KR102327623B1 - SNP for asthma diagnosis and asthma diagnosis method using the same - Google Patents
SNP for asthma diagnosis and asthma diagnosis method using the same Download PDFInfo
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Abstract
Description
본 발명은 천식 진단용 SNP 및 이를 이용한 천식 진단 방법 등에 관한 것이다.The present invention relates to a SNP for diagnosing asthma and a method for diagnosing asthma using the same.
천식(asthma)은 여러가지 자극에 대한 기도의 과민반응성(bronchial hyperresponsiveness)을 그 특징으로 하는 질환으로 만성 기도 염증(chronic airway inflammation)을 일으키며 기도의 광범위한 협착에 의해 발생하는 천명(喘鳴), 호흡곤란, 기침 등의 임상 증세들이 나타나는데 이는 자연적으로 또는 치료에 의해 가역적으로 호전될 수 있다.Asthma is a disease characterized by bronchial hyperresponsiveness to various stimuli, causing chronic airway inflammation, wheezing, dyspnea, Clinical symptoms such as cough appear, which can be reversibly improved either naturally or by treatment.
유전체연구 기술 발달에 힘입어 한 사람에 존재하는 단일염기다형성(Single Nucleotide Polymorphism; SNP)과 질병발생과의 관련성을 동시에 살펴보는 전장 유전체 연관 분석(Genome-wide association study; GWAS) 방법이 대세를 이루게 되었다. 전장 유전체 연관 분석은 약 50만-200만 개 SNP의 유전자형을 탐색하여 질병과의 연관성을 통계적으로 분석하는 방법을 일컫는다. 현재까지 이 방법으로 약 2,000개 이상의 유전변이들이 전 세계적으로 발굴되었으며, GWAS를 이용한 천식에 대한 감수성 유전자들을 동정하고자 하는 시도가 이루어지고 있으며 아직까지 천식의 결정적 인자는 확인되지 않은 상태이다.Thanks to the development of genome research technology, the genome-wide association study (GWAS) method, which simultaneously examines the relationship between single nucleotide polymorphism (SNP) and disease occurrence in a person, has become the mainstream. became Whole genome association analysis refers to a method of statistically analyzing associations with diseases by searching for the genotypes of about 500,000 to 2 million SNPs. To date, more than 2,000 genetic mutations have been discovered worldwide by this method, and attempts are being made to identify susceptibility genes for asthma using GWAS.
이에 본 발명자들은 천식과 관련된 유전자형을 확인하기 위해 동일한 표본 크기를 이용하여 변이(variant)를 검출하는 데에 있어, GWAS 분석을 수행한 결과, 천식과 관련된 유의한 SNP들을 확인하여, 본 발명을 완성하였다.Accordingly, the present inventors completed the present invention by identifying significant SNPs related to asthma as a result of performing GWAS analysis in detecting a variant using the same sample size to confirm the asthma-related genotype. did.
본 발명자들은 천식 진단 또는 천식 발병을 예측하기 위한 마커를 개발하고자 노력한 결과, 본 발명을 완성하게 되었다.The present inventors have completed the present invention as a result of efforts to develop a marker for diagnosing asthma or predicting the onset of asthma.
이에, 본 발명의 목적은 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593으로 이루어진 군으로부터 선택된 하나 이상의 SNP의 검출 제제를 포함하는 천식 진단용 조성물을 제공하는 것이다.Accordingly, an object of the present invention is a single nucleotide polymorphism (SNP) site on
본 발명의 다른 목적은 상기 천식 진단용 조성물을 포함하는, 천식 예측 또는 진단용 키트를 제공하는 것이다.Another object of the present invention is to provide a kit for predicting or diagnosing asthma, comprising the composition for diagnosing asthma.
본 발명의 또 다른 목적은 피검체로부터 수득한 시료 중의 SNP 부위의 염기서열에 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593로 이루어진 군으로부터 선택된 하나 이상의 단일염기다형성이 존재하는 경우, 피검체가 천식 환자이거나 천식에 걸릴 위험이 높은 것으로 결정하는 단계를 포함하는 천식 진단 또는 예측에 필요한 정보를 제공하는 방법을 제공하는 것이다.Another object of the present invention is to provide a single nucleotide polymorphism (SNP) site on
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당해 기술분야의 통상의 기술자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
상기 과제를 해결하기 위하여, 본 발명은 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593으로 이루어진 군으로부터 선택된 하나 이상의 SNP의 검출 제제를 포함하는 천식 진단용 조성물을 제공한다.In order to solve the above problems, the present invention provides a single nucleotide polymorphism (SNP) site on
본 발명의 일 실시예에서, 상기 천식은 한국인에 대한 천식일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the asthma may be asthma for Koreans, but is not limited thereto.
본 발명의 다른 실시예에서, 상기 검출 제제는 rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593으로 이루어진 군으로부터 선택된 하나 이상의 SNP를 검출할 수 있는 프로브일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the detection agent is capable of detecting one or more SNPs selected from the group consisting of rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 and rs17426593. It may be a probe, but is not limited thereto.
본 발명의 또 다른 실시예에서, 상기 검출 제제는 rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593으로 이루어진 군으로부터 선택된 하나 이상의 SNP를 검출할 수 있는 프라이머일 수 있으나, 이에 제한되는 것은 아니다.In another embodiment of the present invention, the detection agent is capable of detecting one or more SNPs selected from the group consisting of rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 and rs17426593. It may be a primer, but is not limited thereto.
또한, 본 발명은 상기 천식 진단용 조성물을 포함하는, 천식 예측 또는 진단용 키트를 제공한다.In addition, the present invention provides a kit for predicting or diagnosing asthma, comprising the composition for diagnosing asthma.
본 발명의 일 실시예에서, 상기 키트는 RT-PCR 키트 또는 마이크로어레이 칩 키트일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the kit may be an RT-PCR kit or a microarray chip kit, but is not limited thereto.
또한, 본 발명은 피검체로부터 수득한 시료 중의 SNP 부위의 염기서열에 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593로 이루어진 군으로부터 선택된 하나 이상의 단일염기다형성이 존재하는 경우, 피검체가 천식 환자이거나 천식에 걸릴 위험이 높은 것으로 결정하는 단계를 포함하는 천식 진단 또는 예측에 필요한 정보를 제공하는 방법을 제공한다.In addition, the present invention provides a GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117452077741, rs1175520, which is a single nucleotide polymorphism (SNP) site on
또한, 본 발명은 피검체로부터 수득한 시료 중의 SNP 부위의 염기서열에 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593로 이루어진 군으로부터 선택된 하나 이상의 단일염기다형성이 존재하는 경우, 피검체가 천식 환자이거나 천식에 걸릴 위험이 높은 것으로 결정하는 단계를 포함하는 천식 진단 방법을 제공한다.In addition, the present invention provides a GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117452077741, rs1175520, which is a single nucleotide polymorphism (SNP) site on
또한, 본 발명은 피검체로부터 수득한 시료 중의 SNP 부위의 염기서열에 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593로 이루어진 군으로부터 선택된 하나 이상의 단일염기다형성이 존재하는 경우, 피검체가 천식 환자이거나 천식에 걸릴 위험이 높은 것으로 결정하는 단계를 포함하는 천식 예측 방법을 제공한다.In addition, the present invention provides a GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117452077741, rs1175520, which is a single nucleotide polymorphism (SNP) site on
본 발명의 일 실시예에서, 상기 방법은 시퀀싱(sequencing), 엑솜 시퀀싱(exome sequencing), 마이크로어레이에 의한 혼성화(microarray hybridization), 대립유전자 특이적인 PCR(allele specific PCR), 다이나믹대립유전자 혼성화 기법(dynamic allele-specific hybridization), PCR 연장 분석 및 Taqman 기법으로 이루어진 군으로부터 선택되는 하나 이상의 방법으로 수행될 수 있으나, 이에 제한되는 것은 아니다.In one embodiment of the present invention, the method includes sequencing, exome sequencing, microarray hybridization, allele specific PCR, dynamic allele hybridization technique ( dynamic allele-specific hybridization), PCR extension analysis, and Taqman technique may be performed by one or more methods selected from the group consisting of, but not limited thereto.
또한, 본 발명은 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593으로 이루어진 군으로부터 선택된 하나 이상의 SNP의 검출 제제를 포함하는 조성물의 천식 진단 용도를 제공한다.In addition, the present invention relates to a single nucleotide polymorphism (SNP) site on
또한, 본 발명은 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593으로 이루어진 군으로부터 선택된 하나 이상의 SNP의 검출 제제를 포함하는 조성물의 천식 발병 예측 용도를 제공한다.In addition, the present invention relates to a single nucleotide polymorphism (SNP) site on
본 발명자들은 천식 환자들의 유전체 DNA의 단백질 코딩 부위를 분석한 결과, 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593가 천식 환자와 밀접하게 연관되어 있는 것으로 규명하였으며, 이를 이용하여 천식의 진단 또는 발병 예측을 위한 유전자 진단 시약을 개발하는데 이용할 수 있다.As a result of analyzing the protein coding region of the genomic DNA of asthma patients, the present inventors found that the single nucleotide polymorphism (SNP) region on
도 1은 샘플에 대한 품질 관리 워크 플로우를 나타낸 것으로, 천식 케이스 및 대조군에서 SNP 및 대상체를 배제하기 위한 제어를 수해하는 다중 스탠다드 품질 관리를 수행하였다.
도 2는 천식 GWAS에 대한 QQ 플롯을 나타낸 것으로, GWAS에서 관찰된 P-값의 분포를 도시한 것이다.
도 3은 MDS 플롯을 나타낸 것으로, 회색 점은 1000G 대상체를 나타내며, 붉은 점과 푸른 점은 각각 천식 환자와 대조군이다.
도 4는 천식 GWAS의 p-값에 대한 맨해튼 플롯을 나타낸 것으로, 염색체 6 상의 한 영역은 로지스틱 회귀에 따른 전장유전체의 유의성(P <5x10-8)을 충족시켰다.
도 5는 염색체 6 상 중요한 SNP의 게놈 지역을 도시한 것이다. a는 염색체 6의 이데오그램(Ideogram)을 나타낸 것이다. b는 천식과 관련된 SNP를 포함하는 3 Mb 영역을 나타낸 것으로, 맨해튼 플롯은 상기 영역에서 유전자형 및 대치된 SNP 모두에 대한 p-값을 나타낸다. c는 유전자형 및 대치된 SNP 둘 다를 나타내는 600kb 영역의 확장된 맨해튼 플롯을 나타낸 것으로, 가장 중요한 rs1770은 자주색으로 표시하고, 다른 SNP는 rs1770과 관련하여 r2 값에 따라 색상을 지정하였다. 상기 범위에는 HLA 클래스 II 베타 사슬 파라로그(HLA class II beta chain paralogs)에 속하는 몇 가지 단백질 코딩 유전자가 있다.1 shows the quality control workflow for the sample, and multiple standard quality control was performed with control to exclude SNPs and subjects from asthma cases and controls.
2 shows a QQ plot for asthma GWAS, showing the distribution of observed P-values in GWAS.
3 shows an MDS plot, where gray dots represent 1000G subjects, and red and blue dots represent asthma patients and controls, respectively.
4 shows a Manhattan plot for the p-value of asthma GWAS, wherein one region on
Figure 5 depicts the genomic regions of important SNPs on
본 발명은 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593으로 이루어진 군으로부터 선택된 하나 이상의 SNP의 검출 제제를 포함하는 천식 진단용 조성물에 관한 것이다.The present invention provides a single nucleotide polymorphism (SNP) site on
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 명세서에서, “폴리뉴클레오티드(polynucleotide)” 또는 “핵산”은 단일 또는 이중 가닥의 형태로 된 데옥시리보핵산(deoxyribonucleic acid, DNA) 또는 리보핵산(ribonucleic acid, RNA)를 말한다. 다른 제한이 없는한, 자연적으로 생성되는 뉴클레오티드와 비슷한 방법으로 핵산에 혼성화되는 자연적 뉴클레오티드의 공지된 아날로그도 포함된다. 일반적으로 DNA는 아데닌(adenine, A), 구아닌(guanine, G), 시토신(cytosine, C), 티민(thymine, T) 등 네 가지 염기로 구성되어 있으며, RNA는 티민 대신 우라실(Uracil, U)을 가지고 있다. 핵산 이중 가닥에서 A는 T 또는 U, C는 G 염기와 수소결합을 이루는데, 이러한 염기의 관계를 ‘상보적(complementary)'이라고 한다.As used herein, "polynucleotide" or "nucleic acid" refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) in the form of single or double strands. Unless otherwise limited, known analogs of natural nucleotides that hybridize to nucleic acids in a manner analogous to naturally occurring nucleotides are also included. In general, DNA consists of four bases: adenine (A), guanine (G), cytosine (C), and thymine (T), and RNA consists of uracil (U) instead of thymine (Uracil, U). has a In a double-stranded nucleic acid, A forms hydrogen bonds with T or U and C with G bases.
본 명세서에서, 유전자의 변이를 표기할 때 ’c.'은 단백질 코딩 부위의 변이를 의미하며, ‘(염기 위치)(염기일문자)(기호 >)(염기일문자)’는 해당 염기 위치에서 선행 표기된 염기가 후행 표기된 염기로 치환된다는 것을 의미한다.In the present specification, when expressing the mutation of a gene, 'c.' means a mutation in the protein coding region, and '(base position) (single nucleotide) (symbol >) (single nucleotide)' means at the base position It means that the preceding indicated base is substituted with the following indicated base.
