Oligonucleotides for dysferlin, a gene mutated in distal myopathy and limb girdle muscular dystrophy

Abstract

A novel gene and the protein encoded therein, i.e., dysferlin, are disclosed. This gene and its expression products are associated with muscular dystrophy, e.g., Miyoshi myopathy and limb girdle musclular dystrophy 2B.

Description

BACKGROUND OF THE INVENTION

The invention relates to genes involved in the onset of muscular dystrophy.

Muscular dystrophies constitute a heterogeneous group of disorders. Most are characterized by weakness and atrophy of the proximal muscles, although in rare myopathies such as “Miyoshi myopathy” symptoms may first arise in distal muscles. Of the various hereditary types of muscular dystrophy, several are caused by mutations or deletions in genes encoding individual components of the dystrophin-associated protein (DAP) complex. It is this DAP complex that links the cytoskeletal protein dystrophin to the extracellular matrix protein, laminin-2.

Muscular dystrophies may be classified according to the gene mutations that are associated with specific clinical syndromes. For example, mutations in the gene encoding the cytoskeletal protein dystrophin result in either Duchenne's Muscular Dystrophy or Becker's Muscular Dystrophy, whereas mutations in the gene encoding the extracellular matrix protein merosin produce Congenital Muscular Dystrophy. Muscular dystrophies with an autosomal recessive mode of inheritance include “Miyoshi myopathy” and the several limb-girdle muscular dystrophies (LGMD2). Of the limb-girdle muscular dystrophies, the deficiencies resulting in LGMD2C, D, E, and F result from mutations in genes encoding the membrane-associated sarcoglycan components of the DAP complex.

SUMMARY OF THE INVENTION

A novel protein, designated dysferlin, is identified and characterized. The dysferlin gene is normally expressed in skeletal muscle cells and is selectively mutated in several families with the hereditary muscular dystrophies, e.g., Miyoshi myopathy (MM) and limb girdle muscular dystrophy-2B (LGMD2B). These characteristics of dysferlin render it a candidate disease gene for both MM and LGMD2B. An additional novel protein, brain-specific dysferlin, has also been identified. Defects in brain-specific dysferlin may predispose to selected disorders of the central nervous system. Moreover, the expression of brain-specific dysferlin may be important as a marker for normal neural development (e.g., in vivo or in neural cells in culture). Manipulation of levels of expression of brain-specific dysferlin, and of the type of expressed brain-specific dysferlin is of use for analyzing the function of brain-specific dysferlin and related dysferlin-associated molecules.

The invention features an isolated DNA which includes a nucleotide sequence hybridizing under stringent hybridization conditions to a strand of SEQ ID NO:3 or SEQ ID NO:117. SEQ ID NO:117 corresponds to nucleotides 374-6613 of wild type dysferlin.

The invention also features an isolated DNA including a nucleotide sequence selected from SEQ ID NOs:4-12. SEQ ID NOs:4-12 are oligonucleotides that span the mutations of 537insA, Q605X, 5966delG, E1883X, 6391+1G to A, I1298V, R2042C, H1857R, and 6071/2delAG, respectively (Table 2).

Also within the invention is an isolated DNA comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:22-30.

Also within the invention is an isolated DNA comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:22-30. SEQ ID NOs:22-30 are oligonucleotides with wild type sequences that span the mutant regions identified in the mutants 537inSA, Q605X, 5966delG, E1883X, 6391+1G to A, I1298V, R2042C, H1857R, and 6071/2delAG, respectively (Table 2).

Also within the invention is a pair of PCR primers consisting of:

(a) a first single stranded oligonucleotide consisting of 14-50 contiguous nucleotides of the sense strand of SEQ ID NO:117; and

(b) a second single stranded oligonucleotide consisting of 14-50 contiguous nucleotides of the antisense strand of SEQ ID NO:117, wherein the sequence of at least one of the oligonucleotides is identical to a portion of a strand of SEQ ID NO:3, and the first oligonucleotide is not complementary to the second oligonucleotide.

Also within the invention is a pair of single stranded oligonucleotides selected from of SEQ ID NOs 130-231, SEQ ID NO:110, and SEQ ID NO:112.

Also within the invention is an isolated DNA including a nucleotide sequence that encodes a protein that shares at least 70% sequence identity with SEQ ID NO:2, or a complement of the nucleotide sequence.

Also within the invention is an isolated DNA including a nucleotide sequence which hybridizes under stringent hybridization conditions to a strand of a nucleic acid, the nucleic acid having a sequence selected from SEQ ID NOs:31-79 and 90-100. SEQ ID NOs:90-100 are intron sequences from a dysferlin gene. Specifically, SEQ ID NOs:90-100 are intron sequence 5′ of exon 50, intron sequence 3′ of exon 50, intron sequence 5′ of exon 51, intron sequence 3′ of exon 51, intron sequence 5′ of exon 52, intron sequence 3′ of exon 52, intron sequence 5′ of exon 53, intron sequence 3′ of exon 53, intron sequence 5′ of exon 54, intron sequence 3′ of exon 54, and intron sequence 5′ of exon 55.

Also within the invention is a single stranded oligonucleotide of 14-50 nucleotides in length having a nucleotide sequence which is identical to a portion of a strand of a nucleic acid selected from SEQ ID NOs:31-79 and 90-100.

Also within the invention is a pair of PCR primers consisting of:

(a) a first single stranded oligonucleotide consisting of 14-50 contiguous nucleotides of the sense strand of a nucleic acid selected from SEQ ID NOs:31-85; and

(b) a second single stranded oligonucleotide consisting of 14-50 contiguous nucleotides of the antisense strand of a nucleic acid selected from SEQ ID NOs:31-85, wherein the sequence of at least one of the oligonucleotides includes a sequence identical to a portion of a strand of a nucleic acid selected from SEQ ID NOs: 31-79 and 90-100, and the first oligonucleotide is not complementary to the second oligonucleotide.

Also within the invention is a pair of single stranded oligonucleotides selected from SEQ ID NOs 101-116, SEQ ID NOs 184-185, SEQ ID NOs 188-191, SEQ ID NOs 210-213, and SEQ ID NOs 216-217.

Also within the invention is a substantially pure protein that has an amino acid sequence sharing at least 70% sequence identity with SEQ ID NO:2.

Also within the invention is a substantially pure protein the sequence of which includes amino acid residues 1-500, 501-1000, 1001-1500, or 1501-2080 of SEQ ID NO:2.

Also within the invention is a substantially pure protein including the amino acid sequence of SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, or SEQ ID NO:89.

In another aspect, the invention features a transgenic non-human mammal having a transgene disrupting or interfering with the expression of a dysferlin gene, the transgene being chromosomally integrated into the germ cells of the animal.

Another embodiment of the invention features a method of decreasing the symptoms of muscular dystrophy in a mammal by introducing into a cell of the mammal (e.g., a muscle cell or a muscle precursor cell) an isolated DNA which hybridizes under stringent hybridization conditions to a strand of SEQ ID NO:3.

Another aspect of the invention provides a method for identifying a patient, a fetus, or a pre-embryo at risk for having a dysferlin-related disorder by (a) providing a sample of genomic DNA from the patient, fetus, or pre-embryo; and (b) determining whether the sample contains a mutation in a dysferlin gene.

In another aspect, the invention provides a method for identifying a patient, a fetus, or a pre-embryo at risk for having a dysferlin-related disorder by (a) providing a sample including dysferlin mRNA from the patient, fetus, or pre-embryo; and (b) determining whether the dysferlin mRNA contains a mutation.

Methods of identifying mutations in a dysferlin sequence are useful for predicting (e.g., predicting whether an individual is at risk for developing a dysferlin-related disorder) or diagnosing disorders associated with dysferlin, e.g., MM and LGMD2B. Such methods can also be used to determine if an individual, fetus, or a pre-embryo is a carrier of a dysferlin mutation, for example in screening procedures. Methods which distinguish between different dysferlin alleles (e.g., a mutant dysferlin allele and a normal dysferlin allele) can be used to determine carrier status.

The invention also features an isolated nucleic acid comprising a nucleotide sequence which hybridizes under stringent hybridization conditions to nucleic acids 3284-3720 of SEQ ID NO:232, or the complement of the nucleotide sequence. An isolated nucleic acid including a nucleotide sequence identical to the sequence of nucleotides 3284-3720 of SEQ ID NO:232, or a complement of the nucleotide sequence is also a feature of the invention. The isolated nucleic acid can include the entire sequence of SEQ ID NO:232 or the complement of SEQ ID NO:232.

Another aspect of the invention features an isolated polypeptide that includes: a) at least 15 contiguous amino acids of the polypeptide comprising amino acids 1-24 of SEQ ID NO:233, b) a naturally occuring allelic variant of a polypeptide comprising amino acids 1-24 of SEQ ID NO:233, or c) an amino acid sequence which is encoded by a nucleic acid molecule which hybridizes under stringent conditions to nucleotides 3284-3720 of SEQ ID NO:232. The polypeptide of this aspect can include the entire sequence of SEQ ID NO:233.

Also included in the invention is a vector comprising the nucleic acid of claim 44 and a cell that contains the vector. Another aspect of the invention features a method of making a polypeptide by culturing the cell which contains the vector.

The invention also features an antibody which specifically binds to a polypeptide of such as those described above. The antibody can bind to a polypeptide selected from amino acids 253-403 of SEQ ID NO:233, amino acids 624-865 of SEQ ID NO:233, and amino acids 1664-1786 of SEQ ID NO:233. Antibodies of the invention can be monclonal or polyclonal antibodies.

An “isolated DNA” is DNA which has a naturally occurring sequence corresponding to part or all of a given gene but is free of the two genes that normally flank the given gene in the genome of the organism in which the given gene naturally occurs. The term therefore includes a recombinant DNA incorporated into a vector, into an autonomously replicating plasmid or virus, or into the genomic DNA of a prokaryote or eukaryote. It also includes a separate molecule such as a cDNA, a genomic fragment, a fragment produced by polymerase chain reaction (PCR), or a restriction fragment, as well as a recombinant nucleotide sequence that is part of a hybrid gene, i.e., a gene encoding a fusion protein. The term excludes intact chromosomes and large genomic segments containing multiple genes contained in vectors or constructs such as cosmids, yeast artificial chromosomes (YACs), and P1-derived artificial chromosome (PAC) contigs.

A “noncoding sequence” is a sequence which corresponds to part or all of an intron of a gene, or to a sequence which is 5′ or 3′ to a coding sequence and so is not normally translated.

An expression control sequence is “operably linked” to a coding sequence when it is within the same nucleic acid and can control expression of the coding sequence.

A “protein” or “polypeptide” is any chain of amino acids linked by peptide bonds, regardless of length or post-translational modification, e.g., glycosylation or phosphorylation.

As used herein, the term “percent sequence identity” means the percentage of identical subunits at corresponding positions in two sequences when the two sequences are aligned to maximize subunit matching, i.e., taking into account gaps and insertions. For purposes of the present invention, percent sequence identity between two polypeptides is to be determined using the Gap program and the default parameters as specified therein. The Gap program is part of the Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705.

The algorithm of Myers and Miller, CABIOS (1989) can also be used to determine whether two sequences are similar or identical. Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

As used herein, the term “stringent hybridization conditions” means the following DNA hybridization and wash conditions: hybridization at 60° C. in the presence of 6×SSC, 0.5% SDS, 5×Denhardt's Reagent, and 100 μg/ml denatured salmon sperm DNA; followed by a first wash at room temperature for 20 minutes in 0.5×SSC and 0.1% SDS and a second wash at 55° C. for 30 minutes in 0.2×SSC and 0.1% SDS.

A “substantially pure protein” is a protein separated from components that naturally accompany it. The protein is considered to be substantially pure when it is at least 60%, by dry weight, free from the proteins and other naturally-occurring organic molecules with which it is naturally associated. Preferably, the purity of the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight. A substantially pure dysferlin protein can be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding a dysferlin polypeptide, or by chemical synthesis. Purity can be measured by any appropriate method, e.g., column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis. A chemically synthesized protein or a recombinant protein produced in a cell type other than the cell type in which it naturally occurs is, by definition, substantially free from components that naturally accompany it. Accordingly, substantially pure proteins include those having sequences derived from eukaryotic organisms but which have been recombinantly produced in E. coli or other prokaryotes.

An antibody that “specifically binds” to an antigen is an antibody that recognizes and binds to the antigen, e.g., a dysferlin polypeptide, but which does not substantially recognize and bind to other molecules in a sample (e.g., a biological sample) which naturally includes the antigen, e.g., a dysferlin polypeptide. An antibody that “specifically binds” to dysferlin is sufficient to detect a dysferlin polypeptide in a biological sample using one or more standard immunological techniques (for example, Western blotting or immunoprecipitation).

A “transgene” is any piece of DNA, other than an intact chromosome, which is inserted by artifice into a cell, and becomes part of the genome of the organism which develops from that cell. Such a transgene may include a gene which is partly or entirely heterologous (i.e., foreign) to the host organism, or may represent a gene homologous to an endogenous gene of the organism.

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. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. The present materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. All the sequences disclosed in the sequence listing are meant to be double-stranded except the sequences of oligonucleotides.

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

DESCRIPTION OF THE DRAWINGS

FIG. 1A is a physical map of the MM locus. Arrows indicate the five new polymorphic markers and filled, vertical rectangular boxes indicate the previously known polymorphic markers. The five ESTs that are expressed in skeletal muscle are highlighted in bold. Detailed information on the minimal tiling path of the PAC contig spanning the MM/LGMD2B region is provided in Liu et al., 1998, Genomics 49:23-29. The minimal candidate MM region is designated by the solid bracket (top) and compared to the previous candidate region (dashed bracket). TGFA and ADD2 are transforming growth factor alpha and β-adducin 2.

FIG. 1B is a representation of the dysferlin cDNA clones. The probes used in the three successive screens are shown in bold (130347, cDNA10, A27-F2R2). The two most 5′ cDNA clones are also shown (B22, B33). The 6.9 kb cDNA for dysferlin (SEQ ID NO:1) is illustrated at the bottom with start and stop codons as shown.

FIG. 1C is a representation of the predicted dysferlin protein. The locations of four C2 domains (SEQ ID NOs: 86-89) are indicated by stippled boxes, while the putative transmembrane region is hatched. Vertical lines above the cDNA denote the positions of the mutations in Table 2; the associated labels indicate the phenotypes (MM—Miyoshi myopathy; LGMD—limb girdle muscular dystrophy; DMAT—distal myopathy with anterior tibial onset).

FIG. 2 is the sequence of the predicted 2,080 amino acids of dysferlin (SEQ ID NO:2). The predicted membrane spanning residues are in bold at the carboxy terminus (residues 2047-2063). Partial C2 domains are underlined. Bold, underlined sequences are putative nuclear targeting residues. Possible membrane retention sequences are enclosed within a box.

FIG. 3 is a comparison of the Kyle-Doolittle hydrophobicity plots of the dysferlin protein and fer-1. On the Y-axis, increasing positivity corresponds to increasing hydrophobicity. Both proteins have a single, highly hydrophobic stretch at the carboxy terminal end (arrow). Both share regions of relative hydrophilicity approximately at residue 1,000 (arrowhead).

FIG. 4 is a SSCP analysis of a representative pedigree with dysferlin mutations. Each member of the pedigree is illustrated above the corresponding SSCP analysis. For each affected individual (solid symbols) shifts are evident in alleles 1 and 2, corresponding respectively to exons 36 and 54. As indicated, the allele 1 and 2 variants are transmitted respectively from the mother and the father. The two affected daughters in this pedigree have the limb girdle muscular dystrophy (LGMD) phenotype while their affected brother has a pattern of weakness suggestive of Miyoshi myopathy (MM).

FIG. 5 is a representation of the genomic structure of dysferlin. The 55 exons of the dysferlin gene and their corresponding SEQ ID NOs are indicated below the 6911 bp cDNA (solid line). The cDNA sequences corresponding to SEQ ID NO:1 and SEQ ID NO:3 are shown relative to the 6911 bp cDNA.

FIGS. 6A-D are the cDNA sequence of brain-specific dysferlin (SEQ ID NO:232) and the predicted amino acid sequence (in single-letter code) of brain-specific dysferlin (SEQ ID NO:233).

DETAILED DESCRIPTION

The Miyoshi myopathy (MM) locus maps to human chromosome 2p12-14 between the genetic markers D2S292 and D2S286 (Bejaoui et al., 1995, Neurology 45:768-72). Further refined genetic mapping in MM families placed the MM locus between markers GGAA-P7430 and D2S2109 (Bejaoui et al., 1998, Neurogenetics 1:189-96). Independent investigation has localized the limb-girdle muscular dystrophy (LGMD-2B) to the same genetic interval (Bashir et al., 1994, Hum. Molec. Genetics 3:455-57; Bashir et al., 1996, Genomics 33:46-52; Passos-Bueno et al., 1995, Genomics 27:192-95). Furthermore, two large, inbred kindreds have been described whose members include both MM and LGMD2B patients (Weiler et al., 1996, Am. J. Hum. Genet. 59:872-78; Illarioshkin et al., 1997, Genomics 42:345-48). In these familial studies, the disease gene(s) for both MM and LGMD2B mapped to essentially the same genetic interval. Moreover, in both pedigrees, individuals with MM or LGMD2B phenotypes share the same haplotypes. This raises the intriguing possibility that the two diseases may arise from the same gene defect and that a particular disease phenotype is the result of modification by additional factors.

A 3-Mb PAC contig spanning the entire MM/LGMD2B candidate region was recently constructed to facilitate the cloning of the MM/LGMD2B gene(s) (Liu et al., 1998, Genomics 49:23-29). This high resolution PAC contig resolved the discrepancies of the order of markers in previous studies (Bejaoui et al., 1998, Neurogenetics 1:189-96; Bashir et al., 1996, Genomics 33:46-52; Hudson et al., 1995, Science 270:1945-54). The physical size of the PAC contig also indicated that the previous minimal size estimation based on YAC mapping data was significantly underestimated.

Identification of Repeat Sequences and Repeat Typing

The PAC contig spanning the MM/LGMD2B region (Liu et al., 1998, Genomics 49:23-29) was used as a source for the isolation of new informative markers to narrow the genetic interval of the disease gene(s). DNA from the PAC clones spanning the MM/LGMD2B region was spotted onto Hybond N+™ membrane filters (Amersham, Arlington Heights, Ill.). The filters were hybridized independently with the following γ- 32 P (Du Pont, Wilmington, Del.) labeled repeat sequences: (1) (CA) 15 ; (2) pool of (ATT) 10 , (GATA) 8 and (GGAA) 8 ; (3) pool of (GAAT) 8 , (GGAT) 8 and (GTAT) 8 ; and (4) pool of (AAG) 10 and (ATC) 10 . Hybridization and washing of the filters were carried out at 55° C. following standard protocols (Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual ( 2nd Edition), Cold Spring Harbor Press, N.Y.).

Miniprep DNAs of PAC clones containing repeat sequences were digested with restriction enzymes HindIII and PstI and ligated into pBluescript II (KS+) vector which is (Stratagene, La Jolla, Calif.) digested with the same enzymes. Filters of the PAC subclones were hybridized to the γ- 32 P labeled repeats that detected the respective PACs. For clones with an insert size greater than 1 kb the repeat sequences of which could not be identified by a single round of sequencing, the inserts were further subcloned by digestion with HaeIII and ligation in EcoRV-digested pZero-2.1 vector (Invitrogen, Inc., Carlsbad, Calif.). Miniprep DNAs of the positive subclones were subjected to manual dideoxy sequencing with Sequenase™ enzyme (US Biochemicals, Inc., Cleveland, Ohio). Primer pairs for amplifying the repeat sequences were selected using the computer program Oligo (Version 4.0, National Biosciences, Inc., Plymouth, Minn.). Primer sequences are shown in Table 1.

TABLE 1
New Polymorphic Markers Mapped to the MM/LGMD2B Region
			Annealing	Size in	No. of
Marker	Repeat	Primers (5′ to 3′)	Tm (° C.)	PAC (bp)	alleles 1	Het 2
PAC3-H52	CA	GATCTAACCCTGCTGCTCACC	57	138	10	0.82
		(SEQ ID NO: 120)
		CTGGTGTGTTGCAGAGCGCTG
		(SEQ ID NO: 121)
Cy172-H32 3	CCAT	CCTCTCTTCTGCTGTCTTCAG	56	199	7	0.72
		(SEQ ID NO: 122)
		TGTGTCTGGTTCCACCTTCGT
		(SEQ ID NO: 123)
PAC35-PH2	CAT	TCCAAATAGAAATGCCTGAAC	56	161	5	0.30
		(SEQ ID NO: 124)
		AGGTATCACCTCCAAGTGTTG
		(SEQ ID NO: 125)
PAC16-H41	Complex	TACCAGCTTCAGAGCTCCCTG	58	280	4	0.41
		(SEQ ID NO: 126)
		TTGATCAGGGTGCTCTTGG
		(SEQ ID NO: 127)
Cy7-PH3	AAGG	GGAGAATTGCTTGAACCCAG	56	211	4	0.32
		(SEQ ID NO: 128)
		TGGCTAATGATGTTGAACATTT
		(SEQ ID NO: 129)
1 Observed in 50 unrelated caucasians.
2 Heterozygosity index.
3 Located within intron 2 of the dysferlin gene.
All oligonucleotides were synthesized by Integrated DNA Technologies, Inc. (Coralville, IA). PCR typing of the repeat markers followed previously described protocols (Bejaoui et al., 1995, Neurology 45: 768-772).

Identification of Repeat Markers and Haplotype Analysis

After hybridization with labeled repeat oligos, 17 different groups of overlapping PACs were identified that contained repeat sequences. Some groups contained previously identified repeat markers. For example, five groups of PACs were positively identified by a pool of repeat probes including (ATT) 10 , (GATA) 8 , and (GGAA) 8 . Of these, three groups contained known markers GGAA-P7430 (GGAA repeat), D2S1394 (GATA repeat) and D2S1398 (GGAA repeat) (Hudson et al., 1992, Nature 13:622-29; Gastier et al., 1995, Hum. Molecular Genetics 4:1829-36). No attempt was made to isolate new repeat markers from these PACs and they were not further analyzed. Similarly, seven groups of PACs that contained known CA repeat markerswere excluded. Seven groups of PACs that contained unidentified repeats were retained for further analysis. For each group, the PAC containing the smallest insert was selected for subcloning. Subclones were re-screened and positive clones were sequenced to identify repeats. In total, seven new repeat sequences were identified within the MM/LGMD2B PAC contig. Of these, five are polymorphic within the population that was tested. The information for these five markers is summarized in Table 1. Based on the PAC contig constructed previously across the MM candidate locus (Liu et al., 1998, Genomics 48:23-29), the five new markers and ten previously published polymorphic markers were placed in an unambiguous order (FIG. 1 ).

These markers were analyzed in a large, consanguineous MM family (Bejaoui et al., 1995, Neurology 45: 768-72; Bejaoui et al., 1998, Neurogenetics 1:189-96). Because MM is a recessive condition, the locus can be defined by identifying regions of the genome that show homozygosity in affected individuals. Conversely, because of the high penetrance of this adult-onset condition, unaffected adult individuals are not expected to be homozygous by descent across the region. Analysis of haplotype homozygosity in this pedigree indicates that the disease gene lies between markers D2S2111 and PAC3-H52. Based on the PAC mapping data, the physical distance for this interval is approximately 2.0 Mb. No recombination events were detected between four informative markers (markers cy172-H32 to PAC16-H41) and the disease locus in family MM-21 (FIG. 1 A).

Identification of Five Muscle-Expressed ESTs

Twenty-two ESTs and two genes (transforming growth factor alpha [TGFα] and beta-adducin [ADD2]) were previously mapped to the MM/LGMD2B PAC contig ( FIG. 1A ) (Liu et al., 1998, Genomics 48:23-29). Two μl (approximately 0.1 ng/μl) of Marathon-ready™ skeletal muscle cDNA (Clontech, Palo Alto, Calif.) were used as template in a 10 μl PCR reaction for analysis of muscle expression of ESTs. The PCR conditions were the same as for the PCR typing of repeat markers. PCR analysis of skeletal muscle cDNA indicated that five of these ESTs (A006G04, stSG1553R, WI-14958, TIGR-A004Z44 and WI-14051) map within the minimal genetic MM interval of MM and are expressed in skeletal muscle.

Probes were selected corresponding to each of these five ESTs for Northern blot analysis. cDNA clones (130347, 48106, 172575, 184080, and 510138) corresponding to the five ESTs that are expressed in muscle (respectively TIGR-A004Z44, WI-14051, WI-14958, stSG1553R and A006G04) were selected from the UniGene database (http:/www.ncbi.nlm.nih.gov/UniGene/) and obtained from Genome Systems, Inc. (St. Louis, Mo.). The cDNA probes were first used to screen the MM/LGMD2B PAC filters to confirm that they mapped to the expected position in the MM/LGMD2B contig.

A Northern blot (Clontech) of multiple human tissues was sequentially hybridized to the five cDNA probes and a control β-actin cDNA at 65° C. following standard hybridization and washing protocols (Sambrook et al., supra). Between hybridizations, probes were removed by boiling the blot at 95-100° C. for 4-10 min with 0.5% SDS. The blot was then re-exposed for 24 h to confirm the absence of previous hybridization signals before proceeding with the next round of hybridization.

The tissue distribution, intensity of the signals and size of transcripts detected by the five cDNA probes varied. Probes corresponding to ESTs stSG1553R, TIGR-A004Z44 and WI-14958 detected strong signals in skeletal muscle. In addition, the cDNA corresponding to TIGR-A004Z44 detected a 3.6-3.8 kb brain-specific transcript instead of the 8.5 kb message that was present in other tissues. It is likely that these five ESTs correspond to different genes since the corresponding cDNA probes used for Northern analysis derive from the 3′ end of messages, map to different positions in the MM/LGMD2B contig (FIG. 1 A), and differ in their expression patterns.

Current database analysis suggests that three of these ESTs (stSG1553R, WI-14958 and WI-14051) do not match any known proteins (Schuler et al., 1996, Science 274:540-46). A006G04 has weak homology with a protein sequence of unknown function that derives from C. elegans. TIGR-A004Z44 has homology only to subdomains present within protein kinase C. Because the five genes corresponding to the ESTs are expressed in skeletal muscle and map within the minimal genetic interval of the MM/LGMD2B gene(s), they are candidate MM/LGMD2B gene(s).

Cloning of Dysferlin cDNA

EST TIGR-A004Z44 gave a particularly strong skeletal muscle signal on the Northern blot. Moreover, it is bracketed by genetic markers that show no recombination with the disease phenotype in family MM-21 (FIG. 1 ). The corresponding transcript was therefore cloned and analyzed as a candidate MM gene. From the Unigene database, a cDNA IMAGE clone (130347, 979 bp) was identified that contained the 483 bp EST TIGR-A004Z44.

Approximately 1×10 6 recombinant clones of a λgt11 human skeletal muscle cDNA library (Clontech) were plated and screened following standard techniques (Sambrook et al., supra). The initial library screening was performed using the insert released from the clone 130347 that contains EST TIGR-A0044Z44, corresponding to the 3′ end of the gene. Positive phages were plaque purified and phage DNA was isolated according to standard procedures (Sambrook et al., supra). The inserts of the positive clones were released by EcoRI digestion of phage DNA and subsequently subcloned into the EcoRI site of pBluescript II (KS+) vector (Stratagene).

Fifty cDNA clones were identified when a human skeletal muscle cDNA library was screened with the 130347 cDNA. Clone cDNA10 with the largest insert (˜6.5 kb) ( FIG. 1B ) was digested independently with BamHI and PstI and further subcloned into pBluescript vector. Miniprep DNA of cDNA clones and subclones of cDNA10 was prepared using the Qiagen plasmid Miniprep kit (Valencia, Calif.). Sequencing was carried out from both ends of each clone using the SequiTherm EXCEL™ long-read DNA sequencing kit (Epicenter, Madison, Wis.), fluorescent-labeled M13 forward and reverse primers, and a LI-COR sequencer (Lincoln, Nebr.). Assembly of cDNA contigs and sequence analysis were performed using Sequencher software (Gene Codes Corporation, Inc., Ann Arbor, Mich.).

Two additional screens, first with the insert of cDNA10 and then a 683 bp PCR product (A27-F2R2) amplified from the 5′ end of the cDNA contig, identified 87 additional cDNA clones. Clones B22 and B33 extended the 5′ end by 94 and 20 bp, respectively. The compiled sequence allowed for the generation of a sequence of 6.9 kb (SEQ ID NO:1) (with 10-fold average coverage).

Although the 5′ end of the gene has not been further extended to the 8.5 kb predicted by Northern analysis, an open reading frame (ORF) of 6,243 bp has been identified within this 6.9 kb sequence. This ORF is preceded by an in-frame stop codon and begins with the sequence cgcaagcATGCTG (SEQ ID NO:118); five of the first seven bp are consistent with the Kozak consensus sequence for a start codon (Kozak, 1989, Nucl. Acids Res. 15:8125-33; Kozak, 1989, J. Cell. Biol. 108:229-41). An alternate start codon, in the same frame, +75 bp downstream, appears less likely as a start site GAGACGATGGGG (SEQ ID NO:119). Thus, the entire coding region of this candidate gene is believed to have been identified, as represented by the 6.9 kb sequence contig.

Isolation of the Brain-Specific Dysferlin Isoform

Identification of the Brain-specific Isoform of Dysferlin

A brain-specific isoform of dysferlin was identified using Northern blot analysis of poly(A+)RNA derived from multiple human adult tissues probed with radiolabeled full-length dysferlin cDNA subclones. A prominent 7.2 kb transcript was detected on Northern blots in skeletal muscle, heart, placenta, lung, and kidney, while a distinct but equally prominent 3.6 kb-3.8 kb transcript was identified exclusively in the brain. Using long exposures, a faint 7.2 kb mRNA was also detected in the brain. This finding suggested that the shorter brain isoform was likely to be a tissue-specific splice variant of the dysferlin gene. To test this hypothesis, a human brain cDNA library (Stratagene) was screened for the dysferlin brain isoform.

Cloning of the Brain-specific Dysferlin Isoform

To identify probes that hybridize to the brain-specific dysferlin sequence and so could be used for library screening, fragments of the full-length dysferlin cDNA clone (derived from a skeletal muscle cDNA library) were generated using restriction enzymes. The fragments were about 1 kb in length and were analyzed by hybridization to a Northern blot that included brain RNA. Sequences suitable for library screening were those that hybridized to the 3.6-3.8 kb brain-specific transcript. A region of the 3′ end of the dysferlin cDNA sequence that is approximately 3 kb in length was identified as hybridizing to brain mRNA. DNA containing sequence from this region was used as a probe for hybridization screening of a human brain cDNA library (Stratagene).

The human brain cDNA library was plated out and screened using standard procedures. Of the approximately 720,000 plaques screened, 63 primary positive clones were identified. Of these, 20 clones were selected for further analysis involving standard methods of hybridization, restriction enzyme mapping, and sequencing. The primary positive clones shared regions of overlap with each other.

Sequencing of positive clones, provided 3671 nucleotides of the brain-specific dysferlin sequence (SEQ ID NO:232; FIGS. 6 A-D). The identified sequence corresponds closely to the size of the brain-specific dysferlin transcript detected on Northern blots. With the exception of the 5′ region of the sequence, the brain-specific sequence is identical to about 3.1 kb of the dysferlin sequence (from nucleotide 3722 to 6904 of the dysferlin sequence). In the dysferlin gene, position 3722 corresponds to the start of exon 32. This finding is consistent with the hypothesis that the brain isoform is a splice-variant of the dysferlin gene. At the 5′ end of the brain isoform, 489 nucleotides are unique to brain-specific dysferlin. The amino acid sequence encoded by the brain dysferlin nucleic acid sequence (SEQ ID NO:233; FIG. 6 ) contains a unique sequence with an initiation codon within a Kozak consensus sequence. The nucleic acid sequence unique to brain-specific dysferlin encodes a novel 24 amino acid sequence.

Identification of Mutations in Miyoshi Myopathy

Two strategies were used to determine whether this 6.9 kb cDNA (SEQ ID NO:1) is mutated in MM. First, the genomic organization of the corresponding gene was determined and the adjoining intronic sequence at each of the 55 exons which make up the cDNA was identified. To identify exon-intron boundaries within the gene, PAC DNA was extracted with the standard Qiagen—Mini Prep protocol. Direct sequencing was performed with DNA Sequence System (Promega, Madison, Wis.) using 32 P end-labeled primers (Benes et al., 1997, Biotechniques 23:98-100). Exon-intron boundaries were identified as the sites where genomic and cDNA sequences diverged. Second, in patients for whom muscle biopsies were available, RT-PCR was also used to prepare cDNA for the candidate gene from the muscle biopsy specimen.

Single strand conformational polymorphism analysis (SSCP) was used to screen each exon in patients from 12 MM families. Putative mutations identified in this way were confirmed by direct sequencing from genomic DNA using exon-specific intronic primers. Approximately 20 ng of total genomic DNA from immortalized lymphocyte cell lines were used as a template for PCR amplification analysis of each exon using primers (below) located in the adjacent introns. SSCP analysis was performed as previously described (Aoki et al., 1998, Ann. Neurol. 43:645-53). In patients for whom muscle biopsies were available, mRNA was isolated using RNA-STAT-60™ (Tel-Test, Friendswood, Tex.) and first-strand cDNA was synthesized from 1-2 μg total RNA with MMLV reverse transcriptase and random hexamer primers (Life Technologies, Gaithersburg, Md.). Three μl of this product were used for PCR amplification. Eight sets of primers were designed for muscle cDNA, and overlapping cDNA fragments suitable for SSCP analysis were amplified. After initial denaturation at 94° C. for 2 min, amplification was performed using 30 cycles at 94° C. for 30 s, 56° C. for 30 s, and 72° C. for 60 s. The sequences of polymorphisms detected by SSCP analysis were determined by the dideoxy termination method using the Sequenase kit (US Biochemicals). In some instances, the base pair changes predicted corresponding changes in restriction enzyme recognition sites. Such alterations in restriction sites were verified by digesting the relevant PCR products with the appropriate restriction enzymes.

Primer pairs used for SSCP screening and exon sequencing are as follows:

(1) exon 3, F3261 5′-tctcttctcctagagggccatag-3′ (SEQ ID NO: 101) and R326 5′-ctgttcctccccatcgtctcatgg-3′ (SEQ ID NO: 102);

(2) exon 20, F3121 5′-gctcctcccgtgaccctctg-3′ (SEQ ID NO: 103) and R3121 5′-gggtcccagccaggagcactg-3′ (SEQ ID NO: 104);

(3) exon 36, F2102 5′-cccctctcaccatctcctgatgtg-3′ (SEQ ID NO: 105) and R2111 5′-tggcttcaccttccctctacctcgg-3′ (SEQ ID NO: 106);

(4) exon 49, F1081 5′-tcctttggtaggaaatctaggtgg-3′ (SEQ ID NO: 107) and R1081 5′-ggaagctggacaggcaagagg-3′ (SEQ ID NO: 108);

(5) exon 50, F1091 5′-atatactgtgttggaaatcttaatgag-3′ (SEQ ID NO: 109) and R1091 5′-gctggcaccacagggaatcgg-3′ (SEQ ID NO: 110);

(6) exon 51, F1101 5′-ctttgcttccttgcatccttctctg-3′ (SEQ ID NO: 111) and R1101 5′-agcccccatgtgcagaatggg-3′ (SEQ ID NO: 112);

(7) exon 52, F1111 5′-ggcagtgatcgagaaacccgg-3′ (SEQ ID NO: 113) and R1111 5′-catgccctccactggggctgg-3′ (SEQ ID NO: 114);

(8) exon 54, F1141 5′-ggatgcccagttgactccggg-3′ (SEQ ID NO: 115) and R1141 5′-ccccaccacagtgtcgtcagg-3′ (SEQ ID NO: 116);

(9) exon 29, F3031 5′-aagtgccaagcaatgagtgaccgg-3′ (SEQ ID NO: 184) and R3021 5′-ctcactcccacccaccacctg-3′ (SEQ ID NO: 185);

(10) exon 31, F2141 5′-gaatctgccataaccagcttcgtg-3′ (SEQ ID NO: 188) and R2141 5′-tatcaccccatagaggcctcgaag-3′ (SEQ ID NO: 189);

(11) exon 32, F2981 5′-cagccactcactctggcacctctg-3′ (SEQ ID NO: 190) and R2981 5′-agcccacagtctctgactctcctg-3′ (SEQ ID NO: 191);

(12) exon 43, F2031 5′-cagccaaaccatatcaacaatg-3′ (SEQ ID NO: 210) and R2021 5′-ctggggaggtgagggctctag-3′ (SEQ ID NO: 211);

(13) exon 44, F2011 5′-gaagtgttttgtctcctcctc-3′ (SEQ ID NO: 212) and R2011 5′-gcaggcagccagcccccatc-3′ (SEQ ID NO: 213);

(14) exon 46, F1041 5′-ctcgtctatgtcttgtgcttgctc-3′ (SEQ ID NO: 216) and R1051 5′-caccatggtttggggtcatgtgg-3′ (SEQ ID NO: 217).

These primers were used in SSCP screening and exon sequencing, and identified eighteen different mutations in fifteen families (Table 2).

TABLE 2
Mutations in Dysferlin in Distal Myopathy and LGMD 1
							Change of
	Nucleotide						restriction
Name	Change	Exon	Consequence	Origin	Family name	Allele	site
Mutations
537insA	ins of A at	3	Frameshift	Arabic	MM59	Hom	no change
	537
Q605X	C AG to T AG at	20	Stop at 605	French	MM67	Hom	−Pst I,
	2186						−Fnu 4H I 1
I1298V	A TC to G TC at	36	Amino acid	Italian	MM, LGMD56	Het	−BamHI,
	4265		change				−BStYI;
							+Ava II
E1883X	G AG to T AG at	49	Stop at 1883	English	MM8	Het	no change
	5870
H1857R	C A T to C G T at	50	Amino acid	English	MM50	Het	no change
	5943		change
5966delG	del of G at	50	Frameshift	Spanish	DMAT71	Hom	no change
	5966
5966delG	del of G at	50	Frameshift	Spanish	MM75	Hom	no change
	5966
6071/6072delAG	del of AG at	51	Frameshift	English	MM58	Het	no change
	6071/6072
6319+1G to A	G g t to G a t at	52	5′ splice site	English	MM8	Het	no change
	6319+1
R2042C	C GT to T GT at	54	Amino acid	Italian	MM56	Het	−Fnu4HI
	6497		change
R1046H	C G C to C A G at	29	Amino acid	Japanese	MM10	Hom	−HinPI,
	3510		change				−Fsp I
3746delG	del of G at	31	Frameshift	Japanese	MM17	Hom	−MboII
	3746
Q1160X	C AG to T AG at	32	Stop at 1160	Mexican	MM46	Hom	−ScrFI,
	3851						−BstNI,
							+MaeI,
							+BfaI
5122/5123delCA	del of CA at	43	Frameshift	Japanese	MM14	Het	no change
	5122/5123, A
	to T at 5121
R1586X	C GA to T GA at	43	Stop at 1586	Japanese	MM12	Hom	+Dde I
	5129
5245delG	del of G at	44	Frameshift	French	MM63	Hom	−Bpm I,
	5245 and G to						−BanII
	C at 5249, or						+AvaII,
	G to C at						+Sau96I
	5245 and del
	G at 5249
E1732X	G AG to T AG at	46	Stop at 1732	Spanish	MM73	Het	−Mbo II
	5567
2573-77	Del of ACCCA at	23	Frameshift	Italian	MM69	Hom	?Please provide
del ACCCA	2573-77
1 MM: Miyoshi myopathy; DMAT: distal myopathy with anterior tibial onset; LGMD: limb girdle muscular dystrophy
2 +: create a new restriction site, −: eliminate an existing restriction site.

