG 4358 CGCCCACTGAGGAGAGAGGAAAA 4359 GCCCACTGAGGAGAGAGGAAA

LDLRex2(27 68 123 30) _68 - 6_il_f 4360 CCTTTTCCTCTCTTCTCAGTGGGCG 4361 CTTTTCCTCTCTTCTCAGTG GG C 4362 TTTTCCTCTCTTCTCAGTGGG

LDLRex2(27 68 123 30) _68 - 6_il_r 4363 CGCCCACTGAGAAGAGAGGAAAAGG 4364 GCCCACTGAGAAGAGAGGAAAAG 4365 CCCACTGAGAAGAGAGGAAAA

LDLRex2(27 68 123 30) _68 - 7_il_f 4366 TCCTTTTCCTCTCCTCTCAGTGGGC 4367 CCTTTTCCTCTCCTCTCAGTGGG 4368 CTTTTCCTCTCCTCTCAGTGG

LDLRex2(27 68 123 30) _68 - 7_il_r 4369 GCCCACTGAGAGGAGAGGAAAAGGA 4370 CCCACTGAGAGGAGAGGAAAAGG 4371 CCACTGAGAGGAGAGGAAAAG

LDLRex2(27 68 123 30) _68 - 8_il_f 4372 CTCCTTTTCCTCTTCTCTCAGTGGG 4373 TCCTTTTCCTCTTCTCTCAGTG G 4374 CCTTTTCCTCTTCTCTCAGTG

LDLRex2(27 68 123 30) _68 - 8_il_r 4375 CCCACTGAGAGAAGAGGAAAAGGAG 4376 CCACTGAGAGAAGAGGAAAAGGA 4377 CACTGAGAGAAGAGGAAAAGG

LDLRex2(27 68 123 30) _68 - 9_il_f 4378 TCTCCTTTTCCTCCTCTCTCAGTGG 4379 CTCCTTTTCCTCCTCTCTCAGTG 4380 TCCTTTTCCTCCTCTCTCAGT

LDLRex2(27 68 123 30) _68 - 9_il_r 4381 CCACTGAGAGAGGAGGAAAAGGAGA 4382 CACTGAGAGAGGAGGAAAAGGAG 4383 ACTGAGAGAGGAGGAAAAGGA

LDLRex2(27 68 123 30) _68. J1J 4384 CCTCTCTCTCAGTTGGGCGACAGAT 4385 CTCTCTCTCAGTTGGGCGACAGA 4386 TCTCTCTCAGTTGGGCGACAG

LDLRex2(27 68 123 30) _68. Jl_r 4387 ATCTGTCGCCCAACTGAGAGAGAGG 4388 TCTGTCGCCCAACTGAGAGAGAG 4389 CTGTCGCCCAACTGAGAGAGA

LDLRex2(27 68 123 30) _69. J1J 4390 CTCTCTCTCAGTGGGGCGACAGATG 4391 TCTCTCTCAGTGGGGCGACAGAT 4392 CTCTCTCAGTGGGGCGACAGA

LDLRex2(27 68 123 30) _69. Jl_r 4393 CATCTGTCGCCCCACTGAGAGAGAG 4394 ATCTGTCGCCCCACTGAGAGAGA 4395 TCTGTCGCCCCACTGAGAGAG

LDLRex2(27 68 123 30) _70. J1J 4396 TCTCTCTCAGTGGGGCGACAGATGC 4397 CTCTCTCAGTGGGGCGACAGATG 4398 TCTCTCAGTGGGGCGACAGAT

LDLRex2(27 68 123 30) _70. Jl_r 4399 GCATCTGTCGCCCCACTGAGAGAGA 4400 CATCTGTCGCCCCACTGAGAGAG 4401 ATCTGTCGCCCCACTGAGAGA

LDLRex2(27;68;123 30) _71 J1J 4402 CTCTCTCAGTGGGGCGACAGATGCG 4403 TCTCTCAGTGGGGCGACAGATGC 4404 CTCTCAGTGGGGCGACAGATG

Table 1

SEQ ID SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _71_ l_r 4405 CGCATCTGTCGCCCCACTGAGAGAG 4406 GCATCTGTCGCCCCACTGAGAGA 4407 CATCTGTCGCCCCACTGAGAG