본 명세서에서,‘다형성(polymorphism)’이란 유전적으로 결정된 집단 내에서 2 이상의 대체적 서열 또는 대립형질(또는 대립유전자)의 발생을 의미하며, ‘단일염기다형성(single nucleotide polymorphism, SNP)'은 하나의 염기의 다형성을 의미한다. 구체적으로 유전체에서 단일염기(A, T, C 또는 G)가 종의 멤버들 간 또는 한 개체(individual)의 쌍 염색체 간에 발생하는 DNA 서열의 다양성을 의미한다. 예를 들어, 서로 다른 개체의 세 개의 DNA 단편들(예를 들어 AAGT[A/A]AG, AAGT[A/G]AG, AAGT[G/G]AG)처럼 단일염기에서 차이를 포함하는 경우, 두 개의 대립유전자(A 또는 G)라고 부르며, 일반적으로 거의 모든 SNP는 두 개의 대립 유전자를 가진다. 또한 SNP가 특정 질환과 유전적으로 밀접하게 연관되어 있는 경우에는, SNP는 확인된 정상인(normal) 또는 야생형(wild-type, WT) 개체 또는 대립유전자와 비교하여 특정 위치의 하나의 염기에 변이가 발생한 것을 의미하기도 한다.As used herein, 'polymorphism' refers to the occurrence of two or more alternative sequences or alleles (or alleles) within a genetically determined population, and 'single nucleotide polymorphism (SNP)' means one polymorphism of the base. Specifically, a single base (A, T, C, or G) in the genome refers to the diversity of DNA sequences occurring between members of a species or between chromosomes of an individual. For example, when three DNA fragments from different individuals (eg, AAGT[A/A]AG, AAGT[A/G]AG, AAGT[G/G]AG) contain differences in a single base , called two alleles (A or G), and in general almost all SNPs have two alleles. In addition, when the SNP is genetically closely related to a specific disease, the SNP is mutated in one base at a specific position compared to an identified normal or wild-type (WT) individual or allele. it also means
한편, 'mRNA(messenger RNA 또는 전령 RNA)'는 단백질 합성 과정에서 특정 유전자의 염기서열의 유전 정보를 리보솜(ribosome)으로 전달하여 폴리펩티드 합성(단백질 번역, translation)의 청사진 역할을 하는 RNA이다. 유전자를 주형(template)으로 하여 단일 가닥의 mRNA가 전사(transcription) 과정을 통하여 합성된다.On the other hand, 'mRNA (messenger RNA or messenger RNA)' is an RNA that serves as a blueprint for polypeptide synthesis (protein translation, translation) by transferring the genetic information of the base sequence of a specific gene to the ribosome during protein synthesis. Using the gene as a template, single-stranded mRNA is synthesized through the transcription process.
본 명세서에서 '단백질'은 '폴리펩타이드(polypeptide)' 또는 '펩타이드(peptide)'와 호환성 있게 사용되며, 예컨대, 자연 상태의 단백질에서 일반적으로 발견되는 바와 같이 아미노산 잔기의 중합체를 말한다.As used herein, 'protein' is used interchangeably with 'polypeptide' or 'peptide', for example, it refers to a polymer of amino acid residues as commonly found in proteins in a natural state.
본 명세서에 사용된 아미노산의 일문자(삼문자)는 생화학 분야에서의 표준 약어 규정에 따라 다음의 아미노산을 의미한다: A(Ala): 알라닌; C(Cys): 시스테인; D(Asp): 아스파르트산; E(Glu): 글루탐산; F(Phe): 페닐알라닌; G(Gly): 글라이신; H(His): 히스티딘; I(IIe): 이소류신; K(Lys): 라이신; L(Leu): 류신; M(Met): 메티오닌; N(Asn): 아스파라진; O(Ply): 피롤라이신; P(Pro): 프롤린; Q(Gln): 글루타민; R(Arg): 아르지닌; S(Ser): 세린; T(Thr): 쓰레오닌; U(Sec):셀레노시스테인; V(Val): 발린; W(Trp): 트립토판; Y(Tyr): 타이로신.As used herein, the one letter (three letters) of an amino acid refers to the following amino acids according to standard abbreviation rules in the field of biochemistry: A(Ala): alanine; C(Cys): cysteine; D(Asp): aspartic acid; E(Glu): glutamic acid; F(Phe): phenylalanine; G(Gly): glycine; H(His): histidine; I(IIe): isoleucine; K(Lys): lysine; L(Leu): leucine; M(Met): methionine; N(Asn): asparagine; O(Ply): pyrrolysine; P(Pro): proline; Q(Gln): glutamine; R(Arg): arginine; S(Ser): serine; T(Thr): threonine; U(Sec):selenocysteine; V(Val): valine; W(Trp): tryptophan; Y (Tyr): Tyrosine.
본 명세서에 표기되는 ‘(아미노산 일문자)(아미노산 위치)(아미노산 일문자)’는 천연형 단백질(wild-type protein)의 해당 아미노산 위치에서 선행 표기된 아미노산이 후행 표기된 아미노산으로 치환된다는 것을 의미한다.“(Amino acid one letter) (amino acid position) (amino acid letter letter)” as used herein means that the amino acid previously marked at the corresponding amino acid position of the wild-type protein is substituted with the amino acid post marked.
본 명세서에서 사용되는 용어 "상보적(complementary)"은 소정의 혼성화 또는 어닐링 조건, 구체적으로는 생리학적 조건 하(세포 내)에서 핵산 분자 내 타겟팅 모이어티가 타겟(예컨대, 상기 SNP)에 선택적으로 혼성화할 정도로 충분히 상보적인 것을 의미하는 것으로 하나 또는 그 이상의 미스매치(mismatch) 염기서열을 가질 수 있으며, 실질적으로 상보적(substantially complementary) 및 완전히 상보적(perfectly complementary)인 것을 모두 포괄하는 의미를 가지며, 보다 구체적으로는 완전히 상보적인 것을 의미한다.As used herein, the term “complementary” means that a targeting moiety in a nucleic acid molecule is selectively directed to a target (eg, the SNP) under certain hybridization or annealing conditions, specifically physiological conditions (in a cell). It means that it is sufficiently complementary to hybridize, it may have one or more mismatched nucleotide sequences, and has a meaning encompassing both substantially complementary and perfectly complementary. , more specifically meaning completely complementary.
본 명세서에서 천식 진단용 조성물은 염색체 6 상의 다형성(polymorphism)을 진단 마커로 검출한다. In the present specification, the composition for diagnosing asthma detects a polymorphism on
본 명세서에서 SNP rs1770은 서열번호 1의 HLA-DQB1(NG_029922.1) 유전자의 12009번째 염기가 C에서 T로 치환된 것이다.In the present specification, SNP rs1770 is one in which the 12009 base of the HLA-DQB1 (NG_029922.1) gene of SEQ ID NO: 1 is substituted from C to T.
본 명세서에서 SNP rs9273508은 서열번호 1의 HLA-DQB1 유전자의 11401번째 염기가 T에서 C로 치환된 것이다. In the present specification, SNP rs9273508 is one in which the base 11401 of the HLA-DQB1 gene of SEQ ID NO: 1 is substituted from T to C.
본 명세서에서 SNP rs9272998은 서열번호 2의 HLA-DQA1(NG_032876.1) 유전자의 11292번째 염기가 G에서 A로 치환된 것이다.In the present specification, SNP rs9272998 is one in which the 11292th base of the HLA-DQA1 (NG_032876.1) gene of SEQ ID NO: 2 is substituted from G to A.
본 명세서에서 SNP rs9271469은 염색체 6 NC_000006.11:g.의 32588630번째 염기가 T에서 C로 치환된 것이다.In the present specification, SNP rs9271469 is one in which the base 32588630 of
본 명세서에서 SNP rs9272221은 서열번호 2의 HLA-DQA1 유전자의 2152번째 염기가 C에서 A 또는 G로 치환된 것이다.In the present specification, SNP rs9272221 is one in which base 2152 of the HLA-DQA1 gene of SEQ ID NO: 2 is substituted from C to A or G.
본 명세서에서 SNP rs9272254은 서열번호 2의 HLA-DQA1 유전자의 2916번째 염기가 C에서 G 또는 T로 치환된 것이다.In the present specification, SNP rs9272254 is one in which the 2916th base of the HLA-DQA1 gene of SEQ ID NO: 2 is substituted from C to G or T.
본 명세서에서 SNP rs118008956은 염색체 6 NC_000006.11:g.의 32582998번째 염기가 T에서 C로 치환된 것이다.In the present specification, SNP rs118008956 is one in which the base 32582998 of
본 명세서에서 SNP rs117477741은 염색체 6 NC_000006.11:g.의 2583910번째 염기가 A에서 T로 치환된 것이다.In the present specification, SNP rs117477741 is one in which the 2583910th base of
본 명세서에서 SNP rs117552038은 염색체 6 NC_000006.11:g.의 32583937번째 염기가 C에서 G로 치환된 것이다.In the present specification, SNP rs117552038 is one in which the 32583937 base of
본 명세서에서 SNP rs11545686은 서열번호 2의 HLA-DQA1 유전자의 5106번째 염기가 T에서 C로 치환된 것이다.In the present specification, SNP rs11545686 is one in which the 5106th base of the HLA-DQA1 gene of SEQ ID NO: 2 is substituted from T to C.
본 명세서에서 SNP rs117316263은 염색체 6 NC_000006.11:g.의 32579695번째 염기가 A에서 G로 치환된 것이다.In the present specification, SNP rs117316263 is one in which the 32579695th base of
본 명세서에서 SNP rs35789108은 서열번호 3의 HLA-DRB1(NG_029921.1) 유전자의 15200번째 염기가 G에서 C로 치환된 것이다.In the present specification, SNP rs35789108 is one in which the 15200th base of the HLA-DRB1 (NG_029921.1) gene of SEQ ID NO: 3 is substituted from G to C.
본 명세서에서 SNP rs17426593은 서열번호 2의 HLA-DQA1 유전자의 7895번째 염기가 T에서 A, C 또는 G로 치환된 것이다.In the present specification, SNP rs17426593 is one in which the 7895th base of the HLA-DQA1 gene of SEQ ID NO: 2 is substituted with A, C or G from T.
본 명세서에서, 상기 염색체 6 상의 SNP는 하기 표 1에 기재된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present specification, the SNP on
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NC_000006.11:g.
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본 명세서에서, 용어 “검출”은 목적하는 물질(본 발명에서의 마커 단백질 또는 마커 SNP)의 존재(발현) 여부를 측정 및 확인하는 것, 또는 목적하는 물질의 존재 수준(발현 수준)의 변화를 측정 및 확인하는 것을 모두 포함하는 의미이다. 같은 맥락에서, 본 발명에서 상기 SNP의 발현수준을 측정하는 것은 발현 여부를 측정하는 것(즉, 발현 유무를 측정하는 것), 또는 상기 SNP의 질적, 양적 변화 수준을 측정하는 것을 의미한다. 상기 측정은 정성적인 방법(분석)과 정량적인 방법을 모두 포함하여 제한 없이 수행될 수 있다. SNP의 측정에 있어서 정성적 방법과 정량적 방법의 종류는 당업계에 잘 알려져 있으며, 본 명세서에서 기술한 실험법들이 이에 포함된다. 각 방법 별로 구체적 SNP 수준 비교 방식은 당업계에 잘 알려져 있다. As used herein, the term “detection” refers to measuring and confirming the presence (expression) of a target substance (marker protein or marker SNP in the present invention), or a change in the presence level (expression level) of a target substance. It is meant to include both measuring and confirming. In the same context, measuring the expression level of the SNP in the present invention means measuring the expression level (ie, measuring the expression presence or absence), or measuring the level of qualitative and quantitative change of the SNP. The measurement may be performed without limitation, including both a qualitative method (analysis) and a quantitative method. Qualitative and quantitative methods for the measurement of SNP are well known in the art, and the experimental methods described herein are included therein. A specific SNP level comparison method for each method is well known in the art.
본 명세서에서, 용어 “천식”은 중증 천식 또는 조절되지 않는 천식일 수 있으나, 이에 제한되는 것은 아니다.As used herein, the term “asthma” may be severe asthma or uncontrolled asthma, but is not limited thereto.
본 명세서에서, 용어 “천식”은 성인 천식일 수 있으나, 이에 제한되는 것은 아니다. 상기 성인은 만 18세 초과인 사람을 의미하는 것일 수 있으나, 이에 제한되는 것은 아니다.As used herein, the term “asthma” may be adult asthma, but is not limited thereto. The adult may mean a person over the age of 18, but is not limited thereto.
본 발명에서 용어, “중증 천식” 또는 “조절되지 않는 천식”은 일반적으로 미국흉부학회 및 유럽호흡기학회(ATS/ERS) 가이드라인에서 말하는 severe asthma 에 해당하나, 이에 제한되는 것은 아니다. As used herein, the term "severe asthma" or "uncontrolled asthma" generally corresponds to severe asthma in the American Thoracic Society and European Respiratory Society (ATS/ERS) guidelines, but is not limited thereto.
본 발명에서 용어 “잘 조절되지 않는 천식”이란 각 천식 중증도에 맞는 흡입스테로이드제 등 적절한 천식의 단계적 치료에도 불구하고 천식 상태가 조절되지 않는 천식일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the term "uncontrolled asthma" may be asthma in which the asthma status is not controlled despite appropriate step-by-step treatment of asthma such as inhaled steroids suitable for each asthma severity, but is not limited thereto.
조절되지 않는 천식의 정의는 하기 조건 중 하나 이상을 포함할 수 있으나, 이에 제한되는 것은 아니다:The definition of uncontrolled asthma may include, but is not limited to, one or more of the following conditions:
1) 낮은 증상 조절: 한국 천식 진료 지침의 부분조절 상태, 또는 천식 조절 검사에서 20점 미만 1) Low symptom control: Partial control status according to the Korean asthma guidelines, or less than 20 points on asthma control test
2) 잦은 천식 악화: 전신 스테로이드가 3일 이상 필요한 정도의 천식 악화가 연 2회 이상 2) Frequent asthma exacerbations: 2 or more exacerbations of asthma that require systemic steroids for 3 days or more
3) 중증 악화: 천식 악화로 입원이나 기계호흡이 필요한 경우 3) Severe exacerbation: When asthma exacerbation requires hospitalization or mechanical ventilation
4) 기류제한: 기관지확장제 사용 후 FEV1 < 80% .4) Airflow restriction: FEV1 < 80% after using bronchodilator.
본 명세서에서, 용어 “진단”은 특정 질병 또는 질환에 대한 한 객체의 감수성(susceptibility)을 판정하는 것, 한 객체가 특정 질병 또는 질환을 현재 가지고 있는지 여부를 판정하는 것, 특정 질병 또는 질환에 걸린 한 객체의 예후(prognosis)를 판정하는 것, 또는 테라메트릭스(therametrics)(예컨대, 치료 효능에 대한 정보를 제공하기 위하여 객체의 상태를 모니터링 하는 것)를 모두 포함하는 개념이다. As used herein, the term “diagnosis” refers to determining the susceptibility of an object to a particular disease or disorder, determining whether an object currently has a particular disease or disorder, or having a particular disease or disorder. It is a concept that includes both determining the prognosis of an object, or therametrics (eg, monitoring the condition of an object to provide information on treatment efficacy).
본 명세서에서, 상기 진단은 천식의 진단을 의미한다. 본 발명에서의 천식은 바람직하게는 유전적 소인(genetic factor)에 의하여 유발되는 유전성(hereditary) 천식일 수 있으며, 유전적 소인에 환경적인 영향이 더해져서 증상이 심화된 것일 수 있다. In the present specification, the diagnosis means diagnosis of asthma. Asthma in the present invention may preferably be a hereditary asthma caused by a genetic factor, and may have aggravated symptoms due to an environmental influence added to the genetic predisposition.