Twelve of the eighteen different mutations are predicted to block dysferlin expression, either through nonsense or frameshift changes. Seven of the thirteen samples are homozygous and thus expected to result in complete loss of dysferlin function. For each mutated exon in these patients, at least 50 control DNA samples (100 chromosomes) were screened to determine the frequencies of the sequence variants. When possible, the parents and siblings of affected individuals were also screened to verify that defined mutations were appropriately co-inherited with the disease in each pedigree (FIG. 4 ). In two families (50, 58 in Table 2) heterozygous mutations were identified in one allele (respectively a missense mutation and a 2 bp deletion). Mutations in the other allele are presumed to have not been detected (or in three of the screened MM families) either because the mutant and normal SSCP products are indistinguishable or because the mutation lies outside of coding sequence (i.e., in the promoter or a regulatory region of an intron). The disease-associated mutations did not appear to arise in the population as common polymorphisms.

More mutations can be identified by using appropriate primer pairs to amplify an exon and analyze its sequence. The following primer pairs are useful for exon amplification.

Exon	Code	Primer Sequence
1	F408	5′-gacccacaagcggcgcctcgg-3′ {SEQ ID NO: 130}
	F4101	5′-gaccccggcgagggtggtcgg-3′ {SEQ ID NO: 131}
2	F4111	5′-tgtctctccattctcccttttgtg-3′ {SEQ ID NO: 132}
	R4111	5′-aggacactgctgagaaggcacctc-3′ {SEQ ID NO: 133}
3	F3262	5-agtgccctggtggcacgaagg-3′ {SEQ ID NO: 134}
	R3261	5-cctacctgcaccttcaagccatgg-3′ {SEQ ID NO: 135}
4	F3251	5-cagaagagccagggtgccttagg-3′ {SEQ ID NO: 136}
	R3251	5-ccttggaccttaacctggcagagg-3′ {SEQ ID NO: 137}
5	F3242	5-cgaggccagcgcaccaacctg-3′ {SEQ ID NO: 138}
	R3242	5-actgccggccattcttgctggg-3′ {SEQ ID NO: 139}
6	F3231	5-ccaggcctcattagggccctc-3′ (SEQ ID NO: 140}
	R3231	5-ctgaagaggagcctggggtcag-3′ {SEQ ID NO: 141}
7	F3222	5-ctgagatttctgactcttggggtg-3′ {SEQ ID NO: 142}
	R3211	5-aaggttctgccctcatgccccatg-3′ {SEQ ID NO: 143}
8	F3561	5-ctggcctgagggatcagcagg-3′ {SEQ ID NO: 144}
	R3561	5-gtgcatacatacagcccacggag-3′ {SEQ ID NO: 145}
9	F3551	5-gagctattgggttggccgtgtggg-3′ {SEQ ID NO: 146}
	R3552	5-accaacacggagaagtgagaactg-3′ {SEQ ID NO: 147}
10	F3201	5-ccacactttatttaacgctttggcgg-3′ {SEQ ID NO: 148}
	R3201	5-cagaaccaaaatgcaaggatacgg-3′ (SEQ ID NO: 149}
11	F3191	5-cttctgattctgggatcaccaaagg-3′ {SEQ ID NO: 150}
	F3191	5-ggaccgtaaggaagacccaggg-3′ {SEQ ID NO: 151}
12	F3181	5-cctgtgctcaggagcgcatgaagg-3′ {SEQ ID NO: 152}
	R3181	5-gcagacctcccacccaagggcg-3′ {SEQ ID NO: 153}
13	F3171	5-gagacagatgggggacagtcaggg-3′ {SEQ ID NO: 154}
	R3171	5-cctcccgagagaaccctcctg-3′ {SEQ ID NO: 155}
14	F3161	5-gggagcccagagtccccatgg-3′ {SEQ ID NO: 156}
	R3161	5-gggcctccttgggtttgctgg-3′ {SEQ ID NO: 157}
15	F3541	5-gcctccccagcatcctgccgg-3′ {SEQ ID NO: 158}
	R3541	5-tcactgagccgaatgaaactgagg-3′ {SEQ ID NO: 159}
16	F3531	5-tgtggcctgagttcctttcctgtg-3′ {SEQ ID NO: 160}
	R3531	5-ggtcaaagggcagaacgaagaggg-3′ {SEQ ID NO: 161}
17	F3151	5-cccgtccttctcccagccatg-3′ {SEQ ID NO: 162}
	R3151	5-ctcccctggttgtccccaagg-3′ {SEQ ID NO: 163}
18	F3141	5-cgacccctctgattgccacttgtg-3′ {SEQ ID NO: 164}
	R3141	5-ggcatcctgcccttgccaggg-3′ {SEQ ID NO: 165}
19	F3522	5-tctgtctcccctgctccttg-3′ {SEQ ID NO: 166}
	R3522	5-cttccctgccccgacgcccag-3′ {SEQ ID NO: 167}
20	F3121	5-gctcctcccgtgaccctctgg-3′ {SEQ ID NO: 103}
	R3121	5-gggtcccagccaggagcactg-3′ {SEQ ID NO: 104}
21	F3111	5-cagcgctcaggcccgtctctc-3′ {SEQ ID NO: 168}
	R3111	5-tgcataggcatgtgcagctttggg-3′ {SEQ ID NO: 169}
22	F3512	5-catgcaccctctgccctgtgg-3′ {SEQ ID NO: 170}
	R3512	5-agttgagccaggagaggtggg-3′ {SEQ ID NO: 171}
23	F3101	5-catcaggcgcattccatctgtccg-3′ {SEQ ID NO: 172}
	R3091	5-agcaggagagcagaagaagaaagg-3′ {SEQ ID NO: 173}
24	F3082	5-gtgtgtcaccatccccaccccg-3′ {SEQ ID NO: 174}
	R3082	5-caagagatgggagaaaggccttatg-3′ {SEQ ID NO: 175}
25	F3073	5-ctgggacatccggatcctgaagg-3′ {SEQ ID NO: 176}
	R3073	5-tccaggtagtgggaggcagagg-3′ {SEQ ID NO: 177}
26	F3061	5-tcccactacctggagctgccttgg-3′ {SEQ ID NO: 178}
	R3051	5-ggctctccccagccctccctg-3′ {SEQ ID NO: 179}
27	F3601	5-cagagcagcagagactctgaccag-3′ {SEQ ID NO: 180}
	R3601	5-tagaccccacctgcccctgag-3′ {SEQ ID NO: 181}
28	F3501	5-tcctctcattgcttgcctgttcgg-3′ {SEQ ID NO: 182}
	R3501	5-ttgagagcttgccggggatgg-3′ {SEQ ID NO: 183}
29	F3031	5-aagtgccaagcaatgagtgaccgg-3′ {SEQ ID NO: 184}
	R3021	5-ctcactcccacccaccacctg-3′ {SEQ ID NO: 185}
30	F3011	5-cccaccggcctctgagtctgc-3′ {SEQ ID NO: 186}
	R3001	5-accctacccaagccaggacaagtg-3′ {SEQ ID NO: 187}
31	F2141	5-gaatctgccataaccagcttcgtg-3′ {SEQ ID NO: 188}
	R2141	5-tatcaccccatagaggcctcgaag-3′ {SEQ ID NO: 189}
32	F2981	5-cagccactcactctggcacctctg-3′ {SEQ ID NO: 190}
	R2981	5-agcccacagtctctgactctcctg-3′ {SEQ ID NO: 191}
33	F2131	5-acatctctcagggtccctgctgtg-3′ #SEQ ID NO: 192}
	R2211	5-cctgtgaggggacgaggcagg-3′ {SEQ ID NO: 193}
34	F2202	5-gccctgggtaagggatgctgattc-3′ {SEQ ID NO: 194}
	R2202	5-cctgcctgggcctcctggatc-3′ {SEQ ID NO: 195}
35	F2111	5-gagggtgatgggggccttagg-3′ {SEQ ID NO: 196}
	R2112	5-gcaatcagtttgaagaaggaaagg-3′ {SEQ ID NO: 197}
36	F2102	5-cccctctcaccatctcctgatgtg-3′ {SEQ ID NO: 105}
	R2111	5-ggcttcaccttccctctacctcgg-3′ {SEQ ID NO: 106}
37	F2101	5-cacctttgtctccattctacctgc-3′ {SEQ ID NO: 198}
	R2101	5-ctcccagcccccacgcccagg-3′ {SEQ ID NO: 199}
38	F2091	5-ctgagccactctcctcattctgtg-3′ {SEQ ID NO: 200}
	R2091	5-tggaaggggacagtagggagg-3′ {SEQ ID NO: 201}
39	F2081	5-ggccagtgcgttcttcctcctc-3′ {SEQ ID NO: 202}
	R2071	5-tccctgacctgcccatcatctc-3′ {SEQ ID NO: 203}
40	F2061	5-gcccctgtcaggcctggatgg-3′ {SEQ ID NO: 204}
	R2061	5-tgacccaggcctccctggagg-3′ {SEQ ID NO: 205}
41	F2051	5-ctgaaatggtctctttctttctac-3′ {SEQ ID NO: 206}
	R2051	5-cacaccgactgtcagactgaagag-3′ {SEQ ID NO: 207}
42	F2041	5-ttgtcccctcctctaatccccatg-3′ {SEQ ID NO: 208}
	R2041	5-gggttagggacgtcttcgagg-3′ {SEQ ID NO: 209}
43	F2031	5-cagccaaaccatatcaacaatg-3′ {SEQ ID NO: 210}
	R2021	5-ctggggaggtgagggctctag-3′ {SEQ ID NO: 211}
44	F2011	5-gaagtgttttgtctcctcctc-3′ {SEQ ID NO: 212}
	R2011	5-gcaggcagccagcccccatc-3′ {SEQ ID NO: 213}
45	F1021	5-gggtgccctgtgttggctgac-3′ {SEQ ID NO: 214}
	R1031	5-gcaggcagccagcccccatc-3′ {SEQ ID NO: 215}
46	F1041	5-ctcgtctatgtcttgtgcttgctc-3′ {SEQ ID NO: 216}
	R1051	5-caccatggtttggggtcatgtgg-3′ {SEQ ID NO: 217}
47	F1061	5-tctcgcttccccagctcctgc-3′ {SEQ ID NO: 218}
	R1061	5-tctggagttcgaggactctggg-3′ {SEQ ID NO: 219}
48	F1071	5-agaagggtggggagagaacgg-3′ {SEQ ID NO: 220}
	R1071	5-cagctcagagcctgtggctgg-3′ {SEQ ID NO: 221}
49	F1082	5-aaggccttcccatcctttggtagg-3′ {SEQ ID NO: 222}
	R1082	5-acaacccagagggagcacggg-3′ {SEQ ID NO: 223}
50	F1092	5-gttgacgatgtatatactgtgttgg-3′ {SEQ ID NO: 224}
	R1091	5-gctggcaccacagggaatcgg-3′ {SEQ ID NO: 110}
51	F1102	5-gcctctctctaactttgcttccttg-3′ {SEQ ID NO: 225}
	R1101	5-agcccccatgtgcagaatggg-3′ {SEQ ID NO: 112}
52	F1112	5-ggctacaggctggcagtgatcgag-3′ {SEQ ID NO: 226}
	R1112	5-ttcccccatgccctccactgg-3′ {SEQ ID NO: 227}
53	F1121	5-agccttcgtgcccctaaccaagtg-3′ {SEQ ID NO: 228}
	R1121	5-ctgtgggcattggggctcagg-3′ {SEQ ID NO: 229}
54	F1141	5-ggatgcccagttgactccggg-3′ {SEQ ID NO: 115}
	R1141	5-ccccaccacagtgtcgtcagg-3′ {SEQ ID NO: 116}
55	F1151	5-gccccagtgggatcaccatg-3′ {SEQ ID NO: 230}
	R116	5-atgctggaggggaccccacgg-3′ {SEQ ID NO: 231}

Comparison of Dysferlin with Other Proteins

The 6,243 bp ORF of this candidate MM gene is predicted to encode 2,080 amino acids ( FIGS. 1C and 2 ; SEQ ID NO:2). At the amino acid level, this protein is highly homologous to the nematode ( Caenorhabditis elegans ) protein fer-1 (27% identical, 57% identical or similar: the sequence alignment and comparison was performed using http://vega.igh.cnrs.fr/bin/nph-align_query.pl.) (Argon & Ward, 1980, Genetics 96:413-33; Achanzar & Ward, 1997, J. Cell Science 110:1073-81). This dystrophy-associated, fer-1-like protein has therefore been designated “dysferlin.”

The fer-1 protein was originally identified through molecular genetic analysis of a class of fertilization-defective C. elegans mutants in which spermatogenesis is abnormal (Argon & Ward, 1980, Genetics 96:413-33). The mutant fer-1 spermatozoa have defective mobility and show imperfect fusion of membranous organelles (Ward et al., 1981, J. Cell Bio. 91:26-44). Like fer-1, dysferlin is a large protein with an extensive, highly charged hydrophilic region and a single predicted membrane spanning region at the carboxy terminus (FIG. 3 ). There is a membrane retention sequence 3′ to the membrane spanning stretch, indicating that the protein may be preferentially targeted to either endoplasmic or sarcoplasmic reticulum, probably as a Type II protein (i.e. with the NH 2 end and most of the following protein located within the cytoplasm) (FIG. 1 C). Several nuclear membrane targeting sequences are predicted within the cytoplasmic domain of the protein (http://psort.nibb.ac.jp/form.html). Immunocytochemical detection of dysferlin suggests that dysferlin is targeted to or anchored within the sarcoplasmic reticulum.

The cytoplasmic component of this protein contains four motifs homologous to C2 domains. C2 domains are intracellular protein modules composed of 80-130 amino acids (Rizo & Sudhof, 1998, J. Biol. Chem. 273:15897). Originally identified within a calcium-dependent isoform of protein kinase C (Nishizuka, 1988, Nature 334:661-65), C2 domains are present in numerous proteins. These domains often arise in approximately homologous pairs described as double C2 or DOC2 domains. One DOC2 protein, DOC2α, is brain specific and highly concentrated in synaptic vesicles (Orita et al., 1995, Biochem. Biophys. Res. Comm. 206:439-48), while another, DOC2β, is ubiquitously expressed (Sakaguchi et al., 1995, Biochem. Biophys. Res. Comm. 217:1053-61). Many C2 modules can fold to bind calcium, thereby initiating signaling events such as phospholipid binding. At distal nerve terminals, for example, the synaptic vesicle protein synaptotagmin has two C2 domains that, upon binding calcium, permit this protein to interact with syntaxin, triggering vesicle fusion with the distal membrane and neurotransmitter release (Sudhof & Rizo, 1996, Neuron 17:379-88).

The four dysferlin C2 domains are located at amino acid positions 32-82, 431-475, 1160-1241, and 1582-1660 (FIGS. 1 C and 3 ). Indeed, it is almost exclusively through these regions that dysferlin has homology to any proteins other than fer-1. Each of these segments in dysferlin is considerably smaller than a typical C2 domain. Moreover, these segments are more widely separated in comparison with the paired C2 regions in synaptotagmin, DOC2α and β and related C2-positive proteins. For this reason, it is difficult to predict whether the four relatively short C2 domains in dysferlin function analogously to conventional C2 modules. That dysferlin might, by analogy with synaptotagmin, signal events such as membrane fusion is suggested by the fact that fer-1 deficient worms show defective membrane organelle fusion within spermatozoa (Ward et al., 1981, J. Cell Bio. 91:26-44).

The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

EXAMPLES

Example 1

Production of Dysferlin Protein

Standard methods can be used to synthesize either wild type or mutant dysferlin, or fragments of either. These methods can also be used to synthesize brain-specific dysferlin polypeptides including full-length or fragments (e.g., a polypeptide unique to brain-specific dysferlin). For example, a recombinant expression vector encoding dysferlin (or a fragment thereof: e.g., dysferlin minus its membrane-spanning region) operably linked to appropriate expression control sequences can be used to express dysferlin in a prokaryotic (e.g., E.coli ) or eukaryotic host (e.g., insect cells, yeast cells, or mammalian cells). The protein is then purified by standard techniques. If desired, DNA encoding part or all of the dysferlin sequence can be joined in-frame to DNA encoding a different polypeptide, to produce a chimeric DNA that encodes a hybrid polypeptide. This can be used, for example, to add a tag that will simplify identification or purification of the expressed protein, or to render the dysferlin (or fragment thereof) more immunogenic.

The preferred means for making short peptide fragments of dysferlin is by chemical synthesis. These fragments, like dysferlin itself, can be used to generate antibodies, or as positive controls for antibody-based assays.

Fusion proteins are useful, e.g., for generating antibodies. Such fusion proteins are generated using known methods. In one example, to construct glutathione S-transferase (GST):dysferlin fusion proteins, the BLAST program (Altschul et al., 1990, J. Molec. Biol. 215:403-410) was used to identify three regions of the dysferlin cDNA that show no homology to any known human proteins (FIG. 1 ). These were subcloned from the dysferlin cDNA as BstYI (881-1333), XmnI (1990-2718) and SalI (5364-5732) fragments ligated respectively into BamHI, SmaI and SalI sites of pGEX-5X-3 (Pharmacia). The three fragments correspond to amino acid sequences at amino acid locations 253-403, 624-865, and 1664-1786 of SEQ ID NO:2, respectively. The resulting GST fusion proteins of BamHI (43 kDa) and SmaI (53.3 kDa) formed isoluble aggregates that were isolated by SDS-PAGE. The fusion protein of SalI (40.2 kDa) was soluble and thus could be purified using a glutathione Sepharose 4B column; the SalI dysferlin fragment (14.2 kDa) was isolated by cleavage from GST using Factor Xa protease. The eluted protein was concentrated and further purified by SDS-PAGE. For all three of the fusion peptides, the resulting SDS-PAGE bands were excised and used to immunize rabbits.

Example 2

Production and Characterization of Anti-dysferlin Antibodies

Techniques for generating both monoclonal and polyclonal antibodies specific for a particular protein are well known. The antibodies can be raised against a short peptide epitope of dysferlin, an epitope linked to a known immunogen to enhance immunogenicity, a long fragment of dysferlin, or the intact protein. Antibodies can also be raised against brain-specific dysferlin polypeptides, e.g., against amino acids 1-24 of SEQ ID NO:233. Such antibodies raised against dysferlin or brain-specific dysferlin polypeptides are useful for e.g., localizing such polypeptides in tissue sections or fractionated cell preparations and diagnosing dysferlin-related disorders.

An isolated dysferlin protein, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that bind dysferlin using standard techniques for polyclonal and monoclonal antibody preparation. The dysferlin immunogen can also be a mutant dysferlin or a fragment of a mutant dysferlin. A full-length dysferlin protein can be used or, alternatively, antigenic peptide fragments of dysferlin can be used as immunogens. The antigenic peptide of dysferlin comprises at least 8 (preferably 10, 15, 20, or 30) amino acid residues of the amino acid sequence shown in SEQ ID NO:2 and encompasses an epitope of such that an antibody raised against the peptide forms a specific immune complex with dysferlin. Preferred epitopes encompassed by the antigenic peptide are regions of dysferlin that are located on the surface of the protein, e.g., hydrophilic regions.

A dysferlin immunogen typically is used to prepare antibodies by immunizing a suitable subject (e.g., rabbit, goat, mouse or other mammal) with the immunogen. An appropriate immunogenic preparation can contain, for example, recombinantly expressed dysferlin protein or a chemically synthesized dysferlin polypeptide. The preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or similar immunostimulatory agent. Immunization of a suitable subject with an immunogenic dysferlin preparation induces a polyclonal anti-dysferlin antibody response.

Polyclonal anti-dysferlin antibodies (“dysferlin antibodies”) can be prepared as described above by immunizing a suitable subject with a dysferlin immunogen. The dysferlin antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized dysferlin. If desired, the antibody molecules directed against dysferlin can be isolated from the mammal (e.g., from the blood) and further purified by well-known techniques, such as protein A chromatography to obtain the IgG fraction. At an appropriate time after immunization, e.g., when the dysferlin antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975) Nature 256:495-497, the human B cell hybridoma technique (Kozbor et al. (1983) Immunol. Today 4:72), the EBV-hybridoma technique (Cole et al. (1985), Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96) or trioma techniques. The technology for producing hybridomas is well known (see generally Current Protocols in Immunology (1994) Coligan et al. (eds.) John Wiley & Sons, Inc., New York, N.Y.). Briefly, an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) from a mammal immunized with a dysferlin immunogen as described above, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds dysferlin.

Any of the many well known protocols used for fusing lymphocytes and immortalized cell lines can be applied for the purpose of generating a monoclonal antibody against dysferlin (see, e.g., Current Protocols in Immunology, supra; Galfre et al. (1977) Nature 266:55052; R. H. Kenneth, in Monoclonal Antibodies: A New Dimension In Biological Analyses, Plenum Publishing Corp., New York, N.Y. (1980); and Lerner (1981) Yale J. Biol. Med., 54:387-402. Moreover, the one in the art will appreciate that there are many variations of such methods which also would be useful. Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind dysferlin, e.g., using a standard ELISA assay.

Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal dysferlin antibody can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with dysferlin to thereby isolate immunoglobulin library members that bind dysferlin. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP™ Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, U.S. Pat. No. 5,223,409; PCT Publication No. WO 92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO 92/20791; PCT Publication No. WO 92/15679; PCT Publication No. WO 93/01288; PCT Publication No. WO 92/01047; PCT Publication No. WO 92/09690; PCT Publication No. WO 90/02809; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum. Antibod. Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffiths et al. (1993) EMBO J. 12:725-734.

As an example, two polyclonal antisera were raised for each of the fusion peptide antigens described above using New Zealand White rabbits. The rabbits were injected with 0.5 mg of antigen using keyhole limpet hemocyanin (KLH) as the adjuvent. Booster injections of 0.25 mg antigen were administered every three weeks over 12 weeks. Serum was prepared from the rabbits and was purified using affinity column chromatography (HiTrap; Pharmacia) or antigen-blotted polyvinylidene difluoride (PVDF) membrane.

Immunoblotting was used to verify that the affinity-purified antisera recognize the cognate fusion peptides by Western immunoblotting (WIB) and that this reactivity was immunoadsorbed by pre-incubation of the antisera with the peptides. Thus, antiserum raised against the polypeptide encoded by the SalI fragment (encoding amino acids 1664-1786) identified the fragment both as a cleaved, 14.2 kDa fragment and as a component of the 40.2 kDa GST-SalI fusion peptide. No reactivity was evident in the fraction containing only the GST fusion partner. Immunoadsorption entirely abolished this staining. Analogous results were detected with all six antisera (to the three different target fusion peptides).

Preparation of Subcellular Fractions

Frozen human muscle (0.3 g) was homogenized in five volumes of 0.25 M sucrose containing proteinase inhibitor (Complete, Boehringer). Subcellular fractions of nuclei, mitochondria, microsomes, and cytosol were separated by differential centrifugation. The purity of each fraction was evaluated by immunoblotting of fraction-specific proteins with antibodies to histone H1 (Calbiochem), cytochrome c (Santa Cruz), Na + —K + ATPase α1 subunit (Research Diagnostics) and cytosolic superoxide dismutase (Calbiochem).

Dysferlin in Subcellular Fractions

Immunoblotting was used to analyze dysferlin expression. Twenty μg of each subcellular fraction and 40 μg of whole homogenate of muscle were separated by SDS-PAGE (4-15% gradient gel) and transferred to a nitrocellulose membrane. Immunoblotting was performed according to standard methods, using chemiluminescence (ECL, Amersham).

Immunoblotting of multi-tissue blots identified prominent dysferlin positively at approximately 230 kDa in heart, placenta, skeletal muscle and kidney. Little or no immuno-positive staining was detected in brain, liver, spleen, ovary, or testis. Lower molecular weight bands (approximately 40 kDa) were also evident. Immunoadsorption with the corresponding fusion peptide abolished both the large and the smaller bands. The 230 kDa band was observed with all of the affinity purified, anti-dysferlin antisera.

Immunoblotting of fractionated human muscle documented distinct 230 kDa bands in the whole muscle homogenate an in microsomal and nuclear fractions. Some immunoreactivity was also evident in the nuclear and mitochondrial fractions. No immunoreactivity was detected in the cytosolic fractions. This pattern was seen with all of the anti-dysferlin antisera, and was eliminated by immunoadsorption. The identity of the assayed fractions was verified by Western blotting using fraction-specific antibodies: histone HI for the nuclear fraction, cytochrome c for the mitochondrial fraction, Na + —K + ATPase α1-subunit for the microsomal fraction, and SOD1 for the cytosolic fraction.

Example 3

Diagnosis

The discovery of mutations in the dysferlin gene that are associated with the MM and LMGD2B phenotypes means that individuals can be tested for the disease gene before symptoms appear. This will permit genetic testing and counseling of those with a family history of the disease. Additionally, individuals diagnosed with the genetic defect can be closely monitored for the appearance of symptoms, thereby permitting early intervention, including genetic therapy, as appropriate. Individuals with a brain-specific dysferlin-related disorder can be diagnosed using such methods.

Diagnosis can be carried out on any suitable genomic DNA sample from the individual to be tested. Typically, a blood sample from an adult or child, or a sample of placental or umbilical cord cells of a newborn would be used; alternatively, one could utilize a fetal sample obtained by amniocentesis or chorionic villi sampling.

It is expected that standard genetic diagnostic methods can be used. For example, PCR can be utilized to identify the presence of a deletion, addition, or substitution of one or more nucleotides within any one of the exons of dysferlin. Following the PCR reaction, the PCR product can be analyzed by methods such as a heteroduplex detection technique based upon that of White et al. (1992, Genomics 12:301-06), or by techniques such as cleavage of RNA-DNA hybrids using RNase A (Myers et al., 1985, Science 230:1242-46), single-stranded conformation polymorphism (SSCP) analysis (Orita et al., 1989, Genomics 10:298-99), di-deoxy-fingerprinting (DDF) (Blaszyk et al., 1995, Biotechniques 18: 256-260) and denaturing gradient gel electrophoresis (DGGE; Myers et al., 1987, Methods Enzymol. 155:501-27). The PCR may be carried out using a primer which adds a G+C rich sequence (termed a “GC-clamp”) to one end of the PCR product, thus improving the sensitivity of the subsequent DGGE procedure (Sheffield et al., 1989, Proc. Natl. Acad. Sci. USA 86:232-36). If the particular mutation present in the patient's family is known to have removed or added a restriction site, or to have significantly increased or decreased the length of a particular restriction fragment, a protocol based upon restriction fragment length polymorphism (RFLP) analysis (perhaps combined with PCR) may be appropriate.

The apparent genetic heterogeneity resulting in the MM/LGMD2B phenotypes means that the nature of the particular mutation carried by affected individuals in the patient's family may have to be ascertained prior to attempting genetic diagnosis of the patient. Alternatively, a battery of tests designed to identify any of several mutations known to result in MM/LGMD2B may be utilized to screen individuals without a defined familial genotype. The analysis can be carried out on any genomic DNA derived from the patient, typically from a blood sample.

Instead of basing the diagnosis on analysis of the genomic DNA of a patient, one could seek evidence of the mutation in the level or nature of the relevant expression products. Well-known techniques for analyzing expression include mRNA-based methods, such as Northern blots and in situ hybridization (using a nucleic acid probe derived from the relevant cDNA), and quantitative PCR (as described in St-Jacques et al., 1994, Endocrinology 134:2645-57). One could also employ polypeptide based methods, including the use of antibodies specific for the polypeptide of interest. These techniques permit quantitation of the amount of expression of a given gene in the tissue of interest, at least relative to positive and negative controls. One would expect an individual who is heterozygous for a genetic defect affecting the level of expression of dysferlin to show up to a 50% loss of expression of this gene in such a hybridization or antibody-based assay. An antibody specific for the carboxy terminal end would be likely to pick up (by failure to bind to) most or all frameshift and premature termination signal mutations, as well as deletions of the carboxy terminal sequence. Use of a battery of monoclonal antibodies specific for different epitopes of dysferlin would be useful for rapidly screening cells to detect those expressing mutant forms of dysferlin (i.e., cells which bind to some dysferlin-specific monoclonal antibodies, but not to others), or for quantifying the level of dysferlin on the surface of cells. One could also use a protein truncation assay (Heim et al., 1994, Nature Genetics 8:218-19) to screen for any genetic defect which results in the production of a truncated polypeptide instead of the wild type protein.

Use of Immunodetection to Identify Normal and Disease-associated Dysferlin

In the following example, immunodetection methods are used to demonstrate a detectable difference in muscles homogenates between normal and disease-associated dysferlin alleles.

Frozen muscle samples (quadriceps) were homogenized in ten volumes of SDS-PAGE sample buffer and boiled for 5 minutes. The final loading volume of SDS-PAGE was adjusted after densitometric measurements (NIH Image) of myosin heavy chain on the Coomassie blue stained gels. Studies were performed on six MM, two LGMD-2B, and three normal muscle samples.

Immunocytochemistry was performed on 8 micron cryostat sections of the muscle that were fixed in 100% cold acetone for 5 minutes and preincubated with PBS containing 1% BSA, 5% heat-inactivated goat serum and 0.2% Triton®X-100. The sections were incubated with primary antibodies overnight at 4° C. and fluorescein-labeled secondary (TAGO Immunologicals) for 30 minutes at room temperature. The primary antibodies were applied in two double staining combinations: SalI-1 anti-dysferlin and anti-dystrophin antibodies, and SalI-2 anti-dysferlin and anti-δ-sarcoglycan antibodies. The sections were mounted in SlowFade (Molecular Probes).

The 230 kDA antigen was absent in samples from all five MM patient in immunoblot assays. All five patients had normal patterns of dystrophin expression. Genetic analysis of the dysferlin gene in the patients predicted that at least two of the five MM patients should have no full-length protein. Two of the other three patients had mutations in at least one allele that are predicted to eliminate normal dysferlin expression. In all five patients, absence of dysferlin immuno-staining was documented with at least two other anti-dysferlin anti-sera.

Immunostaining of dysferlin, dystrophin and δ-sarcoglycan proteins demonstrated distinct membrane-associated positivity for each protein in normal muscle. By contrast, in both MM and LGMD-2B muscle the dysferlin protein was absent, while the dystrophin and δ-sarcoglycan proteins appeared normal.

Therapeutic Treatment

A patient with MM/LGMD2B, or an individual genetically susceptible to contracting one or both of these diseases, can be treated by supplying dysferlin therapeutic agents of the present invention. Dysferlin therapeutic agents include a DNA or a subgenomic polynucleotide coding for a functional dysferlin protein. A DNA (e.g., a cDNA) is prepared which encodes the wild type form of the gene operably linked to expression control elements (e.g., promoter and enhancer) that induce expression in skeletal muscle cells or any other affected cells. The DNA may be incorporated into a vector appropriate for transforming the cells, such as a retrovirus, adenovirus, or adeno-associated virus. One of the many other known types of techniques for introducing DNA into cells in vivo may be used (e.g., liposomes). Particularly useful would be naked DNA techniques, since naked DNA is known to be readily taken up by skeletal muscle cells upon injection into muscle. Wildtype dysferlin protein can also be administered to an individual who either expresses mutant dysferlin protein or expresses an inadequate amount of dysferlin protein, e.g., a MM/LGMD2B patient.

Administration of the dysferlin therapeutic agents of the invention can include local or systemic administration, including injection, oral administration, particle gun, or catheterized administration, and topical administration. Various methods can be used to administer the therapeutic dysferlin composition directly to a specific site in the body. For example, a specific muscle can be located and the therapeutic dysferlin composition injected several times in several different locations within the body of the muscle.

The therapeutic dysferlin composition can be directly administered to the surface of the muscle, for example, by topical application of the composition. X-ray imaging can be used to assist in certain of the above delivery methods. Combination therapeutic agents, including a dysferlin protein or polypeptide or a subgenomic dysferlin polynucleotide and other therapeutic agents, can be administered simultaneously or sequentially.

Receptor-mediated targeted delivery of therapeutic compositions containing dysferlin subgenomic polynucleotides to specific tissues can also be used. Receptor-mediated DNA delivery techniques are described in, for example, Findeis et al. (1993), Trends in Biotechnol. 11, 202-05; Chiou et al. (1994), Gene Therapeutics: Methods and Applications of Direct Gene Transfer (J. A. Wolff, ed.); Wu & Wu (1988), J. Biol. Chem. 263, 621-24; Wu et al. (1994), J. Biol. Chem. 269, 542-46; Zenke et al. (1990), Proc. Natl. Acad. Sci. U.S.A. 87, 3655-59; Wu et al. (1991), J. Biol. Chem. 266, 338-42.

Alternatively, a dysferlin therapeutic composition can be introduced into human cells ex vivo, and the cells then implanted into the human. Cells can be removed from a variety of locations including, for example, from a selected muscle. The removed cells can then be contacted with the dysferlin therapeutic composition utilizing any of the above-described techniques, followed by the return of the cells to the human, preferably to or within the vicinity of a muscle. The above-described methods can additionally comprise the steps of depleting fibroblasts or other contaminating non-muscle cells subsequent to removing muscle cells from a human.

Both the dose of the dysferlin composition and the means of administration can be determined based on the specific qualities of the therapeutic composition, the condition, age, and weight of the patient, the progression of the disease, and other relevant factors. If the composition contains dysferlin protein or polypeptide, effective dosages of the composition are in the range of about 1 μg to about 100 mg/kg of patient body weight, e.g., about 50 μg to about 50 mg/kg of patient body weight, e.g., about 500 μg to about 5 mg/kg of patient body weight.

Therapeutic compositions containing dysferlin subgenomic polynucleotides can be administered in a range of about 0.1 μg to about 10 mg of DNA/dose for local administration in a gene therapy protocol. Concentration ranges of about 0.1 μg to about 10 mg, e.g., about 1 μg to about 1 mg, e.g., about 10 μg to about 100 μg of DNA can also be used during a gene therapy protocol. Factors such as method of action and efficacy of transformation and expression are considerations that will effect the dosage required for ultimate efficacy of the dysferlin subgenomic polynucleotides. Where greater expression is desired over a larger area of tissue, larger amounts of dysferlin subgenomic polynucleotides or the same amounts readministered in a successive protocol of administrations, or several administrations to different adjacent or close tissue portions of for example, a muscle site, may be required to effect a positive therapeutic outcome. In all cases, routine experimentation in clinical trials will determine specific ranges for optimal therapeutic effect.

Animal Model

A line of transgenic animals (e.g., mice, rats, guinea pigs, hamsters, rabbits, or other mammals) can be produced bearing a transgene encoding a defective form of dysferlin. Standard methods of generating such transgenic animals would be used, e.g., as described below.

Alternatively, standard methods of producing null (i.e., knockout) mice could be used to generate a mouse which bears one defective and one wild type allele encoding dysferlin. If desired, two such heterozygous mice could be crossed to produce offspring which are homozygous for the mutant allele. The homozygous mutant offspring would be expected to have a phenotype comparable to the human MM and/or LGMD2B phenotype, and so serve as models for the human disease.

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

A transgenic animal of the invention can be created by introducing a nucleic acid encoding a dysferlin mutation into the male pronuclei of a fertilized oocyte, e.g., by microinjection or retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. A dysferlin cDNA sequence e.g., that of (SEQ ID NO:1 or SEQ ID NO:3) can be introduced as a transgene into the genome of a non-human animal. Alternatively, a nonhuman homologue of the human dysferlin gene can be isolated based on hybridization to the human dysferlin sequence (e.g., cDNA) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, U.S. Pat. No. 4,873,191 and in Hogan, Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the mutant dysferlin transgene in its genome and/or expression of the mutant dysferlin mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene encoding a mutant dysferlin can further be bred to other transgenic animals carrying other transgenes.

