Abstract:
By a detailed analysis of the sequences of the MHC S gene, SEEK1 gene, and HCR gene of Japanese patients with psoriasis and healthy individuals, it was demonstrated that some of the examined polymorphisms significantly correlate with psoriasis in the group of Japanese patients. Based on these correlations, it was demonstrated that psoriasis vulgaris can be detected by analyzing these gene polymorphisms in patients with psoriasis.

Description:
[0001]    This application is a continuation-in-part of PCT/JP00/08624, filed Dec. 6, 2000 which claims priority to Japanese Patent Application No. 11/346867, filed Dec. 6, 1999.  
         TECHNICAL FIELD  
         [0002]    The present invention relates to a method of testing for psoriasis vulgaris and DNA molecules used therefore.  
         BACKGROUND  
         [0003]    Psoriasis vulgaris (MIM 177900) is a skin disease characterized by inflammatory cell infiltration and hyperproliferation of epidermal cells.  
           [0004]    A genetic factor is thought to be deeply involved in the onset of this disease. Investigation into the existing region of the causative gene responsible for the disease is in progress. For example, the sequence of a DNA of 2,229,817 bp, predicted to contain a sensitive gene of psoriasis, has been determined (The MHC sequencing consortium, Nature 400:921-923, 1999). The present inventors narrowed the scope of the existing region of the causative gene of psoriasis vulgaris by microsatellite analyses (Oka et al., Hum. Mol. Genet. 8:2165-2170, 1999) and found three known genes from the genomic sequence of HLA class I [i.e., POU5F1 (OTF3: octamer transcription factor 3), TCF19 (SC1: cell growth regulated gene), and MHC S]; as well as four novel genes within the region [i.e., HCR (helix coiled-coil rod homologue), SPR1 (skin specific proline rich gene 1), SEEK1 (specific expressed gene in epidermal keratinocytes 1), and STG (skin specific telomeric gene) (AB029331, AB031480, AB031479, and AB031481, respectively)] (Oka et al., Hum. Mol. Genet. 8:2165-2170, 1999) (FIG. 1).  
           [0005]    Psoriasis vulgaris is known to show a strong positive association with HLA-Cw6/7 among these genes (Tiilikainen et al., Br. J. Dermatol., 102, 179-184, 1980; Bhalerao et al., Hum. Mol. Genet. 7:1537-1545, 1998). However, it remains to be seen whether the HLA genes themselves are responsible for the onset of psoriasis or whether some other non-HLA genes linked to the HLA genes are responsible.  
           [0006]    Recently, a significant association between psoriasis and dimorphisms (Ser410Leu substitution) at cDNA position +1243 of the MHC S gene (the product of which are also called “corneodesmosin”) were reported in Caucasian populations (Tazi-Ahnini et al., Hum. Mol. Genet. 8:1135-1140, 1999; Allen et al., The Lancet 353:1589-1590, 1999). However, according to these papers, Tazi-Ahnini et al. reported a significant increase of the allele of Leu at position +1243, while Allen et al. reported an increase of another allele (Ser). Thus, the accuracy of these reports has been questioned.  
           [0007]    The present inventors previously observed that psoriasis in a Japanese population was significantly associated with HLA-Cw6/7, as in the case of Caucasian (Ozawa et al., J. Am. Acad. Dermatol. 4:205-230, 1981; Asahina et al., J. Invest. Dermatol. 97:254-258, 1991); however, they also reported that no genetic polymorphism of the MHC S gene, significantly associated with psoriasis vulgaris, could be found (Ishihara et al., Tissue Antigens 48:182-186, 1996).  
           [0008]    Thus, genes responsible for psoriasis vulgaris have not yet been identified. Additionally, only few reports on genetic polymorphisms that may be used as the target of testing for psoriasis vulgaris have been published.  
         SUMMARY  
         [0009]    The present invention provides novel genetic polymorphisms that relate to psoriasis vulgaris. Moreover, the present invention provides a method of testing for psoriasis vulgaris by detecting these polymorphisms, and DNA molecules used for the test.  
           [0010]    By analyzing the sequences of the MHC S gene, SEEK1 gene, and HCR gene of Japanese psoriasis patients and those of healthy individuals in detail, the present inventors discovered polymorphisms existing within the entire genes thereof and analyzed the relationship between the polymorphisms and psoriasis. As a result, the present inventors demonstrated that some of the analyzed polymorphisms significantly correlated to psoriasis in Japanese patients. Moreover, the present inventors discovered that psoriasis vulgaris could be tested by assaying for these genetic polymorphisms in psoriasis patients based on these correlations.  
           [0011]    Thus, the present invention relates to a method of testing for psoriasis vulgaris by detecting the genetic polymorphisms in subjects, and DNA molecules used for the test. More specifically, the present invention provides:  
           [0012]    (1) a primer DNA for detecting psoriasis vulgaris in a patient selected from the group of:  
           [0013]    (a) a primer DNA that hybridizes to a DNA comprising the nucleotide sequence of SEQ ID NO: 1 or the complementary strand thereof and which is designed so that the 4040th nucleotide of SEQ ID NO: 1 or the corresponding nucleotide on the complementary strand thereof is positioned between the primers;  
           [0014]    (b) a primer DNA that hybridizes to a DNA comprising the nucleotide sequence of SEQ ID NO: 2 or the complementary strand thereof and which is designed so that the 6413th nucleotide of SEQ ID NO: 2 or the corresponding nucleotide on the complementary strand thereof is positioned between the primers;  
           [0015]    (c) a primer DNA that hybridizes to a DNA comprising the nucleotide sequence of SEQ ID NO: 2 or the complementary strand thereof, and which is designed so that the 14378th nucleotide of SEQ ID NO: 2 or the corresponding nucleotide on the complementary strand thereof is positioned between the primers; and  
           [0016]    (d) a primer DNA that hybridizes to a DNA comprising the nucleotide sequence of SEQ ID NO: 3 or the complementary strand thereof and which is designed so that the 6196th nucleotide of SEQ ID NO: 3 or the corresponding nucleotide on the complementary strand thereof is positioned between the primers;  
           [0017]    (2) a reagent for testing for psoriasis vulgaris including the primer DNA of (1);  
           [0018]    (3) a method of testing for psoriasis vulgaris, which detects a nucleotide polymorphism selected from the group of:  
           [0019]    (a) a polymorphism involving the 4040th nucleotide of SEQ ID NO: 1 or a corresponding nucleotide on a complementary strand thereof,  
           [0020]    (b) a polymorphism involving the 6413th nucleotide of SEQ ID NO: 2 or a corresponding nucleotide on a complementary strand thereof,  
           [0021]    (c) a polymorphism involving the 14378th nucleotide of SEQ ID NO: 2 or a corresponding nucleotide on a complementary strand thereof; and  
           [0022]    (d) a polymorphism involving the 6196th nucleotide of SEQ ID NO: 3 or a corresponding nucleotide on a complementary strand thereof,  
           [0023]    (4) the method of testing for psoriasis vulgaris according to (3), comprising the steps of:  
           [0024]    (a) preparing a DNA sample from a subject;  
           [0025]    (b) amplifying the DNA derived from the subject using the primer DNA of (1); and  
           [0026]    (c) determining the nucleotide sequence of the amplified DNA;  
           [0027]    (5) the method of testing for psoriasis vulgaris according to (3), comprising the steps of:  
           [0028]    (a) preparing a DNA sample from a subject;  
           [0029]    (b) amplifying the DNA derived from the subject using the DNA of (1) as a primer;  
           [0030]    (c) dissociating the amplified DNA into single strand DNA;  
           [0031]    (d) separating the dissociated single strand DNA on a nondenaturing gel; and  
           [0032]    (e) determining the polymorphism of the subject based on the mobility of the separated single strand DNA on the gel;  
           [0033]    (6) a DNA for testing for psoriasis vulgaris selected from the group of:  
           [0034]    (a) a part or a whole of a DNA consisting of the nucleotide sequence of SEQ ID NO: 1 or the sequence of SEQ ID NO: 1 wherein the 4040th nucleotide has been substituted with another nucleotide, wherein said DNA comprises the 4040th nucleotide of the nucleotide sequence of SEQ ID NO: 1;  
           [0035]    (b) a part or a whole of a DNA consisting of the nucleotide sequence of SEQ ID NO: 2 or the sequence of SEQ ID NO: 2wherein the 6413th nucleotide has been substituted with another nucleotide, wherein said DNA comprises the 6413th nucleotide of the nucleotide sequence of SEQ ID NO: 2;  
           [0036]    (c) a part or a whole of a DNA consisting of the nucleotide sequence of SEQ ID NO: 2 or the sequence of SEQ ID NO: 2 wherein the 14378th nucleotide has been substituted with another nucleotide, wherein said DNA comprises the 14378th nucleotide of the nucleotide sequence of SEQ ID NO: 2; and  
           [0037]    (d) a part or a whole of a DNA consisting of the nucleotide sequence of SEQ ID NO: 3 or the sequence of SEQ ID NO: 3 wherein the 6196th nucleotide has been substituted with another nucleotide, wherein said DNA comprises the 6196th nucleotide of the nucleotide sequence of SEQ ID NO: 3; and  
           [0038]    (7) an oligonucleotide that hybridizes to a region of the DNA according to (6), said region comprising a polymorphic site selected from the group of:  
           [0039]    (a) the 4040th nucleotide of the DNA consisting of the nucleotide sequence of SEQ ID NO: 1 or the sequence of SEQ ID NO: 1 wherein the 4040th nucleotide has been substituted with another nucleotide;  
           [0040]    (b) the 6413th nucleotide of the DNA consisting of the nucleotide sequence of SEQ ID NO: 2 or the sequence of SEQ ID NO: 2 wherein the 6413th nucleotide has been substituted with another nucleotide;  
           [0041]    (c) the 14378th nucleotide of the DNA consisting of the nucleotide sequence of SEQ ID NO: 2 or the sequence of SEQ ID NO: 2 wherein the 14378th nucleotide has been substituted with another nucleotide; and  
           [0042]    (d) the 6196th nucleotide of the DNA consisting of the nucleotide sequence of SEQ ID NO: 3 or the sequence of SEQ ID NO: 3 wherein the 6196th nucleotide has been substituted with another nucleotide.  
           [0043]    The present invention provides a method of testing for psoriasis vulgaris wherein the genetic polymorphisms are detected, and DNA molecules used for the test. The term “testing for psoriasis vulgaris” herein encompasses not only the testing of a subject expressing the symptom of psoriasis vulgaris, but also to testing whether an asymptomatic subject is susceptible to psoriasis vulgaris.  
           [0044]    Polymorphisms of the MHC S gene, SEEK1 gene, and HCR gene are detected in the test for psoriasis vulgaris of this invention. The polymorphism used as the target in the detection is not limited, so long as it is detected with significantly high frequency in psoriasis patients as compared to healthy individuals. For example, the 4040th nucleotide of the genomic DNA sequence of SEQ ID NO: 1 (i.e., the 1236th nucleotide of the cDNA in FIG. 2) is a preferable polymorphic site for the MHC S gene, the 6413th and 14378th nucleotide of the genomic DNA sequence of SEQ ID NO: 2 are the preferred polymorphic sites for the SEEK1 gene, and the 6196th nucleotide of the genomic DNA sequence of SEQ ID NO: 3 (i.e., the 769th nucleotide of the cDNA in FIG. 3) is the preferred polymorphic site for the HCR gene. The nucleotide and amino acid sequences of the MHC S cDNA are shown in FIG. 2, and those of the HCR cDNA are shown in FIG. 3.  
           [0045]    According to an embodiment of the test method of the present invention, the nucleotide sequence of the gene region containing these target sites of a subject are directly determined. More specifically, the method comprises the steps of: (a) preparing a DNA sample from a subject, (b) amplifying the DNA derived from the subject using the primer DNA, and (c) determining the nucleotide sequence of the amplified DNA.  
           [0046]    According to the method, first, a DNA sample is prepared from a subject. A genomic DNA sample can be prepared, for example, from peripheral blood leukocyte collected from a subject using a QIAmpDNA blood kit (QIAGEN). Next, primers are designed so that the target polymorphic sites are amplified, and polymerase chain reaction (PCR) is performed with these primers using the prepared DNA sample as a template. Then, the nucleotide sequence of the obtained PCR product is determined. One of the primer pair used for the above-mentioned PCR is preferably utilized as a sequencing primer in the nucleotide sequencing. As a result of nucleotide sequencing, when the type of the polymorphism detected for a subject corresponds with the type associated with psoriasis vulgaris, the subject is determined to be at a risk of psoriasis vulgaris.  
           [0047]    The primer DNAs that can be used in the test method for MHC S gene are not limited, so long as they hybridize to the DNA consisting of the nucleotide sequence of SEQ ID NO:1 or the complementary strand thereof, and wherein said primer pairs are designed so that the target nucleotide site of the DNA is positioned between these primers. The primer DNAs used in the test for SEEK1 gene are not limited, so long as they hybridize to the DNA consisting of the nucleotide sequence of SEQ ID NO: 2 or the complementary strand thereof and are designed so that the target nucleotide site of the DNA is positioned between primer pairs. The primer DNAs used in the test for HCR gene are not limited, so long as they hybridizes to the DNA consisting of the nucleotide sequence of SEQ ID NO: 3 or the complementary strand thereof, and are designed so that the target nucleotide site of the DNA is positioned between primer pairs. The primer DNAs used in the test of the present invention are generally 15-mer to 100-mer, preferably 15-mer to 40-mer, and more preferably 20-mer to 30-mer. The hybridization of these primer DNAs to the template DNA can be performed under appropriate condition, such as those described in Examples.  
           [0048]    The test method of the present invention may be conducted following various methods, apart from directly determining the nucleotide sequence of the DNA derived from the subject. For example, according to an embodiment of the invention, the method comprises the steps of: (a) preparing a DNA sample from a subject, (b) amplifying the DNA derived from the subject using above-mentioned primer pair DNAs of this invention, (c) dissociating the amplified DNA into single stranded DNAs, (d) separating the dissociated single stranded DNAs on a non-denaturing gel, and (e) comparing the mobility of the separated single stranded DNAs on the gel with those of healthy controls.  
           [0049]    The above method may, for example, utilize the PCR-SSCP (single-strand conformation polymorphism) method (“Cloning and polymerase chain reaction-single-strand conformation polymorphism analysis of anonymous Alu repeats on chromosome 11.” Genomics 12(1):139-146, 1992; “Detection of p53 gene mutations in human brain tumors by single-strand conformation polymorphism analysis of polymerase chain reaction products.” Oncogene 6(8):1313-1318, 1991; “Multiple fluorescence-based PCR-SSCP analysis with postlabeling.” PCR Methods Appl. 4(5):275-282, 1995). This method is particularly preferable for screening many DNA samples, since it has advantages such as: comparative simplicity of operation; small amount of required test sample; and so on. The principle of the method is as follows. A single stranded DNA dissociated from a double-stranded DNA fragment forms a unique higher conformation, depending on respective nucleotide sequence. After electrophoresis on a polyacrylamide gel without a denaturant, complementary single-stranded DNAs having the same chain length of the dissociated DNA strand shift to different positions in accordance with the difference of the respective higher conformations. The conformation of a single-stranded DNA changes even by a substitution of one base, which change results in a different mobility on polyacrylamide gel electrophoresis. Accordingly, the presence of a mutation in a DNA fragment due to even a single point mutation, deletion, insertion, and such can be detected by detecting the changes in the mobility.  
           [0050]    More specifically, a region containing a target site of the MHC S gene, SEEK1 gene, or MCR gene is first amplified by PCR or the like. Preferably, a length of about 100 to 600 bp is amplified. PCR can be performed, for example, under the conditions described in Example 1. The synthesized DNA fragments can be labeled by amplifying the fragments by PCR using primers which are labeled with isotopes, such as  32 P; fluorescent dyes; biotin; and so on, or by adding into the PCR solution substrate nucleotides which are labeled with isotopes, such as  32 P; fluorescent dyes; biotin; and so on. Alternatively, the labeling of the DNA fragments can be carried out by adding after PCR substrate nucleotides labeled with isotopes, such as  32 P; fluorescent dyes; biotin; and so on, to the synthesized DNA fragment using the Klenow enzyme and such. Then, the obtained labeled DNA fragments are denatured by heating and the like, to be subjected to electrophoresis on a polyacrylamide gel without a denaturant, such as urea. The condition for separating DNA fragments in the electrophoresis can be improved by adding appropriate amounts (about 5 to 10%) of glycerol to the polyacrylamide gel. Further, although the condition for electrophoresis varies depending on the character of respective DNA fragments, it is usually carried out at room temperature (20 to 25° C.). In the event a preferable separation is not achieved at this temperature, a temperature to achieve the optimum mobility may be selected from temperatures between 4 to 30° C. After the electrophoresis, the mobility of the DNA fragments is detected by autoradiography with X-ray films, scanner for detecting fluorescence, and the like, to analyze the result. When a band with different mobility is detected, the presence of a mutation can be confirmed by directly excising the band from the gel, amplifying it again by PCR, and directly sequencing the amplified fragment. Further, without using labeled DNAs, the bands can be also detected by staining the gel after electrophoresis with ethidium bromide, silver, and such.  
           [0051]    Another embodiment of the test method of this invention comprises the steps of; (a) preparing a DNA sample from a subject, (b) cleaving the DNA, (d) separating the DNA fragments depending on their length, (e) hybridizing the separated DNA fragment to a detectably labeled probe DNA of this invention, and (f) comparing the length of the detected DNA fragment with that of healthy controls. Moreover, after preparing the DNA sample of (a), a step may be included which consists of amplifying the DNA derived from the subject using the primer DNA of this invention.  
           [0052]    The above method may, for example, utilize the Restriction Fragment Length Polymorphism/RFLP, the PCR-RFLP method, and the like. Restriction enzymes are generally used as enzymes to cleave DNAs. Specifically, when a polymorphic site exists in the recognition site of a restriction enzyme, or when insertion(s) or deletion(s) of nucleotide(s) exists in a DNA fragment generated by a restriction enzyme treatment, the fragments generated after the restriction enzyme treatment differ in terms of size from those of healthy individuals. The portion containing the polymorphic site is amplified by PCR, and then, is treated with respective restriction enzymes to detect the polymorphic site as a difference in the mobility of bands by electrophoresis. Alternatively, a polymorphic site on the chromosomal DNA can be detected by treating the chromosomal DNA with these restriction enzymes, subjecting the fragments to electrophoresis, and then, carrying out Southern blotting with a probe DNA. The restriction enzymes to be used can be appropriately selected in accordance with respective polymorphic sites. The Southern blotting can be conducted not only on the genomic DNA but also on cDNAs directly digested with restriction enzymes, wherein the cDNAs are synthesized by a reverse transcriptase from RNAs prepared from subjects. Alternatively, after amplifying a part or whole of the MHC S gene by PCR using the cDNA as a template, the cDNAs can be digested with restriction enzymes, and the difference of mobility can be examined.  
           [0053]    Another embodiment of the test method of the present invention comprises the steps of: (a) preparing a DNA sample from a subject, (b) amplifying the DNA using a primer of this invention, (c) separating the amplified DNA on a gel comprising DNA denaturant with a gradually increasing concentration, and (d) comparing the mobility of the separated DNA on the gel with that of healthy controls.  
           [0054]    The denaturant gradient gel electrophoresis method (DGGE method) can be exemplified as one of such methods. A region containing a target site of the MHC S gene, SEEK1 gene, or HCR gene is amplified by PCR and the like with a primer of the present invention and such; electrophoresed on a polyacrylamide gel with gradient concentration of denaturant, such as urea; and the result is compared with that of a healthy individual. A polymorphism can be identified by detecting the difference in mobility of the DNA fragments, since the mobility speed of a fragment with mutations slows down to an extreme degree due to the separation into single-stranded DNAs at the part of the gel where the concentration of the denaturant is lower.  
           [0055]    In addition to the above-mentioned methods, the Allele Specific Oligonucleotide (ASO) hybridization method can be also used. An oligonucleotide having a nucleotide sequence, wherein a polymorphism is predicted to exist, is prepared, and is subjected to hybridization with a DNA sample. The efficiency of hybridization is reduced due to the existence of a polymorphic nucleotide that is different from the oligonucleotide in the sample DNA used for hybridization. The decrease of the hybridization efficiency can be detected by the Southern blotting method; methods which utilize specific fluorescent reagents that have a characteristic to quench by intercalation into the gap of the hybrid; and the like.  
           [0056]    Furthermore, the detection may be also conducted by the ribonuclease A mismatch truncation method. Specifically, a region containing a target site of the MHC S gene, SEEK1 gene, or HCR gene is amplified by PCR and the like, and the amplified products are hybridized with labeled RNAs, wherein the RNAs are prepared from a healthy-type cDNA and such to be incorporated into a plasmid vector and the like. A polymorphism can be detected by autoradiography and the like, after cleaving with ribonuclease A sites of the hybrid that form a single-stranded conformation due to the existence of a nucleotide which is different from the healthy-type.  
           [0057]    The present invention also provides DNAs including the polymorphisms of the MHC S gene, SEEK1 gene, and HCR gene, which are useful in the testing of psoriasis vulgaris.  
           [0058]    The DNAs of the invention include DNAs comprising a nucleotide sequence that includes the 4040th nucleotide of the MHC S gene (a DNA consisting of the nucleotide sequence of SEQ ID NO: 1 or the sequence of SEQ ID NO: 1 wherein the 4040th nucleotide has been substituted with another nucleotide); DNAs comprising a nucleotide sequence that includes the 6413th nucleotide of the SEEK1 gene (a DNA consisting of the nucleotide sequence of SEQ ID NO: 2 or the sequence of SEQ ID NO: 2 wherein the 6413th nucleotide has been substituted with another nucleotide); DNAs comprising a nucleotide sequence that includes the 14378th nucleotide of the SEEK1 gene (a DNA consisting of the nucleotide sequence of SEQ ID NO: 2 or the sequence of SEQ ID NO: 2 wherein the 14378th nucleotide has been substituted with another nucleotide), and DNAs comprising a nucleotide sequence that includes the 6196th nucleotide of HCR gene (a DNA consisting of the nucleotide sequence of SEQ ID NO: 3 or the sequence of SEQ ID NO: 3 wherein the 6196th nucleotide has been substituted with another nucleotide).  
           [0059]    Although the length of a DNA of the invention is not limited so long as it contains the above-mentioned polymorphic sites, it is preferably from 10 to 200 bp, more preferably from 15 to 100 bp, and still more preferably from 15 to 30 bp.  
           [0060]    A DNA of the present invention can be obtained by treating genomic DNA from a subject with a restriction enzyme or by conducting polymerase chain reaction with above-mentioned primer DNAs of the invention using the genomic DNA as a template. The DNA can be used as the sample for the detection of above-mentioned polymorphisms in the test for psoriasis vulgaris (the sample for genetic diagnosis). Furthermore, it can be used on a DNA chip (a basal plate bound with oligonucleotides) used in the test for psoriasis vulgaris.  
           [0061]    The present invention also provides oligonucleotides that hybridize to a region containing the polymorphic site of above-mentioned DNA of this invention. Such an oligonucleotide preferably hybridizes specifically to a region containing the polymorphic site of above-mentioned DNA of this invention. Herein, the term “specifically” means that the oligonucleotide hybridizes to a region containing the polymorphic site of above-mentioned DNA of this invention but does not hybridizes to other regions. Such hybridization conditions can be suitably selected by one skilled in the art, and include, for example, low-stringent conditions exemplified as follows. Low-stringent conditions in washing after hybridization include, for example, 42° C., 5× SSC, and 0.1% SDS, and preferably, 50° C., 2× SSC, and 0.1% SDS. High-stringent conditions are more preferable and include, for example, 65° C., 0.1× SSC, and 0.1% SDS. DNAs with high homologies are expected to be efficiently obtained by elevating the temperature and diminishing the salt concentration from the condition comprising, typically, low temperature and high salt concentration. However, several factors, such as temperature and salt concentration, can also influence the stringency of hybridization and one skilled in the art can suitably select the factors to accomplish a similar stringency. Although the length of the oligonucleotide of this invention is not limited, so long as it hybridizes to a DNA region containing above-mentioned polymorphic site, it is preferably from 10 to 200 nucleotides, more preferably from 15 to 100 nucleotides, and still more preferably from 15 to 30 nucleotides. Oligonucleotides of the present invention may be used for purifying the above-described DNA of the invention and for preparing DNA chips to be used to test for psoriasis vulgaris. 
       