본 명세서에서, '프라이머(primer)'는 DNA 합성의 개시점(starting point)으로 작용하는 짧은 단일가닥 올리고뉴클레오티드(single strand oligonucleotide)이다. 프라이머는 적합한 완충액(buffer)와 온도 조건에서 주형(template)인 폴리뉴클레오티드에 특이적으로 결합하고, DNA 중합효소가 프라이머에 주형 DNA에 상보적인 염기를 갖는 뉴클레오사이드 트리포스페이트를 추가하여 연결함으로써 DNA가 합성된다. 프라이머는 일반적으로 15 내지 30개의 염기서열로 이루어져 있으며, 염기 구성과 길이에 따라 주형 가닥에 결합하는 온도(melting temperature, Tm)가 달라진다. 프라이머의 서열은 주형의 일부 염기 서열과 완전하게 상보적인 서열을 가질 필요는 없으며, 주형과 혼성화되어 프라이머 고유의 작용을 할 수 있는 범위 내에서의 충분한 상보성을 가지면 충분하다. 따라서 본 발명에서 상기 SNP 부위의 cDNA 또는 genomic DNA의 염기서열을 참조하여 본 발명에 따른 검출 제제인 프라이머쌍을 용이하게 디자인할 수 있다. SNP를 검출하기 위한 프라이머는 각 유전자 서열에 완벽하게 상보적인 서열을 가질 필요는 없으며, DNA 합성을 통해 mRNA 또는 cDNA의 특정 구간을 증폭하여 mRNA의 양을 측정하려는 목적에 맞는 길이와 상보성을 갖는 것이면 충분하다. 상기 증폭 반응을 위한 프라이머는 증폭하고자 하는 mRNA의 특정 구간의 양쪽 끝부분의 주형(또는 센스, sense)과 반대편(안티센스, antisense)에 각각 상보적으로 결합하는 한 세트(쌍)으로 구성된다. As used herein, a 'primer' is a short single-stranded oligonucleotide that serves as a starting point of DNA synthesis. A primer binds specifically to a polynucleotide as a template under suitable buffer and temperature conditions, and DNA polymerase adds a nucleoside triphosphate having a base complementary to that of the template DNA to the primer to link it. is synthesized A primer generally consists of a sequence of 15 to 30 bases, and the melting temperature (Tm) at which it binds to the template strand varies depending on the base composition and length. The sequence of the primer does not need to have a completely complementary sequence to a partial nucleotide sequence of the template, and it is sufficient if it hybridizes with the template and has sufficient complementarity within a range capable of performing an intrinsic function of the primer. Therefore, in the present invention, the primer pair, which is the detection agent according to the present invention, can be easily designed with reference to the nucleotide sequence of the cDNA or genomic DNA of the SNP site. A primer for detecting SNP does not need to have a sequence that is perfectly complementary to each gene sequence, and if it has a length and complementarity suitable for the purpose of measuring the amount of mRNA by amplifying a specific section of mRNA or cDNA through DNA synthesis Suffice. The primers for the amplification reaction are composed of a set (pair) that complementarily binds to the template (or sense) and the opposite side (antisense) of both ends of a specific section of the mRNA to be amplified.
본 명세서에서, '프로브(probe)'는 특정 유전자의 mRNA나 cDNA(complementary DNA), DNA 등에 특이적으로 결합할 수 있는 짧게는 수개 내지 길게는 수백 개의 염기(base pair) 길이의 RNA 또는 DNA 등 폴리뉴클레오티드의 단편을 의미하며, 표지(labeling)되어 있어서 결합하는 대상 mRNA나 cDNA의 존재 유무, 발현양 등을 확인할 수 있다. 프로브의 선택 및 혼성화 조건은 당업계에 공지된 기술에 따라 적절하게 선택할 수 있다. 상기 프로브는 대립형질(또는 대립유전자, allele)을 검출하기 위한 진단 방법 등에 사용될 수 있다. 상기 진단 방법에는 서던 블롯 등과 같은 핵산의 혼성화에 근거한 검출 방법들이 포함되며, DNA 칩을 이용한 방법에서 DNA 칩의 기판에 미리 결합된 형태로 제공될 수도 있다. 본 발명에서 상기 프라이머 또는 프로브는 포스포아미다이트(phosphoramidite) 고체지지체 합성법이나 기타 널리 공지된 방법을 이용하여 화학적으로 합성할 수 있다. In the present specification, 'probe' refers to RNA or DNA having a length of several to hundreds of base pairs that can specifically bind to mRNA, cDNA (complementary DNA), DNA, etc. of a specific gene. It refers to a fragment of a polynucleotide and is labeled so that the presence or absence of the target mRNA or cDNA to be bound to, the amount of expression, etc. can be confirmed. Probe selection and hybridization conditions can be appropriately selected according to techniques known in the art. The probe may be used in a diagnostic method for detecting an allele (or allele, allele). The diagnostic methods include detection methods based on hybridization of nucleic acids, such as Southern blot, and may be provided in a form previously bound to a substrate of a DNA chip in a method using a DNA chip. In the present invention, the primer or probe may be chemically synthesized using a phosphoramidite solid support synthesis method or other well-known methods.
본 명세서에서, 프라이머 또는 프로브는 포스포아미다이트(phosphoramidite) 고체지지체 합성법이나 기타 널리 공지된 방법을 이용하여 화학적으로 합성할 수 있다. 또한 프라이머 또는 프로브는 검출하고자 하는 표적이 되는 폴리뉴클레오티드와의 혼성화를 방해하지 않는 범위에서 당해 기술분야에 공지된 방법에 따라 다양하게 변형시킬 수 있다. 이러한 변형의 예로는 메틸화, 캡화, 천연 뉴클레오티드 하나 이상의 동족체로의 치환 및 뉴클레오티드 간의 변형, 예를 들면 하전되지 않은 연결체(예: 메틸 포스포네이트, 포스포트리에스테르, 포스포로아미데이트, 카바메이트 등) 또는 하전된 연결체(예: 포스포로티오에이트, 포스포로디티오에이트 등), 그리고 형광 또는 효소를 이용한 표지물질(labeling material)의 결합 등이 있다.In the present specification, the primer or probe may be chemically synthesized using a phosphoramidite solid support synthesis method or other well-known methods. In addition, primers or probes can be variously modified according to methods known in the art within a range that does not interfere with hybridization with a polynucleotide to be detected. Examples of such modifications include methylation, encapsulation, substitution of one or more homologues of natural nucleotides, and modifications between nucleotides, such as uncharged linkages such as methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, etc. ) or charged linkages (eg, phosphorothioate, phosphorodithioate, etc.), and fluorescence or enzymatic binding of a labeling material.
또한, 본 발명은 상기 천식 진단용 조성물을 포함하는, 천식 예측 또는 진단용 키트를 제공한다.In addition, the present invention provides a kit for predicting or diagnosing asthma, comprising the composition for diagnosing asthma.
본 명세서에서, 상기 키트는 RT-PCR 키트 또는 마이크로어레이 칩 키트일 수 있으나, 이에 제한되는 것은 아니다.In the present specification, the kit may be an RT-PCR kit or a microarray chip kit, but is not limited thereto.
상기 키트는 천식 예측 또는 진단용 마커인 SNP 마커를 증폭을 통해 확인하거나, SNP 마커의 발현 수준을 mRNA의 발현 수준을 확인함으로써 천식을 예측 또는 진단할 수 있다.The kit can predict or diagnose asthma by amplifying the SNP marker, which is a marker for prediction or diagnosis of asthma, or checking the expression level of the SNP marker by checking the expression level of the mRNA.
상기 RT-PCR 키트는 상기 SNP 부위를 포함하는 핵산을 증폭할 수 있는 각각의 프라이머 쌍을 포함할 수 있으며, 그 외 테스트 튜브 또는 다른 적절한 컨테이너, 반응 완충액, 데옥시뉴클레오타이드(dNTPs), Taq-중합효소 및 역전사효소와 같은 효소, DNase, RNAse 억제제, DEPC-물(DEPC-water), 멸균수 등을 포함할 수 있다. 또한 정량대조군으로 사용되는 유전자에 특이적인 프라이머 쌍을 포함할 수 있다.The RT-PCR kit may include each pair of primers capable of amplifying a nucleic acid comprising the SNP site, other test tubes or other suitable containers, reaction buffers, deoxynucleotides (dNTPs), Taq-polymerization enzymes and enzymes such as reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, sterile water, and the like. In addition, a primer pair specific for a gene used as a quantitative control may be included.
상기 마이크로어레이 칩 키트는 상기 SNP 부위를 포함하는 핵산이 고정화되어 있는 기판을 갖는 마이크로어레이를 포함할 수 있다. 상기 마이크로어레이는 본 발명의 폴리뉴클레오티드, 프라이머 또는 프로브를 포함하는 것을 제외하고는 통상적인 마이크로어레이로 이루어질 수 있다. 마이크로어레이 상에서의 핵산의 혼성화 및 혼성화 결과의 검출은 당업계에 잘 알려져 있다. 상기 검출은 예를 들면, 핵산 시료를 형광 물질, 예를 들면, Cy3 및 Cy5와 같은 물질을 포함하는 검출 가능한 신호를 발생시킬 수 있는 표지 물질로 표지한 다음, 마이크로어레이 상에 혼성화하고 상기 표지 물질로부터 발생하는 신호를 검출함으로써 혼성화 결과를 검출할 수 있다.The microarray chip kit may include a microarray having a substrate on which a nucleic acid including the SNP site is immobilized. The microarray may be composed of a conventional microarray except for containing the polynucleotide, primer, or probe of the present invention. Hybridization of nucleic acids on microarrays and detection of hybridization results are well known in the art. The detection is, for example, labeling a nucleic acid sample with a label capable of generating a detectable signal including a fluorescent substance, for example, a substance such as Cy3 and Cy5, and then hybridizing on a microarray and the labeling substance. The hybridization result can be detected by detecting a signal generated from
본 발명에서 용어 "개체" 또는 “대상체”는 천식 예측 또는 진단을 하기 위한 피험자를 의미한다. As used herein, the term “subject” or “subject” refers to a subject for predicting or diagnosing asthma.
본 발명에서 “시료”는 천식을 예측 또는 진단하고자 하는 대상체로부터 채취된 것이라면 제한없이 사용할 수 있으며, 예를 들어 생검 등으로 얻어진 세포나 조직, 혈액, 전혈, 혈청, 혈장, 타액, 뇌척수액, 각종 분비물, 소변, 대변 등일 수 있다. 바람직하게는 혈액, 혈장, 혈청, 타액, 비액, 객담, 복수, 질 분비물 및 소변으로 이루어진 군에서 선택될 수 있으며, 바람직하게는 혈액, 혈장, 혈청 또는 폐 조직일 수 있다. 상기 시료는 검출 또는 진단에 사용하기 전에 전처리할 수 있다. 예를 들어, 균질화(homogenization), 여과, 증류, 추출, 농축, 방해 성분의 불활성화, 시약의 첨가 등을 포함할 수 있다.In the present invention, the "sample" can be used without limitation as long as it is collected from a subject for predicting or diagnosing asthma, for example, cells or tissues, blood, whole blood, serum, plasma, saliva, cerebrospinal fluid, and various secretions obtained by biopsy, etc. , urine, feces, etc. Preferably, it may be selected from the group consisting of blood, plasma, serum, saliva, nasal fluid, sputum, ascites, vaginal secretion and urine, and preferably blood, plasma, serum or lung tissue. The sample may be pretreated prior to use for detection or diagnosis. For example, it may include homogenization, filtration, distillation, extraction, concentration, inactivation of interfering components, addition of reagents, and the like.
또한, 본 발명은 피검체로부터 수득한 시료 중의 SNP 부위의 염기서열에 염색체 6 상의 단일염기다형성(SNP) 부위인 GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593로 이루어진 군으로부터 선택된 하나 이상의 단일염기다형성이 존재하는 경우, 피검체가 천식 환자이거나 천식에 걸릴 위험이 높은 것으로 결정하는 단계를 포함하는 천식 진단 또는 예측에 필요한 정보를 제공하는 방법을 제공한다.In addition, the present invention provides a GeneBank SNP database rs1770, rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117452077741, rs1175520, which is a single nucleotide polymorphism (SNP) site on
본 명세서에서, 상기 염기서열을 결정하는 단계는 시퀀싱(sequencing), 엑솜 시퀀싱(exome sequencing), 마이크로어레이에 의한 혼성화(microarray hybridization), 대립유전자 특이적인 PCR(allele specific PCR), 다이나믹대립유전자 혼성화 기법(dynamic allele-specific hybridization), PCR 연장 분석 및 Taqman 기법으로 이루어진 군으로부터 선택되는 하나 이상의 방법으로 수행될 수 있으나, 이에 제한되는 것은 아니다.In the present specification, the step of determining the nucleotide sequence includes sequencing, exome sequencing, microarray hybridization, allele specific PCR, dynamic allele hybridization technique (dynamic allele-specific hybridization), PCR extension analysis, and one or more methods selected from the group consisting of Taqman technique, but is not limited thereto.
본 발명은 다양한 변환을 가할 수 있고 여러 가지 실시예를 가질 수 있는 바, 특정 실시예들을 도면에 예시하고 상세한 설명에 상세하게 설명하고자 한다. 그러나 이는 본 발명을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 본 발명의 사상 및 기술 범위에 포함되는 모든 변환, 균등물 내지 대체물을 포함하는 것으로 이해되어야 한다. 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.Since the present invention can apply various transformations and can have various embodiments, specific embodiments are illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to a specific embodiment, it should be understood to include all transformations, equivalents and substitutes included in the spirit and scope of the present invention. In describing the present invention, if it is determined that a detailed description of a related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.
[실시예][Example]
<실시예 1. 실험 방법><Example 1. Experimental method>
1.1 대상1.1 Target
GWAS의 경우, 대상은 3개의 병원에서 입수하였다: 아산병원(AMC), 서울대학교 병원 강남센터(SNUH) 및 강원대학교 병원(KNUH). 총 1,386명 중 1,293명의 천식 환자는 2005년 1월부터 2018년 12월까지의 아산병원 환자였다.For GWAS, subjects were obtained from three hospitals: Asan Hospital (AMC), Seoul National University Hospital Gangnam Center (SNUH) and Kangwon National University Hospital (KNUH). Among 1,386 patients, 1,293 asthma patients were Asan Hospital patients from January 2005 to December 2018.
포함 기준(criteria)은 다음과 같다 :(1) 18세 초과; (2) 3개월 이상 호흡 곤란, 천명 또는 기침과 같은 증상; 및 (3) 유발 검사(provocation test)를 통해 16 mg/mL(PC 20) 의 메타콜린 용량으로 1초간노력성호기량(FEV1)이 20% 감소로 표시된 기도 과민증이거나; 속효성 β-항진제 흡입 후 FEV1 > 12%(및 적어도 200 mL)에서의 기도 가역성.The inclusion criteria were: (1) over 18 years of age; (2) symptoms such as shortness of breath, wheezing, or cough for more than 3 months; and (3) airway hypersensitivity indicated by a 20% reduction in forced expiratory volume in 1 second (FEV1) at a methacholine dose of 16 mg/mL (PC 20) by a provocation test; Airway reversibility at FEV1 > 12% (and at least 200 mL) after inhalation of short-acting β-agonists.