To create an homologously recombinant animal, a vector is prepared which contains at least a portion of a dysferlin gene into which a deletion, addition or substitution has been introduced to thereby alter a dysferlin gene. In a preferred embodiment, the vector is designed such that, upon homologous recombination, the endogenous dysferlin gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a “knock out” vector). Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous dysferlin gene is mutated or otherwise altered (e.g., contains one of the mutations described in Table 2). In the homologous recombination vector, the altered portion of the dysferlin sequence is flanked at its 5′ and 3′ ends by additional nucleic acid of the dysferlin gene to allow for homologous recombination to occur between the exogenous dysferlin nucleic acid sequence carried by the vector and an endogenous dysferlin gene in an embryonic stem cell. The additional flanking dysferlin nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5′ and 3′ ends) are included in the vector (see, e.g., Thomas and Capecchi (1987) Cell 51:503 for a description of homologous recombination vectors). The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced dysferlin sequence has homologously recombined with the endogenous dysferlin gene are selected (see, e.g., Li et al. (1992) Cell 69:915). The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras (see, e.g., Bradley in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach , Robertson, ed. (IRL, Oxford, 1987) pp. 113-152). A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley (1991) Current Opinion in Bio/Technology 2:823-829 and in PCT Publication Nos. WO 90/11354, WO 91/01140, WO 92/0968, and WO 93/04169.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