LDLRex2(27 68 123 30) _72_ IJ 4408 TCTCTCAGTG GG CCG ACAG ATG CG A 4409 CTCTCAGTG GG CCG ACAG ATG CG 4410 TCTCAGTGGGCCGACAGATGC

LDLRex2(27 68 123 30) _72_ l_r 4411 TCGCATCTGTCGGCCCACTGAGAGA 4412 CGCATCTGTCGGCCCACTGAGAG 4413 GCATCTGTCGGCCCACTGAGA

LDLRex2(27 68 123 30) _73_ IJ 4414 CTCTCAGTGGGCGGACAGATGCGAA 4415 TCTCAGTGGGCGGACAGATGCGA 4416 CTCAGTGGGCGGACAGATGCG

LDLRex2(27 68 123 30) _73_ l_r 4417 TTCGCATCTGTCCGCCCACTGAGAG 4418 TCGCATCTGTCCGCCCACTGAGA 4419 CGCATCTGTCCGCCCACTGAG

LDLRex2(27 68 123 30) _74_ IJ 4420 TCTCAGTGGGCGAACAGATGCGAAA 4421 CTCAGTG GG CG AACAG ATG CG AA 4422 TCAGTG GG CG AACAG ATG CG A

LDLRex2(27 68 123 30) _74_ l_r 4423 TTTCG CATCTGTTCG CCCACTG AG A 4424 TTCG CATCTGTTCG CCCACTG AG 4425 TCGCATCTGTTCGCCCACTGA

LDLRex2(27 68 123 30) _75_ IJ 4426 CTCAGTGGGCGACCAGATGCGAAAG 4427 TCAGTGGGCGACCAGATGCGAAA 4428 CAGTG GG CG ACCAG ATG CG AA

LDLRex2(27 68 123 30) _75_ l_r 4429 CTTTCGCATCTGGTCGCCCACTGAG 4430 TTTCGCATCTGGTCGCCCACTGA 4431 TTCG CATCTG GTCG CCCACTG

LDLRex2(27 68 123 30) _76_ IJ 4432 TCAGTGGGCGACAAGATGCGAAAGA 4433 CAGTGGGCGACAAGATGCGAAAG 4434 AGTG GG CG ACAAG ATG CG AAA

LDLRex2(27 68 123 30) _76_ l_r 4435 TCTTTCG CATCTTGTCG CCCACTG A 4436 CTTTCG CATCTTGTCG CCCACTG 4437 TTTCG CATCTTGTCG CCCACT

LDLRex2(27 68 123 30) _77_ IJ 4438 CAGTGGGCGACAGGATGCGAAAGAA 4439 AGTGGGCGACAGGATGCGAAAGA 4440 GTGGGCGACAGGATGCGAAAG

LDLRex2(27 68 123 30) _77_ l_r 4441 TTCTTTCGCATCCTGTCGCCCACTG 4442 TCTTTCG CATCCTGTCG CCCACT 4443 CTTTCGCATCCTGTCGCCCAC

LDLRex2(27 68 123 30) _78_ IJ 4444 AGTGGGCGACAGAATGCGAAAGAAA 4445 GTGGGCGACAGAATGCGAAAGAA 4446 TGGGCGACAGAATGCGAAAGA

LDLRex2(27 68 123 30) _78_ l_r 4447 TTTCTTTCG CATTCTGTCG CCCACT 4448 TTCTTTCG CATTCTGTCG CCCAC 4449 TCTTTCG CATTCTGTCG CCCA