    
    
     DESCRIPTION OF DRAWINGS  
       [0062]    [0062]FIG. 1 depicts a schematic illustration showing the novel four genes—HCR, SPR1, SEEK1, and STG genes—adjacent to MHC S gene in the HLA class I region. All of these genes are expressed in epidermal keratinocytes. “Cent” and “Tel” indicate centromere and telomere, respectively.  
         [0063]    [0063]FIG. 2 depicts the nucleotide sequence and amino acid sequence of the MHC S gene (comeodesmosomes). The boxes indicate 12 polymorphic sites. K, R, S, W, and Y in the sequence indicate the nucleotide polymorphisms represented in IUB code. Deletion is observed at underlined site “AAG” of +461 to 463. Underlined amino acid sequences in the region of 65 to 175 and 370 to 450 are expected to form glycine loops.  
         [0064]    [0064]FIG. 3 depicts the nucleotide sequence and amino acid sequence of the MRC gene. R, Y, W, K, and M in the sequence indicate the nucleotide polymorphisms represented in IUB code. The underlined sequence is expected to form a leucine zipper.  
     
    
     DETAILED DESCRIPTION  
       [0065]    The present invention will be described in detail below with reference to Examples, but is not be construed as being limited thereto.  
       EXAMPLE 1  
     Detection of Polymorphisms in the MHC S Gene of Japanese Psoriasis Patients  
       [0066]    To clarify the relationship between psoriasis in Japanese patients and the MHC S gene, the present inventors analyzed genomic sequences of the MHC S gene from eighty Japanese patients with psoriasis and 100 healthy individuals. Thirty-nine HLA homozygous B cell lines provided by the 10th International Histocompatibility Workshop; 10IHW) were used. Genomic DNAs were isolated from peripheral blood leukocytes and B cell lines using QIAmpDNA blood kit (QIAGEN).  
         [0067]    All of DNA samples were amplified across the seven target regions in the MHC S locus by PCRs using the following primer sets and amplification conditions (Table 1):  
                                     (i)   5′-GAAACACCCACGACTGCGA-3′   (SEQ ID NO:4)               and                   5′-AGGAGGAGACCAGCCAGCAG-3′   (SEQ ID NO:5)           (63° C., 512 bp);                (ii)   5′-TCCTCGAGCTGCCATCAGTC-3′   (SEQ ID NO:6)           and                   5′-GGCATGAGAGTCGCTTGAACC-3′   (SEQ ID NO:7)           (64° C., 650 bp);               (iii)   5′-CGAGAGGCCGATTACTGAGAT-3′   (SEQ ID NO:8)           and                   5′-GACTAGAGCCAGATCCGGAG-3′   (SEQ ID NO:9)           (60° C., 376 bp);                (iv)   5′-GGGTGGTTCTGCAGGATCTT-3′   (SEQ ID NO:10)           and                   5′-AGAGTGCGAGACGATGGG-3′   (SEQ ID NO:11)           (60° C., 412 bp);                 (v)   5′-CAGTGGCCAAAGCGTCAGC-3′   (SEQ ID NO:12)           and                   5′-AGCCGCCTCCACAGAGCT-3′   (SEQ ID NO:13)           (64° C., 533 bp);                (vi)   5′-AAATACTTCTCCAGCAACCCC-3′   (SEQ ID NO:14)           and                   5′-GGAAAACTTCAGGGTCAGCTAG-3′   (SEQ ID NO:15)           (60° C., 514 bp); and               (vii)   5′-AGATCCCCTGCCGCTCCA-3′   (SEQ ID NO:16)           and                   5′-ACTTCTTCAGGCGTCAGAGGTGC-3′   (SEQ ID NO:17)           (66° C., 504 bp).          
 
         [0068]    PCR was performed in 20 μl of reaction mixture containing 0.5 units of AmpliTaq R (PE Biosystems), 1× GeneAmp R  buffer (PE Biosystems), dNTP mix (40 μM each), primers (0.5 μM of each) and genomic DNA (20 μg). Following assembly, thermal cycling was performed with an initial denaturation at 94° C. for 1 min followed by 30 shuttle cycles of denaturation at 94° C. for 30 sec and primer annealing and extension at specified temperatures described above for 1 min. All reactions were performed in a 96-well plate on a GeneAmp R  PCR system 9700 (PE Biosystems).  
                                                                           TABLE 1                           Primer   Primer sequence   Annealing                    name   Forward (F)   Reverse (R)   temperature   Product                    S1_00   GAAACACCCACGACTGCGA   AGGAGGAGACCAGCCAGCAG   63   8E+05—8E+05               S1_01   TCCTCGAGCTGCCATCAGTC   GGCATGAGAGTCGCTTGAACC   64   8E+05—8E+05               S1_08a   CGAGAGGCCGATTACTGAGAT   GACTAGAGCCAGATCCGGAG   60   8E+05—8E+05               S2_01a   GGGTGGTTCTGCAGGATCTT   AGAGTGCGAGACGATGGG   60   8E+05—8E+05               S2_02a   CAGTGGCCAAAGCGTCAGA   AGCCGCCTCCACAGAGCT   64   8E+05—8E+05               S2_03   AAATACTTCTCCAGCAACCCC   GGAAAACTTCAGGGTCAGCTAG   60   8E+05—8E+05               S2_04   AGATCCCCTGCCGCTCCA   ACTTCTTCAGGCGTCAGAGGTGC   66   8E+05—8E+05                  
 
         [0069]    5 μl of the PCR product was incubated with 2.5 units of exonuclease I (EXO) and 0.5 units of shrimp alkaline phosphatase (SAP) (Amersham) at 37° C. for 15 min followed by 80° C. for 15 min to inactivate the EXO/SAP. Then, an aliquot containing about 10 11  copies of the PCR fragment was mixed in a solution of 20 μl containing 1 μl of BigDye Terminator R  ready reaction mix (PE Biosystems), 3.5 μl of 5× sequencing buffer (PE Biosystems), and 3.2 μM of unilateral primer of the primer set shown in Table 1. Excess dye-terminators were removed using gel. The filtrated sequencing products were automatically loaded onto an ABI PRISM R  3700DNA analyzer (PE Biosystems) and the sequence thereof was determined.  
         [0070]    By sequencing the entire genomic of the MHC S gene for Japanese psoriasis patients and healthy controls, 22 dimorphic sites in total, within two coding exons, were found as shown in Table 2. Twelve of the 22 sites were predicted to result in amino acid alteration, and three of these sites at cDNA positions +619, +1240, and +1243 were previously reported as polymorphisms. There was a-deletion site at nucleotide position +461 to 3 which corresponds to Ser at amino acid position 150, and it was found that the deletion does not alter any amino acids in the following region. Similar amino acid substitutions were found in two domains (the 65 to 175 and 370 to 450 amino acid regions) which form glycine loops that are predicted to be involved in putative adhesion properties of the comeodesmosin (Guerrin et al., J. Biol. Chem. 273:22640-22647, 1998; Steinert et al., Int. J. Biol. Macromol. 13:130-139, 1991).  
                                                           TABLE 2                           Genetic polymorphisms in the coding region of the MHC S gene            Nucleotide   DMA   Amino acid   Amino acid       position   polymorphism   position   substitution                     137 †   C   T   41   Pro   Pro        206 †   C   T   64   Gly   Gly        442   G   A   143   Ser   Asn        461-3   AAG   del AAG   150   Ser   del Ser        465   A   T   151   Ser   Cys        470   C   G   152   Ser   Arg        614 †   A   G   200   Gln   Gln        619 †   C   T   202   Ser   Phe        683   C   T   223   Pro   Pro        722   T   C   236   Ser   Ser        767 †   G   A   251   Arg   Arg        858   C   A   282   Pro   Thr        971 †   T   C   319   Tyr   Tyr       1118 †   G   A   368   Ala   Ala       1215   A   G   401   Ser   Gly       1236   G   T   408   Ala   Ser       1240 †   G   T   409   Gly   Val       1243 †   C   T   410   Ser   Leu       1331   G   C   439   Ser   Ser       1358   T   C   448   Cys   Cys       1372   G   A   453   Ser   Asn       1593   G   A   527   Asp   Asn                          
 
         [0071]    Next, association analyses were conducted for all polymorphic sites in the MHC S gene. Statistical analyses were performed based on the determined sequence information. Allele frequencies were determined by direct counting. The statistically significant differentiation of allele distribution between patients and healthy individuals was tested by the chi-square (χ 2 ) method and Fisher&#39;s exact probability test (P value test). The P value was corrected for multiple comparisons by Bonferroni correction (Pc; corrected probability). A level of Pc&lt;0.05 was accepted as statistically significant. Odds ratio of the risk to psoriasis vulgaris was calculated from the 2×2 contingency table. Odds ratio of homozygotes was calculated by comparing their risk with that for individuals having different alleles.  
         [0072]    As a result, none of the alleles at the twelve positions, including the +1243 position of cDNA, showed either a positive or negative association with the disease when evaluated by simple P value test. This result coincides with previous results of the present inventors. However, the frequency of homozygotes at one of these alleles, position +1236 (position 825706 in the genomic region of FIG. 1, and position 4040 in the genomic DNA of SEQ ID NO: 1), was significantly higher in psoriasis patients as compared with healthy individuals (Table 3). Specifically, the homozygous odds ratio (OR HOM ) of the allele (Ser) at +1236 was significantly higher compared to that of other alleles (OR HOM =5.14, P c =0.00034). Interestingly, there was no individual homozygous for another allele (Ala) at position +1236, within 80 psoriasis patients, as compared with 3 out of 100 healthy individuals (3%).  
                                                                                                         TABLE 3                           Association analyses of MHC S gene polymorphisms in Japanese psoriasis patients            Nucleotide   Allele   Allelic frequencies   Homozygous frequencies                position   (amino acid)   Patients   Healthy   Patients   Healthy   OR HOM * (95% Cl)   Pc                    442   G (Ser)   0.87   0.85   0.74   0.72   1.13 (0.68-2.20)   &gt;0.05           A (Asn)   0.13   0.15   0   0.03       461-3   AAG (Ser)   0.76   0.77   0.6   0.6           del AAG (del Ser)   0.24   0.23   0.09   0.07   1.31 (0.44-3.91)   &gt;0.05       465   A (Ser)   0.98   0.98   0.96   0.95   1.32 (0.31-5.68)   &gt;0.05           T (Cys)   0.02   0.02   0   0       470   C (Ser)   0.98   0.98   0.96   0.95           G (Arg)   0.02   0.02   0   0       619   C (Ser)   0.39   0.23   0.16   0.04   4.66 (1.46-14.9)   &gt;0.05           T (Phe)   0.61   0.77   0.38   0.59       858   C (Pro)   0.99   0.99   0.97   0.98           A (Thr)   0.01   0.01   0   0       1215   A (Ser)   0.97   1   0.94   1           G (Gly)   0.03   0   0   0       1236   G (Ala)   0.06   0.22   0   0.03           T (Ser)   0.94   0.78   0.89   0.59   5.14 (2.30-11.4)   3E−04       1240   G (Gly)   0.91   0.94   0.85   0.89           T (Val)   0.09   0.06   0.03   0.01   2.52 (0.22-28.3)   &gt;0.05       1243   C (Ser)   0.63   0.62   0.42   0.40   1.09 (0.59-1.98)   &gt;0.05           T (Leu)   0.37   0.38   0.15   0.15       1372   G (Ser)   0.85   0.88   0.76   0.98           A (Asn)   0.15   0.12   0.06   0.01   6.55 (0.75-57.3)   &gt;0.05       1539   G (Asp)   0.84   0.82   0.71   0.69   1.15 (0.60-2.21)   &gt;0.05           A (Asn)   0.16   0.18   0.04   0.03                                  
 
         [0073]    Next, 39 B cell lines derived from Caucasian populations which are homozygous for HLA were analyzed. Genome DNA was isolated from each of the cell lines using QIAGEN Genomic-tip system (QIAGEN). As a result, the same allele (Ser) at position +1236 was found (Table 4). Twelve cell lines had this allele concurrently with HLA-Cw6/7, and the linkage disequilibrium between this allele and HLA-Cw6/7 seemed to be stronger than that between any alleles at position +1246 and HLA-Cw6/7. Among these 12 cell lines, COX and VAVY cell lines, which carried an ancestral haplotype (AH8.1) associated with psoriasis (Jenisch et al., Tissue Antigens 53:135-146, 1999), had the same allele (Ser) at position +1236.  
                                                                                             TABLE 4                           +1236 and +1243 polymorphisms of the       MHC S gene in HLA homozygous B cell lines                HLA antigens   MHC S gene                B cell line   A   C   B   1236   1243   Ethnic origin                    9005 HOM2   3   1   27   G   C   Canadian       9092 BM92   25   1   51   G   C   Italian       9067 BTB   2   1   27   G   C   Scandinavian       9037 SWEIG007   29   2   61   T   C   North American                               Caucasoid       9025 DEU   31   4   35   T   C   Dutch       9068 BM9   2   4   35   T   T   Italian       9104 DHIF   31   5   38   T   C   English       9019 DUCAF   30   5   18   G   C   French       9036 SPO010   2   5   44   G   C   Italian       9039 JVM   2   5   18   G   C   Dutch       9020 QBL   26   5   18   G   C   Dutch       9047 PLH   3   6   47   T   C   Scandinavian       9048 LBUF   30   6   13   T   C   English                               Caucasoid       9052 DBB   2   6   57   T   C   Amish       9014 MGAR   26   7   8   T   T   North American                               Hispanic       9013 SCHU   3   7   7   T   T   French       9033 BM14   3   7   7   T   T   Italian       9022 COX †   1   7   8   T   T   South Aflican                               Caucasoid       9023 VAVY †   1   7   8   T   T   French       9040 BM15   1   7   49   T   C   Italian       9065 HHKB   3   7   7   T   T   Dutch       9034 SAVC   3   7   7   T   T   French       9082 HO104   3   7   7   T   T   French       9061 31227ABO   2   7   18   G   C   Italian       9029 WT51   23   8   65   T   T   Italian Aosta       9060 CB6B   1   9   62   T   T   Australian                               Caucasoid       9091 MLF   2   9   62   T   C   English       9032 BSM   2   9   62   T   C   Dutch       9069 MADURA   2   10   60   T   C   Danish       9059 SLE005   2   10   60   T   C   Nouth American                               Caucasoid       9050 MOU   29   —   44   T   C   Danish       9051 PITOUT   29   —   44   T   C   South Aflican                               Caucasoid       9057 TEM   26   —   38   G   C   Jewish       9062 WDV   2   —   38   G   C   Dutch       9003 KAS116   24   —   51   G   C   Yugoslavian       9070 LUY   2   —   51   T   T   Dutch       9011 E4181324   1   —   52   T   T   Australian                               Caucasoid       9026 YAR   26   —   38   G   C   Ashkenasi                               Jewish       9106 MANIKA   3   —   50   T   C   South Aflican                               Caucasoid                          
 
       EXAMPLE 2  
     Detection of Polymorphism in SEEK1 Gene of Japanese Psoriasis Patients  
       [0074]    The present inventors newly analyzed genomic sequences of the SEEK1 gene of 80 Japanese psoriasis patients and 100 healthy individuals to identify the relationship between the SEEK1 gene and Japanese psoriasis. Genomic DNA was isolated from the peripheral blood leukocyte using QIAmpDNA blood kit (QIAGEN).  
         [0075]    All of the DNA samples were amplified across the five target regions in the SEEK1 locus by PCRs using the following primer sets and amplification conditions (Table 5):  
                                 (i)               5′-TGGAGGAGTGTAACGAAGGTTTCTG-3′   (SEQ lID NO:18)       and               5′-TCTGGCAGCCACCCAGGA-3′   (SEQ ID NO:19)       (65°C., 470 bp);                (ii)       5′-GCAGGACTGATGCAAACA-3′   (SEQ ID NO:20)       and               5′-CTCCCTATCATGACCCAGAG-3′   (SEQ ID NO:21)       (55° C., 529 bp);               (iii)       5′-GAAATGGCTTTCTGGACACATTGG-3′   (SEQ ID NO:22)       and               5′-CTCGGTCCTCTGCGGGTG-3′   (SEQ ID NO:23)       (65° C., 586 bp);                (iv)       5′-CTACATGTGGTCCGAATG-3′   (SEQ ID NO:24)       and               5′-ACGAGAGCTCATCACCTG-3′   (SEQ ID NO:25)       (52° C., 529 bp); and                 (v)       5′-CAAGGCCATCAGTGAATCCCT-3′   (SEQ ID NO:26)       and               5′-TGTGCTTCCCCTTTCTACCTTA-3′   (SEQ ID NO:27)       (63° C., 143 bp).          
 
         [0076]    PCR was performed in 20 μl of reaction mixture containing 0.5 units of AmpliTaq R  (PE Biosystems), 1× GeneAmp R  buffer (PE Biosystems), dNTP mix (40 μM each), primers (0.5 μM of each), and genomic DNA (20 μg). Following assembly, thermal cycling was performed with an initial denaturation at 94° C. for 1 min followed by 30 shuttle cycles of denaturation at 94° C. for 30 sec and primer annealing and extension for 1 min at specified temperatures described above. All reactions were performed in a 96-well plate on a GeneAmp R  PCR system 9700 (PE Biosystems).  
                                                                               TABLE 5                           Primer   Primer sequence   Annealing                    name   Forward (F)   Reverse (R)   temperature   Product                    1_05   TGGAGGAGTGTAACGAAGGTTTCTG   TCTGGCAGCCACCCAGGA   65   801924-802393                   1_06   GCAGGACTGATCGAAACA   CTCCCTATCATGACCCAGAG   55   802299-802827               1_08   GAAATGGCTTTCTGGACACATTGG   CTCGGTCCTCTGCGGGTG   65   803235-803820               3_17   CTACATGTGGTCCGAATG   ACGAGAGCTCATCACCTG   52   808104-808632               5_2a   CAAGGCCATCAGTGAATCCCT   TGTGCTTCCCCTTTCTACCTTA   63   816031-816173                  
 
         [0077]    5 μl of the PCR product was incubated with 2.5 units of exonuclease I (EXO) and 0.5 units of shrimp alkaline phospatase (SAP)(Amersham) at 37° C. for 15 min followed by 80° C. for 15 min to inactivate the EXO/SAP. Then, an aliquot containing about 10 11  copies of the PCR fragment was mixed in a solution of 20 μl containing 1 μl of BigDye Terminator R  ready reaction mix (PE Biosystems), 3.5 μl of 5× sequencing buffer (PE Biosystems), and 3.2 μM of unilateral primer of the primer set shown in Table 5. Excess dye-terminators were removed by gel. The filtrated sequencing products were automatically loaded onto an ABI PRISM R  3700DNA analyzer (PE Biosystems) and the sequence was determined.  
                                                                 TABLE 6                                   SEEK1   Nucleotide   Sequencing   DNA               exon   position   primer   polymorphism                                        8   802129   1_05R   G   del G               802205   1_06R   G   A           7   803337   1_08F   G   A               803352   1_08F   G   ins G               803364   1_08R   T   C               803394   1_08R   G   T           6a   803617   1_08R   C   T               803676   1_08R   G   A           6b   803617   1_08R   C   T           4   808327   3_17F   A   G               808422   3_17F   C   A               808428   3_17F   T   C               808452   3_17F   C   T               808453   3_17F   G   A               808524   3_17F   C   T           2a   816288   5_2aF   C   T               816370   5_2aF   C   T               816390   5_2aF   C   T               816393   5_2aF   T   C           2b   816288   5_2aF   C   T                      
 