233 1 6911 DNA Homo sapiens CDS (374)...(6613) 1tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agc atg ctg agg gtc ttc atc ctc tat gcc gag aac gtc 409 Met Leu Arg Val Phe Ile Leu Tyr Ala Glu Asn Val 1 5 10cac aca ccc gac acc gac atc agc gat gcc tac tgc tcc gcg gtg ttt 457His Thr Pro Asp Thr Asp Ile Ser Asp Ala Tyr Cys Ser Ala Val Phe 15 20 25gca ggg gtg aag aag aga acc aaa gtc atc aag aac agc gtg aac cct 505Ala Gly Val Lys Lys Arg Thr Lys Val Ile Lys Asn Ser Val Asn Pro 30 35 40gta tgg aat gag gga ttt gaa tgg gac ctc aag ggc atc ccc ctg gac 553Val Trp Asn Glu Gly Phe Glu Trp Asp Leu Lys Gly Ile Pro Leu Asp 45 50 55 60cag ggc tct gag ctt cat gtg gtg gtc aaa gac cat gag acg atg ggg 601Gln Gly Ser Glu Leu His Val Val Val Lys Asp His Glu Thr Met Gly 65 70 75agg aac agg ttc ctg ggg gaa gcc aag gtc cca ctc cga gag gtc ctc 649Arg Asn Arg Phe Leu Gly Glu Ala Lys Val Pro Leu Arg Glu Val Leu 80 85 90gcc acc cct agt ctg tcc gcc agc ttc aat gcc ccc ctg ctg gac acc 697Ala Thr Pro Ser Leu Ser Ala Ser Phe Asn Ala Pro Leu Leu Asp Thr 95 100 105aag aag cag ccc aca ggg gcc tcg ctg gtc ctg cag gtg tcc tac aca 745Lys Lys Gln Pro Thr Gly Ala Ser Leu Val Leu Gln Val Ser Tyr Thr 110 115 120ccg ctg cct gga gct gtg ccc ctg ttc ccg ccc cct act cct ctg gag 793Pro Leu Pro Gly Ala Val Pro Leu Phe Pro Pro Pro Thr Pro Leu Glu125 130 135 140ccc tcc ccg act ctg cct gac ctg gat gta gtg gca gac aca gga gga 841Pro Ser Pro Thr Leu Pro Asp Leu Asp Val Val Ala Asp Thr Gly Gly 145 150 155gag gaa gac aca gag gac cag gga ctc act gga gat gag gcg gag cca 889Glu Glu Asp Thr Glu Asp Gln Gly Leu Thr Gly Asp Glu Ala Glu Pro 160 165 170ttc ctg gat caa agc gga ggc ccg ggg gct ccc acc acc cca agg aaa 937Phe Leu Asp Gln Ser Gly Gly Pro Gly Ala Pro Thr Thr Pro Arg Lys 175 180 185cta cct tca cgt cct ccg ccc cac tac ccc ggg atc aaa aga aag cga 985Leu Pro Ser Arg Pro Pro Pro His Tyr Pro Gly Ile Lys Arg Lys Arg 190 195 200agt gcg cct aca tct aga aag ctg ctg tca gac aaa ccg cag gat ttc 1033Ser Ala Pro Thr Ser Arg Lys Leu Leu Ser Asp Lys Pro Gln Asp Phe205 210 215 220cag atc agg gtc cag gtg atc gag ggg cgc cag ctg ccg ggg gtg aac 1081Gln Ile Arg Val Gln Val Ile Glu Gly Arg Gln Leu Pro Gly Val Asn 225 230 235atc aag cct gtg gtc aag gtt acc gct gca ggg cag acc aag cgg acg 1129Ile Lys Pro Val Val Lys Val Thr Ala Ala Gly Gln Thr Lys Arg Thr 240 245 250cgg atc cac aag gga aac agc cca ctc ttc aat gag act ctt ttc ttc 1177Arg Ile His Lys Gly Asn Ser Pro Leu Phe Asn Glu Thr Leu Phe Phe 255 260 265aac ttg ttt gac tct cct ggg gag ctg ttt gat gag ccc atc ttt atc 1225Asn Leu Phe Asp Ser Pro Gly Glu Leu Phe Asp Glu Pro Ile Phe Ile 270 275 280acg gtg gta gac tct cgt tct ctc agg aca gat gct ctc ctc ggg gag 1273Thr Val Val Asp Ser Arg Ser Leu Arg Thr Asp Ala Leu Leu Gly Glu285 290 295 300ttc cgg atg gac gtg ggc acc att tac aga gag ccc cgg cac gcc tat 1321Phe Arg Met Asp Val Gly Thr Ile Tyr Arg Glu Pro Arg His Ala Tyr 305 310 315ctc agg aag tgg ctg ctg ctc tca gac cct gat gac ttc tct gct ggg 1369Leu Arg Lys Trp Leu Leu Leu Ser Asp Pro Asp Asp Phe Ser Ala Gly 320 325 330gcc aga ggc tac ctg aaa aca agc ctt tgt gtg ctg ggg cct ggg gac 1417Ala Arg Gly Tyr Leu Lys Thr Ser Leu Cys Val Leu Gly Pro Gly Asp 335 340 345gaa gcg cct ctg gag aga aaa gac ccc tct gaa gac aag gag gac att 1465Glu Ala Pro Leu Glu Arg Lys Asp Pro Ser Glu Asp Lys Glu Asp Ile 350 355 360gaa agc aac ctg ctc cgg ccc aca ggc gta gcc ctg cga gga gcc cac 1513Glu Ser Asn Leu Leu Arg Pro Thr Gly Val Ala Leu Arg Gly Ala His365 370 375 380ttc tgc ctg aag gtc ttc cgg gcc gag gac ttg ccg cag atg gac gat 1561Phe Cys Leu Lys Val Phe Arg Ala Glu Asp Leu Pro Gln Met Asp Asp 385 390 395gcc gtg atg gac aac gtg aaa cag atc ttt ggc ttc gag agt aac aag 1609Ala Val Met Asp Asn Val Lys Gln Ile Phe Gly Phe Glu Ser Asn Lys 400 405 410aag aac ttg gtg gac ccc ttt gtg gag gtc agc ttt gcg ggg aaa atg 1657Lys Asn Leu Val Asp Pro Phe Val Glu Val Ser Phe Ala Gly Lys Met 415 420 425ctg tgc agc aag atc ttg gag aag acg gcc aac cct cag tgg aac cag 1705Leu Cys Ser Lys Ile Leu Glu Lys Thr Ala Asn Pro Gln Trp Asn Gln 430 435 440aac atc aca ctg cct gcc atg ttt ccc tcc atg tgc gaa aaa atg agg 1753Asn Ile Thr Leu Pro Ala Met Phe Pro Ser Met Cys Glu Lys Met Arg445 450 455 460att cgt atc ata gac tgg gac cgc ctg act cac aat gac atc gtg gct 1801Ile Arg Ile Ile Asp Trp Asp Arg Leu Thr His Asn Asp Ile Val Ala 465 470 475acc acc tac ctg agt atg tcg aaa atc tct gcc cct gga gga gaa ata 1849Thr Thr Tyr Leu Ser Met Ser Lys Ile Ser Ala Pro Gly Gly Glu Ile 480 485 490gaa gag gag cct gca ggt gct gtc aag cct tcg aaa gcc tca gac ttg 1897Glu Glu Glu Pro Ala Gly Ala Val Lys Pro Ser Lys Ala Ser Asp Leu 495 500 505gat gac tac ctg ggc ttc ctc ccc act ttt ggg ccc tgc tac atc aac 1945Asp Asp Tyr Leu Gly Phe Leu Pro Thr Phe Gly Pro Cys Tyr Ile Asn 510 515 520ctc tat ggc agt ccc aga gag ttc aca ggc ttc cca gac ccc tac aca 1993Leu Tyr Gly Ser Pro Arg Glu Phe Thr Gly Phe Pro Asp Pro Tyr Thr525 530 535 540gag ctc aac aca ggc aag ggg gaa ggt gtg gct tat cgt ggc cgg ctt 2041Glu Leu Asn Thr Gly Lys Gly Glu Gly Val Ala Tyr Arg Gly Arg Leu 545 550 555ctg ctc tcc ctg gag acc aag ctg gtg gag cac agt gaa cag aag gtg 2089Leu Leu Ser Leu Glu Thr Lys Leu Val Glu His Ser Glu Gln Lys Val 560 565 570gag gac ctt cct gcg gat gac atc ctc cgg gtg gag aag tac ctt agg 2137Glu Asp Leu Pro Ala Asp Asp Ile Leu Arg Val Glu Lys Tyr Leu Arg 575 580 585agg cgc aag tac tcc ctg ttt gcg gcc ttc tac tca gcc acc atg ctg 2185Arg Arg Lys Tyr Ser Leu Phe Ala Ala Phe Tyr Ser Ala Thr Met Leu 590 595 600cag gat gtg gat gat gcc atc cag ttt gag gtc agc atc ggg aac tac 2233Gln Asp Val Asp Asp Ala Ile Gln Phe Glu Val Ser Ile Gly Asn Tyr605 610 615 620ggg aac aag ttc gac atg acc tgc ctg ccg ctg gcc tcc acc act cag 2281Gly Asn Lys Phe Asp Met Thr Cys Leu Pro Leu Ala Ser Thr Thr Gln 625 630 635tac agc cgt gca gtc ttt gac ggg tgc cac tac tac tac cta ccc tgg 2329Tyr Ser Arg Ala Val Phe Asp Gly Cys His Tyr Tyr Tyr Leu Pro Trp 640 645 650ggt aac gtg aaa cct gtg gtg gtg ctg tca tcc tac tgg gag gac atc 2377Gly Asn Val Lys Pro Val Val Val Leu Ser Ser Tyr Trp Glu Asp Ile 655 660 665agc cat aga atc gag act cag aac cag ctg ctt ggg att gct gac cgg 2425Ser His Arg Ile Glu Thr Gln Asn Gln Leu Leu Gly Ile Ala Asp Arg 670 675 680ctg gaa gct ggc ctg gag cag gtc cac ctg gcc ctg aag gcg cag tgc 2473Leu Glu Ala Gly Leu Glu Gln Val His Leu Ala Leu Lys Ala Gln Cys685 690 695 700tcc acg gag gac gtg gac tcg ctg gtg gct cag ctg acg gat gag ctc 2521Ser Thr Glu Asp Val Asp Ser Leu Val Ala Gln Leu Thr Asp Glu Leu 705 710 715atc gca ggc tgc agc cag cct ctg ggt gac atc cat gag aca ccc tct 2569Ile Ala Gly Cys Ser Gln Pro Leu Gly Asp Ile His Glu Thr Pro Ser 720 725 730gcc acc cac ctg gac cag tac ctg tac cag ctg cgc acc cat cac ctg 2617Ala Thr His Leu Asp Gln Tyr Leu Tyr Gln Leu Arg Thr His His Leu 735 740 745agc caa atc act gag gct gcc ctg gcc ctg aag ctc ggc cac agt gag 2665Ser Gln Ile Thr Glu Ala Ala Leu Ala Leu Lys Leu Gly His Ser Glu 750 755 760ctc cct gca gct ctg gag cag gcg gag gac tgg ctc ctg cgt ctg cgt 2713Leu Pro Ala Ala Leu Glu Gln Ala Glu Asp Trp Leu Leu Arg Leu Arg765 770 775 780gcc ctg gca gag gag ccc cag aac agc ctg ccg gac atc gtc atc tgg 2761Ala Leu Ala Glu Glu Pro Gln Asn Ser Leu Pro Asp Ile Val Ile Trp 785 790 795atg ctg cag gga gac aag cgt gtg gca tac cag cgg gtg ccc gcc cac 2809Met Leu Gln Gly Asp Lys Arg Val Ala Tyr Gln Arg Val Pro Ala His 800 805 810caa gtc ctc ttc tcc cgg cgg ggt gcc aac tac tgt ggc aag aat tgt 2857Gln Val Leu Phe Ser Arg Arg Gly Ala Asn Tyr Cys Gly Lys Asn Cys 815 820 825ggg aag cta cag aca atc ttt ctg aaa tat ccg atg gag aag gtg cct 2905Gly Lys Leu Gln Thr Ile Phe Leu Lys Tyr Pro Met Glu Lys Val Pro 830 835 840ggc gcc cgg atg cca gtg cag ata cgg gtc aag ctg tgg ttt ggg ctc 2953Gly Ala Arg Met Pro Val Gln Ile Arg Val Lys Leu Trp Phe Gly Leu845 850 855 860tct gtg gat gag aag gag ttc aac cag ttt gct gag ggg aag ctg tct 3001Ser Val Asp Glu Lys Glu Phe Asn Gln Phe Ala Glu Gly Lys Leu Ser 865 870 875gtc ttt gct gaa acc tat gag aac gag act aag ttg gcc ctt gtt ggg 3049Val Phe Ala Glu Thr Tyr Glu Asn Glu Thr Lys Leu Ala Leu Val Gly 880 885 890aac tgg ggc aca acg ggc ctc acc tac ccc aag ttt tct gac gtc acg 3097Asn Trp Gly Thr Thr Gly Leu Thr Tyr Pro Lys Phe Ser Asp Val Thr 895 900 905ggc aag atc aag cta ccc aag gac agc ttc cgc ccc tcg gcc ggc tgg 3145Gly Lys Ile Lys Leu Pro Lys Asp Ser Phe Arg Pro Ser Ala Gly Trp 910 915 920acc tgg gct gga gat tgg ttc gtg tgt ccg gag aag act ctg ctc cat 3193Thr Trp Ala Gly Asp Trp Phe Val Cys Pro Glu Lys Thr Leu Leu His925 930 935 940gac atg gac gcc ggt cac ctg agc ttc gtg gaa gag gtg ttt gag aac 3241Asp Met Asp Ala Gly His Leu Ser Phe Val Glu Glu Val Phe Glu Asn 945 950 955cag acc cgg ctt ccc gga ggc cag tgg atc tac atg agt gac aac tac 3289Gln Thr Arg Leu Pro Gly Gly Gln Trp Ile Tyr Met Ser Asp Asn Tyr 960 965 970acc gat gtg aac ggg gag aag gtg ctt ccc aag gat gac att gag tgc 3337Thr Asp Val Asn Gly Glu Lys Val Leu Pro Lys Asp Asp Ile Glu Cys 975 980 985cca ctg ggc tgg aag tgg gaa gat gag gaa tgg tcc aca gac ctc aac 3385Pro Leu Gly Trp Lys Trp Glu Asp Glu Glu Trp Ser Thr Asp Leu Asn 990 995 1000cgg gct gtc gat gag caa ggc tgg gag tat agc atc acc atc ccc ccg 3433Arg Ala Val Asp Glu Gln Gly Trp Glu Tyr Ser Ile Thr Ile Pro Pro1005 1010 1015 1020gag cgg aag ccg aag cac tgg gtc cct gct gag aag atg tac tac aca 3481Glu Arg Lys Pro Lys His Trp Val Pro Ala Glu Lys Met Tyr Tyr Thr 1025 1030 1035cac cga cgg cgg cgc tgg gtg cgc ctg cgc agg agg gat ctc agc caa 3529His Arg Arg Arg Arg Trp Val Arg Leu Arg Arg Arg Asp Leu Ser Gln 1040 1045 1050atg gaa gca ctg aaa agg cac agg cag gcg gag gcg gag ggc gag ggc 3577Met Glu Ala Leu Lys Arg His Arg Gln Ala Glu Ala Glu Gly Glu Gly 1055 1060 1065tgg gag tac gcc tct ctt ttt ggc tgg aag ttc cac ctc gag tac cgc 3625Trp Glu Tyr Ala Ser Leu Phe Gly Trp Lys Phe His Leu Glu Tyr Arg 1070 1075 1080aag aca gat gcc ttc cgc cgc cgc cgc tgg cgc cgt cgc atg gag cca 3673Lys Thr Asp Ala Phe Arg Arg Arg Arg Trp Arg Arg Arg Met Glu Pro1085 1090 1095 1100ctg gag aag acg ggg cct gca gct gtg ttt gcc ctt gag ggg gcc ctg 3721Leu Glu Lys Thr Gly Pro Ala Ala Val Phe Ala Leu Glu Gly Ala Leu 1105 1110 1115ggc ggc gtg atg gat gac aag agt gaa gat tcc atg tcc gtc tcc acc 3769Gly Gly Val Met Asp Asp Lys Ser Glu Asp Ser Met Ser Val Ser Thr 1120 1125 1130ttg agc ttc ggt gtg aac aga ccc acg att tcc tgc ata ttc gac tat 3817Leu Ser Phe Gly Val Asn Arg Pro Thr Ile Ser Cys Ile Phe Asp Tyr 1135 1140 1145ggg aac cgc tac cat cta cgc tgc tac atg tac cag gcc cgg gac ctg 3865Gly Asn Arg Tyr His Leu Arg Cys Tyr Met Tyr Gln Ala Arg Asp Leu 1150 1155 1160gct gcg atg gac aag gac tct ttt tct gat ccc tat gcc atc gtc tcc 3913Ala Ala Met Asp Lys Asp Ser Phe Ser Asp Pro Tyr Ala Ile Val Ser1165 1170 1175 1180ttc ctg cac cag agc cag aag acg gtg gtg gtg aag aac acc ctt aac 3961Phe Leu His Gln Ser Gln Lys Thr Val Val Val Lys Asn Thr Leu Asn 1185 1190 1195ccc acc tgg gac cag acg ctc atc ttc tac gag atc gag atc ttt ggc 4009Pro Thr Trp Asp Gln Thr Leu Ile Phe Tyr Glu Ile Glu Ile Phe Gly 1200 1205 1210gag ccg gcc aca gtt gct gag caa ccg ccc agc att gtg gtg gag ctg 4057Glu Pro Ala Thr Val Ala Glu Gln Pro Pro Ser Ile Val Val Glu Leu 1215 1220 1225tac gac cat gac act tat ggt gca gac gag ttt atg ggt cgc tgc atc 4105Tyr Asp His Asp Thr Tyr Gly Ala Asp Glu Phe Met Gly Arg Cys Ile 1230 1235 1240tgt caa ccg agt ctg gaa cgg atg cca cgg ctg gcc tgg ttc cca ctg 4153Cys Gln Pro Ser Leu Glu Arg Met Pro Arg Leu Ala Trp Phe Pro Leu1245 1250 1255 1260acg agg ggc agc cag ccg tcg ggg gag ctg ctg gcc tct ttt gag ctc 4201Thr Arg Gly Ser Gln Pro Ser Gly Glu Leu Leu Ala Ser Phe Glu Leu 1265 1270 1275atc cag aga gag aag ccg gcc atc cac cat att cct ggt ttt gag gtg 4249Ile Gln Arg Glu Lys Pro Ala Ile His His Ile Pro Gly Phe Glu Val 1280 1285 1290cag gag aca tca agg atc ctg gat gag tct gag gac aca gac ctg ccc 4297Gln Glu Thr Ser Arg Ile Leu Asp Glu Ser Glu Asp Thr Asp Leu Pro 1295 1300 1305tac cca cca ccc cag agg gag gcc aac atc tac atg gtt cct cag aac 4345Tyr Pro Pro Pro Gln Arg Glu Ala Asn Ile Tyr Met Val Pro Gln Asn 1310 1315 1320atc aag cca gcg ctc cag cgt acc gcc atc gag atc ctg gca tgg ggc 4393Ile Lys Pro Ala Leu Gln Arg Thr Ala Ile Glu Ile Leu Ala Trp Gly1325 1330 1335 1340ctg cgg aac atg aag agt tac cag ctg gcc aac atc tcc tcc ccc agc 4441Leu Arg Asn Met Lys Ser Tyr Gln Leu Ala Asn Ile Ser Ser Pro Ser 1345 1350 1355ctc gtg gta gag tgt ggg ggc cag acg gtg cag tcc tgt gtc atc agg 4489Leu Val Val Glu Cys Gly Gly Gln Thr Val Gln Ser Cys Val Ile Arg 1360 1365 1370aac ctc cgg aag aac ccc aac ttt gac atc tgc acc ctc ttc atg gaa 4537Asn Leu Arg Lys Asn Pro Asn Phe Asp Ile Cys Thr Leu Phe Met Glu 1375 1380 1385gtg atg ctg ccc agg gag gag ctc tac tgc ccc ccc atc acc gtc aag 4585Val Met Leu Pro Arg Glu Glu Leu Tyr Cys Pro Pro Ile Thr Val Lys 1390 1395 1400gtc atc gat aac cgc cag ttt ggc cgc cgg cct gtg gtg ggc cag tgt 4633Val Ile Asp Asn Arg Gln Phe Gly Arg Arg Pro Val Val Gly Gln Cys1405 1410 1415 1420acc atc cgc tcc ctg gag agc ttc ctg tgt gac ccc tac tcg gcg gag 4681Thr Ile Arg Ser Leu Glu Ser Phe Leu Cys Asp Pro Tyr Ser Ala Glu 1425 1430 1435agt cca tcc cca cag ggt ggc cca gac gat gtg agc cta ctc agt cct 4729Ser Pro Ser Pro Gln Gly Gly Pro Asp Asp Val Ser Leu Leu Ser Pro 1440 1445 1450ggg gaa gac gtg ctc atc gac att gat gac aag gag ccc ctc atc ccc 4777Gly Glu Asp Val Leu Ile Asp Ile Asp Asp Lys Glu Pro Leu Ile Pro 1455 1460 1465atc cag gag gaa gag ttc atc gat tgg tgg agc aaa ttc ttt gcc tcc 4825Ile Gln Glu Glu Glu Phe Ile Asp Trp Trp Ser Lys Phe Phe Ala Ser 1470 1475 1480ata ggg gag agg gaa aag tgc ggc tcc tac ctg gag aag gat ttt gac 4873Ile Gly Glu Arg Glu Lys Cys Gly Ser Tyr Leu Glu Lys Asp Phe Asp1485 1490 1495 1500acc ctg aag gtc tat gac aca cag ctg gag aat gtg gag gcc ttt gag 4921Thr Leu Lys Val Tyr Asp Thr Gln Leu Glu Asn Val Glu Ala Phe Glu 1505 1510 1515ggc ctg tct gac ttt tgt aac acc ttc aag ctg tac cgg ggc aag acg 4969Gly Leu Ser Asp Phe Cys Asn Thr Phe Lys Leu Tyr Arg Gly Lys Thr 1520 1525 1530cag gag gag aca gaa gat cca tct gtg att ggt gaa ttt aag ggc ctc 5017Gln Glu Glu Thr Glu Asp Pro Ser Val Ile Gly Glu Phe Lys Gly Leu 1535 1540 1545ttc aaa att tat ccc ctc cca gaa gac cca gcc atc ccc atg ccc cca 5065Phe Lys Ile Tyr Pro Leu Pro Glu Asp Pro Ala Ile Pro Met Pro Pro 1550 1555 1560aga cag ttc cac cag ctg gcc gcc cag gga ccc cag gag tgc ttg gtc 5113Arg Gln Phe His Gln Leu Ala Ala Gln Gly Pro Gln Glu Cys Leu Val1565 1570 1575 1580cgt atc tac att gtc cga gca ttt ggc ctg cag ccc aag gac ccc aat 5161Arg Ile Tyr Ile Val Arg Ala Phe Gly Leu Gln Pro Lys Asp Pro Asn 1585 1590 1595gga aag tgt gat cct tac atc aag atc tcc ata ggg aag aaa tca gtg 5209Gly Lys Cys Asp Pro Tyr Ile Lys Ile Ser Ile Gly Lys Lys Ser Val 1600 1605 1610agt gac cag gat aac tac atc ccc tgc acg ctg gag ccc gta ttt gga 5257Ser Asp Gln Asp Asn Tyr Ile Pro Cys Thr Leu Glu Pro Val Phe Gly 1615 1620 1625aag atg ttc gag ctg acc tgc act ctg cct ctg gag aag gac cta aag 5305Lys Met Phe Glu Leu Thr Cys Thr Leu Pro Leu Glu Lys Asp Leu Lys 1630 1635 1640atc act ctc tat gac tat gac ctc ctc tcc aag gac gaa aag atc ggt 5353Ile Thr Leu Tyr Asp Tyr Asp Leu Leu Ser Lys Asp Glu Lys Ile Gly1645 1650 1655 1660gag acg gtc gtc gac ctg gag aac agg ctg ctg tcc aag ttt ggg gct 5401Glu Thr Val Val Asp Leu Glu Asn Arg Leu Leu Ser Lys Phe Gly Ala 1665 1670 1675cgc tgt gga ctc cca cag acc tac tgt gtc tct gga ccg aac cag tgg 5449Arg Cys Gly Leu Pro Gln Thr Tyr Cys Val Ser Gly Pro Asn Gln Trp 1680 1685 1690cgg gac cag ctc cgc ccc tcc cag ctc ctc cac ctc ttc tgc cag cag 5497Arg Asp Gln Leu Arg Pro Ser Gln Leu Leu His Leu Phe Cys Gln Gln 1695 1700 1705cat aga gtc aag gca cct gtg tac cgg aca gac cgt gta atg ttt cag 5545His Arg Val Lys Ala Pro Val Tyr Arg Thr Asp Arg Val Met Phe Gln 1710 1715 1720gat aaa gaa tat tcc att gaa gag ata gag gct ggc agg atc cca aac 5593Asp Lys Glu Tyr Ser Ile Glu Glu Ile Glu Ala Gly Arg Ile Pro Asn1725 1730 1735 1740cca cac ctg ggc cca gtg gag gag cgt ctg gct ctg cat gtg ctt cag 5641Pro His Leu Gly Pro Val Glu Glu Arg Leu Ala Leu His Val Leu Gln 1745 1750 1755cag cag ggc ctg gtc ccg gag cac gtg gag tca cgg ccc ctc tac agc 5689Gln Gln Gly Leu Val Pro Glu His Val Glu Ser Arg Pro Leu Tyr Ser 1760 1765 1770ccc ctg cag cca gac atc gag cag ggg aag ctg cag atg tgg gtc gac 5737Pro Leu Gln Pro Asp Ile Glu Gln Gly Lys Leu Gln Met Trp Val Asp 1775 1780 1785cta ttt ccg aag gcc ctg ggg cgg cct gga cct ccc ttc aac atc acc 5785Leu Phe Pro Lys Ala Leu Gly Arg Pro Gly Pro Pro Phe Asn Ile Thr 1790 1795 1800cca cgg aga gcc aga agg ttt ttc ctg cgt tgt att atc tgg aat acc 5833Pro Arg Arg Ala Arg Arg Phe Phe Leu Arg Cys Ile Ile Trp Asn Thr1805 1810 1815 1820aga gat gtg atc ctg gat gac ctg agc ctc acg ggg gag aag atg agc 5881Arg Asp Val Ile Leu Asp Asp Leu Ser Leu Thr Gly Glu Lys Met Ser 1825 1830 1835gac att tat gtg aaa ggt tgg atg att ggc ttt gaa gaa cac aag caa 5929Asp Ile Tyr Val Lys Gly Trp Met Ile Gly Phe Glu Glu His Lys Gln 1840 1845 1850aag aca gac gtg cat tat cgt tcc ctg gga ggt gaa ggc aac ttc aac 5977Lys Thr Asp Val His Tyr Arg Ser Leu Gly Gly Glu Gly Asn Phe Asn 1855 1860 1865tgg agg ttc att ttc ccc ttc gac tac ctg cca gct gag caa gtc tgt 6025Trp Arg Phe Ile Phe Pro Phe Asp Tyr Leu Pro Ala Glu Gln Val Cys 1870 1875 1880acc att gcc aag aag gat gcc ttc tgg agg ctg gac aag act gag agc 6073Thr Ile Ala Lys Lys Asp Ala Phe Trp Arg Leu Asp Lys Thr Glu Ser1885 1890 1895 1900aaa atc cca gca cga gtg gtg ttc cag atc tgg gac aat gac aag ttc 6121Lys Ile Pro Ala Arg Val Val Phe Gln Ile Trp Asp Asn Asp Lys Phe 1905 1910 1915tcc ttt gat gat ttt ctg ggc tcc ctg cag ctc gat ctc aac cgc atg 6169Ser Phe Asp Asp Phe Leu Gly Ser Leu Gln Leu Asp Leu Asn Arg Met 1920 1925 1930ccc aag cca gcc aag aca gcc aag aag tgc tcc ttg gac cag ctg gat 6217Pro Lys Pro Ala Lys Thr Ala Lys Lys Cys Ser Leu Asp Gln Leu Asp 1935 1940 1945gat gct ttc cac cca gaa tgg ttt gtg tcc ctt ttt gag cag aaa aca 6265Asp Ala Phe His Pro Glu Trp Phe Val Ser Leu Phe Glu Gln Lys Thr 1950 1955 1960gtg aag ggc tgg tgg ccc tgt gta gca gaa gag ggt gag aag aaa ata 6313Val Lys Gly Trp Trp Pro Cys Val Ala Glu Glu Gly Glu Lys Lys Ile1965 1970 1975 1980ctg gcg ggc aag ctg gaa atg acc ttg gag att gta gca gag agt gag 6361Leu Ala Gly Lys Leu Glu Met Thr Leu Glu Ile Val Ala Glu Ser Glu 1985 1990 1995cat gag gag cgg cct gct ggc cag ggc cgg gat gag ccc aac atg aac 6409His Glu Glu Arg Pro Ala Gly Gln Gly Arg Asp Glu Pro Asn Met Asn 2000 2005 2010cct aag ctt gag gac cca agg cgc ccc gac acc tcc ttc ctg tgg ttt 6457Pro Lys Leu Glu Asp Pro Arg Arg Pro Asp Thr Ser Phe Leu Trp Phe 2015 2020 2025acc tcc cca tac aag acc atg aag ttc atc ctg tgg cgg cgt ttc cgg 6505Thr Ser Pro Tyr Lys Thr Met Lys Phe Ile Leu Trp Arg Arg Phe Arg 2030 2035 2040tgg gcc atc atc ctc ttc atc atc ctc ttc atc ctg ctg ctg ttc ctg 6553Trp Ala Ile Ile Leu Phe Ile Ile Leu Phe Ile Leu Leu Leu Phe Leu2045 2050 2055 2060gcc atc ttc atc tac gcc ttc ccg aac tat gct gcc atg aag ctg gtg 6601Ala Ile Phe Ile Tyr Ala Phe Pro Asn Tyr Ala Ala Met Lys Leu Val 2065 2070 2075aag ccc ttc agc tgaggactct cctgccctgt agaaggggcc gtggggtccc 6653Lys Pro Phe Ser 2080ctccagcatg ggactggcct gcctcctccg cccagctcgg cgagctcctc cagacctcct 6713aggcctgatt gtcctgccag ggtgggcaga cagacagatg gaccggccca cactcccaga 6773gttgctaaca tggagctctg agatcacccc acttccatca tttccttctc ccccaaccca 6833acgctttttt ggatcagctc agacatattt cagtataaaa cagttggaac cacaaaaaaa 6893aaaaaaaaaa aaaaaaaa 6911 2 2080 PRT Homo sapiens 2Met Leu Arg Val Phe Ile Leu Tyr Ala Glu Asn Val His Thr Pro Asp 1 5 10 15Thr Asp Ile Ser Asp Ala Tyr Cys Ser Ala Val Phe Ala Gly Val Lys 20 25 30Lys Arg Thr Lys Val Ile Lys Asn Ser Val Asn Pro Val Trp Asn Glu 35 40 45Gly Phe Glu Trp Asp Leu Lys Gly Ile Pro Leu Asp Gln Gly Ser Glu 50 55 60Leu His Val Val Val Lys Asp His Glu Thr Met Gly Arg Asn Arg Phe 65 70 75 80Leu Gly Glu Ala Lys Val Pro Leu Arg Glu Val Leu Ala Thr Pro Ser 85 90 95Leu Ser Ala Ser Phe Asn Ala Pro Leu Leu Asp Thr Lys Lys Gln Pro 100 105 110Thr Gly Ala Ser Leu Val Leu Gln Val Ser Tyr Thr Pro Leu Pro Gly 115 120 125Ala Val Pro Leu Phe Pro Pro Pro Thr Pro Leu Glu Pro Ser Pro Thr 130 135 140Leu Pro Asp Leu Asp Val Val Ala Asp Thr Gly Gly Glu Glu Asp Thr145 150 155 160Glu Asp Gln Gly Leu Thr Gly Asp Glu Ala Glu Pro Phe Leu Asp Gln 165 170 175Ser Gly Gly Pro Gly Ala Pro Thr Thr Pro Arg Lys Leu Pro Ser Arg 180 185 190Pro Pro Pro His Tyr Pro Gly Ile Lys Arg Lys Arg Ser Ala Pro Thr 195 200 205Ser Arg Lys Leu Leu Ser Asp Lys Pro Gln Asp Phe Gln Ile Arg Val 210 215 220Gln Val Ile Glu Gly Arg Gln Leu Pro Gly Val Asn Ile Lys Pro Val225 230 235 240Val Lys Val Thr Ala Ala Gly Gln Thr Lys Arg Thr Arg Ile His Lys 245 250 255Gly Asn Ser Pro Leu Phe Asn Glu Thr Leu Phe Phe Asn Leu Phe Asp 260 265 270Ser Pro Gly Glu Leu Phe Asp Glu Pro Ile Phe Ile Thr Val Val Asp 275 280 285Ser Arg Ser Leu Arg Thr Asp Ala Leu Leu Gly Glu Phe Arg Met Asp 290 295 300Val Gly Thr Ile Tyr Arg Glu Pro Arg His Ala Tyr Leu Arg Lys Trp305 310 315 320Leu Leu Leu Ser Asp Pro Asp Asp Phe Ser Ala Gly Ala Arg Gly Tyr 325 330 335Leu Lys Thr Ser Leu Cys Val Leu Gly Pro Gly Asp Glu Ala Pro Leu 340 345 350Glu Arg Lys Asp Pro Ser Glu Asp Lys Glu Asp Ile Glu Ser Asn Leu 355 360 365Leu Arg Pro Thr Gly Val Ala Leu Arg Gly Ala His Phe Cys Leu Lys 370 375 380Val Phe Arg Ala Glu Asp Leu Pro Gln Met Asp Asp Ala Val Met Asp385 390 395 400Asn Val Lys Gln Ile Phe Gly Phe Glu Ser Asn Lys Lys Asn Leu Val 405 410 415Asp Pro Phe Val Glu Val Ser Phe Ala Gly Lys Met Leu Cys Ser Lys 420 425 430Ile Leu Glu Lys Thr Ala Asn Pro Gln Trp Asn Gln Asn Ile Thr Leu 435 440 445Pro Ala Met Phe Pro Ser Met Cys Glu Lys Met Arg Ile Arg Ile Ile 450 455 460Asp Trp Asp Arg Leu Thr His Asn Asp Ile Val Ala Thr Thr Tyr Leu465 470 475 480Ser Met Ser Lys Ile Ser Ala Pro Gly Gly Glu Ile Glu Glu Glu Pro 485 490 495Ala Gly Ala Val Lys Pro Ser Lys Ala Ser Asp Leu Asp Asp Tyr Leu 500 505 510Gly Phe Leu Pro Thr Phe Gly Pro Cys Tyr Ile Asn Leu Tyr Gly Ser 515 520 525Pro Arg Glu Phe Thr Gly Phe Pro Asp Pro Tyr Thr Glu Leu Asn Thr 530 535 540Gly Lys Gly Glu Gly Val Ala Tyr Arg Gly Arg Leu Leu Leu Ser Leu545 550 555 560Glu Thr Lys Leu Val Glu His Ser Glu Gln Lys Val Glu Asp Leu Pro 565 570 575Ala Asp Asp Ile Leu Arg Val Glu Lys Tyr Leu Arg Arg Arg Lys Tyr 580 585 590Ser Leu Phe Ala Ala Phe Tyr Ser Ala Thr Met Leu Gln Asp Val Asp 595 600 605Asp Ala Ile Gln Phe Glu Val Ser Ile Gly Asn Tyr Gly Asn Lys Phe 610 615 620Asp Met Thr Cys Leu Pro Leu Ala Ser Thr Thr Gln Tyr Ser Arg Ala625 630 635 640Val Phe Asp Gly Cys His Tyr Tyr Tyr Leu Pro Trp Gly Asn Val Lys 645 650 655Pro Val Val Val Leu Ser Ser Tyr Trp Glu Asp Ile Ser His Arg Ile 660 665 670Glu Thr Gln Asn Gln Leu Leu Gly Ile Ala Asp Arg Leu Glu Ala Gly 675 680 685Leu Glu Gln Val His Leu Ala Leu Lys Ala Gln Cys Ser Thr Glu Asp 690 695 700Val Asp Ser Leu Val Ala Gln Leu Thr Asp Glu Leu Ile Ala Gly Cys705 710 715 720Ser Gln Pro Leu Gly Asp Ile His Glu Thr Pro Ser Ala Thr His Leu 725 730 735Asp Gln Tyr Leu Tyr Gln Leu Arg Thr His His Leu Ser Gln Ile Thr 740 745 750Glu Ala Ala Leu Ala Leu Lys Leu Gly His Ser Glu Leu Pro Ala Ala 755 760 765Leu Glu Gln Ala Glu Asp Trp Leu Leu Arg Leu Arg Ala Leu Ala Glu 770 775 780Glu Pro Gln Asn Ser Leu Pro Asp Ile Val Ile Trp Met Leu Gln Gly785 790 795 800Asp Lys Arg Val Ala Tyr Gln Arg Val Pro Ala His Gln Val Leu Phe 805 810 815Ser Arg Arg Gly Ala Asn Tyr Cys Gly Lys Asn Cys Gly Lys Leu Gln 820 825 830Thr Ile Phe Leu Lys Tyr Pro Met Glu Lys Val Pro Gly Ala Arg Met 835 840 845Pro Val Gln Ile Arg Val Lys Leu Trp Phe Gly Leu Ser Val Asp Glu 850 855 860Lys Glu Phe Asn Gln Phe Ala Glu Gly Lys Leu Ser Val Phe Ala Glu865 870 875 880Thr Tyr Glu Asn Glu Thr Lys Leu Ala Leu Val Gly Asn Trp Gly Thr 885 890 895Thr Gly Leu Thr Tyr Pro Lys Phe Ser Asp Val Thr Gly Lys Ile Lys 900 905 910Leu Pro Lys Asp Ser Phe Arg Pro Ser Ala Gly Trp Thr Trp Ala Gly 915 920 925Asp Trp Phe Val Cys Pro Glu Lys Thr Leu Leu His Asp Met Asp Ala 930 935 940Gly His Leu Ser Phe Val Glu Glu Val Phe Glu Asn Gln Thr Arg Leu945 950 955 960Pro Gly Gly Gln Trp Ile Tyr Met Ser Asp Asn Tyr Thr Asp Val Asn 965 970 975Gly Glu Lys Val Leu Pro Lys Asp Asp Ile Glu Cys Pro Leu Gly Trp 980 985 990Lys Trp Glu Asp Glu Glu Trp Ser Thr Asp Leu Asn Arg Ala Val Asp 995 1000 1005Glu Gln Gly Trp Glu Tyr Ser Ile Thr Ile Pro Pro Glu Arg Lys Pro 1010 1015 1020Lys His Trp Val Pro Ala Glu Lys Met Tyr Tyr Thr His Arg Arg Arg1025 1030 1035 1040Arg Trp Val Arg Leu Arg Arg Arg Asp Leu Ser Gln Met Glu Ala Leu 1045 1050 1055Lys Arg His Arg Gln Ala Glu Ala Glu Gly Glu Gly Trp Glu Tyr Ala 1060 1065 1070Ser Leu Phe Gly Trp Lys Phe His Leu Glu Tyr Arg Lys Thr Asp Ala 1075 1080 1085Phe Arg Arg Arg Arg Trp Arg Arg Arg Met Glu Pro Leu Glu Lys Thr 1090 1095 1100Gly Pro Ala Ala Val Phe Ala Leu Glu Gly Ala Leu Gly Gly Val Met1105 1110 1115 1120Asp Asp Lys Ser Glu Asp Ser Met Ser Val Ser Thr Leu Ser Phe Gly 1125 1130 1135Val Asn Arg Pro Thr Ile Ser Cys Ile Phe Asp Tyr Gly Asn Arg Tyr 1140 1145 1150His Leu Arg Cys Tyr Met Tyr Gln Ala Arg Asp Leu Ala Ala Met Asp 1155 1160 1165Lys Asp Ser Phe Ser Asp Pro Tyr Ala Ile Val Ser Phe Leu His Gln 1170 1175 1180Ser Gln Lys Thr Val Val Val Lys Asn Thr Leu Asn Pro Thr Trp Asp1185 1190 1195 1200Gln Thr Leu Ile Phe Tyr Glu Ile Glu Ile Phe Gly Glu Pro Ala Thr 1205 1210 1215Val Ala Glu Gln Pro Pro Ser Ile Val Val Glu Leu Tyr Asp His Asp 1220 1225 1230Thr Tyr Gly Ala Asp Glu Phe Met Gly Arg Cys Ile Cys Gln Pro Ser 1235 1240 1245Leu Glu Arg Met Pro Arg Leu Ala Trp Phe Pro Leu Thr Arg Gly Ser 1250 1255 1260Gln Pro Ser Gly Glu Leu Leu Ala Ser Phe Glu Leu Ile Gln Arg Glu1265 1270 1275 1280Lys Pro Ala Ile His His Ile Pro Gly Phe Glu Val Gln Glu Thr Ser 1285 1290 1295Arg Ile Leu Asp Glu Ser Glu Asp Thr Asp Leu Pro Tyr Pro Pro Pro 1300 1305 1310Gln Arg Glu Ala Asn Ile Tyr Met Val Pro Gln Asn Ile Lys Pro Ala 1315 1320 1325Leu Gln Arg Thr Ala Ile Glu Ile Leu Ala Trp Gly Leu Arg Asn Met 1330 1335 1340Lys Ser Tyr Gln Leu Ala Asn Ile Ser Ser Pro Ser Leu Val Val Glu1345 1350 1355 1360Cys Gly Gly Gln Thr Val Gln Ser Cys Val Ile Arg Asn Leu Arg Lys 1365 1370 1375Asn Pro Asn Phe Asp Ile Cys Thr Leu Phe Met Glu Val Met Leu Pro 1380 1385 1390Arg Glu Glu Leu Tyr Cys Pro Pro Ile Thr Val Lys Val Ile Asp Asn 1395 1400 1405Arg Gln Phe Gly Arg Arg Pro Val Val Gly Gln Cys Thr Ile Arg Ser 1410 1415 1420Leu Glu Ser Phe Leu Cys Asp Pro Tyr Ser Ala Glu Ser Pro Ser Pro1425 1430 1435 1440Gln Gly Gly Pro Asp Asp Val Ser Leu Leu Ser Pro Gly Glu Asp Val 1445 1450 1455Leu Ile Asp Ile Asp Asp Lys Glu Pro Leu Ile Pro Ile Gln Glu Glu 1460 1465 1470Glu Phe Ile Asp Trp Trp Ser Lys Phe Phe Ala Ser Ile Gly Glu Arg 1475 1480 1485Glu Lys Cys Gly Ser Tyr Leu Glu Lys Asp Phe Asp Thr Leu Lys Val 1490 1495 1500Tyr Asp Thr Gln Leu Glu Asn Val Glu Ala Phe Glu Gly Leu Ser Asp1505 1510 1515 1520Phe Cys Asn Thr Phe Lys Leu Tyr Arg Gly Lys Thr Gln Glu Glu Thr 1525 1530 1535Glu Asp Pro Ser Val Ile Gly Glu Phe Lys Gly Leu Phe Lys Ile Tyr 1540 1545 1550Pro Leu Pro Glu Asp Pro Ala Ile Pro Met Pro Pro Arg Gln Phe His 1555 1560 1565Gln Leu Ala Ala Gln Gly Pro Gln Glu Cys Leu Val Arg Ile Tyr Ile 1570 1575 1580Val Arg Ala Phe Gly Leu Gln Pro Lys Asp Pro Asn Gly Lys Cys Asp1585 1590 1595 1600Pro Tyr Ile Lys Ile Ser Ile Gly Lys Lys Ser Val Ser Asp Gln Asp 1605 1610 1615Asn Tyr Ile Pro Cys Thr Leu Glu Pro Val Phe Gly Lys Met Phe Glu 1620 1625 1630Leu Thr Cys Thr Leu Pro Leu Glu Lys Asp Leu Lys Ile Thr Leu Tyr 1635 1640 1645Asp Tyr Asp Leu Leu Ser Lys Asp Glu Lys Ile Gly Glu Thr Val Val 1650 1655 1660Asp Leu Glu Asn Arg Leu Leu Ser Lys Phe Gly Ala Arg Cys Gly Leu1665 1670 1675 1680Pro Gln Thr Tyr Cys Val Ser Gly Pro Asn Gln Trp Arg Asp Gln Leu 1685 1690 1695Arg Pro Ser Gln Leu Leu His Leu Phe Cys Gln Gln His Arg Val Lys 1700 1705 1710Ala Pro Val Tyr Arg Thr Asp Arg Val Met Phe Gln Asp Lys Glu Tyr 1715 1720 1725Ser Ile Glu Glu Ile Glu Ala Gly Arg Ile Pro Asn Pro His Leu Gly 1730 1735 1740Pro Val Glu Glu Arg Leu Ala Leu His Val Leu Gln Gln Gln Gly Leu1745 1750 1755 1760Val Pro Glu His Val Glu Ser Arg Pro Leu Tyr Ser Pro Leu Gln Pro 1765 1770 1775Asp Ile Glu Gln Gly Lys Leu Gln Met Trp Val Asp Leu Phe Pro Lys 1780 1785 1790Ala Leu Gly Arg Pro Gly Pro Pro Phe Asn Ile Thr Pro Arg Arg Ala 1795 1800 1805Arg Arg Phe Phe Leu Arg Cys Ile Ile Trp Asn Thr Arg Asp Val Ile 1810 1815 1820Leu Asp Asp Leu Ser Leu Thr Gly Glu Lys Met Ser Asp Ile Tyr Val1825 1830 1835 1840Lys Gly Trp Met Ile Gly Phe Glu Glu His Lys Gln Lys Thr Asp Val 1845 1850 1855His Tyr Arg Ser Leu Gly Gly Glu Gly Asn Phe Asn Trp Arg Phe Ile 1860 1865 1870Phe Pro Phe Asp Tyr Leu Pro Ala Glu Gln Val Cys Thr Ile Ala Lys 1875 1880 1885Lys Asp Ala Phe Trp Arg Leu Asp Lys Thr Glu Ser Lys Ile Pro Ala 1890 1895 1900Arg Val Val Phe Gln Ile Trp Asp Asn Asp Lys Phe Ser Phe Asp Asp1905 1910 1915 1920Phe Leu Gly Ser Leu Gln Leu Asp Leu Asn Arg Met Pro Lys Pro Ala 1925 1930 1935Lys Thr Ala Lys Lys Cys Ser Leu Asp Gln Leu Asp Asp Ala Phe His 1940 1945 1950Pro Glu Trp Phe Val Ser Leu Phe Glu Gln Lys Thr Val Lys Gly Trp 1955 1960 1965Trp Pro Cys Val Ala Glu Glu Gly Glu Lys Lys Ile Leu Ala Gly Lys 1970 1975 1980Leu Glu Met Thr Leu Glu Ile Val Ala Glu Ser Glu His Glu Glu Arg1985 1990 1995 2000Pro Ala Gly Gln Gly Arg Asp Glu Pro Asn Met Asn Pro Lys Leu Glu 2005 2010 2015Asp Pro Arg Arg Pro Asp Thr Ser Phe Leu Trp Phe Thr Ser Pro Tyr 2020 2025 2030Lys Thr Met Lys Phe Ile Leu Trp Arg Arg Phe Arg Trp Ala Ile Ile 2035 2040 2045Leu Phe Ile Ile Leu Phe Ile Leu Leu Leu Phe Leu Ala Ile Phe Ile 2050 2055 2060Tyr Ala Phe Pro Asn Tyr Ala Ala Met Lys Leu Val Lys Pro Phe Ser2065 2070 2075 2080 3 5915 DNA Homo sapiens 3tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaggg 540catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg agacgatggg 600gaggaacagg ttcctggggg aagccaaggt cccactccga gaggtcctcg ccacccctag 660tctgtccgcc agcttcaatg cccccctgct ggacaccaag aagcagccca caggggcctc 720gctggtcctg caggtgtcct acacaccgct gcctggagct gtgcccctgt tcccgccccc 780tactcctctg gagccctccc cgactctgcc tgacctggat gtagtggcag acacaggagg 840agaggaagac acagaggacc agggactcac tggagatgag gcggagccat tcctggatca 900aagcggaggc ccgggggctc ccaccacccc aaggaaacta ccttcacgtc ctccgcccca 960ctaccccggg atcaaaagaa agcgaagtgc gcctacatct agaaagctgc tgtcagacaa 1020accgcaggat ttccagatca gggtccaggt gatcgagggg cgccagctgc cgggggtgaa 1080catcaagcct gtggtcaagg ttaccgctgc agggcagacc aagcggacgc ggatccacaa 1140gggaaacagc ccactcttca atgagactct tttcttcaac ttgtttgact ctcctgggga 1200gctgtttgat gagcccatct ttatcacggt ggtagactct cgttctctca ggacagatgc 1260tctcctcggg gagttccgga tggacgtggg caccatttac agagagcccc ggcacgccta 1320tctcaggaag tggctgctgc tctcagaccc tgatgacttc tctgctgggg ccagaggcta 1380cctgaaaaca agcctttgtg tgctggggcc