LDLRex2(27 68 123 30) _79_ IJ 4450 GTGGGCGACAGATTGCGAAAGAAAC 4451 TGGGCGACAGATTGCGAAAGAAA 4452 GGGCGACAGATTGCGAAAGAA

LDLRex2(27 68 123 30) _79_ l_r 4453 GTTTCTTTCGCAATCTGTCGCCCAC 4454 TTTCTTTCGCAATCTGTCGCCCA 4455 TTCTTTCGCAATCTGTCGCCC

LDLRex2(27 68 123 30) _80_ IJ 4456 TGGGCGACAGATGGCGAAAGAAACG 4457 GGGCGACAGATGGCGAAAGAAAC 4458 GGCGACAGATGGCGAAAGAAA

LDLRex2(27 68 123 30) _80_ l_r 4459 CGTTTCTTTCGCCATCTGTCGCCCA 4460 GTTTCTTTCGCCATCTGTCGCCC 4461 TTTCTTTCGCCATCTGTCGCC

LDLRex2(27 68 123 30) _81_ IJ 4462 GGGCGACAGATGCCGAAAGAAACGA 4463 GGCGACAGATGCCGAAAGAAACG 4464 GCGACAGATGCCGAAAGAAAC

LDLRex2(27 68 123 30) _81_ l_r 4465 TCGTTTCTTTCGGCATCTGTCGCCC 4466 CGTTTCTTTCGG CATCTGTCG CC 4467 GTTTCTTTCGGCATCTGTCGC

LDLRex2(27 68 123 30) _82_ IJ 4468 GGCGACAGATGCGGAAAGAAACGAG 4469 GCGACAGATGCGGAAAGAAACGA 4470 CGACAGATGCGGAAAGAAACG

LDLRex2(27 68 123 30) _82_ l_r 4471 CTCGTTTCTTTCCGCATCTGTCGCC 4472 TCGTTTCTTTCCGCATCTGTCGC 4473 CGTTTCTTTCCGCATCTGTCG

LDLRex2(27 68 123 30) _83_ IJ 4474 GCGACAGATGCGAAAAGAAACGAGT 4475 CGACAGATGCGAAAAGAAACGAG 4476 GACAGATGCGAAAAGAAACGA

LDLRex2(27 68 123 30) _83_ l_r 4477 ACTCGTTTCTTTTCG CATCTGTCG C 4478 CTCG I 1 1 C I 1 1 I CG CATCTGTCG 4479 TCGTTTCTTTTCG CATCTGTC

LDLRex2(27 68 123 30) _84_ IJ 4480 CGACAGATGCGAAAAGAAACGAGTT 4481 GACAGATGCGAAAAGAAACGAGT 4482 ACAGATGCGAAAAGAAACGAG

LDLRex2(27 68 123 30) _84_ l_r 4483 AACTCG 1 1 1 1 1 1 1 CG CATCTGTCG 4484 ACTCGTTTCTTTTCGCATCTGTC 4485 CTCGTTTCTTTTCG CATCTGT

LDLRex2(27 68 123 30) _85_ IJ 4486 GACAGATGCGAAAAGAAACGAGTTC 4487 ACAGATGCGAAAAGAAACGAGTT 4488 CAGATGCGAAAAGAAACGAGT

LDLRex2(27 68 123 30) _85_ l_r 4489 GAACTCGTTTCTTTTCGCATCTGTC 4490 AACTCGTTTCTTTTCG CATCTGT 4491 ACTCGTTTCTTTTCGCATCTG

LDLRex2(27 68 123 30) _86_ IJ 4492 ACAGATGCGAAAGGAAACGAGTTCC 4493 CAG ATG CG AAAG G AAACG AGTTC 4494 AG ATG CG AAAG G AAACG AGTT