         [0078]    By the entire genomic sequencing of the SEEK1 gene of Japanese psoriasis patients and healthy controls, 20 dimorphic sites in total within a single exon were found as shown in Table 6.  
         [0079]    Next, association analyses were conducted for all polymorphic sites in the SEEK1 gene. Statistical analyses were performed based on the determined sequence information. Allele frequencies were determined by direct counting. The statistically significant differentiation of allele distribution between patients and healthy individuals was tested by the chi-square (χ2) method and Fisher&#39;s exact probability test (P value test). The P value was corrected for multiple comparisons by Bonferroni correction (Pc; corrected probability). A level of Pc&lt;0.05 was accepted as statistically significant. Odds ratio of the risk to psoriasis vulgaris was calculated from the 2×2 contingency table. Odds ratio of homozygotes was calculated by comparing their risk with that for individuals having different alleles. SNP polymorphisms displaying statistically significant differentiation are represented by “*”.  
         [0080]    As a result, the frequency of homozygotes for alleles at position 808428 and 816393 in the genomic DNA region of FIG. 1 (position 6413 and 14378 in the genomic DNA sequence of SEQ ID NO: 2) was significantly increased in psoriasis patients as compared with healthy individuals (Table 7).  
                                                                       TABLE 7                           Association analyses of SEEK1 gene polymorphisms in Japanese            Nucleotide       Allelic frequencies   Homozygous frequencies                position   Allele   Patients   Healthy   Patients   Healthy   OR HOM * (95% Cl)   Pc               802129   G   0.84   0.87   0.76   0.76   1.04 (0.52-2.08)   &gt;0.05           del G   0.16   0.13   0.08   0.01   7.87 (0.93-66.8)   &gt;0.05       802205   G   0.83   0.87   0.75   0.76           A   0.18   0.13   0.10   0.01   10.78 (1.32-88.1)    &gt;0.05       803337   G   0.90   0.83   0.81   0.67   2.13 (1.06-4.30)   &gt;0.05           A   0.10   0.18   0.01   0.02       803352   —   0.78   0.84   0.65   0.70           ins G   0.23   0.16   0.10   0.02   5.39 (1.11-26.1)   &gt;0.05       803364   T   0.00   0.00   0.00   0.00           C   1.00   1.00   1.00   1.00       803394   G   0.94   0.96   0.88   0.93           T   0.06   0.04   0.00   0.00       803617   C   0.92   0.82   0.85   0.68   2.63 (1.25-5.54)   &gt;0.05           T   0.08   0.18   0.00   0.03       803676   G   0.08   0.12   0.00   0.01           A   0.92   0.88   0.84   0.78   1.47 (0.69-3.15)   &gt;0.05       808327   A   0.91   0.88   0.84   0.76   1.63 (0.77-3.45)   &gt;0.05           G   0.09   0.12   0.01   0.00       808422   C   0.91   0.90   0.85   0.80   1.42 (0.65-3.12)   &gt;0.05           A   0.09   0.11   0.03   0.01   2.54 (0.23-28.5)   &gt;0.05       808428   T   0.56   0.37   0.31   0.12   3.33 (1.55-7.17)        0.04 *           C   0.44   0.63   0.20   0.38       808452   C   0.91   0.88   0.84   0.75   1.72 (0.81-3.63)   &gt;0.05           T   0.09   0.13   0.01   0.00       808453   G   0.84   0.89   0.74   0.79           A   0.16   0.12   0.05   0.02   2.58 (0.46-14.5)   &gt;0.05       808524   C   0.91   0.88   0.84   0.75   1.72 (0.81-3.63)   &gt;0.05           T   0.09   0.13   0.01   0.00       816288   C   0.76   0.76   0.59   0.56   1.13 (0.62-2.06)   &gt;0.05           T   0.24   0.24   0.08   0.04   1.89 (0.51-6.93)   &gt;0.05       816370   C   0.99   0.97   0.98   0.95   2.10 (0.40-11.1)   &gt;0.05           T   0.01   0.03   0.00   0.01       816390   C   0.84   0.74   0.69   0.55   1.80 (0.97-3.33)   &gt;0.05           T   0.16   0.26   0.01   0.07       816393   T   0.66   0.48   0.44   0.17   3.84 (1.92-7.70)       0.003 *           C   0.34   0.52   0.13   0.20                                  
 
       EXAMPLE 3  
     Detection of Polymorphism in HCR Gene of Japanese Psoriasis Patients  
       [0081]    The present inventors newly analyzed the genomic sequences of the HCR gene of 80 Japanese psoriasis patients and 100 healthy individuals to identify the relationship between the HCR gene and Japanese psoriasis. Genomic DNA was isolated from peripheral blood leukocyte using QIAmpDNA blood kit (QIAGEN).  
         [0082]    All of DNA samples were amplified across the 16 target regions in the HCR locus by PCRs using the following primer sets and amplification conditions (Table 8):  
                                      (i)   5′-CCTCCCACTTTCAAGCTCG-3′   (SEQ ID NO:28)               and                   5′-GAGGAAGGGTCACTAGCAAGC-3′   (SEQ ID NO:29)           (65° C., 247 bp);                 (ii)   5′-CCCTCAACTATCCTTCCAGCA-3′   (SEQ ID NO:30)           and                   5′-TTGGAAGCTACTGCCCAGC-3′   (SEQ ID NO:31)           (60° C., 425 bp);                (iii)   5′-CAGAAAGTGGGAGTGAAGGGA-3′   (SEQ ID NO:32)           and                   5′-ATGGGACAGCCATCAGTGG-3′   (SEQ ID NO:33)           (65° C., 324 bp);                 (iv)   5′-CCAGCAATTAGTGATGTGGTGG-3′   (SEQ ID NO:34)           and                   5′-TCTACACGCTCCTCCAAGGG-3′   (SEQ ID NO:35)           (66° C., 289 bp);                  (v)   5′-CGGGAGAGAAGGTGGTACCTAA-3′   (SEQ ID NO:36)           and                   5′-AACATGAGCTACAGCAAGAGGAGTT-3′   (SEQ ID NO:37)           (62° C., 327 bp);                 (vi)   5′-GAGGAGAAACAAAGATGCCACC-3′   (SEQ ID NO:38)           and                   5′-GATGCCACCTTCATGGAAGG-3′   (SEQ ID NO:39)           (65° C., 294 bp);                (vii)   5′-ACCTGCCACTTTGCTTCCAG-3′   (SEQ ID NO:40)           and                   5′-ATGCAGCAAAGGACAGGGTC-3′   (SEQ ID NO:41)           (65° C., 285 bp);               (viii)   5′-GCTGCAGCCAGGACTTAGG-3′   (SEQ ID NO:42)           and                   5′-AACAAGGTGCCCAGGAACC-3′   (SEQ ID NO:43)           (62° C., 224 bp);                 (ix)   5′-ATGGGACAGGATTAGAGGGAGTT-3′   (SEQ ID NO:44)           and                   5′-GGATGTGGGATCAGAGAGAGCT-3′   (SEQ ID NO:45)           (62° C., 351 bp);                  (x)   5′-CCTTACTCCCTGTCCCCACTT-3′   (SEQ ID NO:46)           and                   5′-CCTCAGTCCTCATGGTTTTGG-3′   (SEQ ID NO:47)           (62° C., 194 bp);                 (xi)   5′-CCCAAAACCATGAGGACTGA-3′   (SEQ ID NO:48)           and                   5′-CTCTCCACCCTCTGGCAAC-3′   (SEQ ID NO:49)           (56° C., 254 bp);                (xii)   5′-AGAGGATGAGGAAAAACCCAGTG-3′   (SEQ ID NO:50)           and                   5′-GGCATATCAGCAGGAGCTTTG-3′   (SEQ ID NO:51)           (63° C., 332 bp);               (xiii)   5′-GGGTGGGAACTGCGAATC-3′   (SEQ ID NO:52)           and                   5′-TGAAGCTTTGAACACACTTTGAG-3′   (SEQ ID NO:53)           (56° C., 256 bp);                (xiv)   5′-TGTTCCTGTCTTCATGGTGCC-3′   (SEQ ID NO:54)           and                   5′-TCTTTCCACACCTCTAGCCCAG-3′   (SEQ ID NO:55)           (61° C., 305 bp);                 (xv)   5′-TGGGCTAGAGGTGTGGAAAGA-3′   (SEQ ID NO:56)           and                   5′-TCATCATGCCAGAGTCTGAAGAG-3′   (SEQ ID NO:57)           (60° .C, 322 bp); and                (xvi)   5′-CCAGCCCTGTTTCCTCTGT-3′   (SEQ ID NO:58)           and                   5′-GTCTGTCCCCACCCACTTC-3′   (SEQ ID NO:59)           (61° C., 266 bp).          
 
         [0083]    [0083]                                                                               TABLE 8                           Primer   Primer sequence   Annealing                    name   Forward primer   Reverse primer   temperature   Product                    HCR_01F,R   CCTCCCACTTTCAAGCTCG   GAGGAAGGGTCACTAGCAAGC   65   765142-785388                   HCR_02F,R   CCCTCAACTATCCTTCCAGCA   TTGGAAGCTACTGCCCAGC   60   787221-787644               HCR_03F,R   CAGAAAGTGGGAGTGAAGGGA   ATGGGACAGCCATCAGTGG   65   790889-791212               HCR_04F,R   CCAGCAATTAGTGATGTGGTGG   TCTACACGCTCCTCCAAGG   66   791158-791446               HCR_05F,R   CGGGAGAGAAGGTGGTACCTAA   AACATGAGCTACAGCAAGAGGAGTT   62   791457-791783               HCR_06F,R   GAGGAGAAACAAAGATGCCACC   GATGCCACCTTCATGGAAGG   65   791798-792091               HCR_07F,R   ACCTGCCACTTTGCTTCCAG   ATGCAGCAAAGGACAGGGTC   65   793286-793570               HCR_08F,R   GCTGCAGCCAGGACTTAGG   AACAAGGTGCCCAGGAACC   62   793528-793751               HCR_09F,R   ATGGGACAGGATTAGAGGGAGTT   GGATGTGGGATCAGAGAGCT   62   796178-796478               HCR_10F,R   CCTTACTCCCTGTCCCCACTT   CCTCAGTCCTCATGGTTTTGG   62   796520-796713               HCR_11F,R   CCCAAAACCATGAGGACTGA   CTCTCCACCCTCTGGCAAC   56   796692-796945               HCR_12F,R   AGAGGATGAGGAAAAACCCAGTG   GGCATATCAGCAGGAGGAGCTTTG   63   796942-797273               HCR_13F,R   GGGTGGGAACTGCGAATC   TGAAGCTTTGAACACACTTTGAG   56   797236-797491               HCR_14F,R   TGTTCCTGTCTTCATGGTGCC   TCTTTCCACACCTCTAGCCCAG   61   798593-798897               HCR_15F,R   TGGGCTAGAGGTGTGGAAAGA   TCATCATGCCAGAGTCTGAAGAG   60   798877-799198               HCR_16F,R   CCAGCCCTGTTTCCTCTGT   GTCTGTCCCCACCCACTTC   61   799296-799561                    
         [0084]    PCR was performed in 20 μl of reaction mixture containing 0.5 units of AmpliTaq R  (PE Biosystems), 1× GeneAmp R  buffer (PE Biosystems), dNTP mix (40 μM each), primers (0.5 μM of each), and genomic DNA (20 μg). Following assembly, thermal cycling was performed with an initial denaturation at 94° C. for 1 min followed by 30 shuttle cycles of denaturation at 94° C. for 30 sec and primer annealing and extension for 1 min at specified temperatures described above. All reactions were performed in a 96-well plate on a GeneAmp R  PCR system 9700 (PE Biosystems).  
         [0085]    5 μl of the PCR product was incubated with 2.5 units of exonuclease I (EXO) and 0.5 units of shrimp alkaline phosphatase (SAP) (Amersham) at 37° C. for 15 min followed by 80° C. for 15 min to inactivate the EXO/SAP. Then, an aliquot containing about 10 11  copies of the PCR fragment was mixed in a solution of 20 μl containing 1 μl of BigDye Terminator R  ready reaction mix (PE Biosystems), 3.5 μl of 5× sequencing buffer (PE Biosystems), and 3.2 μM of unilateral primer of the primer set shown in Table 8. Excess dye-terminators were removed by gel. The filtrated sequencing products were automatically loaded onto an ABI PRISM R  3700DNA analyzer (PE Biosystems) and the sequence was determined.  
         [0086]    By the entire genomic sequencing of the HCR gene of Japanese psoriasis patients and healthy controls, 12 dimorphic sites in total within exons were found as shown in Table 9. Eleven of the 12 sites were predicted to result in amino acid alteration.  
                                                                   TABLE 9                           Genetic polymorphisms in the coding region of the HCR gene            Nucleotide       DMA   Amino acid   Amino acid           position       polymorphism   position   substitution                    249   G   A   76   Arg   Gln       436   G   C   138   Arg   Ser       715   C   G   231   Val   Val       769   A   C   249   Glu   Asp       1193   T   C   391   Try   Arg       1229   T   C   403   Leu   Leu       1824   G   A   601   Arg   Gln       1855   G   A   611   Leu   Ile       1861   G   T   613   Gln   Tyr       1887   A   T   622   Lys   Met       1910   C   T   630   Arg   Cys       2271   G   C   750   Cys   Ser                  
 
         [0087]    Next, association analyses were conducted for all polymorphic sites in the HCR gene. Statistical analyses were performed based on the determined sequence information. Allele frequencies were determined by-direct counting. The statistically significant differentiation of allele distribution between patients and healthy individuals was tested by the chi-square (χ 2 ) method and Fisher&#39;s exact probability test (P value test). The P value was corrected for multiple comparisons by Bonferroni correction (Pc; corrected probability). A level of Pc&lt;0.05 was accepted as statistically significant. Odds ratio of the risk to psoriasis vulgaris was calculated from the 2×2 contingency table. Odds ratio of homozygotes was calculated by comparing their risk with that of individuals having different alleles. SNP polymorphisms displaying statistically significant differentiation are represented by “*”.  
         [0088]    As a result, the frequency of homozygotes at position 769 of the cDNA (position 791356 of the genomic region of FIG. 1, position 6196 of the nucleotide sequence of SEQ ID NO: 3) was demonstrated to be significantly increased in patients compared with healthy individuals (Table 10).  
                                                                                                         TABLE 10                           Genetic polymorphisms in the coding region of the HCR gene            Nucleotide   Allele   Allelic frequencies   Homozygous frequencies                position   (amino add)   Patients   Healthy   Patients   Healthy   OR HOM * (95% Cl)   Pc                    249   G (Arg)   0.82   0.88   0.72   0.75                   A (Gln)   0.18   0.13   0.08   0.00       436   G (Arg)   0.45   0.32   0.19   0.07   3.27 (0.88-12.1)   &gt;0.05           C (Ser)   0.55   0.68   0.28   0.42       769   A (Glu)   0.50   0.66   0.40   0.43           C (Asp)   0.50   0.34   0.40   0.10   5.80 (2.77-12.1)   0.000023       1193   T (Try)   0.23   0.34   0.04   0.09           C (Arg)   0.77   0.66   0.58   0.42   1.98 (1.01-3.87)   &gt;0.05       1824   G (Arg)   0.93   0.99   0.85   0.98           A (Gln)   0.07   0.01   0.00   0.00       1855   G (Leu)   0.77   0.62   0.61   0.40   2.36 (1.27-4.37)   &gt;0.05           A (Ile)   0.23   0.38   0.07   0.16       1861   G (Gln)   0.90   0.82   0.80   0.67   1.97 (0.97-3.99)   &gt;0.05           T (Tyr)   0.10   0.18   0.00   0.02       1887   A (Lys)   0.93   0.87   0.87   0.80   1.67 (0.73-3.81)   &gt;0.05           T (Met)   0.07   0.13   0.00   0.05       1910   C (Arg)   0.92   0.89   0.87   0.77   1.91 (0.84-4.32)   &gt;0.05           T (Cys)   0.08   0.11   0.03   0.00       2271   G (Cys)   0.05   0.02   0.00   0.00           C (Ser)   0.95   0.98   0.91   0.95                                  
 
       INDUSTRIAL APPLICABILITY  
       [0089]    The present invention provides genetic polymorphisms that exist in significantly high frequency in psoriasis vulgaris patients as compared with healthy individuals. Moreover, the present invention provides a test method for psoriasis vulgaris utilizing such genetic polymorphisms, and DNA molecules to be used for the test. The present invention enables one to readily test for psoriasis vulgaris.  
     
       
       
         1 
         
           
             63  
           
           
             1  
             5337  
             DNA  
             Homo sapiens  
             
               exon  
               (1)...(99)  
             
             
               exon  
               (2904)...(5337)  
             
           
            1 

ccgtgcagcc cgagatgggc tcgtctcggg caccctggat ggggcgtgtg ggtgggcacg     60 

ggatgatggc actgctgctg gctggtctcc tcctgccagg taggaggctg ggggccctgg    120 

gaacaggagg gaggcgggag ggagactccg ggagaggacc cagcgaaggg gacgggcagg    180 

ggctctggaa tctgcctttt gagtctgggg gttgctcctc actgtatggt cgcctcaggt    240 

aagtttctta aacttcctga gccccagttt ctgaaattct gaagtggggt taatgacacc    300 

tacctctagt ctgtgtgtct caaattaaat aatgtatgtg atatgtactt tggaaattct    360 

agaggtttat ataaatggtg gtggtgattt ttattatggg agcactacaa gataatgatt    420 

ggacatttaa tagtaataat atcattttta gagccttttt atatgctaga ctctgtttta    480 

agcacatttg gattatatat tagaactttt atttttattt tttttgtgag atggagtccc    540 

actctgtctc caaggctgga gtgcagtggc gtaatctcgg ctcactgcaa cttccacctc    600 

tcaggttcaa gcgactctca tgcctcagcc tctagagtag ctgggacaac aggtgcccat    660 

caccacacct ggctaatttt cttttttttg tatttttagt agaaacaggg ttttaccatt    720 

ttggtcaagc tggtcttgaa ctcctgactc aagtgatccg ctcgcctcgg cctcccaagg    780 

tgctgggatt acaggcatga gccaccacac ccggcctata ttagcacttt tgatcattac    840 

aagaacggta tgaaaagaga tttgctattt ccactctaca gatgaggaca ctgaggctcg    900 

gagaggttag gaaactagct caaaatcatg cattagaagg cagcaaagcc aagatttcaa    960 

ccccaggcca ggcaacccct ggacctgtgt tgttgaccac cgggtactta tagcccttga   1020 

ggaatttctg cgaccttccc atggtctagt gggtggttgg tgtctgaggg aatagcgaaa   1080 

gagagaggca atgcatggtg gattcgtgca gaggactgaa gggaattggc acagctgggg   1140 

ttcggcgtgg aggtgcatgc agagaatttc tttctgagga gagaacaggg acatcacaga   1200 

ggatggcagt ctggttgttg gtggagggat caggatgagt ggcagtaata attcataata   1260 

tataatgctt tacactttct aaaacatctg gccgcacatg atagcttgtg cctgtaatcc   1320 

caacacttca ggaggccaag gcaggtgaat cgcctgaggt caggagttca agaccagcct   1380 

ggccaagatg gtgaaacccc ctctctacta aaaatacaaa aaattagctg ggtgtggtgg   1440 

cgggcacctg tggtcccagc tacttgggag gctgaggcag gagaatcgct tgcaccaagg   1500 

aggcagaggt tacagtgagc tgagaccgtg ttattgcact ttagcctggg caacaagaaa   1560 

ctccatctca caaaaaaaaa aaaaaaaaaa aaaaagaaga aaaaacttcc aggtggatga   1620 

tctcatttag ttttcttcat agtaatgctg tgggaaggca gggaaaattt ggcccctctg   1680 

aatgtataaa ctaaagctca gagaggttca gtaacttgct agtatgtggc tctgtttgta   1740 

acacgtggga cctggagggg ctagggaagg cagaaggaac gcaggtgaaa gagtcatgga   1800 

ggaaccatgg ggtaagttgg gcctggggtt ttgagcaaag gaaaggaaag ataaggaaag   1860 

atgtggctcc acatccctga gggaagtcaa ggcagcagaa gtcagatgag gggctggaca   1920 

gaggcaggtg tgctcagaga gggaagctga ttgtggccag gagcctcgga ggttcgtggg   1980 

gtttcgtcct ggttccctgg gctgggccag cgagagcagg gctggctcag ggtgcggtgt   2040 

cctgacacac tggtaccagc aggttctgaa gcaacaggta gtgaccccac atcctggccc   2100 

ccacccagct ttactggcat ggccagtgct gagataggaa atagggtttc cattcctgac   2160 

cccagcctgg gctctcacga agaagctggt gaccaaatct tagtcctcga gtgccctttc   2220 

ctttatttca gcccctctgc ccccagcttt gtctttttcc agtgtctcct tctatatgtg   2280 

tctccacttc tcagccctcc attgttttgc cttttgtctt cttccctctg gtcccactgt   2340 

ctggcccagg atttttcccc taagaattta cgcctggact cctcagagcc tcagtttccc   2400 

caattctctg tctcttcagg gtcctttctt ttagacctat ttgttcctgc cccttctcca   2460 

ttccctcttc tttttaaaaa aaattttaat taaaaaacaa aatacagatg gggtctatgt   2520 

tgcccaggct ggtcttgaac tctggggcgc atgcaatcct cccacctcag cctcccaaag   2580 

tgctgggatt accggcgtga gccactgtgc ccagccccct cttatattca atgtattcct   2640 

ttgaggtcac tcactttggc acgtaatttt ctatttttct ggttggtgtt tgcccaccct   2700 

tcccaaacaa agaaatgcct ttattcggcc acctcaatat cctttagaga caatagccag   2760 

ttcttcctcc tttctccatc cctaaactct ccctgcgctc tgcttgggag aaacccgaga   2820 

ggccgattac tgagataagg cagaaaggtg agggaggaag ccaagcctct ttggccctta   2880 

ctaaccactg ctttcctcca cagggacctt ggctaagagc attggcacct tctcagaccc   2940 

ctgtaaggac cccacgcgta tcacctcccc taacgacccc tgcctcactg ggaagggtga   3000 

ctccagcggc ttcagtagct acagtggctc cagcagttct ggcagctcca tttccagtgc   3060 

cagaagctct ggtggtggct ccagtggtag ctccagcgga tccagcattg cccagggtgg   3120 

ttctgcagga tcttttaagc caggaacggg gtattcccag gtcagctact cctccggatc   3180 

tggctctagt ctacaaggtg catccggttc ctcccagctg gggagcagca gctctcactc   3240 

gggaagcagc ggctctcact cgggaagcag cagctctcat tcgagcagca gcagcagctt   3300 

tcagttcagc agcagcagct tccaagtagg gaatggctct gctctgccaa ccaatgacaa   3360 

ctcttaccgc ggaatactaa acccttccca gcctggacaa agctcttcct cttcccaaac   3420 

ctctggggta tccagcagtg gccaaagcgt cagctccaac cagcgtccct gtagttcgga   3480 

catccccgac tctccctgca gtggagggcc catcgtctcg cactctggcc cctacatccc   3540 

cagctcccac tctgtgtcag ggggtcagag gcctgtggtg gtggtggtgg accagcacgg   3600 

ttctggtgcc cctggagtgg ttcaaggtcc cccctgtagc aatggtggcc ttccaggcaa   3660 

gccctgtccc ccaatcacct ctgtagacaa atcctatggt ggctacgagg tggtgggtgg   3720 

ctcctctgac agttatctgg ttccaggcat gacctacagt aagggtaaaa tctatcctgt   3780 

gggctacttc accaaagaga accctgtgaa aggctctcca ggggtccctt cctttgcagc   3840 

tgggcccccc atctctgagg gcaaatactt ctccagcaac cccatcatcc ccagccagtc   3900 

ggcagcttcc tcggccattg cgttccagcc agtggggact ggtggggtcc agctctgtgg   3960 

aggcggctcc acgggctcca agggaccctg ctctccctcc agttctcgag tccccagcag   4020 

ttctagcatt tccagcagct ccggttcacc ctaccatccc tgcggcagtg cttcccagag   4080 

cccctgctcc ccaccaggca ccggctcctt cagcagcagc tccagttccc aatcgagtgg   4140 

caaaatcatc cttcagcctt gtggcagcaa gtccagctct tctggtcacc cttgcatgtc   4200 

tgtctcctcc ttgacactga ctgggggccc cgatggctct ccccatcctg atccctccgc   4260 

tggtgccaag ccctgtggct ccagcagtgc tggaaagatc ccctgccgct ccatccggga   4320 

tatcctagcc caagtgaagc ctctggggcc ccagctagct gaccctgaag ttttcctacc   4380 

ccaaggagag ttactcgaca gtccataagt caactgttgt gtgtgtgcat gccttgggca   4440 

caaacaagca catacactat atcccatatg ggagaaggcc agtgcccagg catagggtta   4500 

gctcagtttc cctccttccc aaaagagtgg ttctgctttc tctactaccc taaggttgca   4560 

gactctctct tatcacccct tcctccttcc tcttctcaaa atggtagatt caaagctcct   4620 

ctcttgattc tctcctactg tttaaattcc cattccacca cagtgcccct cagccagatc   4680 

accacccctt acaattccct ctactgtgtt gaaatggtcc attgagtaac acccccatca   4740 

ccttctcaac tgggaaaccc ctgaaatgct ctcagagcac ctctgacgcc tgaagaagtt   4800 

ataccttcct cttccccttt accaaataaa gcaaagtcaa accatcatct ggaaacagtg   4860 

gccacttttc actgacctct cttcgacatc tagtcaaccc acccaatatg ccactgggct   4920 

ttcgctccca attccacccc accctccatt acagagctca ccacgccctc ctagatcacc   4980 

gtccccaaca cacccattgc ctctcaaggc ccttatctca gccccttcct gtggccattt   5040 

ccctcagtgc ccagatgatt ccctgggtga gggagacact ggggcaccct cagaggttgg   5100 

agcaggctcc ctgctgtccc tggatcctgg acagatggct cagtaaactg tggggactag   5160 

gtgcagactt tttgccttct tggagtcctg ggtctcctct gagagtctgg gtggtgctct   5220 

tcctacgcct ctagaggtct ctgtgtccct cattttcctt caaaagcggg ctgtgtttct   5280 

cttctacctt ccagctcctc ccacagagga ggaagacaat aaatatttgt tgaactg      5337 

 
           