tggggacgaa gcgcctctgg agagaaaaga 1440cccctctgaa gacaaggagg acattgaaag caacctgctc cggcccacag gcgtagccct 1500gcgaggagcc cacttctgcc tgaaggtctt ccgggccgag gacttgccgc agatggacga 1560tgccgtgatg gacaacgtga aacagatctt tggcttcgag agtaacaaga agaacttggt 1620ggaccccttt gtggaggtca gctttgcggg gaaaatgctg tgcagcaaga tcttggagaa 1680gacggccaac cctcagtgga accagaacat cacactgcct gccatgtttc cctccatgtg 1740cgaaaaaatg aggattcgta tcatagactg ggaccgcctg actcacaatg acatcgtggc 1800taccacctac ctgagtatgt cgaaaatctc tgcccctgga ggagaaatag aagaggagcc 1860tgcaggtgct gtcaagcctt cgaaagcctc agacttggat gactacctgg gcttcctccc 1920cacttttggg ccctgctaca tcaacctcta tggcagtccc agagagttca caggcttccc 1980agacccctac acagagctca acacaggcaa gggggaaggt gtggcttatc gtggccggct 2040tctgctctcc ctggagacca agctggtgga gcacagtgaa cagaaggtgg aggaccttcc 2100tgcggatgac atcctccggg tggagaagta ccttaggagg cgcaagtact ccctgtttgc 2160ggccttctac tcagccacca tgctgcagga tgtggatgat gccatccagt ttgaggtcag 2220catcgggaac tacgggaaca agttcgacat gacctgcctg ccgctggcct ccaccactca 2280gtacagccgt gcagtctttg acgggtgcca ctactactac ctaccctggg gtaacgtgaa 2340acctgtggtg gtgctgtcat cctactggga ggacatcagc catagaatcg agactcagaa 2400ccagctgctt gggattgctg accggctgga agctggcctg gagcaggtcc acctggccct 2460gaaggcgcag tgctccacgg aggacgtgga ctcgctggtg gctcagctga cggatgagct 2520catcgcaggc tgcagccagc ctctgggtga catccatgag acaccctctg ccacccacct 2580ggaccagtac ctgtaccagc tgcgcaccca tcacctgagc caaatcactg aggctgccct 2640ggccctgaag ctcggccaca gtgagctccc tgcagctctg gagcaggcgg aggactggct 2700cctgcgtctg cgtgccctgg cagaggagcc ccagaacagc ctgccggaca tcgtcatctg 2760gatgctgcag ggagacaagc gtgtggcata ccagcgggtg cccgcccacc aagtcctctt 2820ctcccggcgg ggtgccaact actgtggcaa gaattgtggg aagctacaga caatctttct 2880gaaatatccg atggagaagg tgcctggcgc ccggatgcca gtgcagatac gggtcaagct 2940gtggtttggg ctctctgtgg atgagaagga gttcaaccag tttgctgagg ggaagctgtc 3000tgtctttgct gaaacctatg agaacgagac taagttggcc cttgttggga actggggcac 3060aacgggcctc acctacccca agttttctga cgtcacgggc aagatcaagc tacccaagga 3120cagcttccgc ccctcggccg gctggacctg ggctggagat tggttcgtgt gtccggagaa 3180gactctgctc catgacatgg acgccggtca cctgagcttc gtggaagagg tgtttgagaa 3240ccagacccgg cttcccggag gccagtggat ctacatgagt gacaactaca ccgatgtgaa 3300cggggagaag gtgcttccca aggatgacat tgagtgccca ctgggctgga agtgggaaga 3360tgaggaatgg tccacagacc tcaaccgggc tgtcgatgag caaggctggg agtatagcat 3420caccatcccc ccggagcgga agccgaagca ctgggtccct gctgagaaga tgtactacac 3480acaccgacgg cggcgctggg tgcgcctgcg caggagggat ctcagccaaa tggaagcact 3540gaaaaggcac aggcaggcgg aggcggaggg cgagggctgg gagtacgcct ctctttttgg 3600ctggaagttc cacctcgagt accgcaagac agatgccttc cgccgccgcc gctggcgccg 3660tcgcatggag ccactggaga agacggggcc tgcagctgtg tttgcccttg agggggccct 3720gggcggcgtg atggatgaca agagtgaaga ttccatgtcc gtctccacct tgagcttcgg 3780tgtgaacaga cccacgattt cctgcatatt cgactatggg aaccgctacc atctacgctg 3840ctacatgtac caggcccggg acctggctgc gatggacaag gactcttttt ctgatcccta 3900tgccatcgtc tccttcctgc accagagcca gaagacggtg gtggtgaaga acacccttaa 3960ccccacctgg gaccagacgc tcatcttcta cgagatcgag atctttggcg agccggccac 4020agttgctgag caaccgccca gcattgtggt ggagctgtac gaccatgaca cttatggtgc 4080agacgagttt atgggtcgct gcatctgtca accgagtctg gaacggatgc cacggctggc 4140ctggttccca ctgacgaggg gcagccagcc gtcgggggag ctgctggcct cttttgagct 4200catccagaga gagaagccgg ccatccacca tattcctggt tttgaggtgc aggagacatc 4260aaggatcctg gatgagtctg aggacacaga cctgccctac ccaccacccc agagggaggc 4320caacatctac atggttcctc agaacatcaa gccagcgctc cagcgtaccg ccatcgagat 4380cctggcatgg ggcctgcgga acatgaagag ttaccagctg gccaacatct cctcccccag 4440cctcgtggta gagtgtgggg gccagacggt gcagtcctgt gtcatcagga acctccggaa 4500gaaccccaac tttgacatct gcaccctctt catggaagtg atgctgccca gggaggagct 4560ctactgcccc cccatcaccg tcaaggtcat cgataaccgc cagtttggcc gccggcctgt 4620ggtgggccag tgtaccatcc gctccctgga gagcttcctg tgtgacccct actcggcgga 4680gagtccatcc ccacagggtg gcccagacga tgtgagccta ctcagtcctg gggaagacgt 4740gctcatcgac attgatgaca aggagcccct catccccatc caggaggaag agttcatcga 4800ttggtggagc aaattctttg cctccatagg ggagagggaa aagtgcggct cctacctgga 4860gaaggatttt gacaccctga aggtctatga cacacagctg gagaatgtgg aggcctttga 4920gggcctgtct gacttttgta acaccttcaa gctgtaccgg ggcaagacgc aggaggagac 4980agaagatcca tctgtgattg gtgaatttaa gggcctcttc aaaatttatc ccctcccaga 5040agacccagcc atccccatgc ccccaagaca gttccaccag ctggccgccc agggacccca 5100ggagtgcttg gtccgtatct acattgtccg agcatttggc ctgcagccca aggaccccaa 5160tggaaagtgt gatccttaca tcaagatctc catagggaag aaatcagtga gtgaccagga 5220taactacatc ccctgcacgc tggagcccgt atttggaaag atgttcgagc tgacctgcac 5280tctgcctctg gagaaggacc taaagatcac tctctatgac tatgacctcc tctccaagga 5340cgaaaagatc ggtgagacgg tcgtcgacct ggagaacagg ctgctgtcca agtttggggc 5400tcgctgtgga ctcccacaga cctactgtgt ctctggaccg aaccagtggc gggaccagct 5460ccgcccctcc cagctcctcc acctcttctg ccagcagcat agagtcaagg cacctgtgta 5520ccggacagac cgtgtaatgt ttcaggataa agaatattcc attgaagaga tagaggctgg 5580caggatccca aacccacacc tgggcccagt ggaggagcgt ctggctctgc atgtgcttca 5640gcagcagggc ctggtcccgg agcacgtgga gtcacggccc ctctacagcc ccctgcagcc 5700agacatcgag caggggaagc tgcagatgtg ggtcgaccta tttccgaagg ccctggggcg 5760gcctggacct cccttcaaca tcaccccacg gagagccaga aggtttttcc tgcgttgtat 5820tatctggaat accagagatg tgatcctgga tgacctgagc ctcacggggg agaagatgag 5880cgacatttat gtgaaaggtt ggatgattgg ctttg 5915 4 20 DNA Homo sapiens 4tgggacctca aagggcatcc 20 5 20 DNA Homo sapiens 5accatgctgt aggatgtgga 20 6 20 DNA Homo sapiens 6gggaggtgaa gcaacttcaa 20 7 20 DNA Homo sapiens 7ctcacggggt agaagatgag 20 8 20 DNA Homo sapiens 8cagggccgag atgagcccaa 20 9 20 DNA Homo sapiens 9acatcaaggg tcctggatga 20 10 20 DNA Homo sapiens 10ctgtggcggt gtttccggtg 20 11 20 DNA Homo sapiens 11acagacgtgc gttatcgttc 20 12 20 DNA Homo sapiens 12aagactgagc aaaatcccag 20 13 6912 DNA Homo sapiens 13tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaagg 540gcatccccct ggaccagggc tctgagcttc atgtggtggt caaagaccat gagacgatgg 600ggaggaacag gttcctgggg gaagccaagg tcccactccg agaggtcctc gccaccccta 660gtctgtccgc cagcttcaat gcccccctgc tggacaccaa gaagcagccc acaggggcct 720cgctggtcct gcaggtgtcc tacacaccgc tgcctggagc tgtgcccctg ttcccgcccc 780ctactcctct ggagccctcc ccgactctgc ctgacctgga tgtagtggca gacacaggag 840gagaggaaga cacagaggac cagggactca ctggagatga ggcggagcca ttcctggatc 900aaagcggagg cccgggggct cccaccaccc caaggaaact accttcacgt cctccgcccc 960actaccccgg gatcaaaaga aagcgaagtg cgcctacatc tagaaagctg ctgtcagaca 1020aaccgcagga tttccagatc agggtccagg tgatcgaggg gcgccagctg ccgggggtga 1080acatcaagcc tgtggtcaag gttaccgctg cagggcagac caagcggacg cggatccaca 1140agggaaacag cccactcttc aatgagactc ttttcttcaa cttgtttgac tctcctgggg 1200agctgtttga tgagcccatc tttatcacgg tggtagactc tcgttctctc aggacagatg 1260ctctcctcgg ggagttccgg atggacgtgg gcaccattta cagagagccc cggcacgcct 1320atctcaggaa gtggctgctg ctctcagacc ctgatgactt ctctgctggg gccagaggct 1380acctgaaaac aagcctttgt gtgctggggc ctggggacga agcgcctctg gagagaaaag 1440acccctctga agacaaggag gacattgaaa gcaacctgct ccggcccaca ggcgtagccc 1500tgcgaggagc ccacttctgc ctgaaggtct tccgggccga ggacttgccg cagatggacg 1560atgccgtgat ggacaacgtg aaacagatct ttggcttcga gagtaacaag aagaacttgg 1620tggacccctt tgtggaggtc agctttgcgg ggaaaatgct gtgcagcaag atcttggaga 1680agacggccaa ccctcagtgg aaccagaaca tcacactgcc tgccatgttt ccctccatgt 1740gcgaaaaaat gaggattcgt atcatagact gggaccgcct gactcacaat gacatcgtgg 1800ctaccaccta cctgagtatg tcgaaaatct ctgcccctgg aggagaaata gaagaggagc 1860ctgcaggtgc tgtcaagcct tcgaaagcct cagacttgga tgactacctg ggcttcctcc 1920ccacttttgg gccctgctac atcaacctct atggcagtcc cagagagttc acaggcttcc 1980cagaccccta cacagagctc aacacaggca agggggaagg tgtggcttat cgtggccggc 2040ttctgctctc cctggagacc aagctggtgg agcacagtga acagaaggtg gaggaccttc 2100ctgcggatga catcctccgg gtggagaagt accttaggag gcgcaagtac tccctgtttg 2160cggccttcta ctcagccacc atgctgtagg atgtggatga tgccatccag tttgaggtca 2220gcatcgggaa ctacgggaac aagttcgaca tgacctgcct gccgctggcc tccaccactc 2280agtacagccg tgcagtcttt gacgggtgcc actactacta cctaccctgg ggtaacgtga 2340aacctgtggt ggtgctgtca tcctactggg aggacatcag ccatagaatc gagactcaga 2400accagctgct tgggattgct gaccggctgg aagctggcct ggagcaggtc cacctggccc 2460tgaaggcgca gtgctccacg gaggacgtgg actcgctggt ggctcagctg acggatgagc 2520tcatcgcagg ctgcagccag cctctgggtg acatccatga gacaccctct gccacccacc 2580tggaccagta cctgtaccag ctgcgcaccc atcacctgag ccaaatcact gaggctgccc 2640tggccctgaa gctcggccac agtgagctcc ctgcagctct ggagcaggcg gaggactggc 2700tcctgcgtct gcgtgccctg gcagaggagc cccagaacag cctgccggac atcgtcatct 2760ggatgctgca gggagacaag cgtgtggcat accagcgggt gcccgcccac caagtcctct 2820tctcccggcg gggtgccaac tactgtggca agaattgtgg gaagctacag acaatctttc 2880tgaaatatcc gatggagaag gtgcctggcg cccggatgcc agtgcagata cgggtcaagc 2940tgtggtttgg gctctctgtg gatgagaagg agttcaacca gtttgctgag gggaagctgt 3000ctgtctttgc tgaaacctat gagaacgaga ctaagttggc ccttgttggg aactggggca 3060caacgggcct cacctacccc aagttttctg acgtcacggg caagatcaag ctacccaagg 3120acagcttccg cccctcggcc ggctggacct gggctggaga ttggttcgtg tgtccggaga 3180agactctgct ccatgacatg gacgccggtc acctgagctt cgtggaagag gtgtttgaga 3240accagacccg gcttcccgga ggccagtgga tctacatgag tgacaactac accgatgtga 3300acggggagaa ggtgcttccc aaggatgaca ttgagtgccc actgggctgg aagtgggaag 3360atgaggaatg gtccacagac ctcaaccggg ctgtcgatga gcaaggctgg gagtatagca 3420tcaccatccc cccggagcgg aagccgaagc actgggtccc tgctgagaag atgtactaca 3480cacaccgacg gcggcgctgg gtgcgcctgc gcaggaggga tctcagccaa atggaagcac 3540tgaaaaggca caggcaggcg gaggcggagg gcgagggctg ggagtacgcc tctctttttg 3600gctggaagtt ccacctcgag taccgcaaga cagatgcctt ccgccgccgc cgctggcgcc 3660gtcgcatgga gccactggag aagacggggc ctgcagctgt gtttgccctt gagggggccc 3720tgggcggcgt gatggatgac aagagtgaag attccatgtc cgtctccacc ttgagcttcg 3780gtgtgaacag acccacgatt tcctgcatat tcgactatgg gaaccgctac catctacgct 3840gctacatgta ccaggcccgg gacctggctg cgatggacaa ggactctttt tctgatccct 3900atgccatcgt ctccttcctg caccagagcc agaagacggt ggtggtgaag aacaccctta 3960accccacctg ggaccagacg ctcatcttct acgagatcga gatctttggc gagccggcca 4020cagttgctga gcaaccgccc agcattgtgg tggagctgta cgaccatgac acttatggtg 4080cagacgagtt tatgggtcgc tgcatctgtc aaccgagtct ggaacggatg ccacggctgg 4140cctggttccc actgacgagg ggcagccagc cgtcggggga gctgctggcc tcttttgagc 4200tcatccagag agagaagccg gccatccacc atattcctgg ttttgaggtg caggagacat 4260caaggatcct ggatgagtct gaggacacag acctgcccta cccaccaccc cagagggagg 4320ccaacatcta catggttcct cagaacatca agccagcgct ccagcgtacc gccatcgaga 4380tcctggcatg gggcctgcgg aacatgaaga gttaccagct ggccaacatc tcctccccca 4440gcctcgtggt agagtgtggg ggccagacgg tgcagtcctg tgtcatcagg aacctccgga 4500agaaccccaa ctttgacatc tgcaccctct tcatggaagt gatgctgccc agggaggagc 4560tctactgccc ccccatcacc gtcaaggtca tcgataaccg ccagtttggc cgccggcctg 4620tggtgggcca gtgtaccatc cgctccctgg agagcttcct gtgtgacccc tactcggcgg 4680agagtccatc cccacagggt ggcccagacg atgtgagcct actcagtcct ggggaagacg 4740tgctcatcga cattgatgac aaggagcccc tcatccccat ccaggaggaa gagttcatcg 4800attggtggag caaattcttt gcctccatag gggagaggga aaagtgcggc tcctacctgg 4860agaaggattt tgacaccctg aaggtctatg acacacagct ggagaatgtg gaggcctttg 4920agggcctgtc tgacttttgt aacaccttca agctgtaccg gggcaagacg caggaggaga 4980cagaagatcc atctgtgatt ggtgaattta agggcctctt caaaatttat cccctcccag 5040aagacccagc catccccatg cccccaagac agttccacca gctggccgcc cagggacccc 5100aggagtgctt ggtccgtatc tacattgtcc gagcatttgg cctgcagccc aaggacccca 5160atggaaagtg tgatccttac atcaagatct ccatagggaa gaaatcagtg agtgaccagg 5220ataactacat cccctgcacg ctggagcccg tatttggaaa gatgttcgag ctgacctgca 5280ctctgcctct ggagaaggac ctaaagatca ctctctatga ctatgacctc ctctccaagg 5340acgaaaagat cggtgagacg gtcgtcgacc tggagaacag gctgctgtcc aagtttgggg 5400ctcgctgtgg actcccacag acctactgtg tctctggacc gaaccagtgg cgggaccagc 5460tccgcccctc ccagctcctc cacctcttct gccagcagca tagagtcaag gcacctgtgt 5520accggacaga ccgtgtaatg tttcaggata aagaatattc cattgaagag atagaggctg 5580gcaggatccc aaacccacac ctgggcccag tggaggagcg tctggctctg catgtgcttc 5640agcagcaggg cctggtcccg gagcacgtgg agtcacggcc cctctacagc cccctgcagc 5700cagacatcga gcaggggaag ctgcagatgt gggtcgacct atttccgaag gccctggggc 5760ggcctggacc tcccttcaac atcaccccac ggagagccag aaggtttttc ctgcgttgta 5820ttatctggaa taccagagat gtgatcctgg atgacctgag cctcacgggg gagaagatga 5880gcgacattta tgtgaaaggt tggatgattg gctttgaaga acacaagcaa aagacagacg 5940tgcattatcg ttccctggga ggtgaaggca acttcaactg gaggttcatt ttccccttcg 6000actacctgcc agctgagcaa gtctgtacca ttgccaagaa ggatgccttc tggaggctgg 6060acaagactga gagcaaaatc ccagcacgag tggtgttcca gatctgggac aatgacaagt 6120tctcctttga tgattttctg ggctccctgc agctcgatct caaccgcatg cccaagccag 6180ccaagacagc caagaagtgc tccttggacc agctggatga tgctttccac ccagaatggt 6240ttgtgtccct ttttgagcag aaaacagtga agggctggtg gccctgtgta gcagaagagg 6300gtgagaagaa aatactggcg ggcaagctgg aaatgacctt ggagattgta gcagagagtg 6360agcatgagga gcggcctgct ggccagggcc gggatgagcc caacatgaac cctaagcttg 6420aggacccaag gcgccccgac acctccttcc tgtggtttac ctccccatac aagaccatga 6480agttcatcct gtggcggcgt ttccggtggg ccatcatcct cttcatcatc ctcttcatcc 6540tgctgctgtt cctggccatc ttcatctacg ccttcccgaa ctatgctgcc atgaagctgg 6600tgaagccctt cagctgagga ctctcctgcc ctgtagaagg ggccgtgggg tcccctccag 6660catgggactg gcctgcctcc tccgcccagc tcggcgagct cctccagacc tcctaggcct 6720gattgtcctg ccagggtggg cagacagaca gatggaccgg cccacactcc cagagttgct 6780aacatggagc tctgagatca ccccacttcc atcatttcct tctcccccaa cccaacgctt 6840ttttggatca gctcagacat atttcagtat aaaacagttg gaaccacaaa aaaaaaaaaa 6900aaaaaaaaaa aa 6912 14 6911 DNA Homo sapiens 14tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaggg 540catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg agacgatggg 600gaggaacagg ttcctggggg aagccaaggt cccactccga gaggtcctcg ccacccctag 660tctgtccgcc agcttcaatg cccccctgct ggacaccaag aagcagccca caggggcctc 720gctggtcctg caggtgtcct acacaccgct gcctggagct gtgcccctgt tcccgccccc 780tactcctctg gagccctccc cgactctgcc tgacctggat gtagtggcag acacaggagg 840agaggaagac acagaggacc agggactcac tggagatgag gcggagccat tcctggatca 900aagcggaggc ccgggggctc ccaccacccc aaggaaacta ccttcacgtc ctccgcccca 960ctaccccggg atcaaaagaa agcgaagtgc gcctacatct agaaagctgc tgtcagacaa 1020accgcaggat ttccagatca gggtccaggt gatcgagggg cgccagctgc cgggggtgaa 1080catcaagcct gtggtcaagg ttaccgctgc agggcagacc aagcggacgc ggatccacaa 1140gggaaacagc ccactcttca atgagactct tttcttcaac ttgtttgact ctcctgggga 1200gctgtttgat gagcccatct ttatcacggt ggtagactct cgttctctca ggacagatgc 1260tctcctcggg gagttccgga tggacgtggg caccatttac agagagcccc ggcacgccta 1320tctcaggaag tggctgctgc tctcagaccc tgatgacttc tctgctgggg ccagaggcta 1380cctgaaaaca agcctttgtg tgctggggcc tggggacgaa gcgcctctgg agagaaaaga 1440cccctctgaa gacaaggagg acattgaaag caacctgctc cggcccacag gcgtagccct 1500gcgaggagcc cacttctgcc tgaaggtctt ccgggccgag gacttgccgc agatggacga 1560tgccgtgatg gacaacgtga aacagatctt tggcttcgag agtaacaaga agaacttggt 1620ggaccccttt gtggaggtca gctttgcggg gaaaatgctg tgcagcaaga tcttggagaa 1680gacggccaac cctcagtgga accagaacat cacactgcct gccatgtttc cctccatgtg 1740cgaaaaaatg aggattcgta tcatagactg ggaccgcctg actcacaatg acatcgtggc 1800taccacctac ctgagtatgt cgaaaatctc tgcccctgga ggagaaatag aagaggagcc 1860tgcaggtgct gtcaagcctt cgaaagcctc agacttggat gactacctgg gcttcctccc 1920cacttttggg ccctgctaca tcaacctcta tggcagtccc agagagttca caggcttccc 1980agacccctac acagagctca acacaggcaa gggggaaggt gtggcttatc gtggccggct 2040tctgctctcc ctggagacca agctggtgga gcacagtgaa cagaaggtgg aggaccttcc 2100tgcggatgac atcctccggg tggagaagta ccttaggagg cgcaagtact ccctgtttgc 2160ggccttctac tcagccacca tgctgtagga tgtggatgat gccatccagt ttgaggtcag 2220catcgggaac tacgggaaca agttcgacat gacctgcctg ccgctggcct ccaccactca 2280gtacagccgt gcagtctttg acgggtgcca ctactactac ctaccctggg gtaacgtgaa 2340acctgtggtg gtgctgtcat cctactggga ggacatcagc catagaatcg agactcagaa 2400ccagctgctt gggattgctg accggctgga agctggcctg gagcaggtcc acctggccct 2460gaaggcgcag tgctccacgg aggacgtgga ctcgctggtg gctcagctga cggatgagct 2520catcgcaggc tgcagccagc ctctgggtga catccatgag acaccctctg ccacccacct 2580ggaccagtac ctgtaccagc tgcgcaccca tcacctgagc caaatcactg aggctgccct 2640ggccctgaag ctcggccaca gtgagctccc tgcagctctg gagcaggcgg aggactggct 2700cctgcgtctg cgtgccctgg cagaggagcc ccagaacagc ctgccggaca tcgtcatctg 2760gatgctgcag ggagacaagc gtgtggcata ccagcgggtg cccgcccacc aagtcctctt 2820ctcccggcgg ggtgccaact actgtggcaa gaattgtggg aagctacaga caatctttct 2880gaaatatccg atggagaagg tgcctggcgc ccggatgcca gtgcagatac gggtcaagct 2940gtggtttggg ctctctgtgg atgagaagga gttcaaccag tttgctgagg ggaagctgtc 3000tgtctttgct gaaacctatg agaacgagac taagttggcc cttgttggga actggggcac 3060aacgggcctc acctacccca agttttctga cgtcacgggc aagatcaagc tacccaagga 3120cagcttccgc ccctcggccg gctggacctg ggctggagat tggttcgtgt gtccggagaa 3180gactctgctc catgacatgg acgccggtca cctgagcttc gtggaagagg tgtttgagaa 3240ccagacccgg cttcccggag gccagtggat ctacatgagt gacaactaca ccgatgtgaa 3300cggggagaag gtgcttccca aggatgacat tgagtgccca ctgggctgga agtgggaaga 3360tgaggaatgg tccacagacc tcaaccgggc tgtcgatgag caaggctggg agtatagcat 3420caccatcccc ccggagcgga agccgaagca ctgggtccct gctgagaaga tgtactacac 3480acaccgacgg cggcgctggg tgcgcctgcg caggagggat ctcagccaaa tggaagcact 3540gaaaaggcac aggcaggcgg aggcggaggg cgagggctgg gagtacgcct ctctttttgg 3600ctggaagttc cacctcgagt accgcaagac agatgccttc cgccgccgcc gctggcgccg 3660tcgcatggag ccactggaga agacggggcc tgcagctgtg tttgcccttg agggggccct 3720gggcggcgtg atggatgaca agagtgaaga ttccatgtcc gtctccacct tgagcttcgg 3780tgtgaacaga cccacgattt cctgcatatt cgactatggg aaccgctacc atctacgctg 3840ctacatgtac caggcccggg acctggctgc gatggacaag gactcttttt ctgatcccta 3900tgccatcgtc tccttcctgc accagagcca gaagacggtg gtggtgaaga acacccttaa 3960ccccacctgg gaccagacgc tcatcttcta cgagatcgag atctttggcg agccggccac 4020agttgctgag caaccgccca gcattgtggt ggagctgtac gaccatgaca cttatggtgc 4080agacgagttt atgggtcgct gcatctgtca accgagtctg gaacggatgc cacggctggc 4140ctggttccca ctgacgaggg gcagccagcc gtcgggggag ctgctggcct cttttgagct 4200catccagaga gagaagccgg ccatccacca tattcctggt tttgaggtgc aggagacatc 4260aaggatcctg gatgagtctg aggacacaga cctgccctac ccaccacccc agagggaggc 4320caacatctac atggttcctc agaacatcaa gccagcgctc cagcgtaccg ccatcgagat 4380cctggcatgg ggcctgcgga acatgaagag ttaccagctg gccaacatct cctcccccag 4440cctcgtggta gagtgtgggg gccagacggt gcagtcctgt gtcatcagga acctccggaa 4500gaaccccaac tttgacatct gcaccctctt catggaagtg atgctgccca gggaggagct 4560ctactgcccc cccatcaccg tcaaggtcat cgataaccgc cagtttggcc gccggcctgt 4620ggtgggccag tgtaccatcc gctccctgga gagcttcctg tgtgacccct actcggcgga 4680gagtccatcc ccacagggtg gcccagacga tgtgagccta ctcagtcctg gggaagacgt 4740gctcatcgac attgatgaca aggagcccct catccccatc caggaggaag agttcatcga 4800ttggtggagc aaattctttg cctccatagg ggagagggaa aagtgcggct cctacctgga 4860gaaggatttt gacaccctga aggtctatga cacacagctg gagaatgtgg aggcctttga 4920gggcctgtct gacttttgta acaccttcaa gctgtaccgg ggcaagacgc aggaggagac 4980agaagatcca tctgtgattg gtgaatttaa gggcctcttc aaaatttatc ccctcccaga 5040agacccagcc atccccatgc ccccaagaca gttccaccag ctggccgccc agggacccca 5100ggagtgcttg gtccgtatct acattgtccg agcatttggc ctgcagccca aggaccccaa 5160tggaaagtgt gatccttaca tcaagatctc catagggaag aaatcagtga gtgaccagga 5220taactacatc ccctgcacgc tggagcccgt atttggaaag atgttcgagc tgacctgcac 5280tctgcctctg gagaaggacc taaagatcac tctctatgac tatgacctcc tctccaagga 5340cgaaaagatc ggtgagacgg tcgtcgacct ggagaacagg ctgctgtcca agtttggggc 5400tcgctgtgga ctcccacaga cctactgtgt ctctggaccg aaccagtggc gggaccagct 5460ccgcccctcc cagctcctcc acctcttctg ccagcagcat agagtcaagg cacctgtgta 5520ccggacagac cgtgtaatgt ttcaggataa agaatattcc attgaagaga tagaggctgg 5580caggatccca aacccacacc tgggcccagt ggaggagcgt ctggctctgc atgtgcttca 5640gcagcagggc ctggtcccgg agcacgtgga gtcacggccc ctctacagcc ccctgcagcc 5700agacatcgag caggggaagc tgcagatgtg ggtcgaccta tttccgaagg ccctggggcg 5760gcctggacct cccttcaaca tcaccccacg gagagccaga aggtttttcc tgcgttgtat 5820tatctggaat accagagatg tgatcctgga tgacctgagc ctcacggggg agaagatgag 5880cgacatttat gtgaaaggtt ggatgattgg ctttgaagaa cacaagcaaa agacagacgt 5940gcattatcgt tccctgggag gtgaaggcaa cttcaactgg aggttcattt tccccttcga 6000ctacctgcca gctgagcaag tctgtaccat tgccaagaag gatgccttct ggaggctgga 6060caagactgag agcaaaatcc cagcacgagt ggtgttccag atctgggaca atgacaagtt 6120ctcctttgat gattttctgg gctccctgca gctcgatctc aaccgcatgc ccaagccagc 6180caagacagcc aagaagtgct ccttggacca gctggatgat gctttccacc cagaatggtt 6240tgtgtccctt tttgagcaga aaacagtgaa gggctggtgg ccctgtgtag cagaagaggg 6300tgagaagaaa atactggcgg gcaagctgga aatgaccttg gagattgtag cagagagtga 6360gcatgaggag cggcctgctg gccagggccg ggatgagccc aacatgaacc ctaagcttga 6420ggacccaagg cgccccgaca cctccttcct gtggtttacc tccccataca agaccatgaa 6480gttcatcctg tggcggcgtt tccggtgggc catcatcctc ttcatcatcc tcttcatcct 6540gctgctgttc ctggccatct tcatctacgc cttcccgaac tatgctgcca tgaagctggt 6600gaagcccttc agctgaggac tctcctgccc tgtagaaggg gccgtggggt cccctccagc 6660atgggactgg cctgcctcct ccgcccagct cggcgagctc ctccagacct cctaggcctg 6720attgtcctgc cagggtgggc agacagacag atggaccggc ccacactccc agagttgcta 6780acatggagct ctgagatcac cccacttcca tcatttcctt ctcccccaac ccaacgcttt 6840tttggatcag ctcagacata tttcagtata aaacagttgg aaccacaaaa aaaaaaaaaa 6900aaaaaaaaaa a 6911 15 6910 DNA Homo sapiens 15tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaggg 540catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg agacgatggg 600gaggaacagg ttcctggggg aagccaaggt cccactccga gaggtcctcg ccacccctag 660tctgtccgcc agcttcaatg cccccctgct ggacaccaag aagcagccca caggggcctc 720gctggtcctg caggtgtcct acacaccgct gcctggagct gtgcccctgt tcccgccccc 780tactcctctg gagccctccc cgactctgcc tgacctggat gtagtggcag acacaggagg 840agaggaagac acagaggacc agggactcac tggagatgag gcggagccat tcctggatca 900aagcggaggc ccgggggctc ccaccacccc aaggaaacta ccttcacgtc ctccgcccca 960ctaccccggg atcaaaagaa agcgaagtgc gcctacatct agaaagctgc tgtcagacaa 1020accgcaggat ttccagatca gggtccaggt gatcgagggg cgccagctgc cgggggtgaa 1080catcaagcct gtggtcaagg ttaccgctgc agggcagacc aagcggacgc ggatccacaa 1140gggaaacagc ccactcttca atgagactct tttcttcaac ttgtttgact ctcctgggga 1200gctgtttgat gagcccatct ttatcacggt ggtagactct cgttctctca ggacagatgc 1260tctcctcggg gagttccgga tggacgtggg caccatttac agagagcccc ggcacgccta 1320tctcaggaag tggctgctgc tctcagaccc tgatgacttc tctgctgggg ccagaggcta 1380cctgaaaaca agcctttgtg tgctggggcc tggggacgaa gcgcctctgg agagaaaaga 1440cccctctgaa gacaaggagg acattgaaag caacctgctc cggcccacag gcgtagccct 1500gcgaggagcc cacttctgcc tgaaggtctt ccgggccgag gacttgccgc agatggacga 1560tgccgtgatg gacaacgtga aacagatctt tggcttcgag agtaacaaga agaacttggt 1620ggaccccttt gtggaggtca gctttgcggg gaaaatgctg tgcagcaaga tcttggagaa 1680gacggccaac cctcagtgga accagaacat cacactgcct gccatgtttc cctccatgtg 1740cgaaaaaatg aggattcgta tcatagactg ggaccgcctg actcacaatg acatcgtggc 1800taccacctac ctgagtatgt cgaaaatctc tgcccctgga ggagaaatag aagaggagcc 1860tgcaggtgct gtcaagcctt cgaaagcctc agacttggat gactacctgg gcttcctccc 1920cacttttggg ccctgctaca tcaacctcta tggcagtccc agagagttca caggcttccc 1980agacccctac acagagctca acacaggcaa gggggaaggt gtggcttatc gtggccggct 2040tctgctctcc ctggagacca agctggtgga gcacagtgaa cagaaggtgg aggaccttcc 2100tgcggatgac atcctccggg tggagaagta ccttaggagg cgcaagtact ccctgtttgc 2160ggccttctac tcagccacca tgctgcagga tgtggatgat gccatccagt ttgaggtcag 2220catcgggaac tacgggaaca agttcgacat gacctgcctg ccgctggcct ccaccactca 2280gtacagccgt gcagtctttg acgggtgcca ctactactac ctaccctggg gtaacgtgaa 2340acctgtggtg gtgctgtcat cctactggga ggacatcagc catagaatcg agactcagaa 2400ccagctgctt gggattgctg accggctgga agctggcctg gagcaggtcc acctggccct 2460gaaggcgcag tgctccacgg aggacgtgga ctcgctggtg gctcagctga cggatgagct 2520catcgcaggc tgcagccagc ctctgggtga catccatgag acaccctctg ccacccacct 2580ggaccagtac ctgtaccagc tgcgcaccca tcacctgagc caaatcactg aggctgccct 2640ggccctgaag ctcggccaca gtgagctccc tgcagctctg gagcaggcgg aggactggct 2700cctgcgtctg cgtgccctgg cagaggagcc ccagaacagc ctgccggaca tcgtcatctg 2760gatgctgcag ggagacaagc gtgtggcata ccagcgggtg cccgcccacc aagtcctctt 2820ctcccggcgg ggtgccaact actgtggcaa gaattgtggg aagctacaga caatctttct 2880gaaatatccg atggagaagg tgcctggcgc ccggatgcca gtgcagatac gggtcaagct 2940gtggtttggg ctctctgtgg atgagaagga gttcaaccag tttgctgagg ggaagctgtc 3000tgtctttgct gaaacctatg agaacgagac taagttggcc cttgttggga actggggcac 3060aacgggcctc acctacccca agttttctga cgtcacgggc aagatcaagc tacccaagga 3120cagcttccgc ccctcggccg gctggacctg ggctggagat tggttcgtgt gtccggagaa 3180gactctgctc catgacatgg acgccggtca cctgagcttc gtggaagagg tgtttgagaa 3240ccagacccgg cttcccggag gccagtggat ctacatgagt gacaactaca ccgatgtgaa 3300cggggagaag gtgcttccca aggatgacat tgagtgccca ctgggctgga agtgggaaga 3360tgaggaatgg tccacagacc tcaaccgggc tgtcgatgag caaggctggg agtatagcat 3420caccatcccc ccggagcgga agccgaagca ctgggtccct gctgagaaga tgtactacac 3480acaccgacgg cggcgctggg tgcgcctgcg caggagggat ctcagccaaa tggaagcact 3540gaaaaggcac aggcaggcgg aggcggaggg cgagggctgg gagtacgcct ctctttttgg 3600ctggaagttc cacctcgagt accgcaagac agatgccttc cgccgccgcc gctggcgccg 3660tcgcatggag ccactggaga agacggggcc tgcagctgtg tttgcccttg agggggccct 3720gggcggcgtg atggatgaca agagtgaaga ttccatgtcc gtctccacct tgagcttcgg 3780tgtgaacaga cccacgattt cctgcatatt cgactatggg aaccgctacc atctacgctg 3840ctacatgtac caggcccggg acctggctgc gatggacaag gactcttttt ctgatcccta 3900tgccatcgtc tccttcctgc accagagcca gaagacggtg gtggtgaaga acacccttaa 3960ccccacctgg gaccagacgc tcatcttcta cgagatcgag atctttggcg agccggccac 4020agttgctgag caaccgccca gcattgtggt ggagctgtac gaccatgaca cttatggtgc 4080agacgagttt atgggtcgct gcatctgtca accgagtctg gaacggatgc cacggctggc 4140ctggttccca ctgacgaggg gcagccagcc gtcgggggag ctgctggcct cttttgagct 4200catccagaga gagaagccgg ccatccacca tattcctggt tttgaggtgc aggagacatc 4260aaggatcctg gatgagtctg aggacacaga cctgccctac ccaccacccc agagggaggc 4320caacatctac atggttcctc agaacatcaa gccagcgctc cagcgtaccg ccatcgagat 4380cctggcatgg ggcctgcgga acatgaagag ttaccagctg gccaacatct cctcccccag 4440cctcgtggta gagtgtgggg gccagacggt gcagtcctgt gtcatcagga acctccggaa 4500gaaccccaac tttgacatct gcaccctctt catggaagtg atgctgccca gggaggagct 4560ctactgcccc cccatcaccg tcaaggtcat cgataaccgc cagtttggcc gccggcctgt 4620ggtgggccag tgtaccatcc gctccctgga gagcttcctg tgtgacccct actcggcgga 4680gagtccatcc ccacagggtg gcccagacga tgtgagccta ctcagtcctg gggaagacgt 4740gctcatcgac attgatgaca aggagcccct catccccatc caggaggaag agttcatcga 4800ttggtggagc aaattctttg cctccatagg ggagagggaa aagtgcggct cctacctgga 4860gaaggatttt gacaccctga aggtctatga cacacagctg gagaatgtgg aggcctttga 4920gggcctgtct gacttttgta acaccttcaa gctgtaccgg ggcaagacgc aggaggagac 4980agaagatcca tctgtgattg gtgaatttaa gggcctcttc aaaatttatc ccctcccaga 5040agacccagcc atccccatgc ccccaagaca gttccaccag ctggccgccc agggacccca 5100ggagtgcttg gtccgtatct acattgtccg agcatttggc ctgcagccca aggaccccaa 5160tggaaagtgt gatccttaca tcaagatctc catagggaag aaatcagtga gtgaccagga 5220taactacatc ccctgcacgc tggagcccgt atttggaaag atgttcgagc tgacctgcac 5280tctgcctctg gagaaggacc taaagatcac tctctatgac tatgacctcc tctccaagga 5340cgaaaagatc ggtgagacgg tcgtcgacct ggagaacagg ctgctgtcca agtttggggc 5400tcgctgtgga ctcccacaga cctactgtgt ctctggaccg aaccagtggc gggaccagct 5460ccgcccctcc cagctcctcc acctcttctg ccagcagcat agagtcaagg cacctgtgta 5520ccggacagac cgtgtaatgt ttcaggataa agaatattcc attgaagaga tagaggctgg 5580caggatccca aacccacacc tgggcccagt ggaggagcgt ctggctctgc atgtgcttca 5640gcagcagggc ctggtcccgg agcacgtgga gtcacggccc ctctacagcc ccctgcagcc 5700agacatcgag caggggaagc tgcagatgtg ggtcgaccta tttccgaagg ccctggggcg 5760gcctggacct cccttcaaca tcaccccacg gagagccaga aggtttttcc tgcgttgtat 5820tatctggaat accagagatg tgatcctgga tgacctgagc ctcacggggg agaagatgag 5880cgacatttat gtgaaaggtt ggatgattgg ctttgaagaa cacaagcaaa agacagacgt 5940gcattatcgt tccctgggag gtgaagcaac ttcaactgga ggttcatttt ccccttcgac 6000tacctgccag ctgagcaagt ctgtaccatt gccaagaagg atgccttctg gaggctggac 6060aagactgaga gcaaaatccc agcacgagtg gtgttccaga tctgggacaa tgacaagttc 6120tcctttgatg attttctggg ctccctgcag ctcgatctca accgcatgcc caagccagcc 6180aagacagcca agaagtgctc cttggaccag ctggatgatg ctttccaccc agaatggttt 6240gtgtcccttt ttgagcagaa aacagtgaag ggctggtggc cctgtgtagc agaagagggt 6300gagaagaaaa tactggcggg caagctggaa atgaccttgg agattgtagc agagagtgag 6360catgaggagc ggcctgctgg ccagggccgg gatgagccca acatgaaccc taagcttgag 6420gacccaaggc gccccgacac ctccttcctg tggtttacct ccccatacaa gaccatgaag 6480ttcatcctgt ggcggcgttt ccggtgggcc atcatcctct tcatcatcct cttcatcctg 6540ctgctgttcc tggccatctt catctacgcc ttcccgaact atgctgccat gaagctggtg 6600aagcccttca gctgaggact ctcctgccct gtagaagggg ccgtggggtc ccctccagca 6660tgggactggc ctgcctcctc cgcccagctc ggcgagctcc tccagacctc ctaggcctga 6720ttgtcctgcc agggtgggca gacagacaga tggaccggcc cacactccca gagttgctaa 6780catggagctc tgagatcacc ccacttccat catttccttc tcccccaacc caacgctttt 6840ttggatcagc tcagacatat ttcagtataa aacagttgga accacaaaaa aaaaaaaaaa 6900aaaaaaaaaa 6910 16 6911 DNA Homo sapiens 16tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaggg 540catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg agacgatggg 600gaggaacagg ttcctggggg aagccaaggt cccactccga gaggtcctcg ccacccctag 660tctgtccgcc agcttcaatg cccccctgct ggacaccaag aagcagccca caggggcctc 720gctggtcctg caggtgtcct acacaccgct gcctggagct gtgcccctgt tcccgccccc 780tactcctctg gagccctccc cgactctgcc tgacctggat gtagtggcag acacaggagg 840agaggaagac acagaggacc agggactcac tggagatgag gcggagccat tcctggatca 900aagcggaggc ccgggggctc ccaccacccc aaggaaacta ccttcacgtc ctccgcccca 960ctaccccggg atcaaaagaa agcgaagtgc gcctacatct agaaagctgc tgtcagacaa 1020accgcaggat ttccagatca gggtccaggt gatcgagggg cgccagctgc cgggggtgaa 1080catcaagcct gtggtcaagg ttaccgctgc agggcagacc aagcggacgc ggatccacaa 1140gggaaacagc ccactcttca atgagactct tttcttcaac ttgtttgact ctcctgggga 1200gctgtttgat gagcccatct ttatcacggt ggtagactct cgttctctca ggacagatgc 1260tctcctcggg gagttccgga tggacgtggg caccatttac agagagcccc ggcacgccta 1320tctcaggaag tggctgctgc tctcagaccc tgatgacttc tctgctgggg ccagaggcta 1380cctgaaaaca agcctttgtg tgctggggcc tggggacgaa gcgcctctgg agagaaaaga 1440cccctctgaa gacaaggagg acattgaaag caacctgctc cggcccacag gcgtagccct 1500gcgaggagcc cacttctgcc tgaaggtctt ccgggccgag gacttgccgc agatggacga 1560tgccgtgatg gacaacgtga aacagatctt tggcttcgag agtaacaaga agaacttggt 1620ggaccccttt gtggaggtca gctttgcggg gaaaatgctg tgcagcaaga tcttggagaa 1680gacggccaac cctcagtgga accagaacat cacactgcct gccatgtttc cctccatgtg 1740cgaaaaaatg aggattcgta tcatagactg ggaccgcctg actcacaatg acatcgtggc 1800taccacctac ctgagtatgt cgaaaatctc tgcccctgga ggagaaatag aagaggagcc 1860tgcaggtgct gtcaagcctt cgaaagcctc agacttggat gactacctgg gcttcctccc 1920cacttttggg ccctgctaca tcaacctcta tggcagtccc agagagttca caggcttccc 1980agacccctac acagagctca acacaggcaa gggggaaggt gtggcttatc gtggccggct 2040tctgctctcc ctggagacca agctggtgga gcacagtgaa cagaaggtgg aggaccttcc 2100tgcggatgac atcctccggg tggagaagta ccttaggagg cgcaagtact ccctgtttgc 2160ggccttctac tcagccacca tgctgcagga tgtggatgat gccatccagt ttgaggtcag 2220catcgggaac tacgggaaca agttcgacat gacctgcctg ccgctggcct ccaccactca 2280gtacagccgt gcagtctttg acgggtgcca ctactactac ctaccctggg gtaacgtgaa 2340acctgtggtg gtgctgtcat