심각한 폐 손상, 기관지 확장증 또는 폐 절제 병력이 있는 환자는 제외하였다. Patients with a history of severe lung injury, bronchiectasis, or lung resection were excluded.
SNUH에서 다음 설문지 중 하나에 대해 “예”라고 답변한 93명의 천식 환자가 포함되었다: “천식 진단을 받은 적이 있습니까?” 또는 "천식 약을 한 번 이상 복용한 적이 있습니까?"SNUH included 93 asthma patients who answered “yes” to one of the following questionnaires: “Have you ever been diagnosed with asthma?” or "Have you ever taken asthma medication more than once?"
또한, 5,205명의 대조군 중 5,161명 및 44명 대조군은 각각 SNUH 및 KNUH에서 왔으며 천식 및 만성 폐쇄성 폐질환(COPD)으로 진단되지 않았다.In addition, of the 5,205 controls, 5,161 and 44 controls were from SNUH and KNUH, respectively, and were not diagnosed with asthma or chronic obstructive pulmonary disease (COPD).
본 연구는 모든 참여기관의 기관 검토위원회의 승인을 받았다.This study was approved by the institutional review committee of all participating institutions.
1.2 유전자형 및 품질 관리1.2 Genotyping and quality control
모든 대상은 한국 바이오뱅크 어레이(한국 칩, KoreanChip이라고 함)로 유전자형을 분석하였다. KoreanChip은 Affymerix 맞춤형 SNP 칩이며, 한국인에 최적화되어있고, 혈액 생화학적 특성을 GWAS에서 발견한 결과를 보여준다. Affymetrix에서 제공하는 Best Practices Steps에 따라 변형을 호출했으며 배치 효과를 최소화하기 위해 K-medoid 알고리즘을 적용하였다.All subjects were genotyped with a Korean Biobank Array (Korean Chip, called KoreanChip). KoreanChip is an Affymerix customized SNP chip, optimized for Koreans, and shows the results of finding blood biochemical properties in GWAS. The transformation was called according to the Best Practices Steps provided by Affymetrix, and the K-medoid algorithm was applied to minimize the batch effect.
PLINK28 및 ONETOOL29를 사용하여 대상체 및 SNP의 품질 관리를 수행 하였다. 먼저 각 배치마다 품질 관리를 수행하였다. 다음 조건 중 하나라도 충족되면 SNP가 제외되었다 : 유전자형 호출 속도(genotype call rates)가 95% 미만; 하디 와인버그 평형(HWE) 시험은 P <1x10-5; X 염색체 동형 접합성이 0.2 내지 0.8 인 경우; 또는 SNP의 이형 접합 속도가 이형 접합 속도±3 표준 편차의 평균을 벗어난 경우.Quality control of subjects and SNPs was performed using PLINK28 and ONETOOL29. First, quality control was performed for each batch. SNPs were excluded if any of the following conditions were met: genotype call rates of less than 95%; The Hardy Weinberg Equilibrium (HWE) test was P < 1x10 -5 ; If the X chromosome homozygosity is 0.2 to 0.8; or when the heterozygous rate of the SNP is outside the mean of the heterozygous rate ± 3 standard deviations.
각 배치에 대해 품질 관리를 수행한 후 모든 배치를 풀링하고, 풀링된 샘플에 대해 동일한 품질 관리를 수행하였다. 또한, 각 SNP에 대해 Pearson 카이 제곱 검정을 사용한 배치 중 결손률, HWE 및 마이너 대립 유전자 빈도(MAF)를 비교했으며 1x10-5 유의 수준에서 유의한 SNP를 버렸다. 모든 품질 관리 프로세스를 완료한 후 8,903명의 피험자와 649,085개의 SNP가 남았다. 자세한 절차는 도 1에 나타내었다.After quality control was performed on each batch, all batches were pooled, and the same quality control was performed on the pooled samples. In addition, for each SNP, we compared the deletion rate, HWE, and minor allele frequency (MAF) among batches using the Pearson chi-square test and discarded significant SNPs at the 1x10 -5 significance level. After completing all quality control processes, 8,903 subjects and 649,085 SNPs remained. The detailed procedure is shown in FIG. 1 .
1.3 SNP 유전자형 데이터의 유전자형 대치(imputation)1.3 Genotype imputation of SNP genotype data
대치는 미시간 대치 서버(https://imputationserver.sph.umich.edu)를 사용하여 수행하였다. 또한, Haplotype Reference Consortium release v1.1을 사용했으며 '비유럽인' 또는 'mixed' 인구만 고려하였다.Imputation was performed using the Michigan imputation server (https://imputationserver.sph.umich.edu). In addition, Haplotype Reference Consortium release v1.1 was used and only 'non-European' or 'mixed' populations were considered.
사전 위상 조정 및 대치는 각각 Eagle V 2.4 및 Minimac4으로 수행되었다. 대치 공정 후 다음 SNP는 제거되었다 : Rsq가 0.3 미만이거나 중복된 SNP가 있는 경우; 누락된 유전자형 비율이 0.05보다 큰 경우; HWE에 대한 P-값이 1x10-5 미만; MAF가 0.05 미만.Prephasing and imputation were performed with Eagle V 2.4 and Minimac4, respectively. After the replacement process, the following SNPs were removed: if Rsq was less than 0.3 or if there were duplicate SNPs; the proportion of missing genotypes is greater than 0.05; P-value for HWE less than 1x10 -5; MAF less than 0.05.
또한, IBD(Identity by descent)> 0.9 및 PC 점수가 5xIQRPC를 벗어난 대상체를 제외하였다.In addition, subjects with IBD (Identity by descent) >0.9 and PC scores outside of 5xIQRPC were excluded.
1.4 GWAS(Genome-wide association studies)1.4 Genome-wide association studies (GWAS)
로지스틱 회귀(LR)를 사용하여 GWAS를 수행하였다. PC(Principal components) 스코어는 PLINK로 추정하였고, 집단 하부 구조를 조정하는데 사용되었다. 20개의 가장 큰 고유 값(eigenvalues), 연령 및 성별에 해당하는 20개의 PC 스코어가 공변량으로 포함되었다. 전장유전체의 유의 수준은 5×10-8로 설정되었다. 전장유전체의 유의미한 SNP에 ANNOVAR로 주석을 달았다. LDlink를 사용하여 1000 게놈 프로젝트 데이터의 3 상 haplotype 데이터를 가진 조상 집단에 걸친 LD(linkage disequilibrium)를 평가하였다. GWAS was performed using logistic regression (LR). Principal components (PC) scores were estimated by PLINK and used to adjust the population substructure. The 20 largest eigenvalues and 20 PC scores corresponding to age and sex were included as covariates. The significance level of the whole genome was set to 5×10 -8. Significant SNPs of the whole genome were annotated with ANNOVAR. LDlink was used to evaluate linkage disequilibrium (LD) across ancestral populations with
1.5 PrediXcan을 이용한 RNA 발현 대치 및 천식과의 연관성1.5 RNA expression replacement using PrediXcan and association with asthma
PrediXcan을 사용하여 전혈(whole blood) 및 폐 조직에 대한 염색체 6(chromosome 6)에서 유전자의 RNA 발현 수준을 대치하였다. 유전자형 조직 발현(GTEx, Genotype-Tissue Expression) V7 데이터를 사용하여 48개의 인간 조직에 대한 대상체 수준 유전자 발현 예측을 수행하였다. 그런 다음 선형 회귀를 적용하여 예측된 RNA 발현이 천식 상태와 관련이 있는지 여부를 확인하였다. 선형 회귀 분석에서 상위 20개 PC 스코어, 연령 및 성별이 공변량으로 포함되었다.PrediXcan was used to replace RNA expression levels of genes in
1.6 유전적 유전성의 추정1.6 Estimation of hereditary heritability
GCTA64로 SNP 유전성 분석을 추정하였다. SNP 유전성은 SNP에 의해 설명 된 표현형 분산의 상대적인 비율을 나타낸다. SNP는 기본 옵션으로 PLINK로 잘라낸 다음 나머지 SNP를 사용하여 유전자 관계 매트릭스(GRM, Genetic Relationship Matrix)를 계산하였다. 상기 GRM은 GCTA64에서 SNP 유전성을 추정하는 데 사용되었다. 확인 바이어스(ascertainment bias)의 경우 천식 유병률은 3.9%로 설정되었다.SNP genetic analysis was presumed by GCTA64. SNP heritability refers to the relative proportion of phenotypic variance explained by SNPs. SNPs were cut with PLINK as the default option, and then a Genetic Relationship Matrix (GRM) was calculated using the remaining SNPs. The GRM was used to estimate SNP heritability in GCTA64. For ascertainment bias, the asthma prevalence was set at 3.9%.
<실시예 2. 대상체의 특성><Example 2. Characteristics of an object>
1,386 케이스 및 5,205 대조군이 유전자 연관 분석에 이용되었다. 연구 집단에 대한 인구 통계 정보는 표 2에 나타내었다. 두 그룹 간의 평균 차이는 두 개의 다른 통계 테스트와 비교되었다. 연속 변수의 경우, 이분산성(heteroscedasticity)이 발견되었고 Welch의 t-검정을 사용하였다. 범주형 변수의 경우 카이 제곱 검정을 사용하였다.1,386 cases and 5,205 controls were used for gene association analysis. Demographic information for the study population is presented in Table 2. The mean difference between the two groups was compared with two other statistical tests. For continuous variables, heteroscedasticity was found and Welch's t-test was used. For categorical variables, a chi-square test was used.
케이스와 대조군의 평균 연령은 각각 50.3세와 49.8세였다. 두 그룹 간에 연령과 흡연 이력은 크게 다르지 않았지만, 대조군에서보다 케이스에서의 여성의 비율이 높았다(55.2 % vs. 44.1 %, p <0.001). 체질량 지수(BMI)는 대조군보다 케이스에서 유의하게 더 높았다(24.3 ± 3.6 vs. 23.1 ± 3.1, p <0.001). 케이스는 대조군에 비해 낮은 기준선 FEV1 수준(78.8 ± 20.2 vs. 101.8 ± 12.2, p <0.001) 및 FEV1/노력성 폐활량(FVC)(70.7 ± 0.1 vs. 82.0 ± 0.1, p <0.001)을 나타냈다.The mean age of the case and control group was 50.3 years and 49.8 years, respectively. Although age and smoking history were not significantly different between the two groups, the proportion of women in the case was higher than in the control group (55.2% vs. 44.1%, p < 0.001). Body mass index (BMI) was significantly higher in cases than controls (24.3 ± 3.6 vs. 23.1 ± 3.1, p <0.001). Cases had lower baseline FEV1 levels (78.8 ± 20.2 vs. 101.8 ± 12.2, p <0.001) and FEV1/forced vital capacity (FVC) (70.7 ± 0.1 vs. 82.0 ± 0.1, p <0.001) compared to controls.
<실시예 3. 천식의 GWAS 분석의 염색체 6 상 SNP 식별><Example 3. Identification of SNPs on
GWAS는 로지스틱 회귀분석(LR)으로 1,386명의 천식 환자와 4,935,875개의 SNP에 대한 5,205개의 대조군으로 수행되었다. 도 2는 LR에 대한 Quantile-Quanttile(QQ) 플롯을 나타낸 것이다. 이는 관측된 P-값의 분포가 Genomic Inflation Factor 1.035인 소수의 SNP를 제외한 예상 분포를 충족했음을 보여준다.GWAS was performed by logistic regression analysis (LR) with 1,386 asthmatics and 5,205 controls for 4,935,875 SNPs. 2 shows a Quantile-Quanttile (QQ) plot for LR. This shows that the observed distribution of P-values met the expected distribution except for a few SNPs with Genomic Inflation Factor 1.035.
도 3에 나타난 바와 같이, MDS 플롯은 우리나라 대상체의 인구 계층화에 대한 증거를 보여주지 않으며, 통계 분석이 통계적으로 유효하다는 결론을 내릴 수 있었다.As shown in FIG. 3 , the MDS plot showed no evidence for population stratification of Korean subjects, and it could be concluded that the statistical analysis was statistically valid.
도 4에 나타난 바와 같이, 게놈의 맨해튼 플롯은 오직 4개의 SNP만이 전장유전체의 유의성을 충족시켰음을 나타내었다. As shown in Fig. 4, the Manhattan plot of the genome showed that only 4 SNPs met the significance of the whole genome.
표 3 및 표 4는 가장 유의한 10개의 SNP에 대한 결과 및 HLA-DQB1 상 rs1770과 강한 linkage 관계에 있는 SNP를 나타낸 것이다. 동일한 LD 블록에 여러 전장유전체의 유의한 SNP가 있는 경우, 가장 중요한 SNP에 대한 결과가 포함되었다. 표 3에 따르면, rs1770이 가장 유의한 것으로 나타났다(P-값=4.5 × 10-10).Tables 3 and 4 show the results for the 10 most significant SNPs and SNPs that have a strong linkage relationship with rs1770 on HLA-DQB1. If there were significant SNPs of multiple full genomes in the same LD block, the results for the most significant SNPs were included. According to Table 3, rs1770 was found to be the most significant (P-value=4.5 × 10 -10 ).
도 5에 나타난 바와 같이, rs1770은 염색체 6에서 인간 백혈구 항원(HLA)-DQB1 근처에 위치함을 확인하였다. As shown in FIG. 5 , it was confirmed that rs1770 was located near human leukocyte antigen (HLA)-DQB1 on
또한, rs9271469가 발견되었으며, 이 또한 유의한 마커로 나타났다(P-값=3.74 × 10-8). rs9271469는 HLA-DRB1(dist=31017) 및 HLA-DQA1(dist=16553)의 유전자 간 영역에 존재한다.In addition, rs9271469 was found, which also appeared as a significant marker (P-value=3.74 × 10 −8 ). rs9271469 is present in the intergenic region of HLA-DRB1 (dist=31017) and HLA-DQA1 (dist=16553).
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가지는 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. The foregoing description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.