             2  
             25235  
             DNA  
             Homo sapiens  
             
               exon  
               (1)...(420)  
             
             
               exon  
               (1282)...(1405)  
             
             
               exon  
               (1602)...(1702)  
             
             
               exon  
               (1602)...(1631)  
             
             
               exon  
               (2352)...(2364)  
             
             
               exon  
               (6287)...(6509)  
             
             
               exon  
               (10417)...(10493)  
             
             
               exon  
               (14244)...(14407)  
             
             
               exon  
               (14244)...(14344)  
             
             
               exon  
               (25190)...(25235)  
             
           
            2 

gcggaccagg cagggaacaa cctgggagga atcaaatttt attttggaca tgttacttct     60 

gaaaggctaa cagacttcca ggcagaaagg tccttgaggg aaacattcta ggggtctctc    120 

tgggaggctt agatcaagga gctgagacca aaaggagaat gggagggagg agacgagtac    180 

aatagagttg gagccaaggt cctagaggcg gataggtgga ttcctgaggg aggaggaagg    240 

ggctgaggtt gctggagcct ggcagcttct tccggagcca ttggcaggac tgatgcaaac    300 

agctctgggt gggaagaggg aaccaggata tcctcctgtg tccttccttt tctgcagtca    360 

tcctgggtgg ctgccagatg gaattccttg gatatcattg cttggaggtc ccctgcatgc    420 

ctgaagaagg acatggtgga gagcaggatg cctggatccc atgggggaag ggaagtgccc    480 

aggaaagcac gaagccccag ggggagcttt cagtgcgggg gtgagtgggg aggctggggt    540 

agtagctgac actgtcccag ctgcatccca ggtttgaaag gcacctcctc ccccagcgca    600 

ggcatcctgc ctcccaaccc tgtaattacg gtgcttccca acgcccatcg tgtggtttgc    660 

tcccattctt tggcttccaa tagttgcaag ggatgaaggt ggacatctct gtgattacgg    720 

agatgccaag tgggtattga ctgctccagg gtgtggatgg agggtgtgaa aaccagggtg    780 

gggtgacgca ggctctgggt catgataggg agagcaggca gctgggtcct gggctggagg    840 

actaaaataa gggacgccac cttcaggggt gacacatcag cccaggcctt cccaacgggt    900 

ttgaccagtt ctgttctgat ggtattcctg tgccactggg ctggtccctc ctccactcct    960 

cccctataaa gcctcttggg gttcccaggc acccagactc agcccacccc agctttgggg   1020 

gccagtacat agccatgatc ctcaactgga agctcctggg gatcctggtc ctttgcctgc   1080 

acaccagagg tgaggtggga acagaggcag ggactgcagt ttggggtgat gagggatact   1140 

caagatggcg gaggtgaact ggacgcatgg ggttggggac aggaattcag gggacgcaga   1200 

aggtgcatct ggctcaccag aaatggcttt ctggacacat tgggtggggg acatggtgca   1260 

gaaggtgcat ttggctctca ccagaaatgg tttgctggct ccatgtggca aagtcggtca   1320 

ggattaacgt gggggggacg agtttccttg gagctgggat ctgtgttaag gagctggggt   1380 

ccttgtaaag ctggggtctg tgtgcctggg ggccaaggtg taacccacct tgggttgcag   1440 

gttggcctga ggacaaagct agtggggtac cccaaccagg ggtggatgga gcttatttgg   1500 

agaagtctgg tcagtttaaa gtgggtcaag tgaacggttc agatccatcg ggggtagggg   1560 

ttcatgacat tttaccatca gttaagtatt tacaaaccta ccgagagctc tttgagagtg   1620 

acttttttgg tctgtttgtg ggtcagttca ggctgcgtcc gtccagacag gctcctcctc   1680 

ctggggctgg ggctgggtgg ggctggggag agaagccctc accacctctt acctttctcc   1740 

ttcctccttt acaggcatct caggcagcga gggccacccc tctcacccac ccgcagagga   1800 

ccgagaggag gcaggctccc caacattgcc tcagggcccc ccagtccccg gtgacccttg   1860 

gccaggggca ccccctctct ttgaagatcc tccgcctacc cgccccagtc gtccctggag   1920 

agacctgcct gaaactggag tctggccccc tgaaccgcct agaacggatc ctcctcaacc   1980 

tccccggcct gacgaccctt ggccggcagg accccagccc ccagaaaacc cctggcctcc   2040 

tgcccctgag gtggacaacc gacctcagga ggagccagac ctagacccac cccgggaaga   2100 

gtacagataa tggagtcccc tcagccgttc tgttcccagg catctccagg cacccacgcc   2160 

ctctccaccc tctgattccc cgtgaattct tcccaattta gcctatctcc ttaaacctct   2220 

tcctcattcc ctcggtttta ttctgaaccc gtaaggtggt gttctcaata tttcctgtcc   2280 

cctcctgaga tccatactta gtcctcacat cgcccgtttt ttcctctgac agcctaagcc   2340 

tactctccta cctcgcctcc aggcctcggc cccacctacc tcccacccgg tcttcctgcc   2400 

cgcgcgatcg ctggggcagg gctacggtac tgtgttccct tctgccacct ggtggccggc   2460 

ggcaggaact atcagtagac agctgctgct tccatgaaac ggaaaaataa aaatcatgtt   2520 

ttcttaactc tgaatctagg ctgctgcttt aactaacact tagggtcttt ttcatttatt   2580 

tttatttatt tgtttttttc tttttttgag acgaagtctc gctctgtcgc ccaggctgga   2640 

gtacagtggc acgatctcgg ctcactgcaa gctccgcctc ccgggttcac gctattctgc   2700 

ctcagcctcc cgagtagctg ggactacagg cgcccgccac cacgccaggc taattttttg   2760 

tattttttag tagaggcggg gtttcaccgt gttagccaga gtggtctcga tctcctgacc   2820 

tcgtgatctg cccgcctggg cctcccaaag tgctgggatt acacgcgtga gccacagcgc   2880 

ccggcttctt tcttcttttt ctttcttttt tttttagatg gagtctcact ctatgcccag   2940 

gctggagtgc aatggcacga tctcggctca ctgcaacctc cggctcccgg gttcaagcca   3000 

ttctcctgcc tcagccttct gagtagctgg gattacaggt gcgcaccacc atgcccggct   3060 

aatttttgta ttttagtaga gatggggttt caccatgttg gccaggctgg tctcgaactc   3120 

ctgacatcgt gatctccccg cctcggcctc ccaaagggct gggattacag gcgtgagcca   3180 

ccgtgcccgg ccaacactta tgtttttgac tattaggatg ccctcttcac agtcctaaac   3240 

ttacggagac ctggaagtaa cttgagttcc tatcttgccc atgtccagca tgtaaggctc   3300 

tggggcttag caggaggagg gttggaaatg tcactatgca agtcacaata acattcaggc   3360 

ccacatttct ccctttctga gaacactata ttaaagaatg ggaaggcaag tttcatctct   3420 

gtttaatggc ctatggcttg gataccccta gtggtatatg caaaccttcc caggggtgtg   3480 

tcggcaggac cagttttaag ggaatcagtt tccagattaa tatgtgcccc ccgctagaat   3540 

gaatctcctg cttgtcctgg gcctgaccag agtgcccttc ccagagccgc caaaggtcaa   3600 

taggaaacaa atcaaccttt cccatctcat taagagattc attttctttc ttttcttttt   3660 

tttttttttt tgagacgtat tatctctctg tcgcccaggc tggagtgcag tggcacgaca   3720 

gatatcagct cactgcaagc ttcgcctcct ggattcaagt gattctcctg cctcaacctc   3780 

ccgagtagct gggattacag gtgtgtgcca ccacacccag ataagttttc tatttttagt   3840 

agagatggga ttttgccatg ttggccaggc tggtctcgaa ttcctgatct catgggatct   3900 

gcttgccttg gcctcccaaa gtgctaggat tacaggtgta aaccaccacg cctggccaag   3960 

agatgcattt tcaataagtt acttttcatg tctttttgtg tgtttgtttg agacagggtc   4020 

tccatctgtc atccaggctg gagtgcagtg gcacgatcat ggctcgtata gcttcaacct   4080 

cctgggctca agcaatcctc ctatctcagc ctctggcgta gctgagacta caggtgcacc   4140 

acccctgact aattttttgt atttgtttag tttagttttg tttcgttttt agagatgggg   4200 

ttttaccgtg ttgcccgggc ttgtctcaaa ctccagagct caagtgatcg gcccatcttg   4260 

gcctcccaaa gtgctgagat tacaggcacg agccaccgcg cctgaccaac tttttatgtt   4320 

taatccttgt gaatattcct agttttggtt aactgcaata attgcaatac aaatagaata   4380 

actgtttcta acacttgttc aagggcttgt tcacgtattt tttaaaagga tgctaacaga   4440 

tatgaaagtt ctatggcatt atattcaatt tgctacactt agagtgacgt gcagtctccg   4500 

acagactgag cacaacaaat tgtttttaat tttaaaaact gacatggcca ggcatggtgg   4560 

ctcacgactg taatcccagc atttgggagg ctgaggtagg cagatcactt gaggtcagca   4620 

attcaagacc agcctggaca atggtgaaac tctgtctcta ctaaaaatac aaaaaactta   4680 

gctgggcatc ccagctactc gggaagctag ggcatgagga ttgcttgaac ctgggaggca   4740 

gaggttgcag tgagccgaga tcgcaccact gcactccagc ctgggagaca gagtgagact   4800 

ccatctcaaa aataataaat aaataaataa atacataaat agtgatgtga tttttaacat   4860 

gtatttgcaa ttccctgaaa agcctaccct ttggaatgct attaaattat tacaaatgtt   4920 

aaatgttgac ttaaaaatgt gcaaggggct gggcgaggtg gctcatgcct gtaataccag   4980 

cacttcggga ggccgaatcg ggtggattgc ttgtggccag gagtttgaga ccagcctagg   5040 

caacatggca aaactgtctc tacagaaaat ttaagaaatt agccagatgt ggtggcccgc   5100 

acctgtagtc ccagctactc aggaggctga ggtgggaaga ttgcttgacc ctgggaggtt   5160 

gaggctgtag tgagccaaga tggcaccact gcactccagt ctgggcaaca gagtgagacc   5220 

gtgtctcaaa acaatacaaa tgtgcaaggg acatagtttt tcaaaatcct ttaaagaggc   5280 

aatcaggtta gaaggacagg agctcagaga tcccaatggt ctactgtcaa tcaagtatcc   5340 

gaccagggtt agggatgaag aggggttaaa agaaactgag gttgcataac cttaaatttc   5400 

accacttaga acccagtttg cttatgtggt aactctcatt aaaaactaca tatgagaggc   5460 

cgggcgcggt ggctcacgcc tgtaatccca gcacttcggg aggccaaggc gggcgaatca   5520 

cgaggtcagg agatcgagac catcctggct aacatggtga aacccagtct ctactaaaaa   5580 

atacaaaaaa aattagctgg gcatggtggc cggcgcctgt agtcccagct actcgggagg   5640 

ctgagacagg agaatggcgt gaacctggga ggtggagctt gcagtgagcc gagattgtgc   5700 

cactgcactc cagcctgggc gacagagcga gactccatct caaaaaaaca aacaaataaa   5760 

aaaccaaaaa actacacatg agatcaggcg tggtggctca cacctgtaat cctagcactt   5820 

tgggaggctg aggcgggtgg attacctgag gtcaggagtt cgagaccagc ctcaccaaca   5880 

tggtgaatcc ctgtctctac taaaaataca aaaaaattag ctgggcatgg tggcgggcgc   5940 

ctgtaatccc agcttctcag gaggctgagg caggagaatc cattgaacct gggaggcaga   6000 

ggttgcggtg agccaagatc gtgccactgc actgcagcct gggcgacaga gcaagacccc   6060 

gtctcagaaa acaaaaaaca aaaaaaaact acatgtggtc cgaatgaaac aaaactaagc   6120 

ttagggttta ggaataatct gagaacacat aagaattgta ggttgagcct agtagaatta   6180 

aataggcccc aagctggact ggattcaccc attcattcat tcattatctt acttcctcaa   6240 

tgtgtccacg aatgccgggt gccatgggag aatataagaa tataaataat aaaaatatgt   6300 

agtttctact cagaacttaa aattgagaga gacagaattt acaggcaagt ttaaataaca   6360 

tcaaagacag taaaaatgca tatttcctaa taatgacatg agcgagcgcc aatgtaatag   6420 

ccttggcagt aaacgccgtg agttcagaag agtcacggtg agctggacta gtcaggggag   6480 

gcttctggga ggagggcccg gagcgggacc tgagagaaga acaggcagtg tgtctggagg   6540 

atggaccagg aagggcagac ccggagcctc atacagggtg caggtacaga agctgccccc   6600 

aggtgatgag ctctcgtggc cagaaccacc agctctaggg accagccctt gcgcgtatgt   6660 

gcatcagcct tcgtgtgtgc tgttccctat gtctggaatg gccgtcctct cccaaaccag   6720 

ctgcatttct cctcagggat gcctctgcct acaccactcc ttcccgcacc ccacccgacc   6780 

cccaacgccc ttcaccccag tcaccctatg gcaatgattt attcatgtct gtcttccctt   6840 

cccaggccat gaaccttgtg aggcagggac tgtgttctac gcatttcttc ttgaacccct   6900 

ttaccatttt tgtgcctacg gactcccaga gtgctaaatc actcccaaca gccccgccta   6960 

tgcctctgcc gggacctttt ccaggggcag agagctggaa gcacttggaa atttttctct   7020 

cccacatcct cacatgccac caccctccca ctcccccagc ccgcccccag gccttaacca   7080 

acggtggaca aatatgaagg tgtcagtacc ccagccctcc atgagactta gcttggttcc   7140 

actcatgtgc ttgggtccca ctttcccact ccctttccac tcctccccac cctcattact   7200 

tttttttttt tttaagacag ggtctcactc tgtcacccag gctaaagtgc agtggcacaa   7260 

tcataactca ttgcagtctc aacctcctgg gctcaagtgg tcctcctgcc tcagccttct   7320 

gagtagctgg tactatagat gcactccact cactgggcta attttttaat ttcttgcaga   7380 

aatgatgtct tgccatgttg cccaggctgg tctggaactc ctggactcaa gcaatcttcc   7440 

tgccttggcc tcccaaagca ctgggattac aggtgtgagc catcatgccc agtcccctca   7500 

ttacttttat ttatttattt atttatttat tcaatttttg agacggagtc tccctctcgt   7560 

tgcccagact ggaatgcagt ggtgtgatct cagcccactg caatctccgc ctcctgagtt   7620 

caagcgattc tcctgcctct gcttcctgag tagctgggat tacaggcatg cgccactatg   7680 

cccagctaat ttttgtattt ttagtagaaa cagggtttca ccatgttggc caggctggtc   7740 

tcaaactcct gacctcaggt gatctgcccg ccttggcctc ccaaagtgtc gagattacag   7800 

gcatgagcca ctgtgcctgg cctatttatt tttgagacag ttctcactct gttgcccagg   7860 

ctggagtaca gtggcacgat cacagctcac tgaagcctgg acctaagcga tcctcccacc   7920 

taagcctccc aagtagctgg atcacaggcg catgccacca cgtctggcta attttttttg   7980 

tagagattgg gtcttactat attgcccaac ctggtctcaa actcctgagc tcaagaaacc   8040 

ctcctgcctc cgcctctcaa agtgttggga ttataggcgt gagccaccct gcccaacttc   8100 

tcattagttt taaataaatc tcttttactt gaatctttgt ctcagggcct gcttctgggg   8160 

aatccaacct aggatgcaaa gtatttgcta cacactattg caactacttt ctactgcgca   8220 

tgtgccatag ggcactgttg gtaaatgctc tacagcttaa gctctcgttt aatttgcata   8280 

acaatgctat catgatcatt tcacagaaga cagaaacagg cctagagagg tacagtgacc   8340 

catgcaaggt cacacagggg acaaatggca gaactgggat ttcaatttag gtctgtgcta   8400 

tgctaacaac actgatttta accactacat catcccagct cttttttttt tttttttttt   8460 

tttttgagac ggagtcttgc tcttttcacc caggctagag tgcaatggca cgatcttggc   8520 

tcactgcaac ctccgcctcc tgggttaaag caattctcct gcctcagcct cccacatggc   8580 

tgggattaca ggcacccgcc accatacctg gctaattttt gtagtttttt tttagtagac   8640 

acggggtttc accatgttgg ccaggctggt cttgaactcc cgacctcgtg atccaccagc   8700 

cttggcttcc caaagtgctg ggattacaag cataagccac cgcgcctggc ccatcccagc   8760 

tctttattca tctgtgtaac cctgacagag aatacagtgc ctgggccgtc atgcacactt   8820 

aatgtgtgtt ttgtgaaagg ctaaattatt taatgaaggg cccaattaac aaagagtaga   8880 

tcggaatgat tggagtaaaa taacccgaag aagagagaga catgttggag agacaggtcg   8940 

ggggaaaatt agggaagatc ttggtgccaa gtgcaggagc tcatatctga aagtctctct   9000 

cctctattag aactgtgcct gggcctgggc aacataacaa gaccctgtct ctgaacaaac   9060 

aaaataagtt agctgaacat ggtagggcgc acctgtaatc ccagctattc cagaggctga   9120 

ggtggaagat tgcttgagct caggaggtca aagccagcct gggcaacaca gcaagacccc   9180 

atctctaaaa aaaaaaaaaa ttaaaattaa aaaagggcca ggcacagtgg ctcacacctg   9240 

taatcctagc actttgggag gccaaggcag gaggatcgct tgagctcagg agtttgatac   9300 

cagtgtgggc aacatagtgt gacctcacct ctacaaaaaa aatgtttaac atttggccag   9360 

gttgccaggc gcagtggctc acgcttgtaa tcccagcact ttgggaggcc gaggtgggcg   9420 

gatcgcgagg tcaggagatc gagaccacgg tgaaaccccg tctctactaa aaatacaaaa   9480 

aaaattagcc gggagaggtg gcgggcgcct gtagtcccag ctactcggga ggctgaggta   9540 

ggagaatggc gtgaacccgg gaggcggacg ttgcagtgag ccgaggtcgc accactgcac   9600 

tccagcctgg acgacagagt gagactccat ctcaaaaaaa aaaacaaaca attagccagg   9660 

ccatggtagt gcatgcctgt agtcccagct actcagcagg aagatcacct gagcatgaga   9720 

ggttgaagct ggagtgagat atgattgcac cactgcactc cagcttggat gacagagctg   9780 

tctcagaaaa aaaaaaaaaa ttgtgcctag ggtggggaga aacacataca tctctgggta   9840 

tactgtggca ggaagctaag gatagaaagg aagaaggagg tctggacccc tcaaactgac   9900 

cctcaagcca ataacgtgga attagttagg aggaaaaaaa attaattaat taattaattt   9960 

tttatttttt gagacaggtt cttgctctgt cgcccaggct ggacagtgca gaggtgcagt  10020 

tacagctcac tgcagccttg acctcctggg ctcaagggat cctcctacca cagcgtcctg  10080 

agtagctggg accacaggca tgtgccacca tgtccagcta agagaaattc ttaaagaaga  10140 

gagaaaggag ggaaaggaac tgagcccctg atgttgtcta gggaaaaagc tggggctctt  10200 

tacagcatgc tgccttcttt aattccacag cactatgtgg gtttccatgc ctttatttcc  10260 

ttggaaagta tgagcttctt gaagacagca actgtgcctt gtctttcttt gtatcccttc  10320 

cttctctcct agtacccagc ctagaaggca ctcaataaag caaatgatta gccccatttc  10380 

acagacgagg aaccaacact gagagaggta actcacctgt gcaagtcata tcacaagtgc  10440 

caaagtcaag actggatgga ggactgcctg gctgcaaacc aattcttccc aggctgacat  10500 

ggcaggtagg tgagtgggaa agagaagggg gaggcataag gcaattggag attttagtac  10560 

ctattaatag gcagtggatt ttggcactca aacaggctgt cttcattagc tggggaggag  10620 

actgagtggg cctggatggt atggaggtat ttgcacaggg aaacccattg tgctggctta  10680 

tccattcaga ttagacaatg ctggttcctc tctacctgcc ttggctaagc tcacctagga  10740 

gtaaatgccc cagggacacc gtcacgtcta tgtcaacaca gagtcacgga attaaataac  10800 

agaataggat cacagattta cagaacaata gcccagaacc ttggacatga cagatagtta  10860 

ttaaatgctt ggccaatgaa aaaaaaagaa cctagaacta gtatcacggt aaaatctaat  10920 

tatacaagct aagttacctt gagaaagcac caggcacagc cctgagcctt gggcagcgaa  10980 

tgatgtcttt ggactagaca gaagagatgg ttgtctgccc tgctttgaag ctctctggcc  11040 

agggaaactc caaaccattc atttgttcat ccatttgccc acacaatcaa cattcattga  11100 

gcatctgctc tgtggggtgc tatgtgatgg tgacagtccc aggaagcagt ttcagtcctc  11160 

cctgccctca aggggctctg tgtttaggga ggacaaacat atacatcatg acaataaaat  11220 

ttgataaaaa gttaaattag agagggggca aaccctgacg taggagccca ggagggactc  11280 

ctaacttctc tgccaatttc atgtttcaaa attattagac ccaagactcg ctttggtata  11340 

aacttaagct ctcttactgt acatttttct tctcctgcta atctttaatt aagtgcccac  11400 

caggtgcctg gcactgaatc aaaactcaaa aaacttgctg aattaagcca aatgcacctc  11460 

ctgtgggttt ttccccctaa tatcctcaga ggcagtaatc aattccctcc ccaaattccc  11520 

cagtccccac cccatcccca cctttccttt tgcagtataa tctcaactcc tgtgatgggg  11580 

gcaggcagga tagcatggta gtgagatcaa cagactgtga cttgggttct tgtcgctact  11640 

tagccattca ttctgtatgt gaccttggga tgggacttta gggggatttc tttaataacc  11700 

tctaaactcc cgtgcaatgc tgagagccaa ggtagcggct ctcaggtctt gttccaagaa  11760 

ctgccaccag agggcagcct agagactcct ctcaggtgtt ttcctccaga gcctttgctc  11820 

tttccctcac taatgtcatc cactccctgg gtccaccatc aaggcacaca ggtgtccctt  11880 

tagccgtcaa ggtgaccgtt ctaaggtgag ccaggcatgt gaggcgaggc gagacaggct  11940 

ctgaagccct caggaaaatt caggcacagg ctgcttgtcc aagtggacct cacgatcatc  12000 

atttacacat tctctccctg attatttcat gagccagcgg tctacaggag aggataccac  12060 

agccagtcaa agggatcagg gccctgccct cagggagctg ccttccagtg agggaggaga  12120 

gagatacaca gatgcttaca aggtatctgt agtaggatgt cacctagtga tgaatggtgt  12180 

gacgcagctt aggcagagcg aggaaatagg gatggtccca aacgtgtgtg tgtatgtgtg  12240 