LDLRex2(27;68;123 30) _86_ l_r 4495 GGAACTCGTTTCCTTTCGCATCTGT 4496 GAACTCGTTTCCTTTCGCATCTG 4497 AACTCGTTTCCTTTCG CATCT

Table 1

SEQ ID SEQ ID SEQ ID

insl NO: 25 nt NO: 23 nt NO: 21 nt

LDLRex2(27 68 123 30) _87_ IJ 4498 CAGATGCGAAAGAAAACGAGTTCCA 4499 AGATGCGAAAGAAAACGAGTTCC 4500 GATGCGAAAGAAAACGAGTTC

LDLRex2(27 68 123 30) _87_ l_r 4501 TGGAACTCGTTTTCTTTCGCATCTG 4502 GGAACTCGTTTTCTTTCGCATCT 4503 GAACTCGTTTTCTTTCGCATC

LDLRex2(27 68 123 30) _88_ IJ 4504 AGATGCGAAAGAAAACGAGTTCCAG 4505 GATG CG AAAG AAAACG AGTTCCA 4506 ATGCGAAAGAAAACGAGTTCC

LDLRex2(27 68 123 30) _88_ l_r 4507 CTGGAACTCGTTTTCTTTCGCATCT 4508 TGGAACTCGTTTTCTTTCGCATC 4509 GGAACTCGTTTTCTTTCGCAT

LDLRex2(27 68 123 30) _89_ IJ 4510 GATGCGAAAGAAAACGAGTTCCAGT 4511 ATGCGAAAGAAAACGAGTTCCAG 4512 TG CG AAAG AAAACG AGTTCCA

LDLRex2(27 68 123 30) _89_ l_r 4513 ACTG G AACTCGTTTTCTTTCG CATC 4514 CTGGAACTCGTTTTCTTTCGCAT 4515 TG GAACTCG 1 1 1 I C I 1 I CGCA

LDLRex2(27 68 123 30) _90_ IJ 4516 ATGCGAAAGAAACCGAGTTCCAGTG 4517 TGCGAAAGAAACCGAGTTCCAGT 4518 GCGAAAGAAACCGAGTTCCAG

LDLRex2(27 68 123 30) _90_ l_r 4519 CACTG GAACTCG GTTTCTTTCG CAT 4520 ACTGGAACTCGGTTTCTTTCGCA 4521 CTG GAACTCG GTTTCTTTCG C

LDLRex2(27 68 123 30) _91_ IJ 4522 TGCGAAAGAAACGGAGTTCCAGTGC 4523 GCGAAAGAAACGGAGTTCCAGTG 4524 CGAAAGAAACGGAGTTCCAGT

LDLRex2(27 68 123 30) _91_ l_r 4525 GCACTGGAACTCCGTTTCTTTCGCA 4526 CACTGGAACTCCGTTTCTTTCGC 4527 ACTGGAACTCCGTTTCTTTCG

LDLRex2(27 68 123 30) _92_ IJ 4528 GCGAAAGAAACGAAGTTCCAGTGCC 4529 CGAAAGAAACGAAGTTCCAGTGC 4530 GAAAGAAACGAAGTTCCAGTG

LDLRex2(27 68 123 30) _92_ l_r 4531 GGCACTGGAACTTCGTTTCTTTCGC 4532 GCACTGGAACTTCGTTTCTTTCG 4533 CACTG G AACTTCGTTTCTTTC

LDLRex2(27 68 123 30) _93_ IJ 4534 CGAAAGAAACGAGGTTCCAGTGCCA 4535 GAAAGAAACGAGGTTCCAGTGCC 4536 AAAGAAACGAGGTTCCAGTGC

LDLRex2(27 68 123 30) _93_ l_r 4537 TGG CACTG G AACCTCGTTTCTTTCG 4538 GG CACTG G AACCTCGTTTCTTTC 4539 GCACTGGAACCTCGTTTCTTT