GWAS 전장유전체 연관 분석, Genome-wide association study
SNP 단일 염기 다형성, single nucleotide polymorphism
AERD 아스피린 악화 호흡기 질환, Aspirin exacerbated respiratory disease
FEV1 1초 후 강제 호기량, Forced expiratory volume in 1 second
FVC 강제 폐활량, Forced vital capacity
COPD 만성 폐쇄성 폐 질환, Chronic obstructive pulmonary disease
HWE 하디 와인버그 평형, Hardy-Weinberg equilibrium
MAF 마이너 대립 유전자 빈도, Minor allele frequency
GRM 유전자 관계 매트릭스, Genetic relationship matrix
LR 로지스틱 회귀, Logistic regression
LD 연계 불균형, Linkage disequilibrium
HLA 인간 백혈구 항원, Human leukocyte antigen
TSLP 흉선 기질 림프포이에틴, Thymic stromal lymphopoietin
Chr 염색체, chromosome
Nt 뉴클레오티드, nucleotide
OR 승산 비, odds ratio
SE, 표준 오차, standard error
L95 95 % 신뢰 구간의 하한, lower bound of 95% confidence interval
U95 95 % 신뢰 구간의 상한, upper bound of 95% confidence interval
STAT 로지스틱 회귀 통계량, logistic regression statisticGWAS whole genome association study, Genome-wide association study
SNP single nucleotide polymorphism
AERD Aspirin exacerbated respiratory disease
FEV1 Forced expiratory volume in 1 second
FVC Forced vital capacity
COPD Chronic obstructive pulmonary disease
HWE Hardy-Weinberg equilibrium
MAF Minor allele frequency
GRM Genetic relationship matrix
LR logistic regression
LD linkage disequilibrium
HLA human leukocyte antigen
TSLP Thymic stromal lymphopoietin
Chromosome
Nt nucleotide, nucleotide
OR odds ratio, odds ratio
SE, standard error, standard error
L95 lower bound of 95% confidence interval
U95 upper bound of 95% confidence interval
STAT logistic regression statistic
<110> THE ASAN FOUNDATION University of Ulsan Foundation For Industry Cooperation <120> SNP for asthma diagnosis and asthma diagnosis method using the same <130> MP20-083 <160> 3 <170> KoPatentIn 3.0 <210> 1 <211> 14601 <212> DNA <213> Artificial Sequence <220> <223> HLA-DQB1 (NG_029922.1) <400> 1 tatgtttact gaagcattat tcacaatacc aaaggcatgg aaccaaccca aatgtccatc 60 agtgataggc tggataaaga aaatatggtt catacacacc atggaatact atgcagccat 120 aaaaaggaat gagattatgt cttttgcagg gacatggatg gagctggaag ccattgtcct 180 cagcaaaata atgaaggaac agaaaaccaa atactgcatg ttctcactaa taattgggag 240 ctgaacaatg agaacacatg gacacaggga ggggaacaac acacactggg gcctgtgagg 300 ggtaggggca gggacagcat caggataaat agctcatgca tgctgggctt aatacctagg 360 tgatgggttg atagctgcag caaaccgcca tgccacacgt ttacccatgt aacaaacctg 420 catgtcctac acatgtacgc tagaacataa aacaaaataa aataaaataa acaattcaat 480 tcaaaaatgg gattttttag attcctcata taagtaagat catgcattac ttgtctttcc 540 atgtctggct tatttcactt agcttaatgt cctctaggtt catgcatgtt gtcaaaaata 600 acagtgtgaa agaaaaatag aatcttggga ccccaaactc attatgccaa gggaaagtta 660 atcttgagga ctgaggcacc aatactgtct tccttttgtt cccaaacaga taacggtaat 720 ttcacaaccc cgtgtcataa cctcgtttcc tctactcctt cccccttttc aagttccctt 780 aattttatgt aaaatgtaga tttactgagc ataagataat ttataattaa ctttttcttc 840 tactctcttt tcacaggtaa aatgtagatt tacttaagct aatcaaagac tcaggaatgt 900 aaccacttgt atcatggcct actcttcctc cttttttttc tccttcccct cctgcttgct 960 ctttctcttt taaatactga agttctcaaa accctctttg gcaaaagcat ggatcacaga 1020 tgctcctgtg ttttgtgttt ttcccaggtg tattcctcaa ccttggcaaa ataaaccttt 1080 aattgattga gacctacctc agtcactttt tgacttacaa caggatttcc ttctttttaa 1140 agcctgaata ggatttaatt gtgtatatat accacatttt ctttatcttt tcatccactg 1200 aatgacacag gttgattcta taccttgact attgtgaata atgctgcaag gaacatagga 1260 gtataggtat attttcaaca tgctaatttt aaatactttg tctacatcct gcaaatggga 1320 ttactacatc atatgatagt tctattttta actttttgag gaacttccat actgttttcc 1380 ataatggttg tactaatctg catccccacc aacagtgtac aaatgtttcc ttttgtctac 1440 atccttaaca cttgttatct tttatctttt tgataatagc cattctgact gatgtgaggt 1500 gatatgtcat tgtggtttaa atggaatatc ttaagttttc ctatttgatg atataagagt 1560 actctcccca aaatattact gctgatgttg ctgttttgca tgaaccatgg ccttgagctg 1620 agttcttgga cacatgagtt cttgagtact tggatatgga tttaagtact caagaactat 1680 atatattttt atgtggctga acattagggc ctctctttac tggtaagaac ttacagaaaa 1740 aggagacatt ataaagatct cacagagaaa tatttaagtt ttttctggga atgaaggagc 1800 atggtgacta ctaatctaga ggctggggga agagctgtct ctggaaatat cccaggcatc 1860 actagggaac cagaagtaga gacaggcaga ggtgtgttgg aaagagtgac atgtgtaggc 1920 tagctctggg aggtttaatc accagtggtc caactgaggc aatgcgtgga tgaggagact 1980 gacaggaaaa aggaacctga aaagatagat caggaaacaa agcttcattg tacagcatac 2040 ccacagcagg cagcttgggt ttttgtccca gtcttcttcg gtcttcaagg gctattttca 2100 tagagcatga ggagccgtgg gactggtgag gtctgggctt ctgtgccaag atcactcacg 2160 ttcctcattt gccctcaaat gttccaaatg ctttgtatca cctgattttc taccttcctg 2220 ctaaagcttt tcccatactc ctactccttc acgctccatc atcctccaat tctgacatga 2280 cttccaccct ggagtttcac catggccact tgcttgtggg aggcactgtc tgaacacagc 2340 ccctgaatgc tactgatttg gctctttctt cagattctct agactgagat tttaaagaga 2400 taactttgtg ccaagagaaa ggacctagtt tatatgtgcc atgaaaaatt cttatatata 2460 gctggttacc tagaagttga tataagagaa atatgtaaga agcttcacaa agatttttaa 2520 aaatttaagg ataattgctt gataaatttt aattaaagga aaacaatatt ctgggggcag 2580 catttctagt tatattacca ttggcattaa ggaagccaca gaacctttca gaatatacag 2640 tgattcttga ttcctgaagt aaatgcaggg tagggtcctg gatggtcctt ctggtgacag 2700 ggtggctcct atgttcacat tcaattccac tgaccaagca cagattccaa gagatgttga 2760 ccagagaaga tgatttctcc cttgattttc acaaagaagg agtccacaac ttttccttcc 2820 aacctgaagg aagagaggat gtcccttgaa ttgagtctgc ctactgtaac cctgaccgtc 2880 cctactaatg gcagtggctt tttagcccat ttacccacat ggggtaaatg ctctaattgc 2940 tctgcctcca cagaggctgg gcaggcgatt caggtgagac actcggaata aggatgcttg 3000 acctagtttc tttcttctct ggccttcttc tgcctgaatg ccctgaataa tgcagcaggg 3060 atagggccag ggtagtcaac tgtacagaag gctgggccag gcagacacaa ctggcagaag 3120 cccaaagcaa aacctttcca gtgaggtttt agccaatcag aaaaaggctc taaagtgaca 3180 cttgttgcta gctgaaaagt ctgtgcgaag aggcctgtga gactgaggaa tccccaggtc 3240 tggcgtagca gttgcctcag aataaacctg tgggaagttt ttcccttaga caggaaggaa 3300 aggatggatt agaggcctct attctgaggg acactgaggt gggggctgag gaaggacatt 3360 gagggcagct tcaggtctct ctgcctactc ttccttgccc caactccatt ccaggtgtga 3420 gtatggttcc tcctttatgt gtccatcaca gcagtggaga ccatccttag gctgggttta 3480 ccctgatcct gagtaaacca ctgctgctgg acgcccagtg gcaactttcc cagtctcagg 3540 tgctctagaa ttatgctgtg aataatacag aatattggag tggctcaacg ctttcatgtg 3600 ccactattgc aaacctcttg ctgttgcctc ttccctgctt ctttttacct ggtaaactta 3660 tattctgatt ttagattgta ttctctactt taaaagcaga acctaaaatt ttgggaaaag 3720 aaagagagaa agggagagaa gaagagaggt ggagatattt attgtcttgg ttggggtcag 3780 aagtaatgtt tgccaggcat tgttctaatt gctttataac cattagtact gtccctagtc 3840 actgccaaga ggagcttgat aagttatgct tatttataaa aacacattga tgtagatatg 3900 tccatgagga actgttaaat aaaaaataca tagaattgaa aaaaaccaca ttgatacctc 3960 tgccacttgg gatttgatgt ttagggctgg cacagtacaa tctgtgactc taaacatttt 4020 ctccatcatt aatactattc aggacctagg aaatgcttct ccacagcttt tgctctctct 4080 cctcaaatct agacatgact atatctgaat actgtaaagg tttgtgtatt gtgcctttgc 4140 tgatatcaga tgcacctatt tcatggttca gagaggattt aaacagctga agaacttaga 4200 aaaggaatgt caacttaatt aacttttcaa atactttcac tcgaagagta taaatacaat 4260 atattcttgc gtaatgaaga atcatttacc agcagggatg ggtgtcaatt ttttttggct 4320 tgttttcttg ttccacatat taacctgata gttacacata acagttgagg atccttttgt 4380 aacattaaac aagtcatatt aatcttaaat ttgtatatgt gaagatctag atgtaaaatg 4440 catgaaacat gatccacatt ttacaaagag aagcctgggg caaaaataaa ttcagtaatt 4500 tgttgactct cataaagcac attagtggtg gaactgcaac tcaccattat ttccttctaa 4560 gaactttgct cttttcacca aaacttaagg ctcctcaggg tgtgtctaag acaacagcag 4620 taaaaatgtc tatgacagca attttctctc ccctgaaata tgatccccac ttaatttgcc 4680 ctattgaaag aatcccaagt ataagaacaa ctggttttta atcaatatta caaagatgtt 4740 tactgttgaa tcgcattttt ctttggcttc ttaaaatccc ttaggcattc aatcttcagc 4800 tcttccataa ttgagaggaa attttcacct caaatgttca tccagtgcaa ttgaaagacg 4860 tcacagtgcc aggcactgga ttcagaacct tcacaaaaaa aaaatctgcc cagagacaga 4920 tgaggtcctt cagctccagt gctgattggt tcctttccaa gggaccatcc aatcctacca 4980 cgcatggaaa catccacaga tttttattct ttctgccagg tacatcagat ccatcaggtc 5040 cgagctgtgt tgactaccac ttttcccttc gtctcaatta tgtcttggaa aaaggctttg 5100 cggatccccg gaggccttcg ggcagcaact gtgaccttga tgctgtcgat gctgagcacc 5160 ccagtggctg agggcagaga ctctcccggt aagtgcaggg cagctgctct ccagagccgc 5220 tactctggga acaggctctc cttgggctgg ggtacgggga tggtgatctc cataatctcg 5280 gacacaatct tttatcaaca tttcctctgt tttgggaaag agagctatgt tgcatttcca 5340 tttatctttt aatgatgaag tgaggacaat ccaatcccat cctacaggct taagcctgga 5400 agaggaggag agaggagaga aaagaggaga caaagtgttc atttactacc agtgatagga 5460 caaagtgagc atggggttat ttttgaagat atgaatttct ccaaagacac agcaggattt 5520 gccatttagg cgtgtcccaa gacttgcctg gactaaatat tatgatttcc tgcattggga 5580 aatgcaaggc agcaatggtg tctgtagtct ccgtatttgg ggaaaagttg tctgtattcc 5640 tgacccagtg gagcgtttgt ggaggcaaaa tcttggtact gagggaagct gactggctga 5700 ccacagaaag agagccttca ggtttcactg atttatgggc aaatggtgac ctgagtggga 5760 ttcagatacc cgagttgatg atggactaaa tttagtagaa aggaggatgt aaagaaggga 5820 aataacacat actgtgaaac cactcatttc agacacagaa caatacttta cataaattct 5880 ctctcactcc ttctaacatc ctgtgtgtag atatcatgat tttcttttac acaattatac 5940 ttgtgatatg gatattctgt tacataaact gcccgggctg gtgactgcca cagtttaatg 6000 ggaatctagt ttatcaaatt caaaagcttg tgctctttcg gtgaataaat gtttctttct 6060 aggactcaga gatctaggac tcccttcttt ctaacacaga cgtgagtgaa cctcacaggg 6120 cacttgggag ggtaaatcca ggcatgggaa ggaaggtatt ttacccaggg accaagagaa 6180 taggcgtatc ggaagaggac aggtttaatt cctggacctg tctcgtcatt cccttgaact 6240 gtcaggttta tgtggataac tttatctctg aggtacccag gagctccatg gaaaatgaga 6300 tttcatgcga gaacgccctg atccctctaa gtgcagaggt ccatgtaaaa tcagcccgac 6360 tgcctcttca cttggttcac aggccgagac agggacaggg ctttcctccc tttcctgcct 6420 gtaggaaggc ggattcccga agacccccga gagggcgggc agggctgggc agagccgccg 6480 ggaggatccc aggtctgcag cgcgaggcac gggccggcgg gaacttgtgg tcgcgcgggc 6540 tgttccacag ctccgggccg ggtcagggtg gcggctgcgg gggcggacgg gctgggccgc 6600 actgactggc cggtgattcc tcgcagagga tttcgtgtac cagtttaagg gcatgtgcta 6660 cttcaccaac gggacagagc gcgtgcgtct tgtgagcaga agcatctata accgagaaga 6720 gatcgtgcgc ttcgacagcg acgtggggga gttccgggcg gtgacgctgc tggggctgcc 6780 tgccgccgag tactggaaca gccagaagga catcctggag aggaaacggg cggcggtgga 6840 cagggtgtgc agacacaact accagttgga gctccgcacg accttgcagc ggcgaggtga 6900 gcggcgtcgc ccctctgcga ggcccaccct tggccccaag