cctactggga ggacatcagc catagaatcg agactcagaa 2400ccagctgctt gggattgctg accggctgga agctggcctg gagcaggtcc acctggccct 2460gaaggcgcag tgctccacgg aggacgtgga ctcgctggtg gctcagctga cggatgagct 2520catcgcaggc tgcagccagc ctctgggtga catccatgag acaccctctg ccacccacct 2580ggaccagtac ctgtaccagc tgcgcaccca tcacctgagc caaatcactg aggctgccct 2640ggccctgaag ctcggccaca gtgagctccc tgcagctctg gagcaggcgg aggactggct 2700cctgcgtctg cgtgccctgg cagaggagcc ccagaacagc ctgccggaca tcgtcatctg 2760gatgctgcag ggagacaagc gtgtggcata ccagcgggtg cccgcccacc aagtcctctt 2820ctcccggcgg ggtgccaact actgtggcaa gaattgtggg aagctacaga caatctttct 2880gaaatatccg atggagaagg tgcctggcgc ccggatgcca gtgcagatac gggtcaagct 2940gtggtttggg ctctctgtgg atgagaagga gttcaaccag tttgctgagg ggaagctgtc 3000tgtctttgct gaaacctatg agaacgagac taagttggcc cttgttggga actggggcac 3060aacgggcctc acctacccca agttttctga cgtcacgggc aagatcaagc tacccaagga 3120cagcttccgc ccctcggccg gctggacctg ggctggagat tggttcgtgt gtccggagaa 3180gactctgctc catgacatgg acgccggtca cctgagcttc gtggaagagg tgtttgagaa 3240ccagacccgg cttcccggag gccagtggat ctacatgagt gacaactaca ccgatgtgaa 3300cggggagaag gtgcttccca aggatgacat tgagtgccca ctgggctgga agtgggaaga 3360tgaggaatgg tccacagacc tcaaccgggc tgtcgatgag caaggctggg agtatagcat 3420caccatcccc ccggagcgga agccgaagca ctgggtccct gctgagaaga tgtactacac 3480acaccgacgg cggcgctggg tgcgcctgcg caggagggat ctcagccaaa tggaagcact 3540gaaaaggcac aggcaggcgg aggcggaggg cgagggctgg gagtacgcct ctctttttgg 3600ctggaagttc cacctcgagt accgcaagac agatgccttc cgccgccgcc gctggcgccg 3660tcgcatggag ccactggaga agacggggcc tgcagctgtg tttgcccttg agggggccct 3720gggcggcgtg atggatgaca agagtgaaga ttccatgtcc gtctccacct tgagcttcgg 3780tgtgaacaga cccacgattt cctgcatatt cgactatggg aaccgctacc atctacgctg 3840ctacatgtac caggcccggg acctggctgc gatggacaag gactcttttt ctgatcccta 3900tgccatcgtc tccttcctgc accagagcca gaagacggtg gtggtgaaga acacccttaa 3960ccccacctgg gaccagacgc tcatcttcta cgagatcgag atctttggcg agccggccac 4020agttgctgag caaccgccca gcattgtggt ggagctgtac gaccatgaca cttatggtgc 4080agacgagttt atgggtcgct gcatctgtca accgagtctg gaacggatgc cacggctggc 4140ctggttccca ctgacgaggg gcagccagcc gtcgggggag ctgctggcct cttttgagct 4200catccagaga gagaagccgg ccatccacca tattcctggt tttgaggtgc aggagacatc 4260aaggatcctg gatgagtctg aggacacaga cctgccctac ccaccacccc agagggaggc 4320caacatctac atggttcctc agaacatcaa gccagcgctc cagcgtaccg ccatcgagat 4380cctggcatgg ggcctgcgga acatgaagag ttaccagctg gccaacatct cctcccccag 4440cctcgtggta gagtgtgggg gccagacggt gcagtcctgt gtcatcagga acctccggaa 4500gaaccccaac tttgacatct gcaccctctt catggaagtg atgctgccca gggaggagct 4560ctactgcccc cccatcaccg tcaaggtcat cgataaccgc cagtttggcc gccggcctgt 4620ggtgggccag tgtaccatcc gctccctgga gagcttcctg tgtgacccct actcggcgga 4680gagtccatcc ccacagggtg gcccagacga tgtgagccta ctcagtcctg gggaagacgt 4740gctcatcgac attgatgaca aggagcccct catccccatc caggaggaag agttcatcga 4800ttggtggagc aaattctttg cctccatagg ggagagggaa aagtgcggct cctacctgga 4860gaaggatttt gacaccctga aggtctatga cacacagctg gagaatgtgg aggcctttga 4920gggcctgtct gacttttgta acaccttcaa gctgtaccgg ggcaagacgc aggaggagac 4980agaagatcca tctgtgattg gtgaatttaa gggcctcttc aaaatttatc ccctcccaga 5040agacccagcc atccccatgc ccccaagaca gttccaccag ctggccgccc agggacccca 5100ggagtgcttg gtccgtatct acattgtccg agcatttggc ctgcagccca aggaccccaa 5160tggaaagtgt gatccttaca tcaagatctc catagggaag aaatcagtga gtgaccagga 5220taactacatc ccctgcacgc tggagcccgt atttggaaag atgttcgagc tgacctgcac 5280tctgcctctg gagaaggacc taaagatcac tctctatgac tatgacctcc tctccaagga 5340cgaaaagatc ggtgagacgg tcgtcgacct ggagaacagg ctgctgtcca agtttggggc 5400tcgctgtgga ctcccacaga cctactgtgt ctctggaccg aaccagtggc gggaccagct 5460ccgcccctcc cagctcctcc acctcttctg ccagcagcat agagtcaagg cacctgtgta 5520ccggacagac cgtgtaatgt ttcaggataa agaatattcc attgaagaga tagaggctgg 5580caggatccca aacccacacc tgggcccagt ggaggagcgt ctggctctgc atgtgcttca 5640gcagcagggc ctggtcccgg agcacgtgga gtcacggccc ctctacagcc ccctgcagcc 5700agacatcgag caggggaagc tgcagatgtg ggtcgaccta tttccgaagg ccctggggcg 5760gcctggacct cccttcaaca tcaccccacg gagagccaga aggtttttcc tgcgttgtat 5820tatctggaat accagagatg tgatcctgga tgacctgagc ctcacggggt agaagatgag 5880cgacatttat gtgaaaggtt ggatgattgg ctttgaagaa cacaagcaaa agacagacgt 5940gcattatcgt tccctgggag gtgaaggcaa cttcaactgg aggttcattt tccccttcga 6000ctacctgcca gctgagcaag tctgtaccat tgccaagaag gatgccttct ggaggctgga 6060caagactgag agcaaaatcc cagcacgagt ggtgttccag atctgggaca atgacaagtt 6120ctcctttgat gattttctgg gctccctgca gctcgatctc aaccgcatgc ccaagccagc 6180caagacagcc aagaagtgct ccttggacca gctggatgat gctttccacc cagaatggtt 6240tgtgtccctt tttgagcaga aaacagtgaa gggctggtgg ccctgtgtag cagaagaggg 6300tgagaagaaa atactggcgg gcaagctgga aatgaccttg gagattgtag cagagagtga 6360gcatgaggag cggcctgctg gccagggccg ggatgagccc aacatgaacc ctaagcttga 6420ggacccaagg cgccccgaca cctccttcct gtggtttacc tccccataca agaccatgaa 6480gttcatcctg tggcggcgtt tccggtgggc catcatcctc ttcatcatcc tcttcatcct 6540gctgctgttc ctggccatct tcatctacgc cttcccgaac tatgctgcca tgaagctggt 6600gaagcccttc agctgaggac tctcctgccc tgtagaaggg gccgtggggt cccctccagc 6660atgggactgg cctgcctcct ccgcccagct cggcgagctc ctccagacct cctaggcctg 6720attgtcctgc cagggtgggc agacagacag atggaccggc ccacactccc agagttgcta 6780acatggagct ctgagatcac cccacttcca tcatttcctt ctcccccaac ccaacgcttt 6840tttggatcag ctcagacata tttcagtata aaacagttgg aaccacaaaa aaaaaaaaaa 6900aaaaaaaaaa a 6911 17 6911 DNA Homo sapiens 17tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaggg 540catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg agacgatggg 600gaggaacagg ttcctggggg aagccaaggt cccactccga gaggtcctcg ccacccctag 660tctgtccgcc agcttcaatg cccccctgct ggacaccaag aagcagccca caggggcctc 720gctggtcctg caggtgtcct acacaccgct gcctggagct gtgcccctgt tcccgccccc 780tactcctctg gagccctccc cgactctgcc tgacctggat gtagtggcag acacaggagg 840agaggaagac acagaggacc agggactcac tggagatgag gcggagccat tcctggatca 900aagcggaggc ccgggggctc ccaccacccc aaggaaacta ccttcacgtc ctccgcccca 960ctaccccggg atcaaaagaa agcgaagtgc gcctacatct agaaagctgc tgtcagacaa 1020accgcaggat ttccagatca gggtccaggt gatcgagggg cgccagctgc cgggggtgaa 1080catcaagcct gtggtcaagg ttaccgctgc agggcagacc aagcggacgc ggatccacaa 1140gggaaacagc ccactcttca atgagactct tttcttcaac ttgtttgact ctcctgggga 1200gctgtttgat gagcccatct ttatcacggt ggtagactct cgttctctca ggacagatgc 1260tctcctcggg gagttccgga tggacgtggg caccatttac agagagcccc ggcacgccta 1320tctcaggaag tggctgctgc tctcagaccc tgatgacttc tctgctgggg ccagaggcta 1380cctgaaaaca agcctttgtg tgctggggcc tggggacgaa gcgcctctgg agagaaaaga 1440cccctctgaa gacaaggagg acattgaaag caacctgctc cggcccacag gcgtagccct 1500gcgaggagcc cacttctgcc tgaaggtctt ccgggccgag gacttgccgc agatggacga 1560tgccgtgatg gacaacgtga aacagatctt tggcttcgag agtaacaaga agaacttggt 1620ggaccccttt gtggaggtca gctttgcggg gaaaatgctg tgcagcaaga tcttggagaa 1680gacggccaac cctcagtgga accagaacat cacactgcct gccatgtttc cctccatgtg 1740cgaaaaaatg aggattcgta tcatagactg ggaccgcctg actcacaatg acatcgtggc 1800taccacctac ctgagtatgt cgaaaatctc tgcccctgga ggagaaatag aagaggagcc 1860tgcaggtgct gtcaagcctt cgaaagcctc agacttggat gactacctgg gcttcctccc 1920cacttttggg ccctgctaca tcaacctcta tggcagtccc agagagttca caggcttccc 1980agacccctac acagagctca acacaggcaa gggggaaggt gtggcttatc gtggccggct 2040tctgctctcc ctggagacca agctggtgga gcacagtgaa cagaaggtgg aggaccttcc 2100tgcggatgac atcctccggg tggagaagta ccttaggagg cgcaagtact ccctgtttgc 2160ggccttctac tcagccacca tgctgcagga tgtggatgat gccatccagt ttgaggtcag 2220catcgggaac tacgggaaca agttcgacat gacctgcctg ccgctggcct ccaccactca 2280gtacagccgt gcagtctttg acgggtgcca ctactactac ctaccctggg gtaacgtgaa 2340acctgtggtg gtgctgtcat cctactggga ggacatcagc catagaatcg agactcagaa 2400ccagctgctt gggattgctg accggctgga agctggcctg gagcaggtcc acctggccct 2460gaaggcgcag tgctccacgg aggacgtgga ctcgctggtg gctcagctga cggatgagct 2520catcgcaggc tgcagccagc ctctgggtga catccatgag acaccctctg ccacccacct 2580ggaccagtac ctgtaccagc tgcgcaccca tcacctgagc caaatcactg aggctgccct 2640ggccctgaag ctcggccaca gtgagctccc tgcagctctg gagcaggcgg aggactggct 2700cctgcgtctg cgtgccctgg cagaggagcc ccagaacagc ctgccggaca tcgtcatctg 2760gatgctgcag ggagacaagc gtgtggcata ccagcgggtg cccgcccacc aagtcctctt 2820ctcccggcgg ggtgccaact actgtggcaa gaattgtggg aagctacaga caatctttct 2880gaaatatccg atggagaagg tgcctggcgc ccggatgcca gtgcagatac gggtcaagct 2940gtggtttggg ctctctgtgg atgagaagga gttcaaccag tttgctgagg ggaagctgtc 3000tgtctttgct gaaacctatg agaacgagac taagttggcc cttgttggga actggggcac 3060aacgggcctc acctacccca agttttctga cgtcacgggc aagatcaagc tacccaagga 3120cagcttccgc ccctcggccg gctggacctg ggctggagat tggttcgtgt gtccggagaa 3180gactctgctc catgacatgg acgccggtca cctgagcttc gtggaagagg tgtttgagaa 3240ccagacccgg cttcccggag gccagtggat ctacatgagt gacaactaca ccgatgtgaa 3300cggggagaag gtgcttccca aggatgacat tgagtgccca ctgggctgga agtgggaaga 3360tgaggaatgg tccacagacc tcaaccgggc tgtcgatgag caaggctggg agtatagcat 3420caccatcccc ccggagcgga agccgaagca ctgggtccct gctgagaaga tgtactacac 3480acaccgacgg cggcgctggg tgcgcctgcg caggagggat ctcagccaaa tggaagcact 3540gaaaaggcac aggcaggcgg aggcggaggg cgagggctgg gagtacgcct ctctttttgg 3600ctggaagttc cacctcgagt accgcaagac agatgccttc cgccgccgcc gctggcgccg 3660tcgcatggag ccactggaga agacggggcc tgcagctgtg tttgcccttg agggggccct 3720gggcggcgtg atggatgaca agagtgaaga ttccatgtcc gtctccacct tgagcttcgg 3780tgtgaacaga cccacgattt cctgcatatt cgactatggg aaccgctacc atctacgctg 3840ctacatgtac caggcccggg acctggctgc gatggacaag gactcttttt ctgatcccta 3900tgccatcgtc tccttcctgc accagagcca gaagacggtg gtggtgaaga acacccttaa 3960ccccacctgg gaccagacgc tcatcttcta cgagatcgag atctttggcg agccggccac 4020agttgctgag caaccgccca gcattgtggt ggagctgtac gaccatgaca cttatggtgc 4080agacgagttt atgggtcgct gcatctgtca accgagtctg gaacggatgc cacggctggc 4140ctggttccca ctgacgaggg gcagccagcc gtcgggggag ctgctggcct cttttgagct 4200catccagaga gagaagccgg ccatccacca tattcctggt tttgaggtgc aggagacatc 4260aaggatcctg gatgagtctg aggacacaga cctgccctac ccaccacccc agagggaggc 4320caacatctac atggttcctc agaacatcaa gccagcgctc cagcgtaccg ccatcgagat 4380cctggcatgg ggcctgcgga acatgaagag ttaccagctg gccaacatct cctcccccag 4440cctcgtggta gagtgtgggg gccagacggt gcagtcctgt gtcatcagga acctccggaa 4500gaaccccaac tttgacatct gcaccctctt catggaagtg atgctgccca gggaggagct 4560ctactgcccc cccatcaccg tcaaggtcat cgataaccgc cagtttggcc gccggcctgt 4620ggtgggccag tgtaccatcc gctccctgga gagcttcctg tgtgacccct actcggcgga 4680gagtccatcc ccacagggtg gcccagacga tgtgagccta ctcagtcctg gggaagacgt 4740gctcatcgac attgatgaca aggagcccct catccccatc caggaggaag agttcatcga 4800ttggtggagc aaattctttg cctccatagg ggagagggaa aagtgcggct cctacctgga 4860gaaggatttt gacaccctga aggtctatga cacacagctg gagaatgtgg aggcctttga 4920gggcctgtct gacttttgta acaccttcaa gctgtaccgg ggcaagacgc aggaggagac 4980agaagatcca tctgtgattg gtgaatttaa gggcctcttc aaaatttatc ccctcccaga 5040agacccagcc atccccatgc ccccaagaca gttccaccag ctggccgccc agggacccca 5100ggagtgcttg gtccgtatct acattgtccg agcatttggc ctgcagccca aggaccccaa 5160tggaaagtgt gatccttaca tcaagatctc catagggaag aaatcagtga gtgaccagga 5220taactacatc ccctgcacgc tggagcccgt atttggaaag atgttcgagc tgacctgcac 5280tctgcctctg gagaaggacc taaagatcac tctctatgac tatgacctcc tctccaagga 5340cgaaaagatc ggtgagacgg tcgtcgacct ggagaacagg ctgctgtcca agtttggggc 5400tcgctgtgga ctcccacaga cctactgtgt ctctggaccg aaccagtggc gggaccagct 5460ccgcccctcc cagctcctcc acctcttctg ccagcagcat agagtcaagg cacctgtgta 5520ccggacagac cgtgtaatgt ttcaggataa agaatattcc attgaagaga tagaggctgg 5580caggatccca aacccacacc tgggcccagt ggaggagcgt ctggctctgc atgtgcttca 5640gcagcagggc ctggtcccgg agcacgtgga gtcacggccc ctctacagcc ccctgcagcc 5700agacatcgag caggggaagc tgcagatgtg ggtcgaccta tttccgaagg ccctggggcg 5760gcctggacct cccttcaaca tcaccccacg gagagccaga aggtttttcc tgcgttgtat 5820tatctggaat accagagatg tgatcctgga tgacctgagc ctcacggggg agaagatgag 5880cgacatttat gtgaaaggtt ggatgattgg ctttgaagaa cacaagcaaa agacagacgt 5940gcattatcgt tccctgggag gtgaaggcaa cttcaactgg aggttcattt tccccttcga 6000ctacctgcca gctgagcaag tctgtaccat tgccaagaag gatgccttct ggaggctgga 6060caagactgag agcaaaatcc cagcacgagt ggtgttccag atctgggaca atgacaagtt 6120ctcctttgat gattttctgg gctccctgca gctcgatctc aaccgcatgc ccaagccagc 6180caagacagcc aagaagtgct ccttggacca gctggatgat gctttccacc cagaatggtt 6240tgtgtccctt tttgagcaga aaacagtgaa gggctggtgg ccctgtgtag cagaagaggg 6300tgagaagaaa atactggcgg gcaagctgga aatgaccttg gagattgtag cagagagtga 6360gcatgaggag cggcctgctg gccagggccg agatgagccc aacatgaacc ctaagcttga 6420ggacccaagg cgccccgaca cctccttcct gtggtttacc tccccataca agaccatgaa 6480gttcatcctg tggcggcgtt tccggtgggc catcatcctc ttcatcatcc tcttcatcct 6540gctgctgttc ctggccatct tcatctacgc cttcccgaac tatgctgcca tgaagctggt 6600gaagcccttc agctgaggac tctcctgccc tgtagaaggg gccgtggggt cccctccagc 6660atgggactgg cctgcctcct ccgcccagct cggcgagctc ctccagacct cctaggcctg 6720attgtcctgc cagggtgggc agacagacag atggaccggc ccacactccc agagttgcta 6780acatggagct ctgagatcac cccacttcca tcatttcctt ctcccccaac ccaacgcttt 6840tttggatcag ctcagacata tttcagtata aaacagttgg aaccacaaaa aaaaaaaaaa 6900aaaaaaaaaa a 6911 18 6911 DNA Homo sapiens 18tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaggg 540catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg agacgatggg 600gaggaacagg ttcctggggg aagccaaggt cccactccga gaggtcctcg ccacccctag 660tctgtccgcc agcttcaatg cccccctgct ggacaccaag aagcagccca caggggcctc 720gctggtcctg caggtgtcct acacaccgct gcctggagct gtgcccctgt tcccgccccc 780tactcctctg gagccctccc cgactctgcc tgacctggat gtagtggcag acacaggagg 840agaggaagac acagaggacc agggactcac tggagatgag gcggagccat tcctggatca 900aagcggaggc ccgggggctc ccaccacccc aaggaaacta ccttcacgtc ctccgcccca 960ctaccccggg atcaaaagaa agcgaagtgc gcctacatct agaaagctgc tgtcagacaa 1020accgcaggat ttccagatca gggtccaggt gatcgagggg cgccagctgc cgggggtgaa 1080catcaagcct gtggtcaagg ttaccgctgc agggcagacc aagcggacgc ggatccacaa 1140gggaaacagc ccactcttca atgagactct tttcttcaac ttgtttgact ctcctgggga 1200gctgtttgat gagcccatct ttatcacggt ggtagactct cgttctctca ggacagatgc 1260tctcctcggg gagttccgga tggacgtggg caccatttac agagagcccc ggcacgccta 1320tctcaggaag tggctgctgc tctcagaccc tgatgacttc tctgctgggg ccagaggcta 1380cctgaaaaca agcctttgtg tgctggggcc tggggacgaa gcgcctctgg agagaaaaga 1440cccctctgaa gacaaggagg acattgaaag caacctgctc cggcccacag gcgtagccct 1500gcgaggagcc cacttctgcc tgaaggtctt ccgggccgag gacttgccgc agatggacga 1560tgccgtgatg gacaacgtga aacagatctt tggcttcgag agtaacaaga agaacttggt 1620ggaccccttt gtggaggtca gctttgcggg gaaaatgctg tgcagcaaga tcttggagaa 1680gacggccaac cctcagtgga accagaacat cacactgcct gccatgtttc cctccatgtg 1740cgaaaaaatg aggattcgta tcatagactg ggaccgcctg actcacaatg acatcgtggc 1800taccacctac ctgagtatgt cgaaaatctc tgcccctgga ggagaaatag aagaggagcc 1860tgcaggtgct gtcaagcctt cgaaagcctc agacttggat gactacctgg gcttcctccc 1920cacttttggg ccctgctaca tcaacctcta tggcagtccc agagagttca caggcttccc 1980agacccctac acagagctca acacaggcaa gggggaaggt gtggcttatc gtggccggct 2040tctgctctcc ctggagacca agctggtgga gcacagtgaa cagaaggtgg aggaccttcc 2100tgcggatgac atcctccggg tggagaagta ccttaggagg cgcaagtact ccctgtttgc 2160ggccttctac tcagccacca tgctgcagga tgtggatgat gccatccagt ttgaggtcag 2220catcgggaac tacgggaaca agttcgacat gacctgcctg ccgctggcct ccaccactca 2280gtacagccgt gcagtctttg acgggtgcca ctactactac ctaccctggg gtaacgtgaa 2340acctgtggtg gtgctgtcat cctactggga ggacatcagc catagaatcg agactcagaa 2400ccagctgctt gggattgctg accggctgga agctggcctg gagcaggtcc acctggccct 2460gaaggcgcag tgctccacgg aggacgtgga ctcgctggtg gctcagctga cggatgagct 2520catcgcaggc tgcagccagc ctctgggtga catccatgag acaccctctg ccacccacct 2580ggaccagtac ctgtaccagc tgcgcaccca tcacctgagc caaatcactg aggctgccct 2640ggccctgaag ctcggccaca gtgagctccc tgcagctctg gagcaggcgg aggactggct 2700cctgcgtctg cgtgccctgg cagaggagcc ccagaacagc ctgccggaca tcgtcatctg 2760gatgctgcag ggagacaagc gtgtggcata ccagcgggtg cccgcccacc aagtcctctt 2820ctcccggcgg ggtgccaact actgtggcaa gaattgtggg aagctacaga caatctttct 2880gaaatatccg atggagaagg tgcctggcgc ccggatgcca gtgcagatac gggtcaagct 2940gtggtttggg ctctctgtgg atgagaagga gttcaaccag tttgctgagg ggaagctgtc 3000tgtctttgct gaaacctatg agaacgagac taagttggcc cttgttggga actggggcac 3060aacgggcctc acctacccca agttttctga cgtcacgggc aagatcaagc tacccaagga 3120cagcttccgc ccctcggccg gctggacctg ggctggagat tggttcgtgt gtccggagaa 3180gactctgctc catgacatgg acgccggtca cctgagcttc gtggaagagg tgtttgagaa 3240ccagacccgg cttcccggag gccagtggat ctacatgagt gacaactaca ccgatgtgaa 3300cggggagaag gtgcttccca aggatgacat tgagtgccca ctgggctgga agtgggaaga 3360tgaggaatgg tccacagacc tcaaccgggc tgtcgatgag caaggctggg agtatagcat 3420caccatcccc ccggagcgga agccgaagca ctgggtccct gctgagaaga tgtactacac 3480acaccgacgg cggcgctggg tgcgcctgcg caggagggat ctcagccaaa tggaagcact 3540gaaaaggcac aggcaggcgg aggcggaggg cgagggctgg gagtacgcct ctctttttgg 3600ctggaagttc cacctcgagt accgcaagac agatgccttc cgccgccgcc gctggcgccg 3660tcgcatggag ccactggaga agacggggcc tgcagctgtg tttgcccttg agggggccct 3720gggcggcgtg atggatgaca agagtgaaga ttccatgtcc gtctccacct tgagcttcgg 3780tgtgaacaga cccacgattt cctgcatatt cgactatggg aaccgctacc atctacgctg 3840ctacatgtac caggcccggg acctggctgc gatggacaag gactcttttt ctgatcccta 3900tgccatcgtc tccttcctgc accagagcca gaagacggtg gtggtgaaga acacccttaa 3960ccccacctgg gaccagacgc tcatcttcta cgagatcgag atctttggcg agccggccac 4020agttgctgag caaccgccca gcattgtggt ggagctgtac gaccatgaca cttatggtgc 4080agacgagttt atgggtcgct gcatctgtca accgagtctg gaacggatgc cacggctggc 4140ctggttccca ctgacgaggg gcagccagcc gtcgggggag ctgctggcct cttttgagct 4200catccagaga gagaagccgg ccatccacca tattcctggt tttgaggtgc aggagacatc 4260aagggtcctg gatgagtctg aggacacaga cctgccctac ccaccacccc agagggaggc 4320caacatctac atggttcctc agaacatcaa gccagcgctc cagcgtaccg ccatcgagat 4380cctggcatgg ggcctgcgga acatgaagag ttaccagctg gccaacatct cctcccccag 4440cctcgtggta gagtgtgggg gccagacggt gcagtcctgt gtcatcagga acctccggaa 4500gaaccccaac tttgacatct gcaccctctt catggaagtg atgctgccca gggaggagct 4560ctactgcccc cccatcaccg tcaaggtcat cgataaccgc cagtttggcc gccggcctgt 4620ggtgggccag tgtaccatcc gctccctgga gagcttcctg tgtgacccct actcggcgga 4680gagtccatcc ccacagggtg gcccagacga tgtgagccta ctcagtcctg gggaagacgt 4740gctcatcgac attgatgaca aggagcccct catccccatc caggaggaag agttcatcga 4800ttggtggagc aaattctttg cctccatagg ggagagggaa aagtgcggct cctacctgga 4860gaaggatttt gacaccctga aggtctatga cacacagctg gagaatgtgg aggcctttga 4920gggcctgtct gacttttgta acaccttcaa gctgtaccgg ggcaagacgc aggaggagac 4980agaagatcca tctgtgattg gtgaatttaa gggcctcttc aaaatttatc ccctcccaga 5040agacccagcc atccccatgc ccccaagaca gttccaccag ctggccgccc agggacccca 5100ggagtgcttg gtccgtatct acattgtccg agcatttggc ctgcagccca aggaccccaa 5160tggaaagtgt gatccttaca tcaagatctc catagggaag aaatcagtga gtgaccagga 5220taactacatc ccctgcacgc tggagcccgt atttggaaag atgttcgagc tgacctgcac 5280tctgcctctg gagaaggacc taaagatcac tctctatgac tatgacctcc tctccaagga 5340cgaaaagatc ggtgagacgg tcgtcgacct ggagaacagg ctgctgtcca agtttggggc 5400tcgctgtgga ctcccacaga cctactgtgt ctctggaccg aaccagtggc gggaccagct 5460ccgcccctcc cagctcctcc acctcttctg ccagcagcat agagtcaagg cacctgtgta 5520ccggacagac cgtgtaatgt ttcaggataa agaatattcc attgaagaga tagaggctgg 5580caggatccca aacccacacc tgggcccagt ggaggagcgt ctggctctgc atgtgcttca 5640gcagcagggc ctggtcccgg agcacgtgga gtcacggccc ctctacagcc ccctgcagcc 5700agacatcgag caggggaagc tgcagatgtg ggtcgaccta tttccgaagg ccctggggcg 5760gcctggacct cccttcaaca tcaccccacg gagagccaga aggtttttcc tgcgttgtat 5820tatctggaat accagagatg tgatcctgga tgacctgagc ctcacggggg agaagatgag 5880cgacatttat gtgaaaggtt ggatgattgg ctttgaagaa cacaagcaaa agacagacgt 5940gcattatcgt tccctgggag gtgaaggcaa cttcaactgg aggttcattt tccccttcga 6000ctacctgcca gctgagcaag tctgtaccat tgccaagaag gatgccttct ggaggctgga 6060caagactgag agcaaaatcc cagcacgagt ggtgttccag atctgggaca atgacaagtt 6120ctcctttgat gattttctgg gctccctgca gctcgatctc aaccgcatgc ccaagccagc 6180caagacagcc aagaagtgct ccttggacca gctggatgat gctttccacc cagaatggtt 6240tgtgtccctt tttgagcaga aaacagtgaa gggctggtgg ccctgtgtag cagaagaggg 6300tgagaagaaa atactggcgg gcaagctgga aatgaccttg gagattgtag cagagagtga 6360gcatgaggag cggcctgctg gccagggccg ggatgagccc aacatgaacc ctaagcttga 6420ggacccaagg cgccccgaca cctccttcct gtggtttacc tccccataca agaccatgaa 6480gttcatcctg tggcggcgtt tccggtgggc catcatcctc ttcatcatcc tcttcatcct 6540gctgctgttc ctggccatct tcatctacgc cttcccgaac tatgctgcca tgaagctggt 6600gaagcccttc agctgaggac tctcctgccc tgtagaaggg gccgtggggt cccctccagc 6660atgggactgg cctgcctcct ccgcccagct cggcgagctc ctccagacct cctaggcctg 6720attgtcctgc cagggtgggc agacagacag atggaccggc ccacactccc agagttgcta 6780acatggagct ctgagatcac cccacttcca tcatttcctt ctcccccaac ccaacgcttt 6840tttggatcag ctcagacata tttcagtata aaacagttgg aaccacaaaa aaaaaaaaaa 6900aaaaaaaaaa a 6911 19 6911 DNA Homo sapiens 19tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaggg 540catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg agacgatggg 600gaggaacagg ttcctggggg aagccaaggt cccactccga gaggtcctcg ccacccctag 660tctgtccgcc agcttcaatg cccccctgct ggacaccaag aagcagccca caggggcctc 720gctggtcctg caggtgtcct acacaccgct gcctggagct gtgcccctgt tcccgccccc 780tactcctctg gagccctccc cgactctgcc tgacctggat gtagtggcag acacaggagg 840agaggaagac acagaggacc agggactcac tggagatgag gcggagccat tcctggatca 900aagcggaggc ccgggggctc ccaccacccc aaggaaacta ccttcacgtc ctccgcccca 960ctaccccggg atcaaaagaa agcgaagtgc gcctacatct agaaagctgc tgtcagacaa 1020accgcaggat ttccagatca gggtccaggt gatcgagggg cgccagctgc cgggggtgaa 1080catcaagcct gtggtcaagg ttaccgctgc agggcagacc aagcggacgc ggatccacaa 1140gggaaacagc ccactcttca atgagactct tttcttcaac ttgtttgact ctcctgggga 1200gctgtttgat gagcccatct ttatcacggt ggtagactct cgttctctca ggacagatgc 1260tctcctcggg gagttccgga tggacgtggg caccatttac agagagcccc ggcacgccta 1320tctcaggaag tggctgctgc tctcagaccc tgatgacttc tctgctgggg ccagaggcta 1380cctgaaaaca agcctttgtg tgctggggcc tggggacgaa gcgcctctgg agagaaaaga 1440cccctctgaa gacaaggagg acattgaaag caacctgctc cggcccacag gcgtagccct 1500gcgaggagcc cacttctgcc tgaaggtctt ccgggccgag gacttgccgc agatggacga 1560tgccgtgatg gacaacgtga aacagatctt tggcttcgag agtaacaaga agaacttggt 1620ggaccccttt gtggaggtca gctttgcggg gaaaatgctg tgcagcaaga tcttggagaa 1680gacggccaac cctcagtgga accagaacat cacactgcct gccatgtttc cctccatgtg 1740cgaaaaaatg aggattcgta tcatagactg ggaccgcctg actcacaatg acatcgtggc 1800taccacctac ctgagtatgt cgaaaatctc tgcccctgga ggagaaatag aagaggagcc 1860tgcaggtgct gtcaagcctt cgaaagcctc agacttggat gactacctgg gcttcctccc 1920cacttttggg ccctgctaca tcaacctcta tggcagtccc agagagttca caggcttccc 1980agacccctac acagagctca acacaggcaa gggggaaggt gtggcttatc gtggccggct 2040tctgctctcc ctggagacca agctggtgga gcacagtgaa cagaaggtgg aggaccttcc 2100tgcggatgac atcctccggg tggagaagta ccttaggagg cgcaagtact ccctgtttgc 2160ggccttctac tcagccacca tgctgcagga tgtggatgat gccatccagt ttgaggtcag 2220catcgggaac tacgggaaca agttcgacat gacctgcctg ccgctggcct ccaccactca 2280gtacagccgt gcagtctttg acgggtgcca ctactactac ctaccctggg gtaacgtgaa 2340acctgtggtg gtgctgtcat cctactggga ggacatcagc catagaatcg agactcagaa 2400ccagctgctt gggattgctg accggctgga agctggcctg gagcaggtcc acctggccct 2460gaaggcgcag tgctccacgg aggacgtgga ctcgctggtg gctcagctga cggatgagct 2520catcgcaggc tgcagccagc ctctgggtga catccatgag acaccctctg ccacccacct 2580ggaccagtac ctgtaccagc tgcgcaccca tcacctgagc caaatcactg aggctgccct 2640ggccctgaag ctcggccaca gtgagctccc tgcagctctg gagcaggcgg aggactggct 2700cctgcgtctg cgtgccctgg cagaggagcc ccagaacagc ctgccggaca tcgtcatctg 2760gatgctgcag ggagacaagc gtgtggcata ccagcgggtg cccgcccacc aagtcctctt 2820ctcccggcgg ggtgccaact actgtggcaa gaattgtggg aagctacaga caatctttct 2880gaaatatccg atggagaagg tgcctggcgc ccggatgcca gtgcagatac gggtcaagct 2940gtggtttggg ctctctgtgg atgagaagga gttcaaccag tttgctgagg ggaagctgtc 3000tgtctttgct gaaacctatg agaacgagac taagttggcc cttgttggga actggggcac 3060aacgggcctc acctacccca agttttctga cgtcacgggc aagatcaagc tacccaagga 3120cagcttccgc ccctcggccg gctggacctg ggctggagat tggttcgtgt gtccggagaa 3180gactctgctc catgacatgg acgccggtca cctgagcttc gtggaagagg tgtttgagaa 3240ccagacccgg cttcccggag gccagtggat ctacatgagt gacaactaca ccgatgtgaa 3300cggggagaag gtgcttccca aggatgacat tgagtgccca ctgggctgga agtgggaaga 3360tgaggaatgg tccacagacc tcaaccgggc tgtcgatgag caaggctggg agtatagcat 3420caccatcccc ccggagcgga agccgaagca ctgggtccct gctgagaaga tgtactacac 3480acaccgacgg cggcgctggg tgcgcctgcg caggagggat ctcagccaaa tggaagcact 3540gaaaaggcac aggcaggcgg aggcggaggg cgagggctgg gagtacgcct ctctttttgg 3600ctggaagttc cacctcgagt accgcaagac agatgccttc cgccgccgcc gctggcgccg 3660tcgcatggag ccactggaga agacggggcc tgcagctgtg tttgcccttg agggggccct 3720gggcggcgtg atggatgaca agagtgaaga ttccatgtcc gtctccacct tgagcttcgg 3780tgtgaacaga cccacgattt cctgcatatt cgactatggg aaccgctacc atctacgctg 3840ctacatgtac caggcccggg acctggctgc gatggacaag gactcttttt ctgatcccta 3900tgccatcgtc tccttcctgc accagagcca gaagacggtg gtggtgaaga acacccttaa 3960ccccacctgg gaccagacgc tcatcttcta cgagatcgag atctttggcg agccggccac 4020agttgctgag caaccgccca gcattgtggt ggagctgtac gaccatgaca cttatggtgc 4080agacgagttt atgggtcgct gcatctgtca accgagtctg gaacggatgc cacggctggc 4140ctggttccca ctgacgaggg gcagccagcc gtcgggggag ctgctggcct cttttgagct 4200catccagaga gagaagccgg ccatccacca tattcctggt tttgaggtgc aggagacatc 4260aaggatcctg gatgagtctg aggacacaga cctgccctac ccaccacccc agagggaggc 4320caacatctac atggttcctc agaacatcaa gccagcgctc cagcgtaccg ccatcgagat 4380cctggcatgg ggcctgcgga acatgaagag ttaccagctg gccaacatct cctcccccag 4440cctcgtggta gagtgtgggg gccagacggt gcagtcctgt gtcatcagga acctccggaa 4500gaaccccaac tttgacatct gcaccctctt catggaagtg atgctgccca gggaggagct 4560ctactgcccc cccatcaccg tcaaggtcat cgataaccgc cagtttggcc gccggcctgt 4620ggtgggccag tgtaccatcc gctccctgga gagcttcctg tgtgacccct actcggcgga 4680gagtccatcc ccacagggtg gcccagacga tgtgagccta ctcagtcctg gggaagacgt 4740gctcatcgac attgatgaca aggagcccct catccccatc caggaggaag agttcatcga 4800ttggtggagc aaattctttg cctccatagg ggagagggaa aagtgcggct cctacctgga 4860gaaggatttt gacaccctga aggtctatga cacacagctg gagaatgtgg aggcctttga 4920gggcctgtct gacttttgta acaccttcaa gctgtaccgg ggcaagacgc aggaggagac 4980agaagatcca tctgtgattg gtgaatttaa gggcctcttc aaaatttatc ccctcccaga 5040agacccagcc atccccatgc ccccaagaca gttccaccag ctggccgccc agggacccca 5100ggagtgcttg gtccgtatct acattgtccg agcatttggc ctgcagccca aggaccccaa 5160tggaaagtgt gatccttaca tcaagatctc catagggaag aaatcagtga gtgaccagga 5220taactacatc ccctgcacgc tggagcccgt atttggaaag atgttcgagc tgacctgcac 5280tctgcctctg gagaaggacc taaagatcac tctctatgac tatgacctcc tctccaagga 5340cgaaaagatc ggtgagacgg tcgtcgacct ggagaacagg ctgctgtcca agtttggggc 5400tcgctgtgga ctcccacaga cctactgtgt ctctggaccg aaccagtggc gggaccagct 5460ccgcccctcc cagctcctcc acctcttctg ccagcagcat agagtcaagg cacctgtgta 5520ccggacagac cgtgtaatgt ttcaggataa agaatattcc attgaagaga tagaggctgg 5580caggatccca aacccacacc tgggcccagt ggaggagcgt ctggctctgc atgtgcttca 5640gcagcagggc ctggtcccgg agcacgtgga gtcacggccc ctctacagcc ccctgcagcc 5700agacatcgag caggggaagc tgcagatgtg ggtcgaccta tttccgaagg ccctggggcg 5760gcctggacct cccttcaaca tcaccccacg gagagccaga aggtttttcc tgcgttgtat 5820tatctggaat accagagatg tgatcctgga tgacctgagc ctcacggggg agaagatgag 5880cgacatttat gtgaaaggtt ggatgattgg ctttgaagaa cacaagcaaa agacagacgt 5940gcattatcgt tccctgggag gtgaaggcaa cttcaactgg aggttcattt tccccttcga 6000ctacctgcca gctgagcaag tctgtaccat tgccaagaag gatgccttct ggaggctgga 6060caagactgag agcaaaatcc cagcacgagt ggtgttccag atctgggaca atgacaagtt 6120ctcctttgat gattttctgg gctccctgca gctcgatctc aaccgcatgc ccaagccagc 6180caagacagcc aagaagtgct ccttggacca gctggatgat gctttccacc cagaatggtt 6240tgtgtccctt tttgagcaga aaacagtgaa gggctggtgg ccctgtgtag cagaagaggg 6300tgagaagaaa atactggcgg gcaagctgga aatgaccttg gagattgtag cagagagtga 6360gcatgaggag cggcctgctg gccagggccg ggatgagccc aacatgaacc ctaagcttga 6420ggacccaagg cgccccgaca cctccttcct gtggtttacc tccccataca agaccatgaa 6480gttcatcctg tggcggtgtt tccggtgggc catcatcctc ttcatcatcc tcttcatcct 6540gctgctgttc ctggccatct tcatctacgc cttcccgaac tatgctgcca tgaagctggt 6600gaagcccttc agctgaggac tctcctgccc tgtagaaggg gccgtggggt cccctccagc 6660atgggactgg cctgcctcct ccgcccagct cggcgagctc ctccagacct cctaggcctg 6720attgtcctgc cagggtgggc agacagacag atggaccggc ccacactccc agagttgcta 6780acatggagct ctgagatcac cccacttcca tcatttcctt ctcccccaac ccaacgcttt 6840tttggatcag ctcagacata tttcagtata aaacagttgg aaccacaaaa aaaaaaaaaa 6900aaaaaaaaaa a 6911 20 6911 DNA Homo sapiens 20tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaggg 540catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg agacgatggg 600gaggaacagg ttcctggggg aagccaaggt cccactccga gaggtcctcg ccacccctag 660tctgtccgcc agcttcaatg cccccctgct ggacaccaag aagcagccca caggggcctc 720gctggtcctg caggtgtcct acacaccgct gcctggagct gtgcccctgt tcccgccccc 780tactcctctg gagccctccc cgactctgcc tgacctggat gtagtggcag acacaggagg 840agaggaagac acagaggacc agggactcac tggagatgag gcggagccat tcctggatca 900aagcggaggc ccgggggctc ccaccacccc aaggaaacta ccttcacgtc ctccgcccca 960ctaccccggg atcaaaagaa agcgaagtgc gcctacatct agaaagctgc tgtcagacaa 1020accgcaggat ttccagatca gggtccaggt gatcgagggg cgccagctgc cgggggtgaa 1080catcaagcct gtggtcaagg ttaccgctgc agggcagacc aagcggacgc ggatccacaa 1140gggaaacagc ccactcttca atgagactct tttcttcaac ttgtttgact ctcctgggga 1200gctgtttgat gagcccatct ttatcacggt ggtagactct cgttctctca ggacagatgc 1260tctcctcggg gagttccgga tggacgtggg caccatttac agagagcccc ggcacgccta 1320tctcaggaag tggctgctgc tctcagaccc tgatgacttc tctgctgggg ccagaggcta 1380cctgaaaaca agcctttgtg tgctggggcc tggggacgaa gcgcctctgg agagaaaaga 1440cccctctgaa gacaaggagg acattgaaag caacctgctc cggcccacag gcgtagccct 1500gcgaggagcc cacttctgcc tgaaggtctt ccgggccgag gacttgccgc agatggacga 1560tgccgtgatg gacaacgtga aacagatctt tggcttcgag agtaacaaga agaacttggt 1620ggaccccttt gtggaggtca gctttgcggg gaaaatgctg tgcagcaaga tcttggagaa 1680gacggccaac cctcagtgga accagaacat cacactgcct gccatgtttc cctccatgtg 1740cgaaaaaatg aggattcgta tcatagactg ggaccgcctg actcacaatg acatcgtggc 1800taccacctac ctgagtatgt cgaaaatctc tgcccctgga ggagaaatag aagaggagcc 1860tgcaggtgct gtcaagcctt cgaaagcctc agacttggat gactacctgg gcttcctccc 1920cacttttggg ccctgctaca tcaacctcta tggcagtccc agagagttca caggcttccc 1980agacccctac acagagctca acacaggcaa gggggaaggt gtggcttatc gtggccggct 2040tctgctctcc ctggagacca agctggtgga gcacagtgaa cagaaggtgg aggaccttcc 2100tgcggatgac atcctccggg tggagaagta ccttaggagg cgcaagtact ccctgtttgc 2160ggccttctac tcagccacca tgctgcagga tgtggatgat gccatccagt ttgaggtcag 2220catcgggaac tacgggaaca agttcgacat gacctgcctg ccgctggcct ccaccactca 2280gtacagccgt gcagtctttg acgggtgcca ctactactac ctaccctggg gtaacgtgaa 2340acctgtggtg gtgctgtcat cctactggga ggacatcagc catagaatcg agactcagaa 2400ccagctgctt gggattgctg accggctgga agctggcctg gagcaggtcc acctggccct 2460gaaggcgcag tgctccacgg aggacgtgga ctcgctggtg gctcagctga cggatgagct 2520catcgcaggc tgcagccagc ctctgggtga catccatgag acaccctctg ccacccacct 2580ggaccagtac ctgtaccagc tgcgcaccca tcacctgagc caaatcactg aggctgccct 2640ggccctgaag ctcggccaca gtgagctccc tgcagctctg