LDLRex2(27 68 123 30) _94_ IJ 4540 G AAAG AAACG AGTTTCCAGTG CCAA 4541 AAAGAAACGAGTTTCCAGTGCCA 4542 AAGAAACGAGTTTCCAGTGCC

LDLRex2(27 68 123 30) _94_ l_r 4543 TTGGCACTGGAAACTCGTTTCTTTC 4544 TGGCACTGGAAACTCGTTTCTTT 4545 GGCACTGGAAACTCGTTTCTT

LDLRex2(27 68 123 30) _95_ IJ 4546 AAAGAAACGAGTTTCCAGTGCCAAG 4547 AAGAAACGAGTTTCCAGTGCCAA 4548 AGAAACGAGTTTCCAGTGCCA

LDLRex2(27 68 123 30) _95_ l_r 4549 CTTGG CACTG G AAACTCGTTTCTTT 4550 TTGGCACTGGAAACTCGTTTCTT 4551 TGGCACTGGAAACTCGTTTCT

LDLRex2(27 68 123 30) _96_ IJ 4552 AAGAAACGAGTTCCCAGTGCCAAGA 4553 AGAAACGAGTTCCCAGTGCCAAG 4554 GAAACGAGTTCCCAGTGCCAA

LDLRex2(27 68 123 30) _96_ l_r 4555 TCTTGGCACTGGGAACTCGTTTCTT 4556 CTTGGCACTGGGAACTCGTTTCT 4557 TTGGCACTGGGAACTCGTTTC

LDLRex2(27 68 123 30) _97_ IJ 4558 AGAAACGAGTTCCCAGTGCCAAGAC 4559 GAAACGAGTTCCCAGTGCCAAGA 4560 AAACGAGTTCCCAGTGCCAAG

LDLRex2(27 68 123 30) _97_ l_r 4561 GTCTTGGCACTGGGAACTCGTTTCT 4562 TCTTGGCACTGGGAACTCGTTTC 4563 CTTGGCACTGGGAACTCGTTT

LDLRex2(27 68 123 30) _98_ IJ 4564 GAAACGAGTTCCAAGTGCCAAGACG 4565 AAACGAGTTCCAAGTGCCAAGAC 4566 AACGAGTTCCAAGTGCCAAGA

LDLRex2(27 68 123 30) _98_ l_r 4567 CGTCTTG GCACTTG G AACTCGTTTC 4568 GTCTTGG CACTTG G AACTCGTTT 4569 TCTTG GCACTTG G AACTCGTT

LDLRex2(27 68 123 30) _99_ IJ 4570 AAACGAGTTCCAGGTGCCAAGACGG 4571 AACG AGTTCCAG GTG CCAAGACG 4572 ACGAGTTCCAGGTGCCAAGAC

LDLRex2(27;68;123 30) _99_ l_r 4573 CCGTCTTGGCACCTGGAACTCGTTT 4574 CGTCTTGG CACCTG G AACTCGTT 4575 GTCTTGG CACCTG G AACTCGT

Table 2

Table 4

Table 5

Claims

CLAIMS What is claimed is:

1. A method of designing a library of probes for detecting at least one indel variation in a genetic

variant segment, the method comprising the steps of (a) selecting a nucleic acid variant segment of N nucleotides long, wherein N can be any length between 25 and 5000; (b) selecting N number of probe sets each designed to hybridize to each of the N number of nucleotides in the nucleic acid variant segment; and (c) selecting at least one probe subset for the probe set, wherein the probe subset comprises at least two different probes forming a pair of probes, one designed to specifically hybridize to a normal/wild-type or a control sequence and one designed to specifically hybridize to a sequence with the at least one indel variation.

2. The method of claim 1 , further comprising a step of manufacturing the probe sets selected/designed through steps (a), (b) and (c).

3. The method of any one of the preceding claims, wherein at least one of the steps (a), (b), or (c) is performed using a computer implemented system.

4. The method of any one of the preceding claims, further comprising a step of attaching the probe on a solid surface.

5. The method of any one of the preceding claims, wherein the at least one pair of probes consist of a normal/control probe and a variant probe, both of which interrogate the about same region on the genetic variant segment, wherein the both probes forming the at least one pair of probe sub-set have the same sequence length and are of the same type of nucleic acids.

6. The method of any one of the preceding claims, wherein the normal/control probe comprises the normal sequence or the known SNP polymorphism of genetic variant segment and the variant probe comprises an indel-containing variant sequence of genetic variant segment

7. The method of any one of the preceding claims, wherein each of the at least two different probes has the difference between them located in position -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, - 14, -13, -12, -11, -10, -9,-8, -7, -6, -5, -4, -3, -2, -1, 0, +1, +2, +3, +4, +5, +6, +7, +8, +9, +10, +11, +12, +13, +14, +15, +16, +17, +18, +20, +21, +22, +23, +24 or +25 of the probe, wherein the position 0 is the center nucleotide of the probe when the probe has an odd number of nucleotides; and wherein the position -1 and +1 are the two central nucleotides of the probe when the probe has an even number of nucleotides.

8. The method of any one of the preceding claims, wherein the probes are 15-50 nucleotides long.

9. The method of any one of the preceding claims, wherein each of the at least two different probes has the difference between them located in position -4, -3, -2, -1, 0, +1, +2, +3 or +4 of the probe, wherein the position 0 is the center nucleotide of the probe when the probe has an odd number of nucleotides; and wherein the position -1 and +1 are the two central nucleotides of the probe when the probe has an even number of nucleotides.