tctctgcgcc aggaggggcg 6960 aagggtcgtg gcctctggaa cctgagcccc gtttgttcca ccccagagga caggaggcag 7020 cggcgagagt ggtgggggca ggtgcatcgg aggtgcgggg acctagggca gagcaggggg 7080 acaggcagag ttggccaggc tgcctagtgt cgccccagcc tacccgttcg tcggccttgt 7140 cctctgctct gcatgttctt gcctcgtgcc ttatgcattt gcctcctttt gccttacctt 7200 tgctaagcag ctctctctgc tcagaatgcc cgccctcttc ccctgcccgc ccgcccgccc 7260 cactagcact gccccaccca gcaaggccca cgtgcacagc tcttgcagca ggaagcttca 7320 ggcttagcct ggtggagtta gggctgttcc acaactgcgc gcaggacatt cagcaattac 7380 agttgtgaaa taagatattt taacttttgg cttcaaatca ttattcatcg taattctgtt 7440 ttcttaaatg gctctcattc atggcagaga tctttgaggt gagggtgttt taatcattgc 7500 atgcctagta cctgacacat tgactggtat gtggtgtgag ctcaatgatc ttctgttaaa 7560 ttaatgaata aatgtactca gctgcccatc cacttaggct caagaaaaaa aaagaggtaa 7620 acagagcctt aaaaatggac tttattaatt attttctata attttgctta atgctttaaa 7680 gtaaactctt attgacttgg atcttaatag agtttgtgaa tacaaaatct gaggaaaaaa 7740 gtttttgcta aaaataaaaa caacgcttga aagatattgt aaggcagttt aaatttcttt 7800 tcttttcttt tttttttttt tttgagacgg attctcactc tgtcgcccag gccggagtgc 7860 agtggcgcga tctcggctca ctgcaagctc cgcctcccgg gttcacgcca ttctcctgcc 7920 tcagcctcct gagtaggtgg gattacaggc gcgtgccacc acgcccggct aatttttttg 7980 tatttttagt agaggcgggg tttcaccgtg ttagccagga tggtctggat ctcctgacct 8040 catgatccgc ccgcctcggc ctcccaaagt gctgggatta caggtgtgag ccacagtgcc 8100 cggccggcac ttttaatttc ttagaaaagc tgaacaaatg gcacaatgca aagagcaaaa 8160 gttttggaat aaatagattg aagccattaa attattggat aaaaatagtt tcgggttgct 8220 tttggcctag gttctcccct ccccccatga ctatccactt caggaataaa cattctgaaa 8280 gtcaatttta cccatttagt gagcatttat ttctagacag ttgccttatc aaataccatc 8340 tatgttacgt catttaatct cacagttact tgtgcatcag agattagcat caccacttta 8400 tatattggta catgataaac actttattgg tcatggatgg ggagatggtc actgtaggct 8460 aatattggta catgataaac actttaagta atcagcccat aattgctcac caagacctta 8520 agcctcccaa agtacacaac attctttgtg ttcttcacta cacatccata gagtctaagg 8580 gacgtaaagc ctcgttaaag ccagttttga ccagaagcag caatgagtct attcctgtgt 8640 gttttccatg ttaatgggac aaaatgatac tttcaaggca ttgaaaattc atgattaatc 8700 aatccctagt ctgaccccag tgttatctat gcaggtttgc aaaaccttta gtttacttaa 8760 tactcccttg ccttcttttg attcacatcc taatgccagc aaatacttat gtttttgcta 8820 tttcagttcc atttccataa aatttatttt atcatctttt ctcataaatt tatgccctct 8880 atttttactc ccaatctgtt taagatgaac aaatcttata aggccacata gctgactgtt 8940 atttctgttg gactccagga aggagaacct aaagaaaagt tcaagtccaa gcagaaaccg 9000 tgatttcttc cagatgatgg ctcatgagtg ccatttaatt ggggtgccac ctggtgacct 9060 cagcaaatcc cagctatatt tatgtgttca cattacagga tcattaaccc agaccgacca 9120 ctgcacagat ctcagaatat tttctatgga gaacatacat aataatgcct gatttcagaa 9180 gaagaaagta attctcaata gcaaggggat ggagtagggt agacagctgt aattaaactc 9240 acttgtgtga taaaaagaaa ttaaggaaaa aagaaaatga gagaacatat tactaaataa 9300 agaaagcata cattaaatat ttactatagt ttcacactaa gagaataaag gaaatgcaat 9360 aaagtggcct gaaaggtaaa ggatgagatg tgtaaagggg tgtagtattt ttactatgag 9420 cagcaatctg agaagataaa ggaatcgagt tacgggcaaa catgatgttt gatcagtgtt 9480 atttgttttc aaggcctgcc taaatttttt tcaaatatta caaacttttg aaataacatt 9540 ctttttgttt tttgctgtct gttactaggt tgcacatttt ataaaggcag ggaccatggt 9600 atgttgtttg tctttggatt ctcagtgatt gttatattta tatttgttga aggaacctta 9660 atccaagact tggactccaa gtatctttcc actctggttc caaggaggga ccttcctcac 9720 agcaggcatg ctgtgtggtc tcacatctca ctcctatatc tttccctgtc tgttactgcc 9780 ctcagtggag cccacagtga ccatctcccc atccaggaca gaggccctca accaccacaa 9840 cctgctggtc tgctcggtga cagatttcta tccagcccag atcaaagtcc ggtggtttcg 9900 gaatgaccag gaggagacag ctggcgttgt gtccaccccc cttattagga atggtgactg 9960 gaccttccag atcctggtga tgctggaaat gactccccag cgtggagacg tctacacctg 10020 ccacgtggag caccccagcc tccagagccc catcaccgtg gagtggcgta aggggatatt 10080 gagtttctgt tactgtgggc cccacaagac aaaggacaga gctccttctg acccatccct 10140 tcccatctct tatccctgat gtcactgctg agctgggaat cacaggagac tagagcacct 10200 ctagttccat ggcgagtgca tcagaagaat cctgatctca tcacctttcc agatgctagg 10260 gaaattactc tacatactgt tgctctggat cccagtcctg attgctctga ggaactgatt 10320 attagggctg gtgactggga tcttagggtc taagtttatg gatgagttcc tgaggagtgg 10380 agatctgctt ccccactctg tcacctactc actgtatcca aggacctatt ggctggcctt 10440 tccctccctt aggggtggtc tgaatggaga actaggttcc tttgatgcct tcacctcctg 10500 catctcagac tggacttcag ctcctcatca gggaaactat ggggtatggg gacaaacact 10560 gacactcagg ctctgcttct caggggctca atctgaatct gcccagagca agatgctgag 10620 tggcattgga ggcttcgtgc tggggctgat cttcctcggg ctgggcctta tcatccatca 10680 caggagtcag aaaggtgagg aaccccaggg gaaaagggga agatggcctg tgacccagac 10740 cctctgttca gagaggtcct gtctctagat gtagctcttt cctcctgacc ctgagaggaa 10800 gaaagctgag ctggaagtgg aaggagacag gacaaggttg gaggaggcat tggaatctga 10860 ttttactagc tgaagggtag ccctgtcaca gagctgactg atagagctta ttccagggca 10920 tccttaccat tcatcattgt ctcactggct cctttccaaa aacttcctcc attaagaggg 10980 tcagagcctc ggcctccttg ccttctagtg acaatttcct ttattttagg ggattttaaa 11040 ttagggtgct taaggacttg aagaacatga atgggaagag aatataactc taattaagtc 11100 acatgtgtca ttttcctttg gggtgagaga gtggctgttc atgtaatgag acctttctct 11160 gcataacttc cttttgtaag acctcaaggg cctccaccag caggtaatat ttcagccgtg 11220 atccagtgtg gggagggcac aggtgtaaga gggaagagca tgagctgagt gtacctgaca 11280 gtagtggtct ctgttcatgg tatatttgct gctatgagga tcaagactta ggggtgaagt 11340 ttgccagttt ctaggaatct ccagaggttg ttccccagaa ccaagcctta actttggtgg 11400 tatcttcctg ttaaatgtgg agccagaacc acggcttaaa tgttagacac taggatgatg 11460 cccactttgt gccacatgat ggtggctact gcctgtaggc attttccagt gactgaaaga 11520 ggctgctagt ggtagggatg aggtatcatc caatttccta aaaagattga acccttcata 11580 ttcaccagaa gagtaacagc tgttccccca cctcccacac atctgcatca agctgaagtt 11640 ctgtgtcttc atgagctgat ttcacctttg cacagatctt gggggaggtg atgacaatac 11700 actctggacc tcagctttgt ctgtctgaag ctgcaggagg cccctgaggg gtggggaaga 11760 tggcaggccc accagcgtac cctgtgctga tcatccctct tctctcttct tcagggctcc 11820 tgcactgact cctgagacta ttttaactgg gattggttat cacttttctg taacgcctgc 11880 ttgtccctgc ccagaattcc cagctgtctg tgtcagcctg tccccctgag atcagagtcc 11940 tacagtggct gtcacgcagc caccaggtca tctcctttca tccccacctt gaggcggatg 12000 gctgtgaccc tacttcctgc actgacccac agcctctgcc tgtgcacggc cagctgcatc 12060 tactcaggcc ccaaggggtt tctgtttcta ttctctcctc agactgctca agagaagcac 12120 atgaaaacca ttacctgact ttagagcttt tttacataat taaacatgat cctgagttat 12180 ctgtattctg aacttcctta attgagcaga ggcaggaaat cactgcagaa tgaaggaaca 12240 taccttgagg tgacccagcc aacctgtgcc cagaaggagg gttgtacctt gaaaagacac 12300 tgaaagaatt tggggtgcaa agtcatggtg ggcagaggag gtagaaaatc aactcagttg 12360 ttgcatcatt catggttctt tcatattgat gttcagtgca gtggcctgag aatatcccag 12420 cctctcttct ggtttggtga gtgctatata agtaaacatg gtggaattgt ttgggggcag 12480 atatagtgac ccttggtcac tggtgtttca aacattctgg caagtcacat caatcaagaa 12540 taatttttac ttttaagaaa gcataaccag caataaaagt attatttttg attctaaatg 12600 atagaaaccc aaatatattt tgttcatggt gcaaaggaag cctagagtca agttgatttc 12660 agaagtgact agttccagat acacaatgag atcttcacct ctctttctgt tatatctcta 12720 tctgtgaatc tgcctctctt tctgtgtctc tttgtccctg tatagttctt tctgcgtgtc 12780 tctctgcatc tttgtctctg cccccttgtt gtgtctttca ctacattgtt gcctttctat 12840 ttttctaatc catggtcact gtttatctgc attttttcta tctccgtgtt tctttttgca 12900 tctatttttc tgcatttctc ttccttatca cttcatatct tatctcatct ctctctcttg 12960 ctgtgtgtgt gtgtgtgtgt ctgtttgtct gtctctgtta atatatgttt ctagaatgtc 13020 taccagagtt ttaacaactt taggaaagat tctgattggc caagcctggg taacatgcac 13080 acctctcaaa cacattgtcc tgtgcacggg atgctgacag ccagcattgt gtccatcgct 13140 cttattagga aggaggactg gattttccag atccttgtgg tcctggaaat gacttccagt 13200 gtgcagatgt ctacaccagc catgtggagc acctcagcct ccacagcctc ctcacagtgg 13260 aggggtataa ggggcagttt gtttcttgtg gagcccacag gacaaatggc agagctccct 13320 ctggttctag ggtccctcat tgggggtgcc tgttcatagt cattccactc cttgtctgag 13380 ctccctttgt catagacgtt gtaacctgtt gattcctgat gacactcttt tcccggttat 13440 gagggaggtc actacacact gtggcccctt tgatgtgggc ccagccctga agctggtcta 13500 catctcagtc tctgagtttc gtcatgaagc cagagtctgg gagcttctgc gaggttatgt 13560 aaggccatga ccctgaaagc agacatccca tcttcctttc tccctcaccc acacactggg 13620 cgtgaggagt ctttggcagg ctcttccttc ttatggatga ggtcagagtg gagaactagg 13680 tctccttggg accttcatct cctgtactcc aggctgtcat gcaggtcctc agacagggac 13740 actggcgcac aaagaggcac caacacttga gattctgctc cccagggtta tagtctgaat 13800 tttccccaag caaaattctg aatggagtca aaagttttgt gccgattttg tcctcttcct 13860 cagggtgggc actgtcattc accataggga tcaaaaggga gtaacacttt tggggaaatg 13920 gggaaggcat gtgctgggtt gtccagcgtg tcctcagtct ctgtgtgtag ctcctggctt 13980 ttggccctgc aaagggaaga ggcagggcta gggattgaac aagactcaaa gtttagggga 14040 acatcgagat ctgatttttc tagttgaagc ataagcccta taattggggt gggtgataga 14100 ttatattcta ggacattctt acagttcaac attgtcacac tgagcacaca tgctggaaga 14160 ttctttatta acgagagggt caaaatcgtc ttctctttct tccattgaca gtttcataga 14220 aacaactatg ttttgcaccc agatttcatt ggatagtata atctttaatg gataattaat 14280 taaaataata agtacatcgt ctataaataa gtttgctaac acaaagaact gagtcttact 14340 cagcatataa cttggaggaa agcgtgtggg tgttctagag gacaacctac tggtcttgag 14400 catttgtcct taccttagat aataacagta taacttttgg agacagtgat gcttaccagt 14460 attccaaagc tcctgtacat ttctcagtct tttccgctgt taggttgggg acatttgact 14520 aacagtaacc aatggaactt gcaagtaggt gcatggtggt gtatgagatg ctggaaactc 14580 cataatctga gtcatttgaa t 14601 <210> 2 <211> 13247 <212> DNA <213> Artificial Sequence <220> <223> HLA-DQA1 (NG_032876.1) <400> 2 cccttgagaa agcttcactg tgtttttagt gcagattagt aaagataaga tcttgactgg 60 taggtgagtg ggtggaattt atttcaaata tgggggctct ccaatccttg cacaccaaat 120 tcatttacat attgtcaaaa gccagaggat atttatgata agttgcaaaa atagctacaa 180 attctttgta gctcattctg tcaagaaatg caatctatta atccacctct tgatgtgagc 240 tagtactatg acttgctttg aataacagaa tgtaatggaa gtgatgttgt gagttttaag 300 tttcagctca agacacctac tgtttctatc ttgcacagga gagctttcca gcacctgtga 360 taagcctcag cccgcctgcc ggataatgag cccacatgga ttgagagagg cctcctatcc 420 ctgccaaacc tattgatgct acagagatgt gagggagccc acctgagaaa agctgaacct 480 gcccagtaca taaaaaccac tcaggtgggt tgagcacaat ttcctgtctt acagaatcat 540 gaggagacac taaacaatta tttgaagtca ttaagttttg gagtactttg ttacataaaa 600 aaatctgaca gatacaagag tcttcaaaaa aattttgttt ttcagcaatg tcttagtgct 