gagcaggcgg aggactggct 2700cctgcgtctg cgtgccctgg cagaggagcc ccagaacagc ctgccggaca tcgtcatctg 2760gatgctgcag ggagacaagc gtgtggcata ccagcgggtg cccgcccacc aagtcctctt 2820ctcccggcgg ggtgccaact actgtggcaa gaattgtggg aagctacaga caatctttct 2880gaaatatccg atggagaagg tgcctggcgc ccggatgcca gtgcagatac gggtcaagct 2940gtggtttggg ctctctgtgg atgagaagga gttcaaccag tttgctgagg ggaagctgtc 3000tgtctttgct gaaacctatg agaacgagac taagttggcc cttgttggga actggggcac 3060aacgggcctc acctacccca agttttctga cgtcacgggc aagatcaagc tacccaagga 3120cagcttccgc ccctcggccg gctggacctg ggctggagat tggttcgtgt gtccggagaa 3180gactctgctc catgacatgg acgccggtca cctgagcttc gtggaagagg tgtttgagaa 3240ccagacccgg cttcccggag gccagtggat ctacatgagt gacaactaca ccgatgtgaa 3300cggggagaag gtgcttccca aggatgacat tgagtgccca ctgggctgga agtgggaaga 3360tgaggaatgg tccacagacc tcaaccgggc tgtcgatgag caaggctggg agtatagcat 3420caccatcccc ccggagcgga agccgaagca ctgggtccct gctgagaaga tgtactacac 3480acaccgacgg cggcgctggg tgcgcctgcg caggagggat ctcagccaaa tggaagcact 3540gaaaaggcac aggcaggcgg aggcggaggg cgagggctgg gagtacgcct ctctttttgg 3600ctggaagttc cacctcgagt accgcaagac agatgccttc cgccgccgcc gctggcgccg 3660tcgcatggag ccactggaga agacggggcc tgcagctgtg tttgcccttg agggggccct 3720gggcggcgtg atggatgaca agagtgaaga ttccatgtcc gtctccacct tgagcttcgg 3780tgtgaacaga cccacgattt cctgcatatt cgactatggg aaccgctacc atctacgctg 3840ctacatgtac caggcccggg acctggctgc gatggacaag gactcttttt ctgatcccta 3900tgccatcgtc tccttcctgc accagagcca gaagacggtg gtggtgaaga acacccttaa 3960ccccacctgg gaccagacgc tcatcttcta cgagatcgag atctttggcg agccggccac 4020agttgctgag caaccgccca gcattgtggt ggagctgtac gaccatgaca cttatggtgc 4080agacgagttt atgggtcgct gcatctgtca accgagtctg gaacggatgc cacggctggc 4140ctggttccca ctgacgaggg gcagccagcc gtcgggggag ctgctggcct cttttgagct 4200catccagaga gagaagccgg ccatccacca tattcctggt tttgaggtgc aggagacatc 4260aaggatcctg gatgagtctg aggacacaga cctgccctac ccaccacccc agagggaggc 4320caacatctac atggttcctc agaacatcaa gccagcgctc cagcgtaccg ccatcgagat 4380cctggcatgg ggcctgcgga acatgaagag ttaccagctg gccaacatct cctcccccag 4440cctcgtggta gagtgtgggg gccagacggt gcagtcctgt gtcatcagga acctccggaa 4500gaaccccaac tttgacatct gcaccctctt catggaagtg atgctgccca gggaggagct 4560ctactgcccc cccatcaccg tcaaggtcat cgataaccgc cagtttggcc gccggcctgt 4620ggtgggccag tgtaccatcc gctccctgga gagcttcctg tgtgacccct actcggcgga 4680gagtccatcc ccacagggtg gcccagacga tgtgagccta ctcagtcctg gggaagacgt 4740gctcatcgac attgatgaca aggagcccct catccccatc caggaggaag agttcatcga 4800ttggtggagc aaattctttg cctccatagg ggagagggaa aagtgcggct cctacctgga 4860gaaggatttt gacaccctga aggtctatga cacacagctg gagaatgtgg aggcctttga 4920gggcctgtct gacttttgta acaccttcaa gctgtaccgg ggcaagacgc aggaggagac 4980agaagatcca tctgtgattg gtgaatttaa gggcctcttc aaaatttatc ccctcccaga 5040agacccagcc atccccatgc ccccaagaca gttccaccag ctggccgccc agggacccca 5100ggagtgcttg gtccgtatct acattgtccg agcatttggc ctgcagccca aggaccccaa 5160tggaaagtgt gatccttaca tcaagatctc catagggaag aaatcagtga gtgaccagga 5220taactacatc ccctgcacgc tggagcccgt atttggaaag atgttcgagc tgacctgcac 5280tctgcctctg gagaaggacc taaagatcac tctctatgac tatgacctcc tctccaagga 5340cgaaaagatc ggtgagacgg tcgtcgacct ggagaacagg ctgctgtcca agtttggggc 5400tcgctgtgga ctcccacaga cctactgtgt ctctggaccg aaccagtggc gggaccagct 5460ccgcccctcc cagctcctcc acctcttctg ccagcagcat agagtcaagg cacctgtgta 5520ccggacagac cgtgtaatgt ttcaggataa agaatattcc attgaagaga tagaggctgg 5580caggatccca aacccacacc tgggcccagt ggaggagcgt ctggctctgc atgtgcttca 5640gcagcagggc ctggtcccgg agcacgtgga gtcacggccc ctctacagcc ccctgcagcc 5700agacatcgag caggggaagc tgcagatgtg ggtcgaccta tttccgaagg ccctggggcg 5760gcctggacct cccttcaaca tcaccccacg gagagccaga aggtttttcc tgcgttgtat 5820tatctggaat accagagatg tgatcctgga tgacctgagc ctcacggggg agaagatgag 5880cgacatttat gtgaaaggtt ggatgattgg ctttgaagaa cacaagcaaa agacagacgt 5940gcgttatcgt tccctgggag gtgaaggcaa cttcaactgg aggttcattt tccccttcga 6000ctacctgcca gctgagcaag tctgtaccat tgccaagaag gatgccttct ggaggctgga 6060caagactgag agcaaaatcc cagcacgagt ggtgttccag atctgggaca atgacaagtt 6120ctcctttgat gattttctgg gctccctgca gctcgatctc aaccgcatgc ccaagccagc 6180caagacagcc aagaagtgct ccttggacca gctggatgat gctttccacc cagaatggtt 6240tgtgtccctt tttgagcaga aaacagtgaa gggctggtgg ccctgtgtag cagaagaggg 6300tgagaagaaa atactggcgg gcaagctgga aatgaccttg gagattgtag cagagagtga 6360gcatgaggag cggcctgctg gccagggccg ggatgagccc aacatgaacc ctaagcttga 6420ggacccaagg cgccccgaca cctccttcct gtggtttacc tccccataca agaccatgaa 6480gttcatcctg tggcggcgtt tccggtgggc catcatcctc ttcatcatcc tcttcatcct 6540gctgctgttc ctggccatct tcatctacgc cttcccgaac tatgctgcca tgaagctggt 6600gaagcccttc agctgaggac tctcctgccc tgtagaaggg gccgtggggt cccctccagc 6660atgggactgg cctgcctcct ccgcccagct cggcgagctc ctccagacct cctaggcctg 6720attgtcctgc cagggtgggc agacagacag atggaccggc ccacactccc agagttgcta 6780acatggagct ctgagatcac cccacttcca tcatttcctt ctcccccaac ccaacgcttt 6840tttggatcag ctcagacata tttcagtata aaacagttgg aaccacaaaa aaaaaaaaaa 6900aaaaaaaaaa a 6911 21 6909 DNA Homo sapiens 21tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggggtgaaga agagaaccaa 480agtcatcaag aacagcgtga accctgtatg gaatgaggga tttgaatggg acctcaaggg 540catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg agacgatggg 600gaggaacagg ttcctggggg aagccaaggt cccactccga gaggtcctcg ccacccctag 660tctgtccgcc agcttcaatg cccccctgct ggacaccaag aagcagccca caggggcctc 720gctggtcctg caggtgtcct acacaccgct gcctggagct gtgcccctgt tcccgccccc 780tactcctctg gagccctccc cgactctgcc tgacctggat gtagtggcag acacaggagg 840agaggaagac acagaggacc agggactcac tggagatgag gcggagccat tcctggatca 900aagcggaggc ccgggggctc ccaccacccc aaggaaacta ccttcacgtc ctccgcccca 960ctaccccggg atcaaaagaa agcgaagtgc gcctacatct agaaagctgc tgtcagacaa 1020accgcaggat ttccagatca gggtccaggt gatcgagggg cgccagctgc cgggggtgaa 1080catcaagcct gtggtcaagg ttaccgctgc agggcagacc aagcggacgc ggatccacaa 1140gggaaacagc ccactcttca atgagactct tttcttcaac ttgtttgact ctcctgggga 1200gctgtttgat gagcccatct ttatcacggt ggtagactct cgttctctca ggacagatgc 1260tctcctcggg gagttccgga tggacgtggg caccatttac agagagcccc ggcacgccta 1320tctcaggaag tggctgctgc tctcagaccc tgatgacttc tctgctgggg ccagaggcta 1380cctgaaaaca agcctttgtg tgctggggcc tggggacgaa gcgcctctgg agagaaaaga 1440cccctctgaa gacaaggagg acattgaaag caacctgctc cggcccacag gcgtagccct 1500gcgaggagcc cacttctgcc tgaaggtctt ccgggccgag gacttgccgc agatggacga 1560tgccgtgatg gacaacgtga aacagatctt tggcttcgag agtaacaaga agaacttggt 1620ggaccccttt gtggaggtca gctttgcggg gaaaatgctg tgcagcaaga tcttggagaa 1680gacggccaac cctcagtgga accagaacat cacactgcct gccatgtttc cctccatgtg 1740cgaaaaaatg aggattcgta tcatagactg ggaccgcctg actcacaatg acatcgtggc 1800taccacctac ctgagtatgt cgaaaatctc tgcccctgga ggagaaatag aagaggagcc 1860tgcaggtgct gtcaagcctt cgaaagcctc agacttggat gactacctgg gcttcctccc 1920cacttttggg ccctgctaca tcaacctcta tggcagtccc agagagttca caggcttccc 1980agacccctac acagagctca acacaggcaa gggggaaggt gtggcttatc gtggccggct 2040tctgctctcc ctggagacca agctggtgga gcacagtgaa cagaaggtgg aggaccttcc 2100tgcggatgac atcctccggg tggagaagta ccttaggagg cgcaagtact ccctgtttgc 2160ggccttctac tcagccacca tgctgcagga tgtggatgat gccatccagt ttgaggtcag 2220catcgggaac tacgggaaca agttcgacat gacctgcctg ccgctggcct ccaccactca 2280gtacagccgt gcagtctttg acgggtgcca ctactactac ctaccctggg gtaacgtgaa 2340acctgtggtg gtgctgtcat cctactggga ggacatcagc catagaatcg agactcagaa 2400ccagctgctt gggattgctg accggctgga agctggcctg gagcaggtcc acctggccct 2460gaaggcgcag tgctccacgg aggacgtgga ctcgctggtg gctcagctga cggatgagct 2520catcgcaggc tgcagccagc ctctgggtga catccatgag acaccctctg ccacccacct 2580ggaccagtac ctgtaccagc tgcgcaccca tcacctgagc caaatcactg aggctgccct 2640ggccctgaag ctcggccaca gtgagctccc tgcagctctg gagcaggcgg aggactggct 2700cctgcgtctg cgtgccctgg cagaggagcc ccagaacagc ctgccggaca tcgtcatctg 2760gatgctgcag ggagacaagc gtgtggcata ccagcgggtg cccgcccacc aagtcctctt 2820ctcccggcgg ggtgccaact actgtggcaa gaattgtggg aagctacaga caatctttct 2880gaaatatccg atggagaagg tgcctggcgc ccggatgcca gtgcagatac gggtcaagct 2940gtggtttggg ctctctgtgg atgagaagga gttcaaccag tttgctgagg ggaagctgtc 3000tgtctttgct gaaacctatg agaacgagac taagttggcc cttgttggga actggggcac 3060aacgggcctc acctacccca agttttctga cgtcacgggc aagatcaagc tacccaagga 3120cagcttccgc ccctcggccg gctggacctg ggctggagat tggttcgtgt gtccggagaa 3180gactctgctc catgacatgg acgccggtca cctgagcttc gtggaagagg tgtttgagaa 3240ccagacccgg cttcccggag gccagtggat ctacatgagt gacaactaca ccgatgtgaa 3300cggggagaag gtgcttccca aggatgacat tgagtgccca ctgggctgga agtgggaaga 3360tgaggaatgg tccacagacc tcaaccgggc tgtcgatgag caaggctggg agtatagcat 3420caccatcccc ccggagcgga agccgaagca ctgggtccct gctgagaaga tgtactacac 3480acaccgacgg cggcgctggg tgcgcctgcg caggagggat ctcagccaaa tggaagcact 3540gaaaaggcac aggcaggcgg aggcggaggg cgagggctgg gagtacgcct ctctttttgg 3600ctggaagttc cacctcgagt accgcaagac agatgccttc cgccgccgcc gctggcgccg 3660tcgcatggag ccactggaga agacggggcc tgcagctgtg tttgcccttg agggggccct 3720gggcggcgtg atggatgaca agagtgaaga ttccatgtcc gtctccacct tgagcttcgg 3780tgtgaacaga cccacgattt cctgcatatt cgactatggg aaccgctacc atctacgctg 3840ctacatgtac caggcccggg acctggctgc gatggacaag gactcttttt ctgatcccta 3900tgccatcgtc tccttcctgc accagagcca gaagacggtg gtggtgaaga acacccttaa 3960ccccacctgg gaccagacgc tcatcttcta cgagatcgag atctttggcg agccggccac 4020agttgctgag caaccgccca gcattgtggt ggagctgtac gaccatgaca cttatggtgc 4080agacgagttt atgggtcgct gcatctgtca accgagtctg gaacggatgc cacggctggc 4140ctggttccca ctgacgaggg gcagccagcc gtcgggggag ctgctggcct cttttgagct 4200catccagaga gagaagccgg ccatccacca tattcctggt tttgaggtgc aggagacatc 4260aaggatcctg gatgagtctg aggacacaga cctgccctac ccaccacccc agagggaggc 4320caacatctac atggttcctc agaacatcaa gccagcgctc cagcgtaccg ccatcgagat 4380cctggcatgg ggcctgcgga acatgaagag ttaccagctg gccaacatct cctcccccag 4440cctcgtggta gagtgtgggg gccagacggt gcagtcctgt gtcatcagga acctccggaa 4500gaaccccaac tttgacatct gcaccctctt catggaagtg atgctgccca gggaggagct 4560ctactgcccc cccatcaccg tcaaggtcat cgataaccgc cagtttggcc gccggcctgt 4620ggtgggccag tgtaccatcc gctccctgga gagcttcctg tgtgacccct actcggcgga 4680gagtccatcc ccacagggtg gcccagacga tgtgagccta ctcagtcctg gggaagacgt 4740gctcatcgac attgatgaca aggagcccct catccccatc caggaggaag agttcatcga 4800ttggtggagc aaattctttg cctccatagg ggagagggaa aagtgcggct cctacctgga 4860gaaggatttt gacaccctga aggtctatga cacacagctg gagaatgtgg aggcctttga 4920gggcctgtct gacttttgta acaccttcaa gctgtaccgg ggcaagacgc aggaggagac 4980agaagatcca tctgtgattg gtgaatttaa gggcctcttc aaaatttatc ccctcccaga 5040agacccagcc atccccatgc ccccaagaca gttccaccag ctggccgccc agggacccca 5100ggagtgcttg gtccgtatct acattgtccg agcatttggc ctgcagccca aggaccccaa 5160tggaaagtgt gatccttaca tcaagatctc catagggaag aaatcagtga gtgaccagga 5220taactacatc ccctgcacgc tggagcccgt atttggaaag atgttcgagc tgacctgcac 5280tctgcctctg gagaaggacc taaagatcac tctctatgac tatgacctcc tctccaagga 5340cgaaaagatc ggtgagacgg tcgtcgacct ggagaacagg ctgctgtcca agtttggggc 5400tcgctgtgga ctcccacaga cctactgtgt ctctggaccg aaccagtggc gggaccagct 5460ccgcccctcc cagctcctcc acctcttctg ccagcagcat agagtcaagg cacctgtgta 5520ccggacagac cgtgtaatgt ttcaggataa agaatattcc attgaagaga tagaggctgg 5580caggatccca aacccacacc tgggcccagt ggaggagcgt ctggctctgc atgtgcttca 5640gcagcagggc ctggtcccgg agcacgtgga gtcacggccc ctctacagcc ccctgcagcc 5700agacatcgag caggggaagc tgcagatgtg ggtcgaccta tttccgaagg ccctggggcg 5760gcctggacct cccttcaaca tcaccccacg gagagccaga aggtttttcc tgcgttgtat 5820tatctggaat accagagatg tgatcctgga tgacctgagc ctcacggggg agaagatgag 5880cgacatttat gtgaaaggtt ggatgattgg ctttgaagaa cacaagcaaa agacagacgt 5940gcattatcgt tccctgggag gtgaaggcaa cttcaactgg aggttcattt tccccttcga 6000ctacctgcca gctgagcaag tctgtaccat tgccaagaag gatgccttct ggaggctgga 6060caagactgag caaaatccca gcacgagtgg tgttccagat ctgggacaat gacaagttct 6120cctttgatga ttttctgggc tccctgcagc tcgatctcaa ccgcatgccc aagccagcca 6180agacagccaa gaagtgctcc ttggaccagc tggatgatgc tttccaccca gaatggtttg 6240tgtccctttt tgagcagaaa acagtgaagg gctggtggcc ctgtgtagca gaagagggtg 6300agaagaaaat actggcgggc aagctggaaa tgaccttgga gattgtagca gagagtgagc 6360atgaggagcg gcctgctggc cagggccggg atgagcccaa catgaaccct aagcttgagg 6420acccaaggcg ccccgacacc tccttcctgt ggtttacctc cccatacaag accatgaagt 6480tcatcctgtg gcggcgtttc cggtgggcca tcatcctctt catcatcctc ttcatcctgc 6540tgctgttcct ggccatcttc atctacgcct tcccgaacta tgctgccatg aagctggtga 6600agcccttcag ctgaggactc tcctgccctg tagaaggggc cgtggggtcc cctccagcat 6660gggactggcc tgcctcctcc gcccagctcg gcgagctcct ccagacctcc taggcctgat 6720tgtcctgcca gggtgggcag acagacagat ggaccggccc acactcccag agttgctaac 6780atggagctct gagatcaccc cacttccatc atttccttct cccccaaccc aacgcttttt 6840tggatcagct cagacatatt tcagtataaa acagttggaa ccacaaaaaa aaaaaaaaaa 6900aaaaaaaaa 6909 22 20 DNA Homo sapiens 22tgggacctca agggcatccc 20 23 20 DNA Homo sapiens 23accatgctgc aggatgtgga 20 24 20 DNA Homo sapiens 24gggaggtgaa ggcaacttca 20 25 20 DNA Homo sapiens 25ctcacggggg agaagatgag 20 26 20 DNA Homo sapiens 26ctgtggcggc gtttccggtg 20 27 20 DNA Homo sapiens 27acatcaagga tcctggatga 20 28 20 DNA Homo sapiens 28ctgtggcggc gtttccggtg 20 29 20 DNA Homo sapiens 29acagacgtgc attatcgttc 20 30 20 DNA Homo sapiens 30aagactgaga gcaaaatccc 20 31 507 DNA Homo sapiens 31tcgaccgccc agccaggtgc aaaatgccgt gtcattggga gactccgcag ccggagcatt 60agattacagc tcgacggagc tcgggaaggg cggcgggggt ggaagatgag cagaagcccc 120tgttctcgga acgccggctg acaagcgggg tgagcgcagg cggggcgggg acccagccta 180gcccactgga gcagccgggg gtggcccgtt cccctttaag agcaactgct ctaagccagg 240agccagagat tcgagccggc ctcgcccagc cagccctctc cagcgagggg acccacaagc 300ggcgcctcgg ccctcccgac ctttccgagc cctctttgcg ccctgggcgc acggggccct 360acacgcgcca agcatgctga gggtcttcat cctctatgcc gagaacgtcc acacacccga 420caccgacatc agcgatgcct actgctccgc ggtgtttgca ggtaggaggg gccgaccacc 480ctcgccgggg tcggggtggg gtagagg 507 32 183 DNA Homo sapiens 32aaaggcggga tgtgtctctc cattctccct tttgtgtctc ttgtaggggt gaagaagaga 60accaaagtca tcaagaacag cgtgaaccct gtatggaatg aggtatgtga gtttttctcc 120ttccttttct ctctgtctgc tgcagggggc ttgggaggag gtgccttctc agcagtgtcc 180ttg 183 33 264 DNA Homo sapiens 33cattcatgaa tgcctactca gtgccctggt ggcacgaagg tgaaccagac acagtctctt 60ctcctagagg gccataggtt aagatgcctt ttctcttttt cttccaggga tttgaatggg 120acctcaaggg catccccctg gaccagggct ctgagcttca tgtggtggtc aaagaccatg 180agacgatggg gaggaacagg taaggtggcc agaggggggt gctccatggc ttgaaggtgc 240aggtaggatt gtggagtata caga 264 34 223 DNA Homo sapiens 34cagaagagcc agggtgcctt aggctagttt tctacatttg acttctctct cctctcaggt 60tcctggggga agccaaggtc ccactccgag aggtcctcgc cacccctagt ctgtccgcca 120gcttcaatgc ccccctgctg gacaccaaga agcagcccac aggggtaagt gcccatcagc 180ctctgccagg ttaaggtcca aggcattgcc aggtggcttc ctc 223 35 224 DNA Homo sapiens 35cagtggtccg aggccagcgc accaacctgt cccccacgtc tcatctcttc caggcctcgc 60tggtcctgca ggtgtcctac acaccgctgc ctggagctgt gcccctgttc ccgcccccta 120ctcctctgga gccctccccg actctgcctg acctggatgt agtggcaggt gggtagccca 180cgttggcctg gctgggcccc agcaagaatg gccggcagtg gcac 224 36 315 DNA Homo sapiens 36aggggcaggg gcagggccag agggccaggc ctcattaggg ccctctcctc ttagacacag 60gaggagagga agacacagag gaccagggac tcactggaga tgaggcggag ccattcctgg 120atcaaagcgg aggcccgggg gctcccacca ccccaaggaa actaccttca cgtcctccgc 180cccactaccc cgggatcaaa agaaagcgaa gtgcgcctac atctagaaag ctgctgtcag 240acaaaccgca ggatttccag gtgatgaacg ggctttctct gaccccaggc tcctcttcag 300ccatcagctg cgggt 315 37 249 DNA Homo sapiens 37ccagtggtga gatggtccct gagatttctg actcttgggg tggatggtgg gtggtcctta 60actcttcccc cttctggctt tcagatcagg gtccaggtga tcgaggggcg ccagctgccg 120ggggtgaaca tcaagcctgt ggtcaaggtt accgctgcag ggcagaccaa gcggacgcgg 180atccacaagg gaaacagccc actcttcaat gaggtgggag acatggggca tgagggcaga 240accttgtgg 249 38 185 DNA Homo sapiens 38ccctggcctg agggatcagc aggcactgat atgtctctct ttgctctgaa ccaacagact 60cttttcttca acttgtttga ctctcctggg gagctgtttg atgagcccat ctttatcacg 120gtatgtctca gcagtcaaag tgttctccgt gggctgtatg tatgcacata ggtgtcagtg 180cacac 185 39 196 DNA Homo sapiens 39aagagctatt gggttggccg tgtgggccac atgtccctgt gaatgtgagc catgatcttt 60ctctgcaggt ggtagactct cgttctctca ggacagatgc tctcctcggg gagttccggg 120taattgctta ttttctaaaa gcagtcagtt ctcacttctc cgtgttggtg gagcctctgt 180ggaccatggg cagggg 196 40 178 DNA Homo sapiens 40tggaatcgta taatgcacca cactttattt aacgctttgg cggcaagagt ttgatttgtg 60tctcctctct tgattgcaga tggacgtggg caccatttac agagagcccc gtgagttctc 120accactttgg ccgtatcctt gcattttggt tctggaggct gattggggac actcattt 178 41 231 DNA Homo sapiens 41ggggtcttct gattctggga tcaccaaagg atgttgtctc tcttagggca cgcctatctc 60aggaagtggc tgctgctctc agaccctgat gacttctctg ctggggccag aggctacctg 120aaaacaagcc tttgtgtgct ggggcctggg gacgaagcgc ctgtgagtac atttccctgg 180gtcttcctta cggtccccca cgcggcactt ggttgcggag gcaccaaacc a 231 42 247 DNA Homo sapiens 42gtcaaaaccc tgtgctcagg agcgcatgaa ggaacgtatt tggttttctt tgtagctgga 60gagaaaagac ccctctgaag acaaggagga cattgaaagc aacctgctcc ggcccacagg 120cgtagccctg cgaggagccc acttctgcct gaaggtcttc cgggccgagg acttgccgca 180gagtgcgtgg ggcgcgccct tgggtgggag gtctgcagga ggctggaggc gcagggctgg 240tgggggt 247 43 179 DNA Homo sapiens 43caggcagtga ctggtgtgtc cctcttccca gtggacgatg ccgtgatgga caacgtgaaa 60cagatctttg gcttcgagag taacaagaag aacttggtgg acccctttgt ggaggtcagc 120tttgcgggga aaatggtaag gagcaaggga gcaggagggt tctctcggga ggggacggg 179 44 202 DNA Homo sapiens 44ccccggggga gcccagagtc cccatggagc tgatcaactt gtcccctccc tgtgtcttct 60agctgtgcag caagatcttg gagaagacgg ccaaccctca gtggaaccag aacatcacac 120tgcctgccat ggtgagcctc ctgtccccag caaacccaag gaggcccctg gggctctggg 180cttcgggagg tccagggctc ct 202 45 167 DNA Homo sapiens 45gggaggggct gttctatctt caaaaggact cttctcccaa cacgcctcta ttccttcctc 60agtttccctc catgtgcgaa aaaatgagga ttcgtatcat agactggtga gttctgagtc 120ttggagtctt tagggcgggc tgtcctgagg gggcgctccc tcagttt 167 46 220 DNA Homo sapiens 46tgtggcctga gttcctttcc tgtgtcaggc cctctctgct cccttgctct ctagggaccg 60cctgactcac aatgacatcg tggctaccac ctacctgagt atgtcgaaaa tctctgcccc 120tggaggagaa atagaaggta tgttccctct tcgttctgcc ctttgacccc ctgtgctctc 180cccccctcta tccagcttac acttctagtt ttgagagttt 220 47 172 DNA Homo sapiens 47acagcctgtt catgtaaccc gtccttctcc cagccatgcc caccctaacc ccttttccat 60ttctttacgc ttcagaggag cctgcaggtg ctgtcaagcc ttcgaaagcc tcagactgta 120cgttgctgtc accttgggga caaccagggg agtggggcct tgggttttgg ct 172 48 200 DNA Homo sapiens 48ccgacccctc tgattgccac ttgtgtctcc cagtggatga ctacctgggc ttcctcccca 60cttttgggcc ctgctacatc aacctctatg gcagtcccag agagttcaca ggcttcccag 120acccctacac agagctcaac acaggcaagg taagccggct ggagccctgg caagggcagg 180atgccacatg cccaggtggg 200 49 217 DNA Homo sapiens 49cctcccctct gtctcccctg ctccttgtga cctgacctcc ctggcagggg gaaggtgtgg 60cttatcgtgg ccggcttctg ctctccctgg agaccaagct ggtggagcac agtgaacaga 120aggtggagga ccttcctgcg gatgacatcc tccgggtgga ggtgaggggt gtggctctgg 180gtgggagctg ggcgtcgggg cagggaaggg atggcca 217 50 269 DNA Homo sapiens 50agcctgggtg cctttctttg ctcctcccgt gaccctctgg tctactctct gctctcagaa 60gtaccttagg aggcgcaagt actccctgtt tgcggccttc tactcagcca ccatgctgca 120ggatgtggat gatgccatcc agtttgaggt cagcatcggg aactacggga acaagttcga 180catgacctgc ctgccgctgg cctccaccac tcagtacagc cgtgcagtct ttgacggtga 240ggcagtgctc ctggctggga ccccgatca 269 51 225 DNA Homo sapiens 51actcctggca cagcgctcag gcccgtctct ccattccagg gtgccactac tactacctac 60cctggggtaa cgtgaaacct gtggtggtgc tgtcatccta ctgggaggac atcagccata 120gaatcgagac tcagaaccag ctgcttggga ttgctgaccg gctggtgagt gaaaacttgc 180ccaaagctgc acatgcctat gcatgcacct gctacccccg ctgca 225 52 227 DNA Homo sapiens 52gggtccagca tgcaccctct gccctgtggt gacacacctg acccttgcct gcccattcca 60caggaagctg gcctggagca ggtccacctg gccctgaagg cgcagtgctc cacggaggac 120gtggactcgc tggtggctca gctgacggat gagctcatcg caggctgcag gtagggggga 180cctggcgccc ctggtgccca cctctcctgg ctcaactggg cctgttt 227 53 303 DNA Homo sapiens 53tgggagaccc tgggctcatc aggcgcattc catctgtccg tccctcacag ccagcctctg 60ggtgacatcc atgagacacc ctctgccacc cacctggacc agtacctgta ccagctgcgc 120acccatcacc tgagccaaat cactgaggct gccctggccc tgaagctcgg ccacagtgag 180ctccctgcag ctctggagca ggcggaggac tggctcctgc gtctgcgtgc cctggcagag 240gaggtaatta agcctggggg tgcctttctt cttctgctct cctgctgcct ggaacatcag 300aac 303 54 272 DNA Homo sapiens 54cgtgggcctg gtgtgtcacc atccccaccc cgaccaccac cctctgttca gccccagaac 60agcctgccgg acatcgtcat ctggatgctg cagggagaca agcgtgtggc ataccagcgg 120gtgcccgccc accaagtcct cttctcccgg cggggtgcca actactgtgg caagaattgt 180gggaagctac agacaatctt tctgaaagtg agttttcttt ttccaagtca tgatcgtatt 240tccaacataa ggcctttctc ccatctcttg ct 272 55 219 DNA Homo sapiens 55tgtgggtttc tgtccttctt cggtacccag tatccgatgg agaaggtgcc tggcgcccgg 60atgccagtgc agatacgggt caagctgtgg tttgggctct ctgtggatga gaaggagttc 120aaccagtttg ctgaggggaa gctgtctgtc tttgctgaaa ccgtgagtac ctgccagccc 180ccacctctgc ctcccactac ctggagctgc cttggcccc 219 56 292 DNA Homo sapiens 56tgcctcccac tacctggagc tgccttggcc cccttcacgc ctcattcttc ctggccctcc 60agtatgagaa cgagactaag ttggcccttg ttgggaactg gggcacaacg ggcctcacct 120accccaagtt ttctgacgtc acgggcaaga tcaagctacc caaggacagc ttccgcccct 180cggccggctg gacctgggct ggagattggt tcgtgtgtcc ggagaagacg tgagtcgtgg 240gcagggaggg ctggggagag ccaggccagg ctgcccacca tggactgcac cc 292 57 242 DNA Homo sapiens 57tggatggggg cctctccagc agagcagcag agactctgac cagccctcct ccacagtctg 60ctccatgaca tggacgccgg tcacctgagc ttcgtggaag aggtgtttga gaaccagacc 120cggcttcccg gaggccagtg gatctacatg agtgacaact acaccgatgt ggtaaagcag 180gcactcaggg gcaggtgggg tctagacatt tggtctctgg aggcacctgg tgctcaggga 240ca 242 58 215 DNA Homo sapiens 58tcacatctgt ctgtctcctc tcattgcttg cctgttcggt tttgtcctta gaacggggag 60aaggtgcttc ccaaggatga cattgagtgc ccactgggct ggaagtggga agatgaggaa 120tggtccacag acctcaaccg ggctgtcgat gagcaaggtg ggcagcatgt ggaacctggc 180gagccccatc cccggcaagc tctcaagcca tgcat 215 59 246 DNA Homo sapiens 59agagatggtc ccaggagaga tggggggaag tgccaagcaa tgagtgaccg gttccccctc 60ccccaggctg ggagtatagc atcaccatcc ccccggagcg gaagccgaag cactgggtcc 120ctgctgagaa gatgtactac acacaccgac ggcggcgctg ggtgcgcctg cgcaggaggg 180atctcagcca aatggaagca ctgaaaaagg gtgagccagc aggtggtggg tgggagtgag 240gcctgt 246 60 253 DNA Homo sapiens 60cttcccaccg gcctctgagt ctgccccttc ttgtgcagca caggcaggcg gaggcggagg 60gcgagggctg ggagtacgcc tctctttttg gctggaagtt ccacctcgag taccgcaaga 120cagatgcctt ccgccgccgc cgctggcgcc gtcgcatgga gccactggag aagacggggc 180ctgcagctgt gtttgccctt gagggggccc tggtatgtgg ggctgcactt gtcctggctt 240gggtagggta tat 253 61 177 DNA Homo sapiens 61gaatctgcca taaccagctt cgtgtctcca gggcggcgtg atggatgaca agagtgaaga 60ttccatgtcc gtctccacct tgagcttcgg tgtgaacaga cccacgattt cctgcatatt 120cgactgtaag taggcttcga ggcctctatg gggtgataag ggtgtgtcac cttatgc 177 62 181 DNA Homo sapiens 62aaccactcca gccactcact ctggcacctc tgttttttcc cttggtgaag atgggaaccg 60ctaccatcta cgctgctaca tgtaccaggc ccgggacctg gctgcgatgg acaaggactc 120tttttctggt aggtgggaga gaggcaggag agtcagagac tgtgggctga gatctgggaa 180t 181 63 319 DNA Homo sapiens 63ccccacatgg ctctggagaa gacatctctc agggtccctg ctgtgtaatg tctcccctcc 60ccctctggcc atgcagatcc ctatgccatc gtctccttcc tgcaccagag ccagaagacg 120gtggtggtga agaacaccct taaccccacc tgggaccaga cgctcatctt ctacgagatc 180gagatctttg gcgagccggc cacagttgct gagcaaccgc ccagcattgt ggtggagctg 240tacgaccatg acacttatgt gagtctgccc agctcctgcc tcgtcccctc acagggaggg 300accatgtgca aaggtgggg 319 64 249 DNA Homo sapiens 64gccctgggta agggatgctg attcttgtct ctctacgctt ggtctagggt gcagacgagt 60ttatgggtcg ctgcatctgt caaccgagtc tggaacggat gccacggctg gcctggttcc 120cactgacgag gggcagccag ccgtcggggg agctgctggc ctcttttgag ctcatccaga 180gagagaaggt gaggctggtc tatatccaga tccaggaggc ccaggcagga gtggggtggg 240ggccaaccc 249 65 158 DNA Homo sapiens 65cactgacata gtccatgagt gtcatgaggg tgatgggggc cttaggtgac aagcacatga 60ccagagctct cttttcttca ctccagccgg ccatccacca tattcctggt tttgaggtaa 120gtcttgctct gacctttcct tcttcaaact gattgcca 158 66 132 DNA Homo sapiens 66ctttttcccc ttccaacccc tctcaccatc tcctgatgtg cacatcccat ggctgtgggc 60caggtgcagg agacatcaag gatcctggat gaggtgagct ggcggggccg aggtagaggg 120aaggtgaagc ca 132 67 216 DNA Homo sapiens 67tcttccttcc acctttgtct ccattctacc tgctgtccac tgcagtctga ggacacagac 60ctgccctacc caccacccca gagggaggcc aacatctaca tggttcctca gaacatcaag 120ccagcgctcc agcgtaccgc catcgaggtg agccgtccgg gcctgggcgt gggggctggg 180agcagcctgc ccttcccctt cctggcccca gccttt 216 68 263 DNA Homo sapiens 68cccgggcctt ctgagccact ctcctcattc tgtgtgctta gaatcctggc atggggcctg 60cggaacatga agagttacca gctggccaac atctcctccc ccagcctcgt ggtagagtgt 120gggggccaga cggtgcagtc ctgtgtcatc aggaacctcc ggaagaaccc caactttgac 180atctgcaccc tcttcatgga agtggtgagc cccacctccc tactgtcccc ttccagagtc 240ctggggctag aagttctaca tgt 263 69 249 DNA Homo sapiens 69caggccagtg cgttcttcct cctccaccca gatgctgccc agggaggagc tctactgccc 60ccccatcacc gtcaaggtca tcgataaccg ccagtttggc cgccggcctg tggtgggcca 120gtgtaccatc cgctccctgg agagcttcct gtgtgacccc tactcggcgg agagtccatc 180cccacagggt ggcccaggta ggggaagggg agatgatggg caggtcaggg aagggggagc 240ctagggcaa 249 70 180 DNA Homo sapiens 70aggggcgagc cttttgagag agcccctgtc aggcctggat ggctccctcc cctgcagacg 60atgtgagcct actcagtcct ggggaagacg tgctcatcga cattgatgac aaggagcccc 120tcatccccat ccaggtagga tgggcatcct ccagggaggc ctgggtcacc tttcccctcc 180 71 211 DNA Homo sapiens 71tgctgcttgg cgagtcctgt ttctgaaatg gtctctttct ttctacccac tcaggaggaa 60gagttcatcg attggtggag caaattcttt gcctccatag gggagaggga aaagtgcggc 120tcctacctgg agaaggattt tgacaccctg aaggtaaggc ctctcttcag tctgacagtc 180ggtgtgtgtg tgcgtgctgg gcagtgggag a 211 72 235 DNA Homo sapiens 72gttctacttt ctttctgtct cttgtcccct cctctaatcc ccatgtgtgg caggtctatg 60acacacagct ggagaatgtg gaggcctttg agggcctgtc tgacttttgt aacaccttca 120agctgtaccg gggcaagacg caggaggaga cagaagatcc atctgtgatt ggtgaattta 180aggtaaatcc tcgaagacgt ccctaaccca ggtgggccta agactgtggt gttgg 235 73 268 DNA Homo sapiens 73ggggacacag ccaaaccata tcaacaatga tgataaaata aaattaaccc ttccttcttt 60tcagggcctc ttcaaaattt atcccctccc agaagaccca gccatcccca tgcccccaag 120acagttccac cagctggccg cccagggacc ccaggagtgc ttggtccgta tctacattgt 180ccgagcattt ggcctgcagc ccaaggaccc caatggaaag gtaactttct agagccctca 240cctccccaga gtagcaggct caggtaca 268 74 200 DNA Homo sapiens 74tttggaaagt gttttcacag aagtgttttg tctcctcctc cagtgtgatc cttacatcaa 60gatctccata gggaagaaat cagtgagtga ccaggataac tacatcccct gcacgctgga 120gcccgtattt ggaaagtaaa ttggggcatc ttgggtcttg gggtggagga gccagacagg 180ataacccaca gtctagtggg 200 75 263 DNA Homo sapiens 75cctgttccct tgggtgccct gtgttggctg acattcggga atctgcccct tcctgcagga 60tgttcgagct gacctgcact ctgcctctgg agaaggacct aaagatcact ctctatgact 120atgacctcct ctccaaggac gaaaagatcg gtgagacggt cgtcgacctg gagaacaggc 180tgctgtccaa gtttggggct cgctgtggac tcccacagac ctactgtgtg tacgtggatg 240ggggctggct gcctgcttct ctg 263 76 237 DNA Homo sapiens 76aagcatctcg tctatgtctt gtgcttgctc ctcagctctg gaccgaacca gtggcgggac 60cagctccgcc cctcccagct cctccacctc ttctgccagc agcatagagt caaggcacct 120gtgtaccgga cagaccgtgt aatgtttcag gataaagaat attccattga agagataggt 180gagctgccac atgaccccaa accatggtgg gctctcgctg tatccctccc tctctca 237 77 245 DNA Homo sapiens 77tctctcgctt ccccagctcc tgcaactttt ttgtgttctc tctggggcag aggctggcag 60gatcccaaac ccacacctgg gcccagtgga ggagcgtctg gctctgcatg tgcttcagca 120gcagggcctg gtcccggagc acgtggagtc acggcccctc tacagccccc tgcagccaga 180catcgagcag gtaggacctt acccttggtc ccagagtcct cgaactccag aagcccaacc 240ccagg 245 78 214 DNA Homo sapiens 78ggtgcttggt aacagctggt taaatgagaa gggtggggag agaacggacc tgtctccgca 60ggggaagctg gggaagctgc agatgtgggt cgacctattt ccgaaggccc tggggcggcc 120tggacctccc ttcaacatca ccccacggag agccagaagg tgacttccca gccacaggct 180ctgagctggg ctgaggggtg gggcgttgca gcct 214 79 229 DNA Homo sapiens 79ttcttaaggc cttcccatcc tttggtagga aatctaggtg gattagagtg atacctttcc 60ccaggttttt cctgcgttgt attatctgga ataccagaga tgtgatcctg gatgacctga 120gcctcacggg ggagaagatg agcgacattt atgtgaaagg gtagggagcc agcgtcctct 180tgcctgtcca gcttcccgca gctcccgtgc tccctctggg ttgtgcaca 229 80 261 DNA Homo sapiens 80acgatgtata tactgtgttg gaaatcttaa tgagaactat tctctaaaaa catgtatgtc 60tagttggatg attggctttg aagaacacaa gcaaaagaca gacgtgcatt atcgttccct 120gggaggtgaa ggcaacttca actggaggtt cattttcccc ttcgactacc tgccagctga 180gcaagtctgt accattgcca agaaggtcag tgtccttccg attccctgtg gtgccagcac 240cagggcttct aaagttagcc t 261 81 234 DNA Homo sapiens 81tgcctctctc taactttgct tccttgcatc cttctctgtt cctcttccgg gtcaggatgc 60cttctggagg ctggacaaga ctgagagcaa aatcccagca cgagtggtgt tccagatctg 120ggacaatgac aagttctcct ttgatgattt tctggtgatt ttctgggtaa gcgctattgc 180tagaatccca ttctgcacat gggggctgcc ccagaaccca cactgtgtgt ttat 234 82 297 DNA Homo sapiens 82ggctacaggc tggcagtgat cgagaaaccc ggccaaaaac cacctctctg ttgcaggctc 60cctgcagctc gatctcaacc gcatgcccaa gccagccaag acagccaaga agtgctcctt 120ggaccagctg gatgatgctt tccacccaga atggtttgtg tccctttttg agcagaaaac 180agtgaagggc tggtggccct gtgtagcaga agagggtgag aagaaaatac tggcggtaag 240tctacttcct ccagccccag tggagggcat gggggaagct tcttccatag aaattgt 297 83 237 DNA Homo sapiens 83cctggttact ctccaggcca ctgagcagag ccttcgtgcc cctaaccaag tgctctctgt 60cccctcaggg caagctggaa atgaccttgg agattgtagc agagagtgag catgaggagc 120ggcctgctgg ccagggccgg gatgagccca acatgaaccc taagcttgag gacccaaggt 180cagtgcccag cccctgagcc ccaatgccca caggtctggg ggtataggca cagtcca 237 84 252 DNA Homo sapiens 84ccctagtaaa ggatgcccag ttgactccgg gatctcgctt ccaggcgccc cgacacctcc 60ttcctgtggt ttacctcccc atacaagacc atgaagttca tcctgtggcg gcgtttccgg 120tgggccatca tcctcttcat catcctcttc atcctgctgc tgttcctggc catcttcatc 180tacgccttcc cggtgagcag gcctgacgac actgtggtgg gggaactctg ggtctaatgg 240gggagttcat ca 252 85 391 DNA Homo sapiens 85tggctgtgcc tgccccagtg ggatcaccat gggtccctgt ctcctccctc cctccagaac 60tatgctgcca tgaagctggt gaagcccttc agctgaggac tctcctgccc tgtagaaggg 120gccgtggggt cccctccagc atgggactgg cctgcctcct ccgcccagct cggcgagctc 180ctccagacct cctaggcctg attgtcctgc cagggtgggc agacagacag atggaccggc 240ccacactccc agagttgcta acatggagct ctgagatcac cccacttcca tcatttcctt 300ctcccccaac ccaacgcttt tttggatcag ctcagacata tttcagtata aaacagttgg 360aaccacaaaa aaaaaaaaaa aaaaaaaaaa a 391 86 51 PRT Homo sapiens 86Lys Lys Arg Thr Lys Val Ile Lys Asn Ser Val Asn Pro Val Trp Asn 1 5 10 15Glu Gly Phe Glu Trp Asp Leu Lys Gly Ile Pro Leu Asp Gln Gly Ser 20 25 30Glu Leu His Val Val Val Lys Asp His Glu Thr Met Gly Arg Asn Arg 35 40 45Phe Leu Gly 50 87 45 PRT Homo sapiens 87Ser Lys Ile Leu Glu Lys Thr Ala Asn Pro Gln Trp Asn Gln Asn Ile 1 5 10 15Thr Leu Pro Ala Met Phe Pro Ser Met Cys Glu Lys Met Arg Ile Arg 20 25 30Ile Ile Asp Trp Asp Arg Leu Thr His Asn Asp Ile Val 35 40 45 88 82 PRT Homo sapiens 88Gln Ala Arg Asp Leu Ala Ala Met Asp Lys Asp Ser Phe Ser Asp Pro 1 5 10 15Tyr Ala Ile Val Ser Phe Leu His Gln Ser Gln Lys Thr Val Val Val 20 25 30Lys Asn Thr Leu Asn Pro Thr Trp Asp Gln Thr Leu Ile Phe Tyr Glu 35 40 45Ile Glu Ile Phe Gly Glu Pro Ala Thr Val Ala Glu Gln Pro Pro Ser 50 55 60Ile Val Val Glu Leu Tyr Asp His Asp Thr Tyr Gly Ala Asp Glu Phe 65 70 75 80Met Gly 89 79 PRT Homo sapiens 89Ile Tyr Ile Val Arg Ala Phe Gly Leu Gln Pro