tttttttgag acagagtttc gctcttgtcg cccaggctgg agtgcagtgg tgcgatctca  12300 

gctcactgca acctctacct cccgggttca agtgattctc ctgtctcagc ctcccgggta  12360 

gctgggatta caagtgttca ccaccacacc cggctaattt ttgtattttt agtagagatg  12420 

gggtttcatc atgttggcca ggctgggcta cgagcgaaac tccatctcaa aataataata  12480 

ataataataa taataataat aataataata ataataataa ttcctgtctc ctagggtcat  12540 

tgagagaatg gagatcagtc ctgcacgggc agacctcggc accgagctga atgttacaca  12600 

ctgccaagga gtcggcgccg gtctctggtg aagatgttct agtcccaggg cccaagagaa  12660 

cagagcggga cacgagatgc ctctctaaca ggagtctgtg tttcctggtc acctctgtgt  12720 

gctgggtgat gcctcaggtg ccagggagac actgggcagt aggagaagct ccctcctgtg  12780 

aggactctca cccagaggca ctcagacagc ccagaacaca ggagggaaga tgggccacca  12840 

cagtcccatt cctaggcgct ccaagggcca gcccagccta gaagtccctc ctggtacaag  12900 

tctttccggc ctctcctctc ccgagagcac gttcagactg caccctggcg ctctctttca  12960 

ccctgtcgag gaagctgtga ctctaattct gggtgaccag taacaataaa aaccactaat  13020 

agccctagtg gaaagaatga ctatttaaca ggtgcacata atgagcagac aaggagagct  13080 

cttttccctc acactcactc cgcaggacag agaggggaac agtcttgcta ctgtgacagc  13140 

taatcacagc ctctgtgtgc ctccctcctc gcaagataag aggggtggcc tcagggtgtg  13200 

acggaaacag ccaggaaggc ttcggccagg gagcgactgc cctacagctg actccctgct  13260 

gcttttggga agtgggggtg aagggaaaag actcagggga gcggggggaa gaaagcttgg  13320 

tgggcagaac cccacttgcc aaattcctcc tctttcagga ttcagtggcc aaaggtgagc  13380 

ctggctctgg ccccagtctt cactcccaag tgccggctgc agtgccctgg gcccgtcgga  13440 

ggctggcagg gctgctggga gggtgaggac aggcatggga agagtggaaa gtgggggctg  13500 

acccagccaa gctccaggag gccattccat agaggagaga gccattggac caggagccaa  13560 

gcagggaaga aggaaggaaa ggtagagccg agcaccgccc acaccaggaa taatctcagg  13620 

aagaggatgg tgtggacagg ccccaggaca gggcttctca gctaggggca actcgttatg  13680 

ctgcagtggg ggcacctaac agaaccccct agggtttttt taaagtatac agcacggtcc  13740 

tgcccaccac tggcatcaga tgaatgccat gtccagggga aaccccagta cgtcctcatc  13800 

acagccatgt gaacactgct gtttgttcat aaaaatgtgt tgcatcccta gggggaaata  13860 

aaaggagcta atccaataga gagaagagtg gctcagggga gacagtcacc cgcgaggaat  13920 

gagggcagga cacacaggcc caggccgaga ttgcacaggg tgttgcatga gtggctgtgt  13980 

cagagccaag tgcacatgcc cactgccacc tccgccaagg ccatcagtga atccctccag  14040 

cacctacagg ggctttgcac ataagagctg tgcttgcagg gggtgggggg tgggcacagg  14100 

gcaggaaacc agagaggagg gcaccatgtc cctgagtaag gtagaaaggg gaagcacagc  14160 

ctggacacat tcttccattc ttttatttca aaatatcacc aagtgcctgc cacagctatg  14220 

tgctgggaac tcagtgaacg cacctgtgct ttgcccactg gcatggagcc cacggtccgg  14280 

gggtgatggt ttctgttgca tttcaaagcc actggggcgc tgcatagatg gctggctgca  14340 

gagtctattt gagacgaagg caagaagtca gggcccatgg actgtagatt ccacccttga  14400 

tcgtctacta caggaaagaa gccacagaag tgagggggta ttcccaacag gaaggcagag  14460 

aaggagagat taaaactgag tcaagaagtg tagccagtcc catgggagca cctgggctga  14520 

ggagggtcag tccccgcaga gatgttcgga acacctgatt ggggatgtgc cctctccttc  14580 

tatgttcttg gtcaccagag gaaccaggtg aagagtgtgg atgactcagt ccacccctcc  14640 

ccgcacagga aaaacaactc agaggacatc ccctactggg agtgggccag gagcgctggc  14700 

ttccacgcca aggagaggag ggtgttgctg tggctgcaga ggtgagtcca cagggaagcg  14760 

tgggtgtcat ggagaaagag agaggagagg aaatggcctc tcgctggagc caagcagaga  14820 

ggaacaaagg aggggaggag cccacaggcc ctggagcccc agagcagctc tgggtggccc  14880 

ctttccttct ctcctcagca caaaataagc tgcttttcca ggctttttct cttcctcgtg  14940 

ctcactccat tttccttctt ccaagcctaa gccctggtct accaaggacc cctatgtgaa  15000 

acacttgtgc tagaacttct gtcctgactc tcaggccccc agaggaggaa agctgtggag  15060 

gagggacctc atgagccagt aaccttcact taggaactct tcactttttt ttttttgaga  15120 

cggagtctca ctctgtcacc caggctggag tgcagtggca tgaaatcggc tcactgcagc  15180 

ctccgcctcg ctggttcaaa tgattctcct gcctcagcct cctgagtagc tgggattaca  15240 

ggtgcctgcc cccgcacccg gctaattttt gtatttttag tagagatggt tttgccatgt  15300 

tggccaggct ggtctcaaac tcctgagctc aagtgatcca cctgccttgg cctcccagag  15360 

tgctgggatt acaggcgtga gccaccatac ctggccagct ttgacagcag aaatcttctc  15420 

tctagaaata ttcatataca taaggaattt tgcacacatc cttacagggt ttagggagcc  15480 

tcttaagcct gtccatgaac ctctgccatt catttatagc atggtgtcag ctgcagagta  15540 

ataggatcta tgtgggcctg gaagtccaac aggcctgggt ttgaatcttt ttcaaacatt  15600 

tttgcttgtt agcagctggt ttggacaaat aatttcaact tagttttctc atctgtgaaa  15660 

cagggggaaa aagcacttac cctgtagggc tgttgtgaag attgaacaag acaactcatg  15720 

ttaaataccc aggcaccgtg tccgcctgca gcaggcagtc agtacatggt ggatctcgtg  15780 

ccccaagcct cctctttatg gagtccctca agttgcccca gctggcctcg gattcctccc  15840 

acctccacct cctgggtagc tgggactaca gcacgccatg cttcagcccc ctttgtgatc  15900 

attcaaagcc gtttggttcc ctgcaccctc tcacatttac tgcaattcct atagaatcca  15960 

aattctttta acctggtgtt gtaggtcatc tacaatcccg atccaagcag cctgtccctt  16020 

ctcccacacc actgtcctcc acatgcatgt cccacaccaa cccacgccat ccgctggttc  16080 

taaatacacc tgaagcacca caaggcccca cgtctggctg cctgctctgt gcttctctca  16140 

tcattcctca aggcccgggg aaagtcctgc cacctccctg aagccaagtg cctacccgct  16200 

tctccactct aggctgctct cttacgctgt gtgtccccag ctggatggca gctcctcagg  16260 

gcaaggaaca atttctcttc tttctcagtg caacttccaa aacacagcag aggagcgtgc  16320 

actgggggca aaggctggca cagcaaacac agcagcacag ggctgctgga ggggtggagg  16380 

ggaccggagg ggacagtgac ctgcctgctt cataatacat ggctgggagc cccacctttt  16440 

gcctatggaa gccatgtgct ttgagcttga ttttctcggg tgtagagtgt ctacgccacc  16500 

cacactttct cacccggtcc aatgcacggg cacgggcagg ggcagggcca gaatctgttg  16560 

ctgtagaaca cagcagagct gcctgcagta ctgtggacgt caccaaactg gcagcttcac  16620 

tgaaggtgac cctggcctgt gtgggcactc agctgatgcc cttctcttcc ctcctaagcc  16680 

ccattagctt taggtcttca ccacctgcac tgagagaaag attaatggtg agcaccagag  16740 

taaaatctag cacagaaggc agggtttcag taaaaaacca aaagcatggc agattagagc  16800 

tcaagggccc acaggtgggc aggacagtag aggaactggg cagcccaggg tggcaggatg  16860 

gggtggacag gagtggacag gagagagtag ccaggaggag ggacgtggct gcaccaccag  16920 

tccacgtggg cggctggaga cctggcagga ggccaggaga gactgtgcct cctccagcct  16980 

ggctgtcttg gccaagttct gatggcagcc aggaggactg tgagaaagaa aacaagacaa  17040 

actttgctac ctctggctgg tcaggggaag tttgtgttgg aaaagaagaa gccacagatt  17100 

ccactgttcc gctgccttct cccctcacac cctgggacgg cccagcacct tctagtccac  17160 

tcctccctgc cctctgccac tcccctcact accccagtgc cccctccctc cttgcccagg  17220 

tcctccaggg agccaagcct gagagtctag ggaggcccac aagaggaaat gatgttcgga  17280 

aagagcagca tcactttatt ttttgagatg gagtttccct tttgtcaccc aggctggagt  17340 

gcaatggtgc aatcttggct cactgcaacc tctgcctcca gggttcaagt gattctcctg  17400 

cctcagcctc ccgagtagca gggattacag gcgcccacca ccacgcctgg ctaatttttt  17460 

tgtatttttg gtagagacgg ggtttcgcca tgttggccag gctgatctcg aactcctggc  17520 

ctcaagtgat ccgcccgcat cggcctccca tagtgctggg attacaagcg tgagccaccg  17580 

tgcccagccg agcagcatca ctttaaatgg tatctctgtc tcacatttgt gcctgcacct  17640 

ctatacaagg caggaaggga gcagaagaca ctctgctagc attggctggg ctggagactc  17700 

aggaaaggga gcctggggct gtgggggtga agctggccta tttgtctccc ccagtggaag  17760 

gatgaagaca ggagcacctg cagggctcca tttgctgggc ttcctactgg gggactgcac  17820 

cccttgtccc atttaacctt tttgataatt tcccatttga tgttcacaaa aaccttgcga  17880 

aataagtgtt atttaaaata cccccatttc acagatgagg agatggaagt tcagaaaggt  17940 

ttgaagagcc gcccaaagcc aagaggttag ctgggacttg aacccacgtc atcttcattc  18000 

tgaagccagt gttttttgtt tgtttgtttt tcccaaggca ttagccccct tcaggggacc  18060 

ctgtcctatc ccttcctctc tccacagctc cctcagcccc tctttcctcc cactcccatt  18120 

ctgagtgtca ctagcaagtc aagagcaaga ctagatggca gccactagct gcacgtggcc  18180 

aaccacatca ttacaattaa ttaaaattaa agctccaaat ctttggtggt taaacttgct  18240 

ccatgtggcc agtggctacc gtatcggaca gcacagacag gaaacatttc catcctcctg  18300 

ctggtctgaa cttaaagggc ggtcaggagg tagagggaat gggagagacc agcccaaggg  18360 

gcccagggac agagctgcct ttgtgaggag atgaggtttg ggaagtgagt ttgggtgagg  18420 

ggagcagggg tgtctgaggc ctgggggagg agagggcagc ttgctggact tgcaggcacc  18480 

tccctccgat actgatactc ccgcaatact agtgagcaat taattggctg gggcggggca  18540 

ggggccagag caggagggag gccaacgcaa tggaggagaa gccaccaccc tctcagcaga  18600 

tggcagggct ccggttctcc tggcctcctt tcatcctttg aggacccggg agcctgcctg  18660 

gccctcctcg acctgcccag agctggctgc tgcttcctgc tcgctcatcc agcccagggc  18720 

cagcagatgg gctacggggc caccaccttc ccaattagcc ttcttagcct cttgctcacc  18780 

cttgaggtct gggttaccag ccatggggag gggctgtgag tggcctgtga gtaaccaagg  18840 

cccagctttg acagaggtca tcagcccagg cccctcccct ggctgagccc tggctcccag  18900 

cacccccccc cacccccgcc accatgccgt ccccagaggc ccccagaagc gacaggtcag  18960 

ggagttggtt ttgggaatgt ggtgccccat ttctgagaag gagaaggttc cccaggtgat  19020 

ggaacacgta ataggtatgt ggctggcctg gtacttgggg agtggtggga gggggagcct  19080 

gggggatggg ggcagaactc atatttgaag gaggaaagtg gaggtggagt gatggggtcc  19140 

taaggaagga gcagatcagg ggctgtgaat gggacctcat tggggttggg tgggtggggc  19200 

tggagcgggc acccaagtgt ggaagaaaaa gctgaaacac ccacgactgc gagtggaggg  19260 

cagatggaga gacaggccaa gccacggtag gcaggagagt taaggagcca ggcagctggg  19320 

tcccgtggca agagtggccg ccccagagtg ggtggccgtg gggcagagcg cctggttccg  19380 

ggttaggcaa tgaggagccg gggccaggcc tgtcaggtgg caggatcgtt agagccccgt  19440 

ggccatgggt accccacact gcagccactg ctgctgctga gtaggcagat gcaccgggct  19500 

gattaccacg ctcctcccgg ccacaccaac ttcccccggg gcacccaccc cctccacctc  19560 

tcctcctctc cccacagtga ctcctgccca gggaatgtcc agctctggca taaaggaccc  19620 

aggtgtcctc gagctgccat cagtcaggag gccgtgcagc ccgagatggg ctcgtctcgg  19680 

gcaccctgga tggggcgtgt gggtgggcac gggatgatgg cactgctgct ggctggtctc  19740 

ctcctgccag gtaggaggct gggggccctg ggaacaggag ggaggcggga gggagactcc  19800 

gggagaggac ccagcgaagg ggacgggcag gggctctgga atctgccttt tgagtctggg  19860 

ggttgctcct cactgtatgg tcgcctcagg taagtttctt aaacttcctg agccccagtt  19920 

tctgaaattc tgaagtgggg ttaatgacac ctacctctag tctgtgtgtc tcaaattaaa  19980 

taatgtatgt gatatgtact ttggaaattc tagaggttta tataaatggt ggtggtgatt  20040 

tttattatgg gagcactaca agataatgat tggacattta atagtaataa tatcattttt  20100 

agagcctttt tatatgctag actctgtttt aagcacattt ggattatata ttagaacttt  20160 

tatttttatt ttttttgtga gatggagtcc cactctgtct ccaaggctgg agtgcagtgg  20220 

cgtaatctcg gctcactgca acttccacct ctcaggttca agcgactctc atgcctcagc  20280 

ctctagagta gctgggacaa caggtgccca tcaccacacc tggctaattt tctttttttt  20340 

gtatttttag tagaaacagg gttttaccat tttggtcaag ctggtcttga actcctgact  20400 

caagtgatcc gctcgcctcg gcctcccaag gtgctgggat tacaggcatg agccaccaca  20460 

cccggcctat attagcactt ttgatcatta caagaacggt atgaaaagag atttgctatt  20520 

tccactctac agatgaggac actgaggctc ggagaggtta ggaaactagc tcaaaatcat  20580 

gcattagaag gcagcaaagc caagatttca accccaggcc aggcaacccc tggacctgtg  20640 

ttgttgacca ccgggtactt atagcccttg aggaatttct gcgaccttcc catggtctag  20700 

tgggtggttg gtgtctgagg gaatagcgaa agagagaggc aatgcatggt ggattcgtgc  20760 

agaggactga agggaattgg cacagctggg gttcggcgtg gaggtgcatg cagagaattt  20820 

ctttctgagg agagaacagg gacatcacag aggatggcag tctggttgtt ggtggaggga  20880 

tcaggatgag tggcagtaat aattcataat atataatgct ttacactttc taaaacatct  20940 

ggccgcacat gatagcttgt gcctgtaatc ccaacacttc aggaggccaa ggcaggtgaa  21000 

tcgcctgagg tcaggagttc aagaccagcc tggccaagat ggtgaaaccc cctctctact  21060 

aaaaatacaa aaaattagct gggtgtggtg gcgggcacct gtggtcccag ctacttggga  21120 

ggctgaggca ggagaatcgc ttgcaccaag gaggcagagg ttacagtgag ctgagaccgt  21180 

gttattgcac tttagcctgg gcaacaagaa actccatctc acaaaaaaaa aaaaaaaaaa  21240 

aaaaaagaag aaaaaacttc caggtggatg atctcattta gttttcttca tagtaatgct  21300 

gtgggaaggc agggaaaatt tggcccctct gaatgtataa actaaagctc agagaggttc  21360 

agtaacttgc tagtatgtgg ctctgtttgt aacacgtggg acctggaggg gctagggaag  21420 

gcagaaggaa cgcaggtgaa agagtcatgg aggaaccatg gggtaagttg ggcctggggt  21480 

tttgagcaaa ggaaaggaaa gataaggaaa gatgtggctc cacatccctg agggaagtca  21540 

aggcagcaga agtcagatga ggggctggac agaggcaggt gtgctcagag agggaagctg  21600 

attgtggcca ggagcctcgg aggttcgtgg ggtttcgtcc tggttccctg ggctgggcca  21660 

gcgagagcag ggctggctca gggtgcggtg tcctgacaca ctggtaccag caggttctga  21720 

agcaacaggt agtgacccca catcctggcc cccacccagc tttactggca tggccagtgc  21780 

tgagatagga aatagggttt ccattcctga ccccagcctg ggctctcacg aagaagctgg  21840 

tgaccaaatc ttagtcctcg agtgcccttt cctttatttc agcccctctg cccccagctt  21900 

tgtctttttc cagtgtctcc ttctatatgt gtctccactt ctcagccctc cattgttttg  21960 

ccttttgtct tcttccctct ggtcccactg tctggcccag gatttttccc ctaagaattt  22020 

acgcctggac tcctcagagc ctcagtttcc ccaattctct gtctcttcag ggtcctttct  22080 

tttagaccta tttgttcctg ccccttctcc attccctctt ctttttaaaa aaaattttaa  22140 

ttaaaaaaca aaatacagat ggggtctatg ttgcccaggc tggtcttgaa ctctggggcg  22200 

catgcaatcc tcccacctca gcctcccaaa gtgctgggat taccggcgtg agccactgtg  22260 

cccagccccc tcttatattc aatgtattcc tttgaggtca ctcactttgg cacgtaattt  22320 

tctatttttc tggttggtgt ttgcccaccc ttcccaaaca aagaaatgcc tttattcggc  22380 

cacctcaata tcctttagag acaatagcca gttcttcctc ctttctccat ccctaaactc  22440 

tccctgcgct ctgcttggga gaaacccgag aggccgatta ctgagataag gcagaaaggt  22500 

gagggaggaa gccaagcctc tttggccctt actaaccact gctttcctcc acagggacct  22560 

tggctaagag cattggcacc ttctcagacc cctgtaagga ccccacgcgt atcacctccc  22620 

ctaacgaccc ctgcctcact gggaagggtg actccagcgg cttcagtagc tacagtggct  22680 

ccagcagttc tggcagctcc atttccagtg ccagaagctc tggtggtggc tccagtggta  22740 

gctccagcgg atccagcatt gcccagggtg gttctgcagg atcttttaag ccaggaacgg  22800 

ggtattccca ggtcagctac tcctccggat ctggctctag tctacaaggt gcatccggtt  22860 

cctcccagct ggggagcagc agctctcact cgggaagcag cggctctcac tcgggaagca  22920 

gcagctctca ttcgagcagc agcagcagct ttcagttcag cagcagcagc ttccaagtag  22980 

ggaatggctc tgctctgcca accaatgaca actcttaccg cggaatacta aacccttccc  23040 

agcctggaca aagctcttcc tcttcccaaa cctctggggt atccagcagt ggccaaagcg  23100 

tcagctccaa ccagcgtccc tgtagttcgg acatccccga ctctccctgc agtggagggc  23160 

ccatcgtctc gcactctggc ccctacatcc ccagctccca ctctgtgtca gggggtcaga  23220 

ggcctgtggt ggtggtggtg gaccagcacg gttctggtgc ccctggagtg gttcaaggtc  23280 

ccccctgtag caatggtggc cttccaggca agccctgtcc cccaatcacc tctgtagaca  23340 

aatcctatgg tggctacgag gtggtgggtg gctcctctga cagttatctg gttccaggca  23400 

tgacctacag taagggtaaa atctatcctg tgggctactt caccaaagag aaccctgtga  23460 

aaggctctcc aggggtccct tcctttgcag ctgggccccc catctctgag ggcaaatact  23520 

tctccagcaa ccccatcatc cccagccagt cggcagcttc ctcggccatt gcgttccagc  23580 

cagtggggac tggtggggtc cagctctgtg gaggcggctc cacgggctcc aagggaccct  23640 

gctctccctc cagttctcga gtccccagca gttctagcat ttccagcagc tccggttcac  23700 

cctaccatcc ctgcggcagt gcttcccaga gcccctgctc cccaccaggc accggctcct  23760 

tcagcagcag ctccagttcc caatcgagtg gcaaaatcat ccttcagcct tgtggcagca  23820 

agtccagctc ttctggtcac ccttgcatgt ctgtctcctc cttgacactg actgggggcc  23880 

ccgatggctc tccccatcct gatccctccg ctggtgccaa gccctgtggc tccagcagtg  23940 

ctggaaagat cccctgccgc tccatccggg atatcctagc ccaagtgaag cctctggggc  24000 

cccagctagc tgaccctgaa gttttcctac cccaaggaga gttactcgac agtccataag  24060 

tcaactgttg tgtgtgtgca tgccttgggc acaaacaagc acatacacta tatcccatat  24120 

gggagaaggc cagtgcccag gcatagggtt agctcagttt ccctccttcc caaaagagtg  24180 

gttctgcttt ctctactacc ctaaggttgc agactctctc ttatcacccc ttcctccttc  24240 

ctcttctcaa aatggtagat tcaaagctcc tctcttgatt ctctcctact gtttaaattc  24300 

ccattccacc acagtgcccc tcagccagat caccacccct tacaattccc tctactgtgt  24360 

tgaaatggtc cattgagtaa cacccccatc accttctcaa ctgggaaacc cctgaaatgc  24420 

tctcagagca cctctgacgc ctgaagaagt tataccttcc tcttcccctt taccaaataa  24480 

agcaaagtca aaccatcatc tggaaacagt ggccactttt cactgacctc tcttcgacat  24540 

ctagtcaacc cacccaatat gccactgggc tttcgctccc aattccaccc caccctccat  24600 

tacagagctc accacgccct cctagatcac cgtccccaac acacccattg cctctcaagg  24660 

cccttatctc agccccttcc tgtggccatt tccctcagtg cccagatgat tccctgggtg  24720 

agggagacac tggggcaccc tcagaggttg gagcaggctc cctgctgtcc ctggatcctg  24780 

gacagatggc tcagtaaact gtggggacta ggtgcagact ttttgccttc ttggagtcct  24840 

gggtctcctc tgagagtctg ggtggtgctc ttcctacgcc tctagaggtc tctgtgtccc  24900 

tcattttcct tcaaaagcgg gctgtgtttc tcttctacct tccagctcct cccacagagg  24960 

aggaagacaa taaatatttg ttgaactgaa agcagagatt gcctggcctc ccagatcctt  25020 

ccgccatttc cctcctctct cattgctcca ggaaatccat tctcttccca ttcctcattc  25080 

accgtggggt cccccttccc cttatttagg gccctcagtg ttttctctcc ctcccctccc  25140 

ctcccctccc cacccaaact ccttttcttc caccattagc attcctcacc ttctagatgc  25200 

catcctctct gggagtcatg agtctcgatt tcctg                             25235 

 
           