660 tctgtggctc acaggctccc acatgcctgg agtgctacag ggagaaggtt aaatgaatga 720 ggaaaaattg ataggctttc ccagcccaaa gcatgatgtt attatcatta tcattattaa 780 tatttgtctt tatataggag ctaccacttg ggaatagttg ctatgtgtca gacactggat 840 tgtatttaac tttataattg tacttatcta tcatttcatt ttaccatatt aactatcatc 900 taataatttt ccttctgttt tatagaaaat aaccttaagg ctcaggagtt ttgagtagct 960 tgcccaaggt gatgcagctg ataaaatgaa aagcagcatg gaatacatat ttatcttatt 1020 acaaaatctg tattcttttt actttgctac tctagactct cttattattg tgaagcagct 1080 ttaactactg caagacagaa gtcttggcct tcagagtaaa acttcaccag tgcataaagt 1140 cagactaaag caatttgaaa atatacagtc ttagagaatg ttataactgt ttattagaac 1200 taacataaat tctacctaat ttcttagagg gctcttaatg atgtcaatta taatggcaca 1260 tcccattgtt attttagtca tggaatcaat ggcatgtcaa taagtgcttt ctgagaaaat 1320 tgttggacaa agtactattt tgaactccaa attttattcc cactattaat ttatgaagag 1380 ggccttttct ctttctacta gacaaaggta acaaattagc tcttgttaaa atggtatgct 1440 gttcttctga gtctcattta cttattactt taccttacat taaaattatg acctgaagac 1500 ataagcaact ggaacaacgt tcactgtgtt atggccggat gaagcaggaa gaggaaagag 1560 acaaaactag gttaaagata gaaatggcat ctattgggcc agtcgtggcc tcacgcctgt 1620 aattccagca ctttgggagg ccaaggcagg cagatcacga ggtcaggaga tcgagaccat 1680 cctggttaac acagtgaaac cccatctcta ctaaaaatac aaaaaattag ccgggcgtgg 1740 tggcaggtgc ctgtagtccc agctacttgc agtgagccga gattacgcca ctgcactcca 1800 gcctgggcga cagagcaaga ctgtctcaaa aaaagaaaaa aagaaatggc gtctattatc 1860 tcttcaatga ctttgccttg cttggacttt cccttcaccc cacaggatgt gaggtctgaa 1920 acggcaccct caacttccca tccaagatac aattctaatc ctacatttaa caccctaact 1980 tcttaactgg agttgagtta tttaaactgt aattttaata ggtgaaattc tggactacca 2040 tcccaaaaca ttttgctcat ttgccaaagt cctaaggaat ttccatgaga tacaaagcag 2100 gtaagtctgg atacaggaaa aaagataaaa acatgttatt tgctacacag ccagaagggt 2160 attgagtggc aaagggagca catctcaaag gggacctcaa aaaccctctt catccacaat 2220 ggcaggagct agaaagaata aagccaccta tagggtcaaa tatctctcct aatcatgtta 2280 aggcactgga ttctgaattt gcacagaagg agactctcac ccatcactcc tcacaaggac 2340 tcatggcttg ccccatagca tcacatctgt gctgcttacc agctgcgtga ccctgggaaa 2400 agtccttcaa ctctctgggc tttaatgtcc tcctcggaaa atgagaacga tattaaaata 2460 tgacaagtat atgtaaagag tccaggaatt tttcattcca agtgcagtgt atgtacattt 2520 ctcacaactg cctaatgagg tacctcaatg cctccagcca aagaccagca ggagcataca 2580 agcaatgaac aagtcagctt tattgtttat tgcaatgatg gataaaactc accatgagaa 2640 tcatgcagcc cctcagtaag agattgttgg aaccaaagaa gtagaaccac gagaatacat 2700 atattaagag aatgatgcaa ggaattaatt tttgcatctg tgggggtggg ctaggcaagt 2760 cagagatcct ctgggaggta gttatcagga agggcaggct ggaactctca gcacaggctg 2820 acacactgtc cagagtggaa tttctgtttc ctcagagaaa cctcagctct gctcttaagg 2880 cttttcaaca gcttagatta agctcaccca gttttcctag gataaattct taaagtcaac 2940 tgattatgaa cttcaatgac atctacaaaa tatcttcaca gcaacatcta gattattagt 3000 gtttgactga ataactgggg atcacagtct agctgacaca taaaattgac cattaatcag 3060 ttgtaaggtt tgtgcttgtt ttaggtgatt ttggggagga tttaagaaag agggattttg 3120 cttttaattg gattctgaca gaaagtggag ggttggggtg gcaatgttat gattgggtag 3180 cttcataaat cctacctaga gggacagaag actatcctga ggctacagac gtggttggta 3240 aagaagcagt aatcactccc aagagagaga tgtgcctggt catttttgtg gtttggacaa 3300 tatttatgtt ttgtctgggt tcagacatga tgactgagca ttcaggtgtt ctgtctcaat 3360 ccactgtgct cacagagtac ctgtctgatt ctgatgttct atgaaatcct ttatctccaa 3420 caggagaacc aaaaccacct gggagtgcca ggctagctgc tagcaacccc aagcctttgt 3480 taattacatc cagacagctc tcaggtgtca ggacattttt ttttttgttt tacttttttt 3540 ttttacagtc tctgccagta ggaggtaaaa catagtgctg agaatctcag aaggccattt 3600 atcaaggaca gagtgattct aaatagaagc tccattaact tacggtttct atcacataca 3660 gaaaatagat gcatctgaaa aaacataata agtttccctc taaggactaa ctttagctca 3720 atctctagtc ccttgcaaat atttggaatt ttaatggggt aggataacaa gttttaaaag 3780 atctgatagt ttaagaaaag aaaaccattt ttctaaggca gtgcaattct tattctaccc 3840 tcaacttttg acttcatatt cttaattaaa aaaaaaattc ttagagtaat tgagccagcc 3900 aaattttaaa tgtaatcaat gtccctaaat ttcctttaaa cgtactcaag aagcaccaaa 3960 acacagaaca taaggattac tcaatgcaaa gaaaaactgt ataaagtctc atatagttac 4020 tatagacagc cccatctgac attataaccc ctttttattg ccctggccaa aaccacctgg 4080 agcttttgag cacttgagaa gaacttaccc agctggattt atacaagtag aaaaggcaaa 4140 ggtattgctt gggctaccac cagcagagat ccctaggtag gtggggtcag cttaacattt 4200 ggagaattcc atacgcactg tggaagctaa aagaaaaaca gctaacccac atacagaagc 4260 cagagaaagg gcaggggatg gggactgcca gggagggaaa tcaactcagg gaaaaattcc 4320 tggaggttgt aagccagaac atcctgaagg atgccgtata actgatgacc tcatctatcc 4380 acgaggctgc tcagaaatgc ccacccctgg ccaggcgcgg tggctcatgc ctgtaatctg 4440 agtactttgg gaggctgaga cgggcagatc atgaggtcag gagttcaaga ccagcgtggc 4500 caacatagtg aaaccccgtc tctactaaaa atacaaaaat tagctgggcg tggtggcagg 4560 tgcctgcagt cccagctact tgggagggtg agggaggaga atcgcttgaa tccgggaggc 4620 aaaggttgca gtgagccgag accttgccat tgtacctcag cctgggtgac agagtgagac 4680 tacgtctcaa aaaaaaagaa aaagaaaaga aaaaggaaaa aaaagaaaaa cacccatccc 4740 tcttgcgact ggcagacatg cacacaccag agaagattcc aatttaatgt cctcccttta 4800 ttcatagaac aattcctcaa gtccactctg agtagaggct gcatcacaag gggattgccc 4860 cgtctccttc cagggctctt aatacaaact cttcaactag taactgagat gtcaccatag 4920 gggatttttc taattggcca aaacctgact tggcagggtt tggtttgggt gtcttcagat 4980 ttccttgtct tgaggtcctc acaattactc tacagctcag aacaccaact gctgaggctg 5040 ccttgggaag aggatgatcc taaacaaagc tctgctgctg ggggccctcg ctctgaccac 5100 cgtgatgagc ccctgtggag gtgaagacat tgtgggtgag tgcatgagtg agggatgttc 5160 tctggagctg aaaaacagta aattgaagga aaagagataa agcgatttgc agagaaactg 5220 tagagatttc ctaagggccc tttcagtatt aagacaatta aaaattatag ctgttcctcc 5280 ttcaggaaac cagagcccca acctactctt tttgttatct atgctgttgt gttcactaag 5340 gacgctattc tgtttatatt atattcagtg actacggcct ggaggtctct atgtcgttcc 5400 atcatgattg cctcaaaaat tagtgaggtt tccatcagtg gataattttt tattattaaa 5460 aatttatgaa gtgtcattct caaatttccc tgaacaactt ttgaagcttt tcggatgtct 5520 ccggtggtag atcttggggt cattccatca attatgtact ctatagatat ttaaaatgtt 5580 gcccgtttct ttctctcaga cttactcaca tttccacatg ggaactggca caggtgggga 5640 gtgggtaaag gagtccagca ggctgaatgc cttcaacaat cattttacca catggtcctc 5700 acttactctc agctgcctca tatgtgtcac ctcacaagta atcaaataaa atgggcatgt 5760 ggctaagctt tgtaaatagt gaaaacatga atgtcaattt tttttacata tttctattac 5820 agatatagct tcacatttct tttctttagc aaaataaggg atcattttat tttaaaattg 5880 agaagtagaa aaaattggta aaataaatca ttttattctc aaattatcaa cccaaattac 5940 ctgttcttca cctcatctaa taaagtccta taaaaagaaa agtgggccag acaaggtggc 6000 tcatgcctgt aatcccagca ctttgggagg ccgaggcagg aggatcattt gagcctggga 6060 gcttgagacc agcctgggca acatagcaag acctcatctc tacaaaaaaa gaaaaataaa 6120 aattagccag gcatggtggt gtgtgcctgt ggtgccagct actcagaagg ctgccgtggg 6180 aggaccactt gagtccatga ggcggaagct gcagtgagcc atggtggcac cactacactc 6240 cagccagggc aacagagaga ggcgctgtct caaaaagaaa gaggaaagaa agcgaggaag 6300 gaaggaagga aggagaagga aggaaggaag gaaaagaaaa gaaaagggaa gggaggaagg 6360 aagggaaaaa gaaagacaga aagaaagagg aaggaaggaa gaaaggaagc acagattaat 6420 tatttggtct cttactctcc tctgcctttg tcgtccatct ctttccacct ctcttcatgc 6480 atccctttct ccctcttccc tttcaggatc catctctgac tccctgctcc tttatagaga 6540 tggacagtgg gtttgtaaaa caaaagttga aaagtcagat agttaaaagg ggaagtgaac 6600 tggaaggtac tttaaacttt cacaacttta ttaaccgtgg ctgctcccat tatgattttg 6660 ttcggcagtg gaagtttcac ctgcttctcc agagcgcttg gcgtctttgt tccaaatttc 6720 ctttcttcaa cctcacacca gagtgccctg gtcaggcttg gctcattcat taggcacaat 6780 gtgggcagtg caggggaccc tccatactgt aaagccacat gagaaggttt taactccttt 6840 taaaattaga aaaataatgg aatattagag cctaagaaaa tgttttaact tttaattcag 6900 cctagattat attgtcttta taccaattca gtcataaaat ataattttcc atatttttgt 6960 ggaggaagag gcccatacaa gcaagaatgc tcggggctca catgtcagaa tgcagccttg 7020 gtcatgactg atcctggcct tcgtatggtt ctgctacctg tgtgcctgcc cgtcttcccc 7080 aaaatctatg tggtcctcga atatagcaac tgtcattcaa tacacatgtt tgagcacaca 7140 gtgagctaag ttttaaggat tcaaagatga aaagtcatgc tgtcttccct gcagagggtg 7200 ctcagattag tgatggaaac agtatggggt gcaggaaagc agaaggccat tgctgagcag 7260 ggcagtggac ccagcagagg ctgaaacaat acaagtgact tggttccagg tgggccagca 7320 gggtgacgtc ctctagcaaa atttggcacc caagacaagt accagaagaa aagaaagact 7380 gcatgtattc cacatatatt catgtttgaa caaggagtca agatttatgg caaggataag 7440 gaggctttgt tggtgacctg ttaagaccaa ccagggcagt catgctggat agggaagaag 7500 gtgagctgga agaggaacag acaacttgga cagccagatg ttgagacgga ggggttggag 7560 gtcataatgt ggtcaaaaac atgttgatga gaggactcag ctacaaagtt gttaacttaa 7620 gcagaaacct caaggatgga ttttagaatt tctccaggaa gtcctaaaag ataattccat 7680 ttcagggaga aaaacaacag accactgcaa agaccaggga acatgaaagg ataatgtagt 7740 ttgtcttgct tggcagatac ttttgaagga tgttggactg taaggctgtc gatatcctcc 7800 tcagagaact tactacagta cattgtatct gttcccttac ctacctgact cttccactat 7860 tcagtttgtt ccttaatagt agaccatgcc tgattggtgt tttacacatc tccggctatg 7920 tctgacactt gtggatgctc agaaagtggg gaaggaagga aagatacgat ggtaaaaggc 7980 ttacacatgt cttgacaaaa aagtccagtt tggctcattt ggctggagtc gtactgcatg 8040 gctgccattc tgctctggca tcctcagaca agcacactgc ccattagagg aaaaagtgtg 8100 atataagtgt tgagtcagaa tgctgtagac atttagtaat ctccttcaca ggaaaaaaaa 8160 aaaaaaggtg gggggaatga cagaaatcca aaaactagta gagcttccac ttttcatttc 8220 agaagaaatc agttgctctc ctctaaggac cattactatt aacaaaacag agaccttaga 8280 aggaggcatt gtttatttat tatatatttt gtaatgttat taccaatctt gttatactct 8340 ttcttatacc ctacaattgt tagcagaaat tattttaaat taataagatc ctgcatgctt 8400 ttcctttaaa aaaaaaaaaa agaaagatct ctgtgtagag tgtcctattc tgagccagtc 8460 ctgagaggaa aggaagtata atcaatttgt tattaaccaa tgaaagaatt aagtgaaaga 8520 taaatctcag gaagcagagg gaagtaaacc taatttctga ctaagaaagc taaatactat 8580 gataactcat tcattccttc ttttgttcaa ttacattatt taatcataag tccatgacat 8640 gccaggcact caggaaatag taaaaattgg acatgcgata ttctgccctt gtgtagcgca 8700 cactagagtg ggaaagaaag tgcactttta actggacaac taccaacatg aagaggggag 8760 gaagcagggg ctggaaatgt ccacagactg tgccaaaaaa tgaagcccat aatatttgaa 8820 agtcagtttc ttccatcatt ttgtgtatta aggttctttc ttcccctgtt ctccgccttc 8880 ctgcttgtca tcttcactca tcagctgacc acgttgcctc ttgtggtgta aacttgtacc 8940 agttttacgg tccctctggc cagtacaccc atgaatttga tggagatgag cagttctacg 9000 tggacctgga gaggaaggag actgcctggc ggtggcctga gttcagcaaa tttggaggtt 9060 ttgacccgca gggtgcactg agaaacatgg ctgtggcaaa acacaacttg aacatcatga 9120 