10. The method of any one of the preceding claims, wherein the probes are DNA, RNA or PNA.

11. The method of any one of the preceding claims, wherein the indel variation is a deletion, an insertion or a duplication of nucleotide.

12. The method of any one of the preceding claims, wherein the deletion is selected from a group

consisting of one, two, three, four, five, six, seven, eight, nine, ten, and up to fifty nucleotides.

13. The method of any one of the preceding claims, wherein the insertion is selected from a group

14. The method of any one of the preceding claims, wherein the duplication is selected from a group consisting of one, two, three, four, five, six, seven, eight, nine, ten, and up to fifty nucleotides.

15. The method of any one of the preceding claims, wherein the probes of the at least one probe sub-set is complementary to the sense strand of the genetic variant segment.

16. The method of any one of the preceding claims, wherein probes of the at least one probe sub-set is complementary to the anti-sense strand of the genetic variant segment.

17. The method of any one of the preceding claims, wherein only one kind of indel is detected, the

method comprising a step of selecting one set of probe sets and as many probe sets as the length or number of nt (or base pairs) in the variant segment under interrogation, wherein each probe set comprises a single probe sub-set, wherein each probe sub-set comprises at least a pair of probes consisting of one control or normal/wild type probe (C) and one variation probe (V).

18. The method of any one of the preceding claims, wherein at least two types of indels are designed to be detected, the method comprising the step of designing each probe set to comprise at least two probe sub-sets, wherein each probe sub-set comprises at least one pair of probes, wherein each pair of probes consists of one control or normal probe and one variation probe, wherein the member probes of each pair of probes within each probe sub-set is designed to differ from each other in terms of length, indel variation location inside the probe and strand of interrogation of the variant segment.

19. The method of any one of the preceding claims, wherein more than two types of indels are to be detected, further comprising a step of designing as many probe sub-sets as there are indels that need to be detected, and wherein each pair of probes within a probe sub-set is designed to differ from each other in terms of length, interrogating position inside the probe and strand of interrogation of the variant segment.

20. A library of probes prepared by the method of any one of the preceding claims.

21. A library of probes, wherein the probes are selected from the probes set forth in Table 1, SEQ ID NO: 1-4575.

22. The library of probes according to claim 20, wherein the probes consist of SEQ ID No: 1-4575.

23. Use of the library of probes according to any one of claims 20-22.

24. A DNA-chip comprising the library of probes of any one of claims 20-22.

25. Use of the DNA chip of claim 24.

26. A collection of microbeads comprising the library of probes of any one of claims 20-22.

27. Use of the collection of microbeads of claim 26.

8. The method of detecting and analyzing an indel in a genetic variant segment having a length of N nucleotide bases comprises:

(a) providing at least a tNA sample.

(b) providing at least two cNA samples.

(d) providing a set of probe sets designed to hybridize to the at least one genetic variant segment, wherein the set of probe sets comprising at least one probe set, wherein the at least one probe set for the genetic variant segment comprises at least one probe sub-set, wherein the at least one probe subsets comprise at least one pair of probes: a normal probe and a variation probe, wherein the normal probe of the pair is complementary to the normal (wild type or control) sequence of the genetic variant segment, and the variation probe is complementary to the normal sequence except for a position corresponding to the indel variation, and wherein the probes are placed on the solid support as probe features;

(e) contacting optionally in parallel the at least one genetic variant segment from the at least tNA sample and the at least one genetic variant segment from the at least two cNA samples with the solid support, thereby allowing NA hybridization between the genetic variant segments from the tNA and the cNAs to the genetic variant probe features thereby forming NA-probe complexes, wherein each complex is detectably labeled;

(i) . computing a ratio for each pair of probes:

Ration = intensity value for normal probe

(intensity value for normal probe + intensity value for variation probe)

(ii) . computing the mean and the standard deviation of the ratios obtained for all the control NA samples; and

(iii) . comparing the ratios obtained for each of the tNA sample with the mean ratio obtained for the cNA samples in step (ii), wherein if the ratio of the tNA sample is at least 5 standard deviations away from the mean ratio obtained with the cNA sample, the test NA has the indel variation at position k, either in an heterozygous or a homozygous state; wherein k has values from 1 to N-l where 1 represent the first oligonucleotide of the variant segment and N is the last base.