             3  
             14483  
             DNA  
             Homo sapiens  
             
               exon  
               (1)...(174)  
             
             
               exon  
               (2121)...(2424)  
             
             
               exon  
               (5808)...(5971)  
             
             
               exon  
               (6070)...(6205)  
             
             
               exon  
               (6365)...(6475)  
             
             
               exon  
               (6715)...(6864)  
             
             
               exon  
               (8203)...(8313)  
             
             
               exon  
               (8420)...(8526)  
             
             
               exon  
               (11115)...(11227)  
             
             
               exon  
               (11430)...(11475)  
             
             
               exon  
               (11620)...(11756)  
             
             
               exon  
               (11850)...(12038)  
             
             
               exon  
               (12135)...(12236)  
             
             
               exon  
               (13510)...(13663)  
             
             
               exon  
               (13789)...(13960)  
             
             
               exon  
               (14207)...(14483)  
             
           
            3 

gcccctttca actctgccaa gaatggctcc cacctggctc tcagacattc ccctggtcca     60 

acccccaggc catcaagatg tctcagagag gcggctagac acccagagac ctcaagtgac    120 

catgtgggaa cgggatgttt ccagtgacag gcaggagcca gggcggagag gcaggtaggg    180 

atccatccac gccgttttct caggcttgct tgctagtgac ccttcctcac tggaataaac    240 

tccttaccct atttcggccc tagtttccag aacgtactca tttttatgta agcaattagt    300 

tcctacagtg cataaataat aaagcagtgt gctaagtgct agggatgagg ataacaatag    360 

tgaataagac aaatcctgac ttaaatttgt aattaataag gaatctaaaa tcctaagagg    420 

ggagatagat tgaccaccag ctgatggtaa agcatggtat gaggcaagat gaagaagtgc    480 

aaactagagg tagagaccca gcactgtggc agtgtgggtt cattctgatg gaagaaagcc    540 

tttacagagg acatgctgtg ggagctggcc atgctgtcgt attatctgta aacattctta    600 

ttcttgtttc atgtgtcttt tcccagatgt actgggatat cattctgcca ttttgctcca    660 

gaataggatt acattagaag aagcagcatg atgaagaagg aatactagac tgggtgtcag    720 

gagacagaga ctctatttct agtttggcta ccagctagag gacatttggc aagtcactta    780 

atttccctag cctacagatc gctgctacta aagaaaagaa agaaagagcg agccagatat    840 

ggcggctcac acctataatc ctagcacttt gggagctgag gcaggaggat cacttgagcc    900 

caggagttca tgaccagcgt gggcaacaaa gcgagactcc gtctccacag aaaataatta    960 

gctggctgtg gtggcatgca tttgtagtcc tagctactca ggaggctaag gtggtaggac   1020 

cccttgagct cagaagttga agactgcagt gacctatgat ccagccactg cattgaggcc   1080 

tgggtgacac agtgataccc tgtctctaaa aacgacaaca acaacaatct cttatagtcc   1140 

tgggtctcag agagctgcct caggagccat gttccaagct ggattaaact tcacgtgaca   1200 

ttggtagacg atttctctaa aggctggcac tgtgttattt atgtactgtt ctctcagact   1260 

cctcataaag tatacctaac actcaataaa tgcctttttt tttttttttt ttttttgaga   1320 

tggagtctca ctctgtcgcc caggctggag tgcactgggg agatcttggc tcactgcaag   1380 

ctccgcctcc caggttgacg ccattctcct gcctcagcct cccaagcagc tgggactaca   1440 

ggcacctgcc accacgccca gctagttttt tatattttta gtagagatgg ggtttcaccg   1500 

tgttaaccag gatgatctcg atctcctgac ctcgtgatcc gcccgcctcg gcctcccaaa   1560 

gtgctgggat tacaggcatg agccaccgcg cccagccaat aaatgccttt taactagcac   1620 

ctggcctcac catattgata ctggaagctt acgacctctc tatgcccatt cctccctcaa   1680 

acttcttgcc cttaaattag aattgagaag tccctgtgtg ttcttccaac ctttccactt   1740 

aaaatgtgtg gcctaaaaat aaaaaaataa ataagacaaa aaaaccacca aaaaacaaaa   1800 

agaatgtgtg gcctaatgat atacacattt gatgttgaat cctcctgtat gtagctctct   1860 

ctagggagat catgttccac gatctcagcc agactttagg tcctgtgagt ccaggcactg   1920 

gactcaacat gctcaatagg gctttgatga atgatgatga tgtcaatgca gacatcccca   1980 

taccccagct tcagcacccc cttcacctcc ccacacggaa gcagaggggt cctcttttcc   2040 

ttctcctggc tatgtttatg ccctcaacta tccttccagc actggagaca agtctcacct   2100 

gcactaacct gtctttgaag gtcctggggg ctggaggggt cacaggccct gagccagcag   2160 

gctgaggtga tcgttcggca gctgcaagag ctgcggcggc tggaggagga ggtccggctc   2220 

ctgcgggaga cctcgctgca gcagaagatg aggctagagg cccaggccat ggagctagag   2280 

gctctggcac gggcggagaa ggccggccga gctgaggctg agggcctgcg tgctgctttg   2340 

gctggggctg aggttgtccg gaagaacttg gaagagggga ggcagcggga gctggaagag   2400 

gttcagaggc tgcaccaaga gcaggtgaat gcaggggtag aaaggattca aattcataac   2460 

ggagagctgg gcagtagctt ccaagcaaag aacaggtatt gcagaaaaga ccctccatga   2520 

gtagtgagta gtagagtgat gagacctttg gtgaaaataa acacacatgg gctagaaaga   2580 

tggagaattt gggtactttt atcttaattc aggttgcact tttcccccaa gactcaggtg   2640 

gcctcccacc acttgaagcc ctgcttccct ttctagtagg aaatagtttg cctccctact   2700 

ttactccagg taccaattca tcaggggtat tgtggagggc agtgaggaag gtgggtataa   2760 

gggggctatg gtggactggg agagagagat tattcagtcc tcaaactcag tacttactct   2820 

gccatctcta agactcagtg accaaattag cctgagtcct gccttcgtgg atggaactga   2880 

cagcctcgtg ggggatatac acatccacat ttaatttaat cataattaat tgcaatcagg   2940 

aggaatgcct tgaaggagaa ggactagaaa gcactaactt agtctggggt tcagggaagg   3000 

ccactgtaac cagttgacat gtcaaggaaa gaaaccatag ccctgggcgc agtggctcac   3060 

gcctgtaatc ccagcatttt gggaggccga agcaggcaga tcacaaggtc aggagttcaa   3120 

gaccagcctg gccaacatgg cgaaaccctg tctctactaa aaataaaaaa attcaccagg   3180 

catggtggtg cgcacctgta atcccagcta cttgggaggc cgaggcagga gaatcacttg   3240 

aacctgggca gtggaggttg cagtgagccg agactgtgcc attgcactcc agcctgggcg   3300 

acagagcaag actctgtctc aaaaaataaa ataaaaaagg aactgggaga aaacaaggga   3360 

gaattccttt ataaccttgt agtgggcaag gcctttctac ctgtgagtca aaatccaaaa   3420 

tctagaagcc ataaaggaaa aaattgatcc attgacttta taacatgaac attaggaata   3480 

gccaaaaaga aaaaaaaaag ctatatttat agctcagatc acaagaaaag ggtaatatcc   3540 

ctaatataaa atgtgtgcct agaaattggt aagggaaaga ccagcaatcc aatcagaaaa   3600 

tggacaaagg agatttatga aagaaactta gaaacaagaa gctaggccag gcacagtggc   3660 

tcatgcctgt aatcccagca ctttgggagg ccgaggtggg cggatcactt gaggccagga   3720 

gttaaagacc aacctggcca acatgaagaa ctctacaaaa aaatacaaaa attagccggg   3780 

tatagtcgtg ggcgcctgta atcccccagc ttcttgggag gctgaggcag gagaattgct   3840 

tgaacctggg agacagaggt tacagtgagc tgacatcaca ctccagcctg ggcagcagag   3900 

cgagactaaa aaaacaacaa gctaccgttt gtgctgaata ggagttggcc agtgaagagg   3960 

cgtgtgaagt ccagtggtag ctggaagaca cttggtggga caacaggtga aggcggggac   4020 

aggaggccag aaggctgggg cacagagatg aggggcactg agtgtgctgc agagcccagg   4080 

acccagggca caaggctttg gccacttcag aacttgctac tttcccataa gagcaatgag   4140 

caggctgggc acagtggctc atacctgtaa tcctagcact ttgggaggcc aaggtggaag   4200 

gatcatttga gcccaggagt ttgagaccag cctgggcaac aaagcgagac ccccatctct   4260 

attttatgga agaaattagg gctgggcatg gttgctcaca tgtgtaatcc tagcactttg   4320 

ggaagctgag gcgggtggat cacttgaggt caggagttcg agaccagcct ggccaacatg   4380 

gtaaaacctc atctctacta aaaatacaaa aattagctgg gcgtggtggc tcatgcctgt   4440 

aatctcagct actcgggagg gtgaggcggg agggtgaggc aggagaatcg cttgaacctg   4500 

ggaggcagcg tttgcagtga gctgagatcg tgccattgca ctccagtcta ggcaacaaag   4560 

tgaaactcca tctccaaaaa aacaaacaaa aaaaaattgt tttttcaagt aataagcaac   4620 

cgttgaaagg ttgttttttt ttttttttga gatggagtct cgctctgtcg cccaggctgg   4680 

agtgcagtgg cgcgatcttg gctcactgca agctccgcct cccgggttca tgtcattctt   4740 

ccgagtagct gggactacag gcgcccgcca ccacgcccag ctaatttttt gtattttaat   4800 

agagacgggg tttcaccgtg ttagccagga tgatctcaat ctcctgacct tgtgatccac   4860 

ccacctcggc ctcccaaagt gctggaatta caggaatgag ccactgcgcc cggcctgttg   4920 

aaaggtttta agcagggaaa taacatgatt agatttgtat tttatgtcta aaaaattttg   4980 

tcatttatgt cccccaaatt aattttattg ttgtatggag acagggctag aggaggcaga   5040 

ccaggaagca gggtgggcac tttgccctcc tttccagtcc atcccatgac tcttggtggc   5100 

tctgacaccc ctgcaacact ttgaggtgcc atgagcaaaa gacacaaaat tcctcctttc   5160 

ctggagcttt ccttccagtg tggtccgaca gatagtaaca catacacata agcaagatat   5220 

ggtcagtgct aagtgctcag gaggacgtga acagctgatg gggcagagta gggtggggag   5280 

ggacagtatt agagggccca gtgaagccac cctgaggagg ggctatcgcc tggggtctgt   5340 

ggagcaagga ggggccgctg tctggttctc agcagactcc ccgtggccgg agcggggagc   5400 

agtgggagag cctccagggt gagctcagga ggtaggcaga ggccgggtcc cctggcctgc   5460 

aggtgtggag agacacctgg gttttgttgt gaatgctgtg agaagccact gagggtttgt   5520 

aaagactagt taggagatgg tcgctgttgc ccaggcaaaa gatgagggtt ggtggcagtg   5580 

gagacggaga cagagaggtg aagatatgtt ttgggggaga tcggacaaga actcctgatg   5640 

ggttgtgggg cagctgcgga gagtgagttg ccagctctcc atttgctgtg cacagttggc   5700 

tgattggttg ggtcattctc taaggtcaca gaaagtggga gtgaagggaa caaggaaggc   5760 

ctccatgtgg ggtcgagcct ctgctgagcc ccctcttctt tccgcagctg tcctctttga   5820 

cacaggctca cgaggaggct ctttccagtt tgaccagcaa ggctgagggc ttggagaagt   5880 

ctctgagtag tctggaaacc agaagagcag gggaagccaa ggagctggcc gaggctcaga   5940 

gggaggccga gctgcttcgg aagcagctga ggtaggtggg cggacgccga cgggagccca   6000 

gcaattagtg atgtggtgga tctgcagggc gccccactga tggctgtccc attcccaccc   6060 

caaccctagc aagacccagg aagacttgga ggctcaggtg accctggttg agaatctaag   6120 

aaaatatgtt ggggaacaag tcccttctga ggtccacagc cagacatggg aactggagcg   6180 

acagaagctt ctggacacca tgcaggtgag ggtgcaggaa tgtatctgtg tgcagactta   6240 

gggatcaggt tgggaggcaa gcgtggccct tggaggagcg tgtagagcac agcctccggg   6300 

agagaaggtg gtacctaagg cggcatggag gccctacaga ggggctgctt tcctctgccc   6360 

gcagcacttg caggaggacc gggacagcct gcatgccacc gcggagctgc tgcaggtgcg   6420 

ggtgcagagc ctcacacaca tcctcgccct gcaggaggag gagctgacca ggaaggtaca   6480 

gcccaacccc cagacccctc accctcagcc gcatcctgca tctactgtcc cctgcctccc   6540 

tccctgtggg caggaggggt caatgtgccc cagaacctgc ttagatctcc ttcctgtgaa   6600 

ctcctcttgc tgtagctcat gttgcccagg caggacagag gagaaacaaa gatgccacct   6660 

ccttcctctc ctcccccagg agcccacact tttctcccac tccttctccc tcaggttcaa   6720 

ccttcagatt ccctggagcc tgagtttacc aggaagtgcc agtccctgct gaaccgctgg   6780 

cgggagaagg tgtttgccct catggtgcag ctaaaggccc aggagctgga acacagtgac   6840 

tctgttaagc agctgaaggg acaggtcact gcactctctt ttctcccggt attccctccc   6900 

agcaccttgc tccttccatg aaggtggcat ccattcaacc agtgtttatt gagtggttgc   6960 

cacatgctgg gcacacagcc ctgaacaaaa ctaaaatgtg gagcttgcat tctagaacag   7020 

agacacagaa cacgcaagta aacagataat gttgggtaat tatatgtgcg atagaaagat   7080 

tgaagccggg tgcagtggct cacacctata atgcgatcac tttggtctcc aactcctgac   7140 

ctcaggtgat tcacctgcct cagcctccca aagtgatggg attacaggtg tgagccaccg   7200 

tgcccagtca agtaatgcca acagtttggg agaccgaggc aggtggatca ctggaggtca   7260 

ggagttcgag accagcctgg gcaacatgtg aaatcccgtc tctactaaaa atacaaaaaa   7320 

ttagccgggc atagtggctc attcctgtag tcccagctac tctggaggat gaggtgggag   7380 

gatcacctga ggctgggagg tcgaggcgag gccacagtga actgtgatcc catcactgca   7440 

ctctagcctg ggtgacaaag cgagatcttt tctcaaaaaa aaagaaagta gtaagaaaaa   7500 

ttcaaaagat aatgtgacgg agagactgtg gggtgagtca gcctcaggta ggatgctcag   7560 

agacagcctc tctgaggagg tgacagcatc tgaggagagt ggcatggtca gttggtgggt   7620 

cttgtggggt gtgtcaaggg ctattcccat cttcgagtgg gcacatggaa tgtggaacat   7680 

ggaacactgg gctcagattc catcctcaga acctaagctt ctgtctccct gcgtggcatt   7740 

cattcttttt cttttctttt cttttttttt ttttttttga gaaggagtct tgttcttgtc   7800 

acccaggctg gagtgcagtg gcctgatctc agctcactgc aacctccgcc tcccaggttc   7860 

aagtgattct cctgcctcag cctcccgagt agctgggatt acaggcacat gccatcacgc   7920 

tcagctaatt tttgtatttt tagtagagac aggctttcac catgttggcc aggctgatct   7980 

tgaacccctg acctcaagtg atccatctgc ctcggcctcc caaagtgctg ggattacagg   8040 

tgtgagccac cgtgctgcga cccacccccg tcgcccgccc tccctccccc cagcccctgc   8100 

atggcattct tacagagatc tctgcacctg ccactttgct tccagtgccc ccctcatctt   8160 

ttagctctag agggccctgc ccagctctct ctcctccccc aggtggcctc actccaggaa   8220 

aaagtgacat cccagagcca ggagcaggcc atcctgcagc gatccctgca ggacaaagcc   8280 

gcagaggtgg aggtggagcg tatgggtgcc aaggttggtg tcagcctact agagactcgg   8340 

ggagggcaag ggagcccctg ttccggggct gcagccagga cttagggagg gaccctgtcc   8400 

tttgctgcat cctccccagg gcctgcagtt ggagctgagc cgtgctcagg aggccaggcg   8460 

tcggtggcag cagcagacag cctcagccga ggagcagctg aggcttgtgg tcaatgctgt   8520 

cagcaggtat cagggatgga ggggtgggtg gagtagtgtt tctgccacct caggttcctg   8580 

ggcaccttgt tgctgaggat cctcaggcaa gaggggctgg aaagtggcca ctggaggcta   8640 

cagggctggg cagatttagc tctatcaatg ttcctgtgtt cgtttctttt cctggggaag   8700 

ccccttctgc attcatacct gattgcttgt tatgaatttc ccgttgcatg tttggctgga   8760 

ggtgaggcct tgcttcctcc tgcagttcag tctagtaatg gcttgagcta aatagagcac   8820 

ccgggaggat cttcacttgc agtattgttc aaggatggag agtgtagaca cttcatcttc   8880 

cttttttttt ctaaaatttt acgggcaatc cgtttcactg gagaaaaatt tagtctattt   8940 

atttatttat tttgagacaa agtctcgctc tgtcacccag gctggagtgc aatggcacaa   9000 

tcttggctca ctgcaacctc acctccctgg ttcaagtgat tctcctgcct cagcctcccg   9060 

agtagctgga ttacaggcat cctccaccag tgtcctccac tacgcccggc taatttttgc   9120 

atttttagta gggacggggt ttcaccatgt tggccaggct ggtcttgaac tcctgacctc   9180 

aggtgatcca cccacctcag cctcccaaag tgctggaatt ataggtgtga gccactgcac   9240 

ctggcctagt ctatttattt aaagctgtat acttacttgc ttattatata cttaacttgc   9300 

ttactattcc atctaaaatg taagccagtt agtttccttc taaatcaatt gccagccttt   9360 

gtctctccta ccaacttcct agttgtttca ttacctacaa ttgttgtatg accttcagaa   9420 

aaacctctaa gaaaacagca aagcttcttt gtgctggtga tgacttcccc tcagccttag   9480 

acactgaggt acccaaggca agtagttctt tttttttttt tttgagacag agtctcgcac   9540 

tgtcacccag gctggagtgc aatggcacga tctcagctca ctgcaacctc tgcctcccgg   9600 

gttcacacga ttttcctgcc tcagcctcct gagtagctgg gattacaggt gcacaccacc   9660 

acacccggct acttttttgt atttttagta gagacagggt ttcactgtgt tggccaggct   9720 

ggtctcaaac ttctgacctc gtgatccgcc cgcctcggcc tcccaaagtg ctgggattac   9780 

aggcttgagc caccgtgccc ggccggcagg tagttcttag cacagtctct ggcttgtaaa   9840 

tgtttattgt tatcgtgagg ctcttcttga tgggttaatt tagataaaga taatttttgg   9900 

tttagcgaaa ttaagatgca ggatgagtcc ttgcccacca cttccttctc ttgggtttgt   9960 

accttaggga ctaatttagc tttaaaaatt atgaaaaatt tcaaacttgc acggaattaa  10020 

actagttata atgacctacc acccaggttc aatccatcgc gggtgccccc tacctccagg  10080 

agaacagaaa gatgcactgt ggacagggtt tgactttggt accaggtgat cacagaaatg  10140 

gtctgtgtaa tgatgcattt gccgaaagtc ctccaggctt aaagcagtcc aaactctgat  10200 

tgttgctggg tttattagat tgtctctagg taattggaga ctttaataag agctgtggta  10260 

ggtgttggaa gcatctactg gaacaatttc cagatcaaag tgaactttgc tgtgctgctg  10320 

gggatgcagc tgcaagcctt catcatcatg tgtttttctg tgggtgcaga cctggactct  10380 

cctgaggaaa ccccagcccg gccccagaca ctccttggcc tcctcctggg gcctgtttaa  10440 

gctgctcagt tttcatgagc caggttggtc ctacttctgg cacagccagc tggtaaagca  10500 

tgtggacctg cccgtcattg gtgctagatc gacactcctg ggcttggaga ggataacttt  10560 

gttttctttt gtttttttga gatggagtct cgctctgtca cccagtcttg agggcagggg  10620 

tgcgatcttg gctcactgga acctccacct cctaggttca agtgattctc gtgcctcagc  10680 

ctctggagta gctgggatta caggcatgag ccaccatgcc cggctaattt ttgtgttttt  10740 

aagtagagag agtttcacca tgttggccag gctagtctcc aattcctgac ttcaggtgat  10800 

ccgcccgcct cggcctccca aagtgctggg attacaggca ggagccactg cccctgacca  10860 

gagaggataa ctttactctt tgatacacga tagtgagcaa aacacagttg tgagaaataa  10920 

gcttaacagg ttgcttaaaa agatagtcat ttaatgcatt cttggggcaa gggtccttta  10980 

gataattgac ggaagctgtg cgttctgtac ttgtataatg ggacaggatt agagggagtt  11040 

gtctatacaa ggcacagcaa gtcctttggg aatgagggga ggcatggagg atcagtgact  11100 

tgtgccctct ccagctctca gatctggctc gagaccacca tggctaaggt ggaaggggct  11160 

gccgcccagc ttcccagcct caacaaccga ctcagctatg ctgtccgcaa ggtccacacc  11220 

attcggggtg cgtaggacaa ctgcgagcca cgtcctgccc ccaccccacc agctcggact  11280 

ttcttcttcc tgacccagct ctctctgatc ccacatccat tcaccttcct cctttcacca  11340 

gtccttgcat ctctttttcc cttactccct gtccccactt tctcccatgc aaacttcatc  11400 

tctttttctc cctgcttttt cccctccagg cctgattgct cgaaagcttg cccttgctca  11460 

gctgcgccag gagaggtgaa gtttgtgcac tttgaggtgg atggggcttt agggcattgg  11520 

ctgctgggac ccccaaaacc atgaggactg aggtgggatg ggggctttgg gatcaggcag  11580 

ctgggttatt tctcctgact ctttctcttc cccgtcccag ctgtccccta ccaccaccgg  11640 

tcacagatgt gagccttgag ttgcagcagc tgcgggaaga acggaaccgc ctggatgcag  11700 

aactgcagct gagtgcccgc ctcatccagc aggaggtggg ccgggctcgg gagcaaggta  11760 

cacctggttg ccagagggtg gagaggatga ggaaaaaccc agtgtctagg gtgctgggag  11820 

aggcctgacc cagcaccccc tccttttagg ggaggcagag cggcagcagc tgagcaaggt  11880 

ggcccagcag ctggagcagg agctgcagca gacccaggag tccctggcta gcttggggct  11940 

gcagctggag gtagcacgcc agggccagca ggagagcaca gaggaggctg ccagtctgcg  12000 

gcaggagctg acccagcagc aggaactcta cgggcaaggt gtcgagaggg aaatgggtgc  12060 

ttcccttgga gggtggggtg ggaactgcga atcaaagctc ctgctgatat gccccgtctg  12120 

cactttcacc ccagccctgc aagaaaaggt ggctgaagtg gaaactcggc tgcgggagca  12180 

actctcagac acagagagga ggctgaacga ggctcggagg gagcatgcca aggccggtga  12240 

gccttgccag ggtggatagg gccttccagg aagaaggaag tgttaagaca taaggttatt  12300 

attttcccct caaagtgtgt tcaaagcttc attacaggaa gtaatgaagg tatccaggag  12360 

tagcacagat gaattatcac atcgtgaaca cacccatgta gccagcacca gattaagaaa  12420 

cagcatatgg ccggtcgcgg tggcttatgc ctgtaatcca agcactttgg gaggccgagg  12480 

tgggtgtatc acctgaggtc aggagtttga ggccagcctg gacaacatgg cgaaaccctg  12540 

tctcgactaa aaatacaaaa attagctagg cctggtggtg ggcacctgta ccccaagctt  12600 

acttgtgagg ctgatgtggg aagactacat gaacccggga ggtcgaggct gcagtgagcc  12660 

aagattgtgc cactgcactc aagcctgggt gatagagaaa gaccatgtgt caaaaaaaga  12720 

attgtgtaat gaatgtatct tctctaacta aatatagcag ttaacatttg ccacatttgg  12780 

tctcttatct atatacacac atatttgtac atcttttgaa tcactttaag ttgtaatcat  12840 

ttaatgtttt gttgttgttg ttgtttgaga cagagtcttc ctctgtcacc agctggagtg  12900 

cagtggcatg atcttggctc actgtgacct ctgcctcccg ggttcaagcc attctcctgg  12960 

ctcagcctcc caagtagctg ggattacagg cgcccaccac catgcccagc tagtttttgt  13020 

atttgcagta gagacgggat tacaccatgt tggccaggat ggtctcgagc tcctgacctc  13080 

gtgatccgcc cgctttggca tcccaaagtg ctgggattat aggcgtgagc caccacgcct  13140 

aagtaagttg taaacataag ttgttcagcc gcatctccca aagccagtaa attctcctat  13200 

atagctgcaa tcatcacact ttaagacagt gaacactaat tgcacaaaat ctaacccagt  13260 

tcatgttcag atttcccctg aggaactcca ggatggttca gggatgagga agatacttag  13320 

gttcagattc ccaggctcct agagcatcag cccacccctc caactgtaca gaagagacag  13380 

atccacagag cagaacagcc tccccaagcc acagagttgg tgacccagcg tttgttcctg  13440 

tcttcatggt gcctggctgc ctctggcctg actcacacct gcctcctctg tgccttggcc  13500 

tctctgtagt ggtctccttg cgccagattc agcgcagagc cgcccaggaa aaggagcgga  13560 

gccaggaact caggcgtctg caggaggagg cccggaagga ggaggggcag cgactggccc  13620 

ggcgcttgca ggagctagag agggataaga acctcatgct ggtaggagac aggagggcag  13680 

acaggcagac actagggccc atcctgggct ggttcctggg ctagaggtgt ggaaagagga  13740 

tggtgaggga ggctctatcc gggctaggtt taaccctctc cttcccaggc caccttgcag  13800 

caggaaggtc tcctctcccg ttacaagcag cagcgactgt tgacagttct tccttcccta  13860 

ctggataaga agaaatctgt ggtgtccagc cccaggcctc cagagtgttc agcatctgca  13920 

cctgtagcag cagcagtgcc caccagggag tccataaaag gtcttgggcc aagcacaaag  13980 

ggacaaggga caaatgcgcg cacttcagga atctcctctt cagactctgg catgatgagt  14040 

gttgttctct gcggtccttc gaggccctta gcctctttta gcgatgccca gcttggacca  14100 