Lys Asp Pro Asn Gly 1 5 10 15Lys Cys Asp Pro Tyr Ile Lys Ile Ser Ile Gly Lys Lys Ser Val Ser 20 25 30Asp Gln Asp Asn Tyr Ile Pro Cys Thr Leu Glu Pro Val Phe Gly Lys 35 40 45Met Phe Glu Leu Thr Cys Thr Leu Pro Leu Glu Lys Asp Leu Lys Ile 50 55 60Thr Leu Tyr Asp Tyr Asp Leu Leu Ser Lys Asp Glu Lys Ile Gly 65 70 75 90 152 DNA Homo sapiens 90acgatgtata tactgtgttg gaaatcttaa tgagaactat tctctaaaaa catgtatgtc 60tagttggatg attggctttg aagaacacaa gcaaaagaca gacgtgcatt atcgttccct 120gggaggtgaa ggcaacttca actggaggtt ca 152 91 56 DNA Homo sapiens 91gtcagtgtcc ttccgattcc ctgtggtgcc agcaccaggg cttctaaagt tagcct 56 92 55 DNA Homo sapiens 92tgcctctctc taactttgct tccttgcatc cttctctgtt cctcttccgg gtcag 55 93 68 DNA Homo sapiens 93gtaagcgcta ttgctagaat cccattctgc acatgggggc tgccccagaa cccacactgt 60gtgtttat 68 94 56 DNA Homo sapiens 94ggctacaggc tggcagtgat cgagaaaccc ggccaaaaac cacctctctg ttgcag 56 95 62 DNA Homo sapiens 95gtaagtctac ttcctccagc cccagtggag ggcatggggg aagcttcttc catagaaatt 60gt 62 96 68 DNA Homo sapiens 96cctggttact ctccaggcca ctgagcagag ccttcgtgcc cctaaccaag tgctctctgt 60cccctcag 68 97 59 DNA Homo sapiens 97gtcagtgccc agcccctgag ccccaatgcc cacaggtctg ggggtatagg cacagtcca 59 98 44 DNA Homo sapiens 98ccctagtaaa ggatgcccag ttgactccgg gatctcgctt ccag 44 99 60 DNA Homo sapiens 99gtgagcaggc ctgacgacac tgtggtgggg gaactctggg tctaatgggg gagttcatca 60 100 57 DNA Homo sapiens 100tggctgtgcc tgccccagtg ggatcaccat gggtccctgt ctcctccctc cctccag 57 101 23 DNA Homo sapiens 101tctcttctcc tagagggcca tag 23 102 24 DNA Homo sapiens 102ctgttcctcc ccatcgtctc atgg 24 103 20 DNA Homo sapiens 103gctcctcccg tgaccctctg 20 104 21 DNA Homo sapiens 104gggtcccagc caggagcact g 21 105 24 DNA Homo sapiens 105cccctctcac catctcctga tgtg 24 106 25 DNA Homo sapiens 106tggcttcacc ttccctctac ctcgg 25 107 24 DNA Homo sapiens 107tcctttggta ggaaatctag gtgg 24 108 21 DNA Homo sapiens 108ggaagctgga caggcaagag g 21 109 27 DNA Homo sapiens 109atatactgtg ttggaaatct taatgag 27 110 21 DNA Homo sapiens 110gctggcacca cagggaatcg g 21 111 25 DNA Homo sapiens 111ctttgcttcc ttgcatcctt ctctg 25 112 21 DNA Homo sapiens 112agcccccatg tgcagaatgg g 21 113 21 DNA Homo sapiens 113ggcagtgatc gagaaacccg g 21 114 21 DNA Homo sapiens 114catgccctcc actggggctg g 21 115 21 DNA Homo sapiens 115ggatgcccag ttgactccgg g 21 116 21 DNA Homo sapiens 116ccccaccaca gtgtcgtcag g 21 117 6240 DNA Homo sapiens 117atgctgaggg tcttcatcct ctatgccgag aacgtccaca cacccgacac cgacatcagc 60gatgcctact gctccgcggt gtttgcaggg gtgaagaaga gaaccaaagt catcaagaac 120agcgtgaacc ctgtatggaa tgagggattt gaatgggacc tcaagggcat ccccctggac 180cagggctctg agcttcatgt ggtggtcaaa gaccatgaga cgatggggag gaacaggttc 240ctgggggaag ccaaggtccc actccgagag gtcctcgcca cccctagtct gtccgccagc 300ttcaatgccc ccctgctgga caccaagaag cagcccacag gggcctcgct ggtcctgcag 360gtgtcctaca caccgctgcc tggagctgtg cccctgttcc cgccccctac tcctctggag 420ccctccccga ctctgcctga cctggatgta gtggcagaca caggaggaga ggaagacaca 480gaggaccagg gactcactgg agatgaggcg gagccattcc tggatcaaag cggaggcccg 540ggggctccca ccaccccaag gaaactacct tcacgtcctc cgccccacta ccccgggatc 600aaaagaaagc gaagtgcgcc tacatctaga aagctgctgt cagacaaacc gcaggatttc 660cagatcaggg tccaggtgat cgaggggcgc cagctgccgg gggtgaacat caagcctgtg 720gtcaaggtta ccgctgcagg gcagaccaag cggacgcgga tccacaaggg aaacagccca 780ctcttcaatg agactctttt cttcaacttg tttgactctc ctggggagct gtttgatgag 840cccatcttta tcacggtggt agactctcgt tctctcagga cagatgctct cctcggggag 900ttccggatgg acgtgggcac catttacaga gagccccggc acgcctatct caggaagtgg 960ctgctgctct cagaccctga tgacttctct gctggggcca gaggctacct gaaaacaagc 1020ctttgtgtgc tggggcctgg ggacgaagcg cctctggaga gaaaagaccc ctctgaagac 1080aaggaggaca ttgaaagcaa cctgctccgg cccacaggcg tagccctgcg aggagcccac 1140ttctgcctga aggtcttccg ggccgaggac ttgccgcaga tggacgatgc cgtgatggac 1200aacgtgaaac agatctttgg cttcgagagt aacaagaaga acttggtgga cccctttgtg 1260gaggtcagct ttgcggggaa aatgctgtgc agcaagatct tggagaagac ggccaaccct 1320cagtggaacc agaacatcac actgcctgcc atgtttccct ccatgtgcga aaaaatgagg 1380attcgtatca tagactggga ccgcctgact cacaatgaca tcgtggctac cacctacctg 1440agtatgtcga aaatctctgc ccctggagga gaaatagaag aggagcctgc aggtgctgtc 1500aagccttcga aagcctcaga cttggatgac tacctgggct tcctccccac ttttgggccc 1560tgctacatca acctctatgg cagtcccaga gagttcacag gcttcccaga cccctacaca 1620gagctcaaca caggcaaggg ggaaggtgtg gcttatcgtg gccggcttct gctctccctg 1680gagaccaagc tggtggagca cagtgaacag aaggtggagg accttcctgc ggatgacatc 1740ctccgggtgg agaagtacct taggaggcgc aagtactccc tgtttgcggc cttctactca 1800gccaccatgc tgcaggatgt ggatgatgcc atccagtttg aggtcagcat cgggaactac 1860gggaacaagt tcgacatgac ctgcctgccg ctggcctcca ccactcagta cagccgtgca 1920gtctttgacg ggtgccacta ctactaccta ccctggggta acgtgaaacc tgtggtggtg 1980ctgtcatcct actgggagga catcagccat agaatcgaga ctcagaacca gctgcttggg 2040attgctgacc ggctggaagc tggcctggag caggtccacc tggccctgaa ggcgcagtgc 2100tccacggagg acgtggactc gctggtggct cagctgacgg atgagctcat cgcaggctgc 2160agccagcctc tgggtgacat ccatgagaca ccctctgcca cccacctgga ccagtacctg 2220taccagctgc gcacccatca cctgagccaa atcactgagg ctgccctggc cctgaagctc 2280ggccacagtg agctccctgc agctctggag caggcggagg actggctcct gcgtctgcgt 2340gccctggcag aggagcccca gaacagcctg ccggacatcg tcatctggat gctgcaggga 2400gacaagcgtg tggcatacca gcgggtgccc gcccaccaag tcctcttctc ccggcggggt 2460gccaactact gtggcaagaa ttgtgggaag ctacagacaa tctttctgaa atatccgatg 2520gagaaggtgc ctggcgcccg gatgccagtg cagatacggg tcaagctgtg gtttgggctc 2580tctgtggatg agaaggagtt caaccagttt gctgagggga agctgtctgt ctttgctgaa 2640acctatgaga acgagactaa gttggccctt gttgggaact ggggcacaac gggcctcacc 2700taccccaagt tttctgacgt cacgggcaag atcaagctac ccaaggacag cttccgcccc 2760tcggccggct ggacctgggc tggagattgg ttcgtgtgtc cggagaagac tctgctccat 2820gacatggacg ccggtcacct gagcttcgtg gaagaggtgt ttgagaacca gacccggctt 2880cccggaggcc agtggatcta catgagtgac aactacaccg atgtgaacgg ggagaaggtg 2940cttcccaagg atgacattga gtgcccactg ggctggaagt gggaagatga ggaatggtcc 3000acagacctca accgggctgt cgatgagcaa ggctgggagt atagcatcac catccccccg 3060gagcggaagc cgaagcactg ggtccctgct gagaagatgt actacacaca ccgacggcgg 3120cgctgggtgc gcctgcgcag gagggatctc agccaaatgg aagcactgaa aaggcacagg 3180caggcggagg cggagggcga gggctgggag tacgcctctc tttttggctg gaagttccac 3240ctcgagtacc gcaagacaga tgccttccgc cgccgccgct ggcgccgtcg catggagcca 3300ctggagaaga cggggcctgc agctgtgttt gcccttgagg gggccctggg cggcgtgatg 3360gatgacaaga gtgaagattc catgtccgtc tccaccttga gcttcggtgt gaacagaccc 3420acgatttcct gcatattcga ctatgggaac cgctaccatc tacgctgcta catgtaccag 3480gcccgggacc tggctgcgat ggacaaggac tctttttctg atccctatgc catcgtctcc 3540ttcctgcacc agagccagaa gacggtggtg gtgaagaaca cccttaaccc cacctgggac 3600cagacgctca tcttctacga gatcgagatc tttggcgagc cggccacagt tgctgagcaa 3660ccgcccagca ttgtggtgga gctgtacgac catgacactt atggtgcaga cgagtttatg 3720ggtcgctgca tctgtcaacc gagtctggaa cggatgccac ggctggcctg gttcccactg 3780acgaggggca gccagccgtc gggggagctg ctggcctctt ttgagctcat ccagagagag 3840aagccggcca tccaccatat tcctggtttt gaggtgcagg agacatcaag gatcctggat 3900gagtctgagg acacagacct gccctaccca ccaccccaga gggaggccaa catctacatg 3960gttcctcaga acatcaagcc agcgctccag cgtaccgcca tcgagatcct ggcatggggc 4020ctgcggaaca tgaagagtta ccagctggcc aacatctcct cccccagcct cgtggtagag 4080tgtgggggcc agacggtgca gtcctgtgtc atcaggaacc tccggaagaa ccccaacttt 4140gacatctgca ccctcttcat ggaagtgatg ctgcccaggg aggagctcta ctgccccccc 4200atcaccgtca aggtcatcga taaccgccag tttggccgcc ggcctgtggt gggccagtgt 4260accatccgct ccctggagag cttcctgtgt gacccctact cggcggagag tccatcccca 4320cagggtggcc cagacgatgt gagcctactc agtcctgggg aagacgtgct catcgacatt 4380gatgacaagg agcccctcat ccccatccag gaggaagagt tcatcgattg gtggagcaaa 4440ttctttgcct ccatagggga gagggaaaag tgcggctcct acctggagaa ggattttgac 4500accctgaagg tctatgacac acagctggag aatgtggagg cctttgaggg cctgtctgac 4560ttttgtaaca ccttcaagct gtaccggggc aagacgcagg aggagacaga agatccatct 4620gtgattggtg aatttaaggg cctcttcaaa atttatcccc tcccagaaga cccagccatc 4680cccatgcccc caagacagtt ccaccagctg gccgcccagg gaccccagga gtgcttggtc 4740cgtatctaca ttgtccgagc atttggcctg cagcccaagg accccaatgg aaagtgtgat 4800ccttacatca agatctccat agggaagaaa tcagtgagtg accaggataa ctacatcccc 4860tgcacgctgg agcccgtatt tggaaagatg ttcgagctga cctgcactct gcctctggag 4920aaggacctaa agatcactct ctatgactat gacctcctct ccaaggacga aaagatcggt 4980gagacggtcg tcgacctgga gaacaggctg ctgtccaagt ttggggctcg ctgtggactc 5040ccacagacct actgtgtctc tggaccgaac cagtggcggg accagctccg cccctcccag 5100ctcctccacc tcttctgcca gcagcataga gtcaaggcac ctgtgtaccg gacagaccgt 5160gtaatgtttc aggataaaga atattccatt gaagagatag aggctggcag gatcccaaac 5220ccacacctgg gcccagtgga ggagcgtctg gctctgcatg tgcttcagca gcagggcctg 5280gtcccggagc acgtggagtc acggcccctc tacagccccc tgcagccaga catcgagcag 5340gggaagctgc agatgtgggt cgacctattt ccgaaggccc tggggcggcc tggacctccc 5400ttcaacatca ccccacggag agccagaagg tttttcctgc gttgtattat ctggaatacc 5460agagatgtga tcctggatga cctgagcctc acgggggaga agatgagcga catttatgtg 5520aaaggttgga tgattggctt tgaagaacac aagcaaaaga cagacgtgca ttatcgttcc 5580ctgggaggtg aaggcaactt caactggagg ttcattttcc ccttcgacta cctgccagct 5640gagcaagtct gtaccattgc caagaaggat gccttctgga ggctggacaa gactgagagc 5700aaaatcccag cacgagtggt gttccagatc tgggacaatg acaagttctc ctttgatgat 5760tttctgggct ccctgcagct cgatctcaac cgcatgccca agccagccaa gacagccaag 5820aagtgctcct tggaccagct ggatgatgct ttccacccag aatggtttgt gtcccttttt 5880gagcagaaaa cagtgaaggg ctggtggccc tgtgtagcag aagagggtga gaagaaaata 5940ctggcgggca agctggaaat gaccttggag attgtagcag agagtgagca tgaggagcgg 6000cctgctggcc agggccggga tgagcccaac atgaacccta agcttgagga cccaaggcgc 6060cccgacacct ccttcctgtg gtttacctcc ccatacaaga ccatgaagtt catcctgtgg 6120cggcgtttcc ggtgggccat catcctcttc atcatcctct tcatcctgct gctgttcctg 6180gccatcttca tctacgcctt cccgaactat gctgccatga agctggtgaa gcccttcagc 6240 118 13 DNA Homo sapiens 118cgcaagcatg ctg 13 119 12 DNA Homo sapiens 119gagacgatgg gg 12 120 21 DNA Homo sapiens 120gatctaaccc tgctgctcac c 21 121 21 DNA Homo sapiens 121ctggtgtgtt gcagagcgct g 21 122 21 DNA Homo sapiens 122cctctcttct gctgtcttca g 21 123 21 DNA Homo sapiens 123tgtgtctggt tcaccttcgt g 21 124 21 DNA Homo sapiens 124tccaaataga aatgcctgaa c 21 125 21 DNA Homo sapiens 125aggtatcacc tccaagtgtt g 21 126 21 DNA Homo sapiens 126taccagcttc agagctccct g 21 127 19 DNA Homo sapiens 127ttgatcaggg tgctcttgg 19 128 20 DNA Homo sapiens 128ggagaattgc ttgaacccag 20 129 22 DNA Homo sapiens 129tggctaatga tgttgaacat tt 22 130 21 DNA Homo sapiens 130gacccacaag cggcgcctcg g 21 131 21 DNA Homo sapiens 131gaccccggcg agggtggtcg g 21 132 24 DNA Homo sapiens 132tgtctctcca ttctcccttt tgtg 24 133 24 DNA Homo sapiens 133aggacactgc tgagaaggca cctc 24 134 21 DNA Homo sapiens 134agtgccctgg tggcacgaag g 21 135 24 DNA Homo sapiens 135cctacctgca ccttcaagcc atgg 24 136 23 DNA Homo sapiens 136cagaagagcc agggtgcctt agg 23 137 24 DNA Homo sapiens 137ccttggacct taacctggca gagg 24 138 21 DNA Homo sapiens 138cgaggccagc gcaccaacct g 21 139 22 DNA Homo sapiens 139actgccggcc attcttgctg gg 22 140 21 DNA Homo sapiens 140ccaggcctca ttagggccct c 21 141 22 DNA Homo sapiens 141ctgaagagga gcctggggtc ag 22 142 24 DNA Homo sapiens 142ctgagatttc tgactcttgg ggtg 24 143 24 DNA Homo sapiens 143aaggttctgc cctcatgccc catg 24 144 21 DNA Homo sapiens 144ctggcctgag ggatcagcag g 21 145 23 DNA Homo sapiens 145gtgcatacat acagcccacg gag 23 146 24 DNA Homo sapiens 146gagctattgg gttggccgtg tggg 24 147 24 DNA Homo sapiens 147accaacacgg agaagtgaga actg 24 148 26 DNA Homo sapiens 148ccacacttta tttaacgctt tggcgg 26 149 24 DNA Homo sapiens 149cagaaccaaa atgcaaggat acgg 24 150 25 DNA Homo sapiens 150cttctgattc tgggatcacc aaagg 25 151 22 DNA Homo sapiens 151ggaccgtaag gaagacccag gg 22 152 24 DNA Homo sapiens 152cctgtgctca ggagcgcatg aagg 24 153 22 DNA Homo sapiens 153gcagacctcc cacccaaggg cg 22 154 24 DNA Homo sapiens 154gagacagatg ggggacagtc aggg 24 155 21 DNA Homo sapiens 155cctcccgaga gaaccctcct g 21 156 21 DNA Homo sapiens 156gggagcccag agtccccatg g 21 157 21 DNA Homo sapiens 157gggcctcctt gggtttgctg g 21 158 21 DNA Homo sapiens 158gcctccccag catcctgccg g 21 159 24 DNA Homo sapiens 159tcactgagcc gaatgaaact gagg 24 160 24 DNA Homo sapiens 160tgtggcctga gttcctttcc tgtg 24 161 24 DNA Homo sapiens 161ggtcaaaggg cagaacgaag aggg 24 162 21 DNA Homo sapiens 162cccgtccttc tcccagccat g 21 163 21 DNA Homo sapiens 163ctcccctggt tgtccccaag g 21 164 24 DNA Homo sapiens 164cgacccctct gattgccact tgtg 24 165 21 DNA Homo sapiens 165ggcatcctgc ccttgccagg g 21 166 20 DNA Homo sapiens 166tctgtctccc ctgctccttg 20 167 21 DNA Homo sapiens 167cttccctgcc ccgacgccca g 21 168 21 DNA Homo sapiens 168cagcgctcag gcccgtctct c 21 169 24 DNA Homo sapiens 169tgcataggca tgtgcagctt tggg 24 170 21 DNA Homo sapiens 170catgcaccct ctgccctgtg g 21 171 21 DNA Homo sapiens 171agttgagcca ggagaggtgg g 21 172 24 DNA Homo sapiens 172catcaggcgc attccatctg tccg 24 173 24 DNA Homo sapiens 173agcaggagag cagaagaaga aagg 24 174 22 DNA Homo sapiens 174gtgtgtcacc atccccaccc cg 22 175 25 DNA Homo sapiens 175caagagatgg gagaaaggcc ttatg 25 176 23 DNA Homo sapiens 176ctgggacatc cggatcctga agg 23 177 22 DNA Homo sapiens 177tccaggtagt gggaggcaga gg 22 178 24 DNA Homo sapiens 178tcccactacc tggagctgcc ttgg 24 179 21 DNA Homo sapiens 179ggctctcccc agccctccct g 21 180 24 DNA Homo sapiens 180cagagcagca gagactctga ccag 24 181 21 DNA Homo sapiens 181tagaccccac ctgcccctga g 21 182 24 DNA Homo sapiens 182tcctctcatt gcttgcctgt tcgg 24 183 21 DNA Homo sapiens 183ttgagagctt gccggggatg g 21 184 24 DNA Homo sapiens 184aagtgccaag caatgagtga ccgg 24 185 21 DNA Homo sapiens 185ctcactccca cccaccacct g 21 186 21 DNA Homo sapiens 186cccaccggcc tctgagtctg c 21 187 24 DNA Homo sapiens 187accctaccca agccaggaca agtg 24 188 24 DNA Homo sapiens 188gaatctgcca taaccagctt cgtg 24 189 24 DNA Homo sapiens 189tatcacccca tagaggcctc gaag 24 190 24 DNA Homo sapiens 190cagccactca ctctggcacc tctg 24 191 24 DNA Homo sapiens 191agcccacagt ctctgactct cctg 24 192 24 DNA Homo sapiens 192acatctctca gggtccctgc tgtg 24 193 21 DNA Homo sapiens 193cctgtgaggg gacgaggcag g 21 194 24 DNA Homo sapiens 194gccctgggta agggatgctg attc 24 195 21 DNA Homo sapiens 195cctgcctggg cctcctggat c 21 196 21 DNA Homo sapiens 196gagggtgatg ggggccttag g 21 197 24 DNA Homo sapiens 197gcaatcagtt tgaagaagga aagg 24 198 24 DNA Homo sapiens 198cacctttgtc tccattctac ctgc 24 199 21 DNA Homo sapiens 199ctcccagccc ccacgcccag g 21 200 24 DNA Homo sapiens 200ctgagccact ctcctcattc tgtg 24 201 21 DNA Homo sapiens 201tggaagggga cagtagggag g 21 202 22 DNA Homo sapiens 202ggccagtgcg ttcttcctcc tc 22 203 22 DNA Homo sapiens 203tccctgacct gcccatcatc tc 22 204 21 DNA Homo sapiens 204gcccctgtca ggcctggatg g 21 205 21 DNA Homo sapiens 205tgacccaggc ctccctggag g 21 206 24 DNA Homo sapiens 206ctgaaatggt ctctttcttt ctac 24 207 24 DNA Homo sapiens 207cacaccgact gtcagactga agag 24 208 24 DNA Homo sapiens 208ttgtcccctc ctctaatccc catg 24 209 21 DNA Homo sapiens 209gggttaggga cgtcttcgag g 21 210 22 DNA Homo sapiens 210cagccaaacc atatcaacaa tg 22 211 21 DNA Homo sapiens 211ctggggaggt gagggctcta g 21 212 21 DNA Homo sapiens 212gaagtgtttt gtctcctcct c 21 213 20 DNA Homo sapiens 213gcaggcagcc agcccccatc 20 214 21 DNA Homo sapiens 214gggtgccctg tgttggctga c 21 215 20 DNA Homo sapiens 215gcaggcagcc agcccccatc 20 216 24 DNA Homo sapiens 216ctcgtctatg tcttgtgctt gctc 24 217 23 DNA Homo sapiens 217caccatggtt tggggtcatg tgg 23 218 21 DNA Homo sapiens 218tctcgcttcc ccagctcctg c 21 219 22 DNA Homo sapiens 219tctggagttc gaggactctg gg 22 220 21 DNA Homo sapiens 220agaagggtgg ggagagaacg g 21 221 21 DNA Homo sapiens 221cagctcagag cctgtggctg g 21 222 24 DNA Homo sapiens 222aaggccttcc catcctttgg tagg 24 223 21 DNA Homo sapiens 223acaacccaga gggagcacgg g 21 224 25 DNA Homo sapiens 224gttgacgatg tatatactgt gttgg 25 225 25 DNA Homo sapiens 225gcctctctct aactttgctt ccttg 25 226 24 DNA Homo sapiens 226ggctacaggc tggcagtgat cgag 24 227 21 DNA Homo sapiens 227ttcccccatg ccctccactg g 21 228 24 DNA Homo sapiens 228agccttcgtg cccctaacca agtg 24 229 21 DNA Homo sapiens 229ctgtgggcat tggggctcag g 21 230 20 DNA Homo sapiens 230gccccagtgg gatcaccatg 20 231 21 DNA Homo sapiens 231atgctggagg ggaccccacg g 21 232 3671 DNA Homo sapiens CDS (418)...(3381) 232tcctggttca agcgattctc tggcctcagc ctcccgagta gctgggatta caggcatgct 60ccaccaagcc cgggtaattt tgtattttta atagagacgg ggttttgcca tgttggtcag 120gctggtctcg aactcctgac ctcaggtgat ctgcccacct tggcctccca acgtgctgag 180attacaggca tgagtcactg tgcccggcag agatggtcta attcatatga aagaactctg 240aaaaaagtag aaagtgattt tctaaaataa ggtacaaata attaatgtaa gcataatcac 300ctaaccttgt ggaatttttt ttttttgaga agcaaattgc aaatttgtga tagatctaaa 360ggagattgac taagagggtg accatctgga aatgacgtca tgtgagaatg gttaaag atg 420 Met 1ctc ggg aga ttg agc cta gag aaa gga aga ttt gtg aac cca gga ggc 468Leu Gly Arg Leu Ser Leu Glu Lys Gly Arg Phe Val Asn Pro Gly Gly 5 10 15aga ggt aga gat cca gga gag ggc ggc gtg atg gat gac aag agt gaa 516Arg Gly Arg Asp Pro Gly Glu Gly Gly Val Met Asp Asp Lys Ser Glu 20 25 30gat tcc atg tcc gtc tcc acc ttg agc ttc ggt gtg aac aga ccc acg 564Asp Ser Met Ser Val Ser Thr Leu Ser Phe Gly Val Asn Arg Pro Thr 35 40 45att tcc tgc ata ttc gac tat ggg aac cgc tac cat cta cgc tgc tac 612Ile Ser Cys Ile Phe Asp Tyr Gly Asn Arg Tyr His Leu Arg Cys Tyr 50 55 60 65atg tac cag gcc cgg gac ctg gct gcg atg gac aag gac tct ttt tct 660Met Tyr Gln Ala Arg Asp Leu Ala Ala Met Asp Lys Asp Ser Phe Ser 70 75 80gat ccc tat gcc atc gtc tcc ttc ctg cac cag agc cag aag acg gtg 708Asp Pro Tyr Ala Ile Val Ser Phe Leu His Gln Ser Gln Lys Thr Val 85 90 95gtg gtg aag aac acc ctt aac ccc acc tgg gac cag acg ctc atc ttc 756Val Val Lys Asn Thr Leu Asn Pro Thr Trp Asp Gln Thr Leu Ile Phe 100 105 110tac gag atc gag atc ttt ggc gag ccg gcc aca gtt gct gag caa ccg 804Tyr Glu Ile Glu Ile Phe Gly Glu Pro Ala Thr Val Ala Glu Gln Pro 115 120 125ccc agc att gtg gtg gag ctg tac gac cat gac act tat ggt gca gac 852Pro Ser Ile Val Val Glu Leu Tyr Asp His Asp Thr Tyr Gly Ala Asp130 135 140 145gag ttt atg ggt cgc tgc atc tgt caa ccg agt ctg gaa cgg atg cca 900Glu Phe Met Gly Arg Cys Ile Cys Gln Pro Ser Leu Glu Arg Met Pro 150 155 160cgg ctg gcc tgg ttc cca ctg acg agg ggc agc cag ccg tcg ggg gag 948Arg Leu Ala Trp Phe Pro Leu Thr Arg Gly Ser Gln Pro Ser Gly Glu 165 170 175ctg ctg gcc tct ttt gag ctc atc cag aga gag aag ccg gcc atc cac 996Leu Leu Ala Ser Phe Glu Leu Ile Gln Arg Glu Lys Pro Ala Ile His 180 185 190cat att cct ggt ttt gag gtg cag gag aca tca agg atc ctg gat gag 1044His Ile Pro Gly Phe Glu Val Gln Glu Thr Ser Arg Ile Leu Asp Glu 195 200 205tct gag gac aca gac ctg ccc tac cca cca ccc cag agg gag gcc aac 1092Ser Glu Asp Thr Asp Leu Pro Tyr Pro Pro Pro Gln Arg Glu Ala Asn210 215 220 225atc tac atg gtt cct cag aac atc aag cca gcg ctc cag cgt acc gcc 1140Ile Tyr Met Val Pro Gln Asn Ile Lys Pro Ala Leu Gln Arg Thr Ala 230 235 240atc gag atc ctg gca tgg ggc ctg cgg aac atg aag agt tac cag ctg 1188Ile Glu Ile Leu Ala Trp Gly Leu Arg Asn Met Lys Ser Tyr Gln Leu 245 250 255gcc aac atc tcc tcc ccc agc ctc gtg gta gag tgt ggg ggc cag acg 1236Ala Asn Ile Ser Ser Pro Ser Leu Val Val Glu Cys Gly Gly Gln Thr 260 265 270gtg cag tcc tgt gtc atc agg aac ctc cgg aag aac ccc aac ttt gac 1284Val Gln Ser Cys Val Ile Arg Asn Leu Arg Lys Asn Pro Asn Phe Asp 275 280 285atc tgc acc ctc ttc atg gaa gtg atg ctg ccc agg gag gag ctc tac 1332Ile Cys Thr Leu Phe Met Glu Val Met Leu Pro Arg Glu Glu Leu Tyr290 295 300 305tgc ccc ccc atc acc gtc aag gtc atc gat aac cgc cag ttt ggc cgc 1380Cys Pro Pro Ile Thr Val Lys Val Ile Asp Asn Arg Gln Phe Gly Arg 310 315 320cgg cct gtg gtg ggc cag tgt acc atc cgc tcc ctg gag agc ttc ctg 1428Arg Pro Val Val Gly Gln Cys Thr Ile Arg Ser Leu Glu Ser Phe Leu 325 330 335tgt gac ccc tac tcg gcg gag agt cca tcc cca cag ggt ggc cca gac 1476Cys Asp Pro Tyr Ser Ala Glu Ser Pro Ser Pro Gln Gly Gly Pro Asp 340 345 350gat gtg agc cta ctc agt cct ggg gaa gac gtg ctc atc gac att gat 1524Asp Val Ser Leu Leu Ser Pro Gly Glu Asp Val Leu Ile Asp Ile Asp 355 360 365gac aag gag ccc ctc atc ccc atc cag gag gaa gag ttc atc gat tgg 1572Asp Lys Glu Pro Leu Ile Pro Ile Gln Glu Glu Glu Phe Ile Asp Trp370 375 380 385tgg agc aaa ttc ttt gcc tcc ata ggg gag agg gaa aag tgc ggc tcc 1620Trp Ser Lys Phe Phe Ala Ser Ile Gly Glu Arg Glu Lys Cys Gly Ser 390 395 400tac ctg gag aag gat ttt gac acc ctg aag gtc tat gac aca cag ctg 1668Tyr Leu Glu Lys Asp Phe Asp Thr Leu Lys Val Tyr Asp Thr Gln Leu 405 410 415gag aat gtg gag gcc ttt gag ggc ctg tct gac ttt tgt aac acc ttc 1716Glu Asn Val Glu Ala Phe Glu Gly Leu Ser Asp Phe Cys Asn Thr Phe 420 425 430aag ctg tac cgg ggc aag acg cag gag gag aca gaa gat cca tct gtg 1764Lys Leu Tyr Arg Gly Lys Thr Gln Glu Glu Thr Glu Asp Pro Ser Val 435 440 445att ggt gaa ttt aag ggc ctc ttc aaa att tat ccc ctc cca gaa gac 1812Ile Gly Glu Phe Lys Gly Leu Phe Lys Ile Tyr Pro Leu Pro Glu Asp450 455 460 465cca gcc atc ccc atg ccc cca aga cag ttc cac cag ctg gcc gcc cag 1860Pro Ala Ile Pro Met Pro Pro Arg Gln Phe His Gln Leu Ala Ala Gln 470 475 480gga ccc cag gag tgc ttg gtc cgt atc tac att gtc cga gca ttt ggc 1908Gly Pro Gln Glu Cys Leu Val Arg Ile Tyr Ile Val Arg Ala Phe Gly 485 490 495ctg cag ccc aag gac ccc aat gga aag tgt gat cct tac atc aag atc 1956Leu Gln Pro Lys Asp Pro Asn Gly Lys Cys Asp Pro Tyr Ile Lys Ile 500 505 510tcc ata ggg aag aaa tca gtg agt gac cag gat aac tac atc ccc tgc 2004Ser Ile Gly Lys Lys Ser Val Ser Asp Gln Asp Asn Tyr Ile Pro Cys 515 520 525acg ctg gag ccc gta ttt gga aag atg ttc gag ctg acc tgc act ctg 2052Thr Leu Glu Pro Val Phe Gly Lys Met Phe Glu Leu Thr Cys Thr Leu530 535 540 545cct ctg gag aag gac cta aag atc act ctc tat gac tat gac ctc ctc 2100Pro Leu Glu Lys Asp Leu Lys Ile Thr Leu Tyr Asp Tyr Asp Leu Leu 550 555 560tcc aag gac gaa aag atc ggt gag acg gtc gtc gac ctg gag aac agg 2148Ser Lys Asp Glu Lys Ile Gly Glu Thr Val Val Asp Leu Glu Asn Arg 565 570 575ctg ctg tcc aag ttt ggg gct cgc tgt gga ctc cca cag acc tac tgt 2196Leu Leu Ser Lys Phe Gly Ala Arg Cys Gly Leu Pro Gln Thr Tyr Cys 580 585 590gtc tct gga ccg aac cag tgg cgg gac cag ctc cgc ccc tcc cag ctc 2244Val Ser Gly Pro Asn Gln Trp Arg Asp Gln Leu Arg Pro Ser Gln Leu 595 600 605ctc cac ctc ttc tgc cag cag cat aga gtc aag gca cct gtg tac cgg 2292Leu His Leu Phe Cys Gln Gln His Arg Val Lys Ala Pro Val Tyr Arg610 615 620 625aca gac cgt gta atg ttt cag gat aaa gaa tat tcc att gaa gag ata 2340Thr Asp Arg Val Met Phe Gln Asp Lys Glu Tyr Ser Ile Glu Glu Ile 630 635 640gag gct ggc agg atc cca aac cca cac ctg ggc cca gtg gag gag cgt 2388Glu Ala Gly Arg Ile Pro Asn Pro His Leu Gly Pro Val Glu Glu Arg 645 650 655ctg gct ctg cat gtg ctt cag cag cag ggc ctg gtc ccg gag cac gtg 2436Leu Ala Leu His Val Leu Gln Gln Gln Gly Leu Val Pro Glu His Val 660 665 670gag tca cgg ccc ctc tac agc ccc ctg cag cca gac atc gag cag ggg 2484Glu Ser Arg Pro Leu Tyr Ser Pro Leu Gln Pro Asp Ile Glu Gln Gly 675 680 685aag ctg cag atg tgg gtc gac cta ttt ccg aag gcc ctg ggg cgg cct 2532Lys Leu Gln Met Trp Val Asp Leu Phe Pro Lys Ala Leu Gly Arg Pro690 695 700 705gga cct ccc ttc aac atc acc cca cgg aga gcc aga agg ttt ttc ctg 2580Gly Pro Pro Phe Asn Ile Thr Pro Arg Arg Ala Arg Arg Phe Phe Leu 710 715 720cgt tgt att atc tgg aat acc aga gat gtg atc ctg gat gac ctg agc 2628Arg Cys Ile Ile Trp Asn Thr Arg Asp Val Ile Leu Asp Asp Leu Ser 725 730 735ctc acg ggg gag aag atg agc gac att tat gtg aaa ggt tgg atg att 2676Leu Thr Gly Glu Lys Met Ser Asp Ile Tyr Val Lys Gly Trp Met Ile 740 745 750ggc ttt gaa gaa cac aag caa aag aca gac gtg cat tat cgt tcc ctg 2724Gly Phe Glu Glu His Lys Gln Lys Thr Asp Val His Tyr Arg Ser Leu 755 760 765gga ggt gaa ggc aac ttc aac tgg agg ttc att ttc ccc ttc gac tac 2772Gly Gly Glu Gly Asn Phe Asn Trp Arg Phe Ile Phe Pro Phe Asp Tyr770 775 780 785ctg cca gct gag caa gtc tgt acc att gcc aag aag gat gcc ttc tgg 2820Leu Pro Ala Glu Gln Val Cys Thr Ile Ala Lys Lys Asp Ala Phe Trp 790 795 800agg ctg gac aag act gag agc aaa atc cca gca cga gtg gtg ttc cag 2868Arg Leu Asp Lys Thr Glu Ser Lys Ile Pro Ala Arg Val Val Phe Gln 805 810 815atc tgg gac aat gac aag ttc tcc ttt gat gat ttt ctg ggc tcc ctg 2916Ile Trp Asp Asn Asp Lys Phe Ser Phe Asp Asp Phe Leu Gly Ser Leu 820 825 830cag ctc gat ctc aac cgc atg ccc aag cca gcc aag aca gcc aag aag 2964Gln Leu Asp Leu Asn Arg Met Pro Lys Pro Ala Lys Thr Ala Lys Lys 835 840 845tgc tcc ttg gac cag ctg gat gat gct ttc cac cca gaa tgg ttt gtg 3012Cys Ser Leu Asp Gln Leu Asp Asp Ala Phe His Pro Glu Trp Phe Val850 855 860 865tcc ctt ttt gag cag aaa aca gtg aag ggc tgg tgg ccc tgt gta gca 3060Ser Leu Phe Glu Gln Lys Thr Val Lys Gly Trp Trp Pro Cys Val Ala 870 875 880gaa gag ggt gag aag aaa ata ctg gcg ggc aag ctg gaa atg acc ttg 3108Glu Glu Gly Glu Lys Lys Ile Leu Ala Gly Lys Leu Glu Met Thr Leu 885 890 895gag att gta gca gag agt gag cat gag gag cgg cct gct ggc cag ggc 3156Glu Ile Val Ala Glu Ser Glu His Glu Glu Arg Pro Ala Gly Gln Gly 900 905 910cgg gat gag ccc aac atg aac cct aag ctt gag gac cca agg cgc ccc 3204Arg Asp Glu Pro Asn Met Asn Pro Lys Leu Glu Asp Pro Arg Arg Pro 915 920 925gac acc tcc ttc ctg tgg ttt acc tcc cca tac aag acc atg aag ttc 3252Asp Thr Ser Phe Leu Trp Phe Thr Ser Pro Tyr Lys Thr Met Lys Phe930 935 940 945atc ctg tgg cgg cgt ttc cgg tgg gcc atc atc ctc ttc atc atc ctc 3300Ile Leu Trp Arg Arg Phe Arg Trp Ala Ile Ile Leu Phe Ile Ile Leu 950 955 960ttc atc ctg ctg ctg ttc ctg gcc atc ttc atc tac gcc ttc ccg aac 3348Phe Ile Leu Leu Leu Phe Leu Ala Ile Phe Ile Tyr Ala Phe Pro Asn 965 970 975tat gct gcc atg aag ctg gtg aag ccc ttc agc tgaggactct cctgccctgt 3401Tyr Ala Ala Met Lys Leu Val Lys Pro Phe Ser 980 985agaaggggcc gtggggtccc ctccagcatg ggactggcct gcctcctccg cccagctcgg 3461cgagctcctc cagacctcct aggcctgatt gtcctgccag ggtgggcaga cagacagatg 3521gaccggccca cactcccaga gttgctaaca tggagctctg agatcacccc acttccatca 3581tttccttctc ccccaaccca acgctttttt ggatcagctc agacatattt cagtataaaa 3641cagttggaac cacaaaaaaa aaaaaaaaaa 3671 233 988 PRT Homo sapiens 233Met Leu Gly Arg Leu Ser Leu Glu Lys Gly Arg Phe Val Asn Pro Gly 1 5 10 15Gly Arg Gly Arg Asp Pro Gly Glu Gly Gly Val Met Asp Asp Lys Ser 20 25 30Glu Asp Ser Met Ser Val Ser Thr Leu Ser Phe Gly Val Asn Arg Pro 35 40 45Thr Ile Ser Cys Ile Phe Asp Tyr Gly Asn Arg Tyr His Leu Arg Cys 50 55 60Tyr Met Tyr Gln Ala Arg Asp Leu Ala Ala Met Asp Lys Asp Ser Phe 65 70 75 80Ser Asp Pro Tyr Ala Ile Val Ser Phe Leu His Gln Ser Gln Lys Thr 85 90 95Val Val Val Lys Asn Thr Leu Asn Pro Thr Trp Asp Gln Thr Leu Ile 100 105 110Phe Tyr Glu Ile Glu Ile Phe Gly Glu Pro Ala Thr Val Ala Glu Gln 115 120 125Pro Pro Ser Ile Val Val Glu Leu Tyr Asp His Asp Thr Tyr Gly Ala 130 135 140Asp Glu Phe Met Gly Arg Cys Ile Cys Gln Pro Ser Leu Glu Arg Met145 150 155 160Pro Arg Leu Ala Trp Phe Pro Leu Thr Arg Gly Ser Gln Pro Ser Gly 165 170 175Glu Leu Leu Ala Ser Phe Glu Leu Ile Gln Arg Glu Lys Pro Ala Ile 180 185 190His His Ile Pro Gly Phe Glu Val Gln Glu Thr Ser Arg Ile Leu Asp 195 200 205Glu Ser Glu Asp Thr Asp Leu Pro Tyr Pro Pro Pro Gln Arg Glu Ala 210 215 220Asn Ile Tyr Met Val Pro Gln Asn Ile Lys Pro Ala Leu Gln Arg Thr225 230 235 240Ala Ile Glu Ile Leu Ala Trp Gly Leu Arg Asn Met Lys Ser Tyr Gln 245 250 255Leu Ala Asn Ile Ser Ser Pro Ser Leu Val Val Glu Cys Gly Gly Gln 260 265 270Thr Val Gln Ser Cys Val Ile Arg Asn Leu Arg Lys Asn Pro Asn Phe 275 280 285Asp Ile Cys Thr Leu Phe Met Glu Val Met Leu Pro Arg Glu Glu Leu 290 295 300Tyr Cys Pro Pro Ile Thr Val Lys Val Ile Asp Asn Arg Gln Phe Gly305 310 315 320Arg Arg Pro Val Val Gly Gln Cys Thr Ile Arg Ser Leu Glu Ser Phe 325 330 335Leu Cys Asp Pro Tyr Ser Ala Glu Ser Pro Ser Pro Gln Gly Gly Pro 340 345 350Asp Asp Val Ser Leu Leu Ser Pro Gly Glu Asp Val Leu Ile Asp Ile 355 360 365Asp Asp Lys Glu Pro Leu Ile Pro Ile Gln Glu Glu Glu Phe Ile Asp 370 375 380Trp Trp Ser Lys Phe Phe Ala Ser Ile Gly Glu Arg Glu Lys Cys Gly385 390 395 400Ser Tyr Leu Glu Lys Asp Phe Asp Thr Leu Lys Val Tyr Asp Thr Gln 405 410 415Leu Glu Asn Val Glu Ala Phe Glu Gly Leu Ser Asp Phe Cys Asn Thr 420 425 430Phe Lys Leu Tyr Arg Gly Lys Thr Gln Glu Glu Thr Glu Asp Pro Ser 435 440 445Val Ile Gly Glu Phe Lys Gly Leu Phe Lys Ile Tyr Pro Leu Pro Glu 450 455 460Asp Pro Ala Ile Pro Met Pro Pro Arg Gln Phe His Gln Leu Ala Ala465 470 475 480Gln Gly Pro Gln Glu Cys Leu Val Arg Ile Tyr Ile Val Arg Ala Phe 485 490 495Gly Leu Gln Pro Lys Asp Pro Asn Gly Lys Cys Asp Pro Tyr Ile Lys 500 505 510Ile Ser Ile Gly Lys Lys Ser Val Ser Asp Gln Asp Asn Tyr Ile Pro 515 520 525Cys Thr Leu Glu Pro Val Phe Gly Lys Met Phe Glu Leu Thr Cys Thr 530 535 540Leu Pro Leu Glu Lys Asp Leu Lys Ile Thr Leu Tyr Asp Tyr Asp Leu545 550 555 560Leu Ser Lys Asp Glu Lys Ile Gly Glu Thr Val Val Asp Leu Glu Asn 565 570 575Arg Leu Leu Ser Lys Phe Gly Ala Arg Cys Gly Leu Pro Gln Thr Tyr 580 585 590Cys Val Ser Gly Pro Asn Gln Trp Arg Asp Gln Leu Arg Pro Ser Gln 595 600 605Leu Leu His Leu Phe Cys Gln Gln His Arg Val Lys Ala Pro Val Tyr 610 615 620Arg Thr Asp Arg Val Met Phe Gln Asp Lys Glu Tyr Ser Ile Glu Glu625 630 635 640Ile Glu Ala Gly Arg Ile Pro Asn Pro His Leu Gly Pro Val Glu Glu 645 650 655Arg Leu Ala Leu His Val Leu Gln Gln Gln Gly Leu Val Pro Glu His 660 665 670Val Glu Ser Arg Pro Leu Tyr Ser Pro Leu Gln Pro Asp Ile Glu Gln 675 680 685Gly Lys Leu Gln Met Trp Val Asp Leu Phe Pro Lys Ala Leu Gly Arg 690 695 700Pro Gly Pro Pro Phe Asn Ile Thr Pro Arg Arg Ala Arg Arg Phe Phe705 710 715 720Leu Arg Cys Ile Ile Trp Asn Thr Arg Asp Val Ile Leu Asp Asp Leu 725 730 735Ser Leu Thr Gly Glu Lys Met Ser Asp Ile Tyr Val Lys Gly Trp Met 740 745 750Ile Gly Phe Glu Glu His Lys Gln Lys Thr Asp Val His Tyr Arg Ser 755 760 765Leu Gly Gly Glu Gly Asn Phe Asn Trp Arg Phe Ile Phe Pro Phe Asp 770 775 780Tyr Leu Pro Ala Glu Gln Val Cys Thr Ile Ala Lys Lys Asp Ala Phe785 790 795 800Trp Arg Leu Asp Lys Thr Glu Ser Lys Ile Pro Ala Arg Val Val Phe 805 810 815Gln Ile Trp Asp Asn Asp Lys Phe Ser Phe Asp Asp Phe Leu Gly Ser 820 825 830Leu Gln Leu Asp Leu Asn Arg Met Pro Lys Pro Ala Lys Thr Ala Lys 835 840 845Lys Cys Ser Leu Asp Gln Leu Asp Asp Ala Phe His Pro Glu Trp Phe 850 855 860Val Ser Leu Phe Glu Gln Lys Thr Val Lys Gly Trp Trp Pro Cys Val865 870 875 880Ala Glu Glu Gly Glu Lys Lys Ile Leu Ala Gly Lys Leu Glu Met Thr 885 890 895Leu Glu Ile Val Ala Glu Ser Glu His Glu Glu Arg Pro Ala Gly Gln 900 905 910Gly Arg Asp Glu Pro Asn Met Asn Pro Lys Leu Glu Asp Pro Arg Arg 915 920 925Pro Asp Thr Ser Phe Leu Trp Phe Thr Ser Pro Tyr Lys Thr Met Lys 930 935 940Phe Ile Leu Trp Arg Arg Phe Arg Trp Ala Ile Ile Leu Phe Ile Ile945 950 955 960Leu Phe Ile Leu Leu Leu Phe Leu Ala Ile Phe Ile Tyr Ala Phe Pro 965 970 975Asn Tyr Ala Ala Met Lys Leu Val Lys Pro Phe Ser 980 985

Claims

1. A single stranded oligonucleotide of 14-50 nucleotides in length having a nucleotide sequence identical to a portion of SEQ ID NO:3, or a complement thereof.