aagagcctcc tctctcccat tcctcatttc ctgtgccagc cctgtttcct ctgtaaccac  14160 

gagcaccttc ccttgtctgg tgctcatctg ctgtcttcct tcccagggtc cctctctgtc  14220 

ctgctcgatg acctgcagga cctgagtgaa gccatttcca aagaggaagc tgtttgtcaa  14280 

ggagacaacc ttgacagatg ctccagctcc aatccccaga tgagcagcta agcagctgac  14340 

agttggaggg aaagccagcc tgggggctgg gaggatcctg gagaagtggg tggggacaga  14400 

ccagcccttc cccatcctgg ggttgccctg ggggatacca gctgagtctg aattctgctc  14460 

taaataaaga cgactacaga agg                                          14483 

 
           
             4  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            4 

gaaacaccca cgactgcga                                                  19 

 
           
             5  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            5 

aggaggagac cagccagcag                                                 20 

 
           
             6  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            6 

tcctcgagct gccatcagtc                                                 20 

 
           
             7  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            7 

ggcatgagag tcgcttgaac c                                               21 

 
           
             8  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            8 

cgagaggccg attactgaga t                                               21 

 
           
             9  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            9 

gactagagcc agatccggag                                                 20 

 
           
             10  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            10 

gggtggttct gcaggatctt                                                 20 

 
           
             11  
             18  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            11 

agagtgcgag acgatggg                                                   18 

 
           
             12  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            12 

cagtggccaa agcgtcagc                                                  19 

 
           
             13  
             18  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            13 

agccgcctcc acagagct                                                   18 

 
           
             14  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            14 

aaatacttct ccagcaaccc c                                               21 

 
           
             15  
             22  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            15 

ggaaaacttc agggtcagct ag                                              22 

 
           
             16  
             18  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            16 

agatcccctg ccgctcca                                                   18 

 
           
             17  
             23  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            17 

acttcttcag gcgtcagagg tgc                                             23 

 
           
             18  
             25  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            18 

tggaggagtg taacgaaggt ttctg                                           25 

 
           
             19  
             18  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            19 

tctggcagcc acccagga                                                   18 

 
           
             20  
             18  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            20 

gcaggactga tgcaaaca                                                   18 

 
           
             21  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            21 

ctccctatca tgacccagag                                                 20 

 
           
             22  
             24  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            22 

gaaatggctt tctggacaca ttgg                                            24 

 
           
             23  
             18  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            23 

ctcggtcctc tgcgggtg                                                   18 

 
           
             24  
             18  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            24 

ctacatgtgg tccgaatg                                                   18 

 
           
             25  
             18  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            25 

acgagagctc atcacctg                                                   18 

 
           
             26  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            26 

caaggccatc agtgaatccc t                                               21 

 
           
             27  
             22  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            27 

tgtgcttccc ctttctacct ta                                              22 

 
           
             28  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            28 

cctcccactt tcaagctcg                                                  19 

 
           
             29  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            29 

gaggaagggt cactagcaag c                                               21 

 
           
             30  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            30 

ccctcaacta tccttccagc a                                               21 

 
           
             31  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            31 

ttggaagcta ctgcccagc                                                  19 

 
           
             32  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            32 

cagaaagtgg gagtgaaggg a                                               21 

 
           
             33  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            33 

atgggacagc catcagtgg                                                  19 

 
           
             34  
             22  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            34 

ccagcaatta gtgatgtggt gg                                              22 

 
           
             35  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            35 

tctacacgct cctccaaggg                                                 20 

 
           
             36  
             22  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            36 

cgggagagaa ggtggtacct aa                                              22 

 
           
             37  
             25  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            37 

aacatgagct acagcaagag gagtt                                           25 

 
           
             38  
             22  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            38 

gaggagaaac aaagatgcca cc                                              22 

 
           
             39  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            39 

gatgccacct tcatggaagg                                                 20 

 
           
             40  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            40 

acctgccact ttgcttccag                                                 20 

 
           
             41  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            41 

atgcagcaaa ggacagggtc                                                 20 

 
           
             42  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            42 

gctgcagcca ggacttagg                                                  19 

 
           
             43  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            43 

aacaaggtgc ccaggaacc                                                  19 

 
           
             44  
             23  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            44 

atgggacagg attagaggga gtt                                             23 

 
           
             45  
             22  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            45 

ggatgtggga tcagagagag ct                                              22 

 
           
             46  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            46 

ccttactccc tgtccccact t                                               21 

 
           
             47  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            47 

cctcagtcct catggttttg g                                               21 

 
           
             48  
             20  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            48 

cccaaaacca tgaggactga                                                 20 

 
           
             49  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            49 

ctctccaccc tctggcaac                                                  19 

 
           
             50  
             23  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            50 

agaggatgag gaaaaaccca gtg                                             23 

 
           
             51  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            51 

ggcatatcag caggagcttt g                                               21 

 
           
             52  
             18  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            52 

gggtgggaac tgcgaatc                                                   18 

 
           
             53  
             23  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            53 

tgaagctttg aacacacttt gag                                             23 

 
           
             54  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            54 

tgttcctgtc ttcatggtgc c                                               21 

 
           
             55  
             22  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            55 

tctttccaca cctctagccc ag                                              22 

 
           
             56  
             21  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            56 

tgggctagag gtgtggaaag a                                               21 

 
           
             57  
             23  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            57 

tcatcatgcc agagtctgaa gag                                             23 

 
           
             58  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            58 

ccagccctgt ttcctctgt                                                  19 

 
           
             59  
             19  
             DNA  
             Artificial Sequence  
             
               Artificially synthesized primer sequence  
             
           
            59 

gtctgtcccc acccacttc                                                  19 

 
           
             60  
             1725  
             DNA  
             Homo sapiens  
             
               CDS  
               (15)...(1601)  
             
           
            60 

ccgtgcagtc cgag atg ggc tcg tct cgg gca ccc tgg atg ggg cgt gtg       50 
                Met Gly Ser Ser Arg Ala Pro Trp Met Gly Arg Val 
                 1               5                   10 

ggt ggg cac ggg atg atg gca ctg ctg ctg gct ggt ctc ctc ctg cca       98 
Gly Gly His Gly Met Met Ala Leu Leu Leu Ala Gly Leu Leu Leu Pro 
         15                  20                  25 

ggg acc ttg gct aag agc att ggc acc ttc tca gac ccc tgt aag gac      146 
Gly Thr Leu Ala Lys Ser Ile Gly Thr Phe Ser Asp Pro Cys Lys Asp 
     30                  35                  40 

ccc acg cgt atc acc tcc cct aac gac ccc tgc ctc act ggg aag ggt      194 
Pro Thr Arg Ile Thr Ser Pro Asn Asp Pro Cys Leu Thr Gly Lys Gly 
 45                  50                  55                  60 

gac tcc agc ggc ttc agt agc tac agt ggc tcc agc agt tct ggc agc      242 
Asp Ser Ser Gly Phe Ser Ser Tyr Ser Gly Ser Ser Ser Ser Gly Ser 
                 65                  70                  75 

tcc att tcc agt gcc aga agc tct ggt ggt ggc tcc agt ggt agc tcc      290 
Ser Ile Ser Ser Ala Arg Ser Ser Gly Gly Gly Ser Ser Gly Ser Ser 
             80                  85                  90 

agc gga tcc agc att gcc cag ggt ggt tct gca gga tct ttt aag cca      338 
Ser Gly Ser Ser Ile Ala Gln Gly Gly Ser Ala Gly Ser Phe Lys Pro 
         95                 100                 105 

gga acg ggg tat tcc cag gtc agc tac tcc tcc gga tct ggc tct agt      386 
Gly Thr Gly Tyr Ser Gln Val Ser Tyr Ser Ser Gly Ser Gly Ser Ser 
    110                 115                 120 

cta caa ggt gca tcc ggt tcc tcc cag ctg ggg agc agc agc tct cac      434 
Leu Gln Gly Ala Ser Gly Ser Ser Gln Leu Gly Ser Ser Ser Ser His 
125                 130                 135                 140 

tcg gga arc agc ggc tct cac tcg gga agc ygc ags tct cat tcg agc      482 
Ser Gly Xaa Ser Gly Ser His Ser Gly Ser Xaa Xaa Ser His Ser Ser 
                145                 150                 155 

agc agc agc agc ttt cag ttc agc agc agc agc ttc caa gta ggg aat      530 
Ser Ser Ser Ser Phe Gln Phe Ser Ser Ser Ser Phe Gln Val Gly Asn 
            160                 165                 170 

ggc tct gct ctg cca acc aat gac aac tct tac cgc gga ata cta aac      578 
Gly Ser Ala Leu Pro Thr Asn Asp Asn Ser Tyr Arg Gly Ile Leu Asn 
        175                 180                 185 

cct tcc cag cct gga caa agc tct tcc tct tcc caa acc tyt ggg gta      626 
Pro Ser Gln Pro Gly Gln Ser Ser Ser Ser Ser Gln Thr Xaa Gly Val 
    190                 195                 200 

tcc agc agt ggc caa agc gtc agc tcc aac cag cgt ccc tgt agt tcg      674 
Ser Ser Ser Gly Gln Ser Val Ser Ser Asn Gln Arg Pro Cys Ser Ser 
205                 210                 215                 220 

gac atc ccc gac tct ccc tgc agt gga ggg ccc atc gtc tcg cac tct      722 
Asp Ile Pro Asp Ser Pro Cys Ser Gly Gly Pro Ile Val Ser His Ser 
                225                 230                 235 

ggc ccc tac atc ccc agc tcc cac tct gtg tca ggg ggt cag agg cct      770 
Gly Pro Tyr Ile Pro Ser Ser His Ser Val Ser Gly Gly Gln Arg Pro 
            240                 245                 250 

gtg gtg gtg gtg gtg gac cag cac ggt tct ggt gcc cct gga gtg gtt      818 
Val Val Val Val Val Asp Gln His Gly Ser Gly Ala Pro Gly Val Val 
        255                 260                 265 

caa ggt ccc ccc tgt agc aat ggt ggc ctt cca ggc aag wcc tgt ccc      866 
Gln Gly Pro Pro Cys Ser Asn Gly Gly Leu Pro Gly Lys Xaa Cys Pro 
    270                 275                 280 

cca atc acc tct gta gac aaa tcc tat ggt ggc tac gag gtg gtg ggt      914 
Pro Ile Thr Ser Val Asp Lys Ser Tyr Gly Gly Tyr Glu Val Val Gly 
285                 290                 295                 300 

ggc tcc tct gac agt tat ctg gtt cca ggc atg acc tac agt aag ggt      962 
Gly Ser Ser Asp Ser Tyr Leu Val Pro Gly Met Thr Tyr Ser Lys Gly 
                305                 310                 315 

aaa atc tat cct gtg ggc tac ttc acc aaa gag aac cct gtg aaa ggc     1010 
Lys Ile Tyr Pro Val Gly Tyr Phe Thr Lys Glu Asn Pro Val Lys Gly 
            320                 325                 330 

tct cca ggg gtc cct tcc ttt gca gct ggg ccc ccc atc tct gag ggc     1058 
Ser Pro Gly Val Pro Ser Phe Ala Ala Gly Pro Pro Ile Ser Glu Gly 
        335                 340                 345 

aaa tac ttc tcc agc aac ccc atc atc ccc agc cag tcg gca gct tcc     1106 
Lys Tyr Phe Ser Ser Asn Pro Ile Ile Pro Ser Gln Ser Ala Ala Ser 
    350                 355                 360 

tcg gcc att gcg ttc cag cca gtg ggg act ggt ggg gtc cag ctc tgt     1154 
Ser Ala Ile Ala Phe Gln Pro Val Gly Thr Gly Gly Val Gln Leu Cys 
365                 370                 375                 380 

gga ggc ggc tcc acg ggc tcc aag gga ccc tgc tct ccc tcc agt tct     1202 
Gly Gly Gly Ser Thr Gly Ser Lys Gly Pro Cys Ser Pro Ser Ser Ser 
                385                 390                 395 

cga gtc ccc agc rgt tct agc att tcc agc agc kcc gkt tya ccc tac     1250 
Arg Val Pro Ser Xaa Ser Ser Ile Ser Ser Ser Xaa Xaa Xaa Pro Tyr 
            400                 405                 410 

cat ccc tgc ggc agt gct tcc cag agc ccc tgc tcc cca cca ggc acc     1298 
His Pro Cys Gly Ser Ala Ser Gln Ser Pro Cys Ser Pro Pro Gly Thr 
        415                 420                 425 

ggc tcc ttc agc agc agc tcc agt tcc caa tcg agt ggc aaa atc atc     1346 
Gly Ser Phe Ser Ser Ser Ser Ser Ser Gln Ser Ser Gly Lys Ile Ile 
    430                 435                 440 

ctt cag cct tgt ggc agc aag tcc arc tct tct ggt cac cct tgc atg     1394 
Leu Gln Pro Cys Gly Ser Lys Ser Xaa Ser Ser Gly His Pro Cys Met 
445                 450                 455                 460 

tct gtc tcc tcc ttg aca ctg act ggg ggc ccc gat ggc tct ccc cat     1442 
Ser Val Ser Ser Leu Thr Leu Thr Gly Gly Pro Asp Gly Ser Pro His 
                465                 470                 475 

cct gat ccc tcc gct ggt gcc aag ccc tgt ggc tcc agc agt gct gga     1490 
Pro Asp Pro Ser Ala Gly Ala Lys Pro Cys Gly Ser Ser Ser Ala Gly 
            480                 485                 490 

aag atc ccc tgc cgc tcc atc cgg gat atc cta gcc caa gtg aag cct     1538 
Lys Ile Pro Cys Arg Ser Ile Arg Asp Ile Leu Ala Gln Val Lys Pro 
        495                 500                 505 

ctg ggg ccc cag cta gct gac cct gaa gtt ttc cta ccc caa gga gag     1586 
Leu Gly Pro Gln Leu Ala Asp Pro Glu Val Phe Leu Pro Gln Gly Glu 
    510                 515                 520 

tta ctc rac agt cca taagtcaact gttgtgtgtg tgcatgcctt gggcacaaac     1641 
Leu Leu Xaa Ser Pro 
525 

aagcacatac actatatccc atatgggaga aggccagtgc ccaggcatag ggttagctca   1701 

gtttccctcc ttcccaaaag agtg                                          1725 

 
           
             61  
             529  
             PRT  
             Homo sapiens  
             
               VARIANT  
               143  
               Xaa = Ser or Asn  
             
           
            61 

Met Gly Ser Ser Arg Ala Pro Trp Met Gly Arg Val Gly Gly His Gly 
 1               5                  10                  15 

Met Met Ala Leu Leu Leu Ala Gly Leu Leu Leu Pro Gly Thr Leu Ala 
            20                  25                  30 

Lys Ser Ile Gly Thr Phe Ser Asp Pro Cys Lys Asp Pro Thr Arg Ile 
        35                  40                  45 

Thr Ser Pro Asn Asp Pro Cys Leu Thr Gly Lys Gly Asp Ser Ser Gly 
    50                  55                  60 

Phe Ser Ser Tyr Ser Gly Ser Ser Ser Ser Gly Ser Ser Ile Ser Ser 
65                  70                  75                  80 

Ala Arg Ser Ser Gly Gly Gly Ser Ser Gly Ser Ser Ser Gly Ser Ser 
                85                  90                  95 

Ile Ala Gln Gly Gly Ser Ala Gly Ser Phe Lys Pro Gly Thr Gly Tyr 
            100                 105                 110 

Ser Gln Val Ser Tyr Ser Ser Gly Ser Gly Ser Ser Leu Gln Gly Ala 
        115                 120                 125 

Ser Gly Ser Ser Gln Leu Gly Ser Ser Ser Ser His Ser Gly Xaa Ser 
    130                 135                 140 

Gly Ser His Ser Gly Ser Xaa Xaa Ser His Ser Ser Ser Ser Ser Ser 
145                 150                 155                 160 

Phe Gln Phe Ser Ser Ser Ser Phe Gln Val Gly Asn Gly Ser Ala Leu 
                165                 170                 175 

Pro Thr Asn Asp Asn Ser Tyr Arg Gly Ile Leu Asn Pro Ser Gln Pro 
            180                 185                 190 

Gly Gln Ser Ser Ser Ser Ser Gln Thr Xaa Gly Val Ser Ser Ser Gly 
        195                 200                 205 

Gln Ser Val Ser Ser Asn Gln Arg Pro Cys Ser Ser Asp Ile Pro Asp 
    210                 215                 220 

Ser Pro Cys Ser Gly Gly Pro Ile Val Ser His Ser Gly Pro Tyr Ile 
225                 230                 235                 240 

Pro Ser Ser His Ser Val Ser Gly Gly Gln Arg Pro Val Val Val Val 
                245                 250                 255 

Val Asp Gln His Gly Ser Gly Ala Pro Gly Val Val Gln Gly Pro Pro 
            260                 265                 270 

Cys Ser Asn Gly Gly Leu Pro Gly Lys Xaa Cys Pro Pro Ile Thr Ser 
        275                 280                 285 

Val Asp Lys Ser Tyr Gly Gly Tyr Glu Val Val Gly Gly Ser Ser Asp 
    290                 295                 300 

Ser Tyr Leu Val Pro Gly Met Thr Tyr Ser Lys Gly Lys Ile Tyr Pro 
305                 310                 315                 320 

Val Gly Tyr Phe Thr Lys Glu Asn Pro Val Lys Gly Ser Pro Gly Val 
                325                 330                 335 

Pro Ser Phe Ala Ala Gly Pro Pro Ile Ser Glu Gly Lys Tyr Phe Ser 
            340                 345                 350 

Ser Asn Pro Ile Ile Pro Ser Gln Ser Ala Ala Ser Ser Ala Ile Ala 
        355                 360                 365 

Phe Gln Pro Val Gly Thr Gly Gly Val Gln Leu Cys Gly Gly Gly Ser 
    370                 375                 380 

Thr Gly Ser Lys Gly Pro Cys Ser Pro Ser Ser Ser Arg Val Pro Ser 
385                 390                 395                 400 

Xaa Ser Ser Ile Ser Ser Ser Xaa Xaa Xaa Pro Tyr His Pro Cys Gly 
                405                 410                 415 

Ser Ala Ser Gln Ser Pro Cys Ser Pro Pro Gly Thr Gly Ser Phe Ser 
            420                 425                 430 

Ser Ser Ser Ser Ser Gln Ser Ser Gly Lys Ile Ile Leu Gln Pro Cys 
        435                 440                 445 

Gly Ser Lys Ser Xaa Ser Ser Gly His Pro Cys Met Ser Val Ser Ser 
    450                 455                 460 

Leu Thr Leu Thr Gly Gly Pro Asp Gly Ser Pro His Pro Asp Pro Ser 
465                 470                 475                 480 

Ala Gly Ala Lys Pro Cys Gly Ser Ser Ser Ala Gly Lys Ile Pro Cys 
                485                 490                 495 

Arg Ser Ile Arg Asp Ile Leu Ala Gln Val Lys Pro Leu Gly Pro Gln 
            500                 505                 510 

Leu Ala Asp Pro Glu Val Phe Leu Pro Gln Gly Glu Leu Leu Xaa Ser 
        515                 520                 525 

Pro 

 
           
             62  
             2474  
             DNA  
             Homo sapiens  
             
               CDS  
               (23)...(2290)  
             
           
            62 

cgccctttca actctgccaa ga atg gct ccc acc tgg ctc tca gac att ccc      52 
                         Met Ala Pro Thr Trp Leu Ser Asp Ile Pro 
                          1               5                   10 

ctg gtc caa ccc cca ggc cat caa gat gtc tca gag agg cgg cta gac      100 
Leu Val Gln Pro Pro Gly His Gln Asp Val Ser Glu Arg Arg Leu Asp 
                 15                  20                  25 

acc cag aga cct caa gtg acc atg tgg gaa cgg gat gtt tcc agt gac      148 
Thr Gln Arg Pro Gln Val Thr Met Trp Glu Arg Asp Val Ser Ser Asp 
             30                  35                  40 

agg cag gag cca ggg cgg aga ggc agg tcc tgg ggg ctg gag ggg tca      196 
Arg Gln Glu Pro Gly Arg Arg Gly Arg Ser Trp Gly Leu Glu Gly Ser 
         45                  50                  55 

cag gcc ctg agc cag cag gct gag gtg atc gtt cgg cag ctg caa gag      244 
Gln Ala Leu Ser Gln Gln Ala Glu Val Ile Val Arg Gln Leu Gln Glu 
     60                  65                  70 

ctg crg tgg ctg gag gag gag gtc tgg ctc ctg cgg gag acc tcg ctg      292 
Leu Xaa Trp Leu Glu Glu Glu Val Trp Leu Leu Arg Glu Thr Ser Leu 
 75                  80                  85                  90 

cag cag aag atg agg cta gag gcc cag gcc atg gag cta gag gct ctg      340 
Gln Gln Lys Met Arg Leu Glu Ala Gln Ala Met Glu Leu Glu Ala Leu 
                 95                 100                 105 

gca cgg gcg gag aag gcc ggc cga gct gag gct gag ggc ctg cgt gct      388 
Ala Arg Ala Glu Lys Ala Gly Arg Ala Glu Ala Glu Gly Leu Arg Ala 
            110                 115                 120 

gct ttg gct ggg gct gag gtt gtc cgg aag aac ttg gaa gag ggg ags      436 
Ala Leu Ala Gly Ala Glu Val Val Arg Lys Asn Leu Glu Glu Gly Xaa 
        125                 130                 135 

cag cgg gag ctg gaa gag gtt cag agg ctg cac caa gag cag ctg tcc      484 
Gln Arg Glu Leu Glu Glu Val Gln Arg Leu His Gln Glu Gln Leu Ser 
    140                 145                 150 

tct ttg aca cag gct cac gag gag gct ctt tcc agt ttg acc agc aag      532 
Ser Leu Thr Gln Ala His Glu Glu Ala Leu Ser Ser Leu Thr Ser Lys 
155                 160                 165                 170 

gct gag ggc ttg gag aag tct ctg agt agt ctg gaa acc aga aga gca      580 
Ala Glu Gly Leu Glu Lys Ser Leu Ser Ser Leu Glu Thr Arg Arg Ala 
                175                 180                 185 

ggg gaa gcc aag gag ctg gcc gag gct cag agg gag gcc gag ctg ctt      628 
Gly Glu Ala Lys Glu Leu Ala Glu Ala Gln Arg Glu Ala Glu Leu Leu 
            190                 195                 200 

cgg aag cag ctg agc aag acc cag gaa gac ttg gag gct cag gtg acc      676 
Arg Lys Gln Leu Ser Lys Thr Gln Glu Asp Leu Glu Ala Gln Val Thr 
        205                 210                 215 

ctg gtt gag aat cta aga aaa tat gtt ggg gaa caa gtc cct tct gag      724 
Leu Val Glu Asn Leu Arg Lys Tyr Val Gly Glu Gln Val Pro Ser Glu 
    220                 225                 230 

gtc cac agc cag aca tgg gaa ctg gag cga cag aag ctt ctg gam acc      772 
Val His Ser Gln Thr Trp Glu Leu Glu Arg Gln Lys Leu Leu Xaa Thr 
235                 240                 245                 250 

atg cag cac ttg cag gag gac cgg gac agc ctg cat gcc acc gcg gag      820 
Met Gln His Leu Gln Glu Asp Arg Asp Ser Leu His Ala Thr Ala Glu 
                255                 260                 265 

ctg ctg cag gtg cgg gtg cag agc ctc aca cac atc ctc gcc ctg cag      868 
Leu Leu Gln Val Arg Val Gln Ser Leu Thr His Ile Leu Ala Leu Gln 
            270                 275                 280 

gag gag gag ctg acc agg aag gtt caa cct tca gat tcc ctg gag cct      916 
Glu Glu Glu Leu Thr Arg Lys Val Gln Pro Ser Asp Ser Leu Glu Pro 
        285                 290                 295 

gag ttt acc agg aag tgc cag tcc ctg ctg aac cgc tgg cgg gag aag      964 
Glu Phe Thr Arg Lys Cys Gln Ser Leu Leu Asn Arg Trp Arg Glu Lys 
    300                 305                 310 

gtg ttt gcc ctc atg gtg cag cta aag gcc cag gag ctg gaa cac agt     1012 
Val Phe Ala Leu Met Val Gln Leu Lys Ala Gln Glu Leu Glu His Ser 
315                 320                 325                 330 

gac tct gtt aag cag ctg aag gga cag gtg gcc tca ctc cag gaa aaa     1060 
Asp Ser Val Lys Gln Leu Lys Gly Gln Val Ala Ser Leu Gln Glu Lys 
                335                 340                 345 

gtg aca tcc cag agc cag gag cag gcc atc ctg cag cga tcc ctg cag     1108 
Val Thr Ser Gln Ser Gln Glu Gln Ala Ile Leu Gln Arg Ser Leu Gln 
            350                 355                 360 

gac aaa gcc gca gag gtg gag gtg gag cgt atg ggt gcc aag ggc ctg     1156 
Asp Lys Ala Ala Glu Val Glu Val Glu Arg Met Gly Ala Lys Gly Leu 
        365                 370                 375 

cag ttg gag ctg agc cgt gct cag gag gcc agg cgt ygg tgg cag cag     1204 
Gln Leu Glu Leu Ser Arg Ala Gln Glu Ala Arg Arg Xaa Trp Gln Gln 
    380                 385                 390 

cag aca gcc tca gcc gag gag cag ttg agg ctt gtg gtc aat gct gtc     1252 
Gln Thr Ala Ser Ala Glu Glu Gln Leu Arg Leu Val Val Asn Ala Val 
395                 400                 405                 410 

agc agc tct cag atc tgg ctc gag acc acc atg gct aag gtg gaa ggg     1300 
Ser Ser Ser Gln Ile Trp Leu Glu Thr Thr Met Ala Lys Val Glu Gly 
                415                 420                 425 

gct gcc gcc cag ctt ccc agc ctc aac aac cga ctc agc tat gct gtc     1348 
Ala Ala Ala Gln Leu Pro Ser Leu Asn Asn Arg Leu Ser Tyr Ala Val 
            430                 435                 440 

cgc aag gtc cac acc att cgg ggc ctg att gct cga aag ctt gcc ctt     1396 
Arg Lys Val His Thr Ile Arg Gly Leu Ile Ala Arg Lys Leu Ala Leu 
        445                 450                 455 

gct cag ctg cgc cag gag agc tgt ccc cta cca cca ccg gtc aca gat     1444 
Ala Gln Leu Arg Gln Glu Ser Cys Pro Leu Pro Pro Pro Val Thr Asp 
    460                 465                 470 

gtg agc ctt gag ttg cag cag ctg cgg gaa gaa cgg aac cgc ctg gat     1492 
Val Ser Leu Glu Leu Gln Gln Leu Arg Glu Glu Arg Asn Arg Leu Asp 
475                 480                 485                 490 

gca gaa ctg cag ctg agt gcc cgc ctc atc cag cag gag gtg ggc cgg     1540 
Ala Glu Leu Gln Leu Ser Ala Arg Leu Ile Gln Gln Glu Val Gly Arg 
                495                 500                 505 

gct cgg gag caa ggg gag gca gag cgg cag cag ctg agc aag gtg gcc     1588 
Ala Arg Glu Gln Gly Glu Ala Glu Arg Gln Gln Leu Ser Lys Val Ala 
            510                 515                 520 

cag cag ctg gag cag gag ctg cag cag acc cag gag tcc ctg gct agc     1636 
Gln Gln Leu Glu Gln Glu Leu Gln Gln Thr Gln Glu Ser Leu Ala Ser 
        525                 530                 535 

ttg ggg ctg cag ctg gag gta gca cgc cag tgc cag cag gag agc aca     1684 
Leu Gly Leu Gln Leu Glu Val Ala Arg Gln Cys Gln Gln Glu Ser Thr 
    540                 545                 550 

gag gag gct gcc agt ctg cgg cag gag ctg acc cag cag cag gaa ctc     1732 
Glu Glu Ala Ala Ser Leu Arg Gln Glu Leu Thr Gln Gln Gln Glu Leu 
555                 560                 565                 570 

tac ggg caa gcc ctg caa gaa aag gtg gct gaa gtg gaa act cgg ctg     1780 
Tyr Gly Gln Ala Leu Gln Glu Lys Val Ala Glu Val Glu Thr Arg Leu 
                575                 580                 585 

cgg gag caa ctc tca gac aca gag agg agg ctg aac gag gct crg agg     1828 
Arg Glu Gln Leu Ser Asp Thr Glu Arg Arg Leu Asn Glu Ala Xaa Arg 
            590                 595                 600 

gag cat gcc aag gcc gtg gtc tcc ttr cgc cak att cag cgc aga gcc     1876 
Glu His Ala Lys Ala Val Val Ser Xaa Arg Xaa Ile Gln Arg Arg Ala 
        605                 610                 615 

gcc cag gaa awg gag cgg agc cag gaa ctc agg ygt ctg cag gag gag     1924 
Ala Gln Glu Xaa Glu Arg Ser Gln Glu Leu Arg Xaa Leu Gln Glu Glu 
    620                 625                 630 

gcc cgg aag gag gag ggg cag cga ctg gcc cgg cgc ttg cag gag cta     1972 
Ala Arg Lys Glu Glu Gly Gln Arg Leu Ala Arg Arg Leu Gln Glu Leu 
635                 640                 645                 650 

gag agg gat aag aac ctc atg ctg gcc acc ttg cag cag gaa ggt ctc     2020 
Glu Arg Asp Lys Asn Leu Met Leu Ala Thr Leu Gln Gln Glu Gly Leu 
                655                 660                 665 

ctc tcc cgt tac aag cag cag cga ctg ttg aca gtt ctt cct tcc cta     2068 
Leu Ser Arg Tyr Lys Gln Gln Arg Leu Leu Thr Val Leu Pro Ser Leu 
            670                 675                 680 

ctg gat aag aag aaa tct gtg gtg tcc agc ccc agg cct cca gag tgt     2116 
Leu Asp Lys Lys Lys Ser Val Val Ser Ser Pro Arg Pro Pro Glu Cys 
        685                 690                 695 

tca gca tct gca cct gta gca gca gca gtg ccc acc agg gag tcc ata     2164 
Ser Ala Ser Ala Pro Val Ala Ala Ala Val Pro Thr Arg Glu Ser Ile 
    700                 705                 710 

aaa ggg tcc ctc tct gtc ctg ctc gat gac ctg cag gac ctg agt gaa     2212 
Lys Gly Ser Leu Ser Val Leu Leu Asp Asp Leu Gln Asp Leu Ser Glu 
715                 720                 725                 730 

gcc att tcc aaa gag gaa gct gtt tgt caa gga gac aac ctt gac aga     2260 
Ala Ile Ser Lys Glu Glu Ala Val Cys Gln Gly Asp Asn Leu Asp Arg 
                735                 740                 745 

tgc tcc agc tsc aat ccc cag atg agc agc taagcagctg acagttggag       2310 
Cys Ser Ser Xaa Asn Pro Gln Met Ser Ser 
            750                 755 

ggaaagccag cctgggggct gggaggatcc tggagaagtg ggtggggaca gaccagccct   2370 

tccccatcct ggggttgccc tgggggatac cagctgagtc tgaattctgc tctaaataaa   2430 

gacgactaca gaaggaaaaa aaaaaaaaaa aaaaaaaaaa aaaa                    2474 

 
           
             63  
             756  
             PRT  
             Homo sapiens  
             
               VARIANT  
               76  
               Xaa = Arg or Gln  
             
           
            63 

Met Ala Pro Thr Trp Leu Ser Asp Ile Pro Leu Val Gln Pro Pro Gly 
 1               5                  10                  15 

His Gln Asp Val Ser Glu Arg Arg Leu Asp Thr Gln Arg Pro Gln Val 
            20                  25                  30 

Thr Met Trp Glu Arg Asp Val Ser Ser Asp Arg Gln Glu Pro Gly Arg 
        35                  40                  45 

Arg Gly Arg Ser Trp Gly Leu Glu Gly Ser Gln Ala Leu Ser Gln Gln 
    50                  55                  60 

Ala Glu Val Ile Val Arg Gln Leu Gln Glu Leu Xaa Trp Leu Glu Glu 
65                  70                  75                  80 

Glu Val Trp Leu Leu Arg Glu Thr Ser Leu Gln Gln Lys Met Arg Leu 
                85                  90                  95 

Glu Ala Gln Ala Met Glu Leu Glu Ala Leu Ala Arg Ala Glu Lys Ala 
            100                 105                 110 

Gly Arg Ala Glu Ala Glu Gly Leu Arg Ala Ala Leu Ala Gly Ala Glu 
        115                 120                 125 

Val Val Arg Lys Asn Leu Glu Glu Gly Xaa Gln Arg Glu Leu Glu Glu 
    130                 135                 140 

Val Gln Arg Leu His Gln Glu Gln Leu Ser Ser Leu Thr Gln Ala His 
145                 150                 155                 160 

Glu Glu Ala Leu Ser Ser Leu Thr Ser Lys Ala Glu Gly Leu Glu Lys 
                165                 170                 175 

Ser Leu Ser Ser Leu Glu Thr Arg Arg Ala Gly Glu Ala Lys Glu Leu 
            180                 185                 190 

Ala Glu Ala Gln Arg Glu Ala Glu Leu Leu Arg Lys Gln Leu Ser Lys 
        195                 200                 205 

Thr Gln Glu Asp Leu Glu Ala Gln Val Thr Leu Val Glu Asn Leu Arg 
    210                 215                 220 

Lys Tyr Val Gly Glu Gln Val Pro Ser Glu Val His Ser Gln Thr Trp 
225                 230                 235                 240 

Glu Leu Glu Arg Gln Lys Leu Leu Xaa Thr Met Gln His Leu Gln Glu 
                245                 250                 255 

Asp Arg Asp Ser Leu His Ala Thr Ala Glu Leu Leu Gln Val Arg Val 
            260                 265                 270 

Gln Ser Leu Thr His Ile Leu Ala Leu Gln Glu Glu Glu Leu Thr Arg 
        275                 280                 285 

Lys Val Gln Pro Ser Asp Ser Leu Glu Pro Glu Phe Thr Arg Lys Cys 
    290                 295                 300 

Gln Ser Leu Leu Asn Arg Trp Arg Glu Lys Val Phe Ala Leu Met Val 
305                 310                 315                 320 

Gln Leu Lys Ala Gln Glu Leu Glu His Ser Asp Ser Val Lys Gln Leu 
                325                 330                 335 

Lys Gly Gln Val Ala Ser Leu Gln Glu Lys Val Thr Ser Gln Ser Gln 
            340                 345                 350 

Glu Gln Ala Ile Leu Gln Arg Ser Leu Gln Asp Lys Ala Ala Glu Val 
        355                 360                 365 

Glu Val Glu Arg Met Gly Ala Lys Gly Leu Gln Leu Glu Leu Ser Arg 
    370                 375                 380 

Ala Gln Glu Ala Arg Arg Xaa Trp Gln Gln Gln Thr Ala Ser Ala Glu 
385                 390                 395                 400 

Glu Gln Leu Arg Leu Val Val Asn Ala Val Ser Ser Ser Gln Ile Trp 
                405                 410                 415 

Leu Glu Thr Thr Met Ala Lys Val Glu Gly Ala Ala Ala Gln Leu Pro 
            420                 425                 430 

Ser Leu Asn Asn Arg Leu Ser Tyr Ala Val Arg Lys Val His Thr Ile 
        435                 440                 445 

Arg Gly Leu Ile Ala Arg Lys Leu Ala Leu Ala Gln Leu Arg Gln Glu 
    450                 455                 460 

Ser Cys Pro Leu Pro Pro Pro Val Thr Asp Val Ser Leu Glu Leu Gln 
465                 470                 475                 480 

Gln Leu Arg Glu Glu Arg Asn Arg Leu Asp Ala Glu Leu Gln Leu Ser 
                485                 490                 495 

Ala Arg Leu Ile Gln Gln Glu Val Gly Arg Ala Arg Glu Gln Gly Glu 
            500                 505                 510 

Ala Glu Arg Gln Gln Leu Ser Lys Val Ala Gln Gln Leu Glu Gln Glu 
        515                 520                 525 

Leu Gln Gln Thr Gln Glu Ser Leu Ala Ser Leu Gly Leu Gln Leu Glu 
    530                 535                 540 

Val Ala Arg Gln Cys Gln Gln Glu Ser Thr Glu Glu Ala Ala Ser Leu 
545                 550                 555                 560 

Arg Gln Glu Leu Thr Gln Gln Gln Glu Leu Tyr Gly Gln Ala Leu Gln 
                565                 570                 575 

Glu Lys Val Ala Glu Val Glu Thr Arg Leu Arg Glu Gln Leu Ser Asp 
            580                 585                 590 

Thr Glu Arg Arg Leu Asn Glu Ala Xaa Arg Glu His Ala Lys Ala Val 
        595                 600                 605 

Val Ser Xaa Arg Xaa Ile Gln Arg Arg Ala Ala Gln Glu Xaa Glu Arg 
    610                 615                 620 

Ser Gln Glu Leu Arg Xaa Leu Gln Glu Glu Ala Arg Lys Glu Glu Gly 
625                 630                 635                 640 

Gln Arg Leu Ala Arg Arg Leu Gln Glu Leu Glu Arg Asp Lys Asn Leu 
                645                 650                 655 

Met Leu Ala Thr Leu Gln Gln Glu Gly Leu Leu Ser Arg Tyr Lys Gln 
            660                 665                 670 

Gln Arg Leu Leu Thr Val Leu Pro Ser Leu Leu Asp Lys Lys Lys Ser 
        675                 680                 685 

Val Val Ser Ser Pro Arg Pro Pro Glu Cys Ser Ala Ser Ala Pro Val 
    690                 695                 700 

Ala Ala Ala Val Pro Thr Arg Glu Ser Ile Lys Gly Ser Leu Ser Val 
705                 710                 715                 720 

Leu Leu Asp Asp Leu Gln Asp Leu Ser Glu Ala Ile Ser Lys Glu Glu 
                725                 730                 735 

Ala Val Cys Gln Gly Asp Asn Leu Asp Arg Cys Ser Ser Xaa Asn Pro 
            740                 745                 750 

Gln Met Ser Ser 
        755