ttaaacgcta caactctacc gctgctacca atggtatgcg tccaccattc tgcctctctt 9180 tacttaagtt atccctccat accagggttc attattttct tcccaagagg tccccagatc 9240 ttcttatggc aattgctgaa attttatcat ctcccatctc taaaatcaca tattcccatg 9300 taatacaagg gtctttccat tatgcattca gcaaatcctt ctaggagagg tctcatcaac 9360 ctcctacttt attaaacatg cccacagaga gaagggcaca ggaataaagc agaggcaatg 9420 tgtcgttgct cccaagcaga aggtaaataa gacctctttg actatcaggt ggtgaaatgc 9480 tggtaggagg gctcttccag gatgtaatgc agaacttcag ggcagagcta ttcacacttc 9540 acaccagtgc tgtttcctca ccacagaggt tcctgaggtc acagtgtttt ccaagtctcc 9600 cgtgacactg ggtcagccca acaccctcat ttgtcttgtg gacaacatct ttcctcctgt 9660 ggtcaacatc acatggctga gcaatgggca gtcagtcaca gaaggtgttt ctgagaccag 9720 cttcctctcc aagagtgatc attccttctt caagatcagt tacctcacct tcctcccttc 9780 tgctgatgag atttatgact gcaaggtgga gcactggggc ctggaccagc ctcttctgaa 9840 acactggggt aaggatgagt ttcatcattt tttgattctt tcttgtctgt caagttcaga 9900 acttcctgcc ttttactcct atatccaaaa acttgttttc cacacttcat gggtttcttt 9960 tctgtctctc tttttttttt gaaagaataa agcaaaaaaa gcagagattt attgaaaatg 10020 aaagtacact ctacaggatg ggagtgggcc tgccacttca tggttttcta atgatagact 10080 tcactcttct ccctaagcct ggggccttga gtctttgcag agccaaccct ctaccccatc 10140 ccatcccaca cacatgcaca tgagcacact ctgcattctg acctcaacaa cttcacttcc 10200 acagagcctg agattccagc ccctatgtca gagctcacag agactgtggt ctgtgccctg 10260 gggttgtctg tgggcctcat gggcattgtg gtgggcactg tcttcatcat ccaaggcctg 10320 cgttcagttg gtgcttccag acaccaaggg ccattgtgaa tcccatcctg gaagggaagg 10380 taagattgag actggttaca gttgaagcgg cagtatgaaa ggaaggaaag tgggagggcg 10440 ttgtggacat gaatgtggtt gaaagttgta ggggaattgg gaagtggcat gatgatgaca 10500 caggagcccc ctcggaccca ttgatctcat gtctgccctg ttgcaggtgc atcgccatct 10560 acaggagcag aagaatggac ttgctaaatg acctagcact attctctggc ccgatttatc 10620 atatcccttt tctcctccaa atatttctcc tctcaccttt tctctgggac ttaagctgct 10680 atatcccctc agagctcaca aatgccttta cattctttcc ctgacctcct gatttttttt 10740 ttcttttctc aaatgttacc tacaaagaca tgcctggggt aagccacccg gctacctaat 10800 tcctcagtaa cctccatcta aaatctccaa ggaagcaata aattcctttt atgagatcta 10860 tgtcaaattt ttccatcttt catccagggc tgactgaaac tatggctaat aattggggta 10920 ctcttatgtt tcaatccaat ttaacctcat ttcccagatc atttttcatg tccagtaaca 10980 cagaagccac caagtacagt atagcctgat aatatgttga tttcttagct gacattaata 11040 tttcttgctt ccttgtgttc ccacccttgg cactgccacc cacccctcaa ttcaggcaac 11100 aatgaaatta atggataccg tctgcccttg gcccagaatt gttatagcaa aaattttaga 11160 accaaaaaat aagtctgtac taatttcaat gtggctttta aaagtatgac agagaaataa 11220 gttaggataa aggaaatttg aatctcaaaa atatcaaaag taaaaatgta ttctcaaaac 11280 tttaaattta tgaagaatga tgacagtaga agccttcctc ttcccttgtc accttgagat 11340 aaaaattctt taggcaggaa aagaaatgga agtcagaaaa acattagaat aagacaataa 11400 tgtgggtgtc tgaaaaggaa caaatactta ttcctcacat agggttagtg acaatgggaa 11460 aagggacggg agtagaagcc acagacatat ctaggagccc tgaatagagg cgcagtctgc 11520 ctcacctcct gaatgaagct gtactagata accatgtagc tttccctgtg ccactctggc 11580 atgaaggaga cagtatagtg aatatggcta caggatgttt cttggaaaca tgccaatatc 11640 ttcagaaatc cccagccctt tcccctaacc cctcctgact aaggaaagca tgagcttatg 11700 agagaaaccc taggaagaac aacacagttg agacaatgta gcagcagcag tgggtgctgt 11760 gtcctccact ggattcgcca tctccgagga gaaactctca cagaggaaat gggtcagcag 11820 cgacctcatg gctctaaaca gctatgaaat ccatgaggat atttctaacc atgctacctg 11880 catcagtgag tttaaatttt aattggagaa aaaatacaaa acattaatgc aataattgat 11940 acagtatagt ttggtgcaaa gaaccctaaa tccaaatcca ggactcagta ctttgaagct 12000 agtattttaa actttataaa tgtgtgaagt ctctaacatt tctggcctta cttttctcat 12060 ccacaatgta ggagtaataa tactttcctt gcagagttat tgataaaatt tgaataattt 12120 tgatatttag tcaatgcctt acacatagta catgaacaca taagaaaaca ttgtggttat 12180 atttataatt aatttattta aaagaatgga tcatattata tgaaaagcac ttttgttttt 12240 ctcagcctct taatgattta ggagattcaa atgtagagct atgggtgaat ttcttttcat 12300 atgataattg aaggatattt ttctttttcc agaatgagag aggctgagat tggattggta 12360 agagaactct tagcactaga agttgtaata tttgactttg gttttcaact ctctaagagg 12420 gaatatattc cctccttatg gcccataagt gtttattcaa ggtatatcat atacaacaga 12480 tctttatgcc tgtttacttt ggggaagaag tgaagatagt tcaaggagaa aataatttaa 12540 aacacagact gggaatcagt aagcacagga aatctgaacc agtgatgatc atgaaaatgt 12600 ccatcacaga gcacagatga ttttcagggc aataaaacta ttctgtttga taccacaatg 12660 gtgaaaaatg tcattataca tttgctcaaa tccacagaat atataacacc aagagttaga 12720 cttaatgtaa actatggact ttgggtgata atgatgtgcc aatgtaagtt cataaattat 12780 agcaaatgta ccactcagat gggagatgtt gctaatgggg gaggctatgc atgtgtggga 12840 gcagagtgta tctggcagca gtccccagcc tttttggcag cagggaccag ttttatggaa 12900 gacaattttt ccacagatag ttgggggaat gggggtatga tctggggatg aaactgtgaa 12960 actattccac ctcagatcaa caagcattag ttagattctc ataaggaaca tgcaacctag 13020 atctcttgca tgcacagtta aaaatagggt tcgcactcct atgagaatct aatgccacca 13080 ctgatctgac ggaaggcggg gctcagttgg taatgctggc tcacccactg cgtggtccag 13140 tttctaacag gccaccaact ggtactggtc catggcccgg gggttgggga cctctgggat 13200 acctctgcac cttctgctca gtttttctgt gaacctacaa ccgcttt 13247 <210> 3 <211> 20403 <212> DNA <213> Artificial Sequence <220> <223> HLA-DRB1 (NG_029921.1) <400> 3 gaggttgcag ttagacaaga tcacgccact gcactccagc ctggcaacag agtgagactc 60 tgtctcaaaa aaaataaaag aaaaaaagaa aagaaaaaaa aagaattaag tgtttaagtc 120 ctgttctgga gagaaaataa acccatgtct atgtattttg cctcagtgga agaaccagtt 180 gcttttagaa ctgattcttg ttatgctttt ttgtttttca tagctttaga acttgtaata 240 gcaataaaga ttcctcactt ctggaaaaac tcaaaaattt cgaataatcc ttatattatc 300 ttctgctgtg gttattataa agtattttct tctggttaat tatatagcta tggcttagat 360 tattttttac tagctgatac cttttttctt attctaacaa ttgactagac acctccttaa 420 ggtcaaatcc aaaattctga actgtggata ctgacaggct tttgtttgca cccagatcat 480 ctttagcatc tctagattga tacgtagtag taccaagttt tccaccttta tcttgctagt 540 gtaccccttg aatgaacaca agaccaaaac agggatgcta gcaatagtta gtgtggttct 600 tatgctttat ttttctcaaa actgctgtat gatactgaga gttgctttgt ttgacaggca 660 cacagggtag gaagagatgt catgacaaaa ggaatcgtta atttttttgc acatatataa 720 gttgatttta tttaggtaaa atattgttaa cataaataag tactagtaag tttacttttt 780 caagataata aattgtctac aaggatgaac tgttagaaaa ataactgcta aaagatttta 840 ttatttattt taaataaaat aagcaacaaa ccaggcacac actttatagg acagattgag 900 aagttggtac agttcaacag gttcatcaat ttcttcactg tccacactgc agtcactggg 960 gagtgggcta gtggagcacc aaaatgaaat tttgaaaaat aatctggcct attttggact 1020 ggatagatag gtggatactt accgcagtac aattaacata agatctagaa acagaaataa 1080 aaagaaaatt ctttgtactt acaatattag tacaaaggcc tatgggaatt ctagttgttc 1140 tctctattaa ctatgcaatg gcaagcattc tgttataaaa cagctaagtt gagtcaaaga 1200 atgacatttg gaagttgaag aagtcctgtc aactgaccta gatagtgtca tggtgtaatg 1260 attggcacta ccaaagttcc tcaatggagg acattgctga aattttactg gaaagggtcc 1320 tgtcaagtgt gatgaatact agtaaggcct ttaaatggca ccgttttctg tttcaggata 1380 catatcttcc atgctaagaa gaaactggtc ctgtttatcc atttattgtt attatcattt 1440 tttctttaga tataaggatt agtaacctgc tttttacttt aaattccaga ttagtggtgg 1500 ttgctttctg aaaacccctg agaacatttt gagactactt ggacaagtgg cagacattct 1560 atgataacta aggcttgctg atagccaaaa gagcctattt ttccaaaatg tgttgcaagc 1620 tttcaggctt actacaagtg agccccattc tgtgacaatc agtaggactc aagacatgct 1680 gtaatcctac caatgtcaac ctgcctgttg ttcaacaaaa gtctgtgctt ccgattttac 1740 ctgtttagtc ctgggaatgt tgggatttat ttcccgtaaa accaaaccta tggtttcatg 1800 catcaagacc agagaccatg gaagttccgt actgaaagcc actttcttcc agaaaccaat 1860 ttaattgtca tttcctcagg aaataagctc tcatatttga cacctctcac agccagctga 1920 gttgagagga ttattctctt ttttccgtga aaaagttcag cctattagac cacctatgtg 1980 actgatggtt tggtgagagt tgctacattg tttagcctga actatcctta tattgaatat 2040 tgaaggaaag tgtgagatat ataatttaaa gaagcacatc tgttgtagta taagtgtgtc 2100 tcctttaaaa ttcaggtagg gctcctcact catgaatggg attaaggccc ttgtaaaaca 2160 cgcttcacac agtttttagc ctctcatcct tccaccttct acaatgtaag tacacagcgt 2220 tcatcccctc tggaggatgc aagacgccat cttggaagtg gcgaccatgc cctttgccag 2280 acattgaacc tgttggtgcc ttaatcttgg acttctcagc ctccatgtgt tctttataaa 2340 ttacccagtc tactgtattt tatcacagca caaataaact aagacaacat ctttgttact 2400 cataaatgta taaaacatac agaatttagt tcattgccat tggccatctt tttaaatata 2460 aatttgtatg atttataaat agtgtgtcaa atttatataa acaagttttg aaagtttcct 2520 tttaactgta ttttagtaca ttcttgatgt agaattactt atttttgcct aattaactaa 2580 ttaactaatt gtgatgtggt gacctaggaa aggaagctaa ggttcacctt agtattacag 2640 gataaaagca ggagctatgg atgtccttac gtaacataaa cgcaaattgt gtcatttcca 2700 gaggagagta accatggtga tgaggggaat cttttgaaat aactagaatt gctacaaagt 2760 atctacccca aggtctataa aatgttgcca ttcattaaaa gaagtagtct tactgatttg 2820 cacagccatg aattaaagtg ataaaaataa ttttagtata atggacataa ttctctttag 2880 aaattgaatg tgaggtagta taatataacg acagagcttg aggggtttgg aattacatat 2940 ataataactt ggttcaatag aattgacaga acaactctgc tttaaaataa ttaatatttt 3000 atgtgaagag tgttcagtct cttactcctg gttcccatta tgatttcctc atttgtttga 3060 ggctatggcc ctttactatt ccacttctct ggttttatcg taagggaaga tataagaaga 3120 ttttgcaggc cagacgtggt ggctcacgcc tgtaatccca gcactttggg aggccgagtt 3180 actgtttact agccttgcat ctttgcaaaa gttgtttaat ctccatcatt ttattctctt 3240 cacttgtagg gatgaaaagg ttatatccct cattcagcta atgtgagaat tgattaaaaa 3300 tatgatgtat ggaaagctct gtacaattct gagtacaaag caaaatgctc aaaaattgct 3360 aagaaatttt agtcattttt attgcagcat ggtgagtatc ccattcctag aaacactaag 3420 gcacataagg aatgactgcc tatcagaact gtggtagggt gtgaattaat gcagaacttt 3480 atctgcatag ttatactttg aagtccgttc tgaatcttag atgctacatt tatataaata 3540 caaagcataa tagctatcta aatgtagaat tgtatgttta aaattatatg attacatcaa 3600 ctgatgtaaa tcacagattt tccctagggt tctgtttcct gaacattctg taacgtatta 3660 gttagcaaag tctttttttt ttaaaactga gtctcgccgc atcaaccaga ccggagtgca 3720 gtggcgtgct cccaactcac tgcaacctct acctcccaga atcaagcaat tcttgtgcct 3780 cagcctcccg agaagctggg attacaggca tgcaccacca agaccagctg atttttctat 3840 tttttttttt tagtagagac ggggtttcac catcttggcc aggctggtct tgaactcctg 3900 acctcaagtg atctgcccac ctcagcctcc caaagtgctg ggattatagg catgacccac 3960 cacgtcctgc cagcaaagtc ttcttatata ttcccttacg ataaaacaag agaagtggaa 4020 tagtaaaggg ccatagtctc aatcaaatga ggaaatccta atgggaacca ggaatgaggg 4080 attgaacact cttcacataa aatattattt taaaacaaaa ttgttctgtc aacagctgac 4140 tttgagtcct tgatcgatct ctcagaccca tgaatacttg gattgcacag ttgaccttat 4200 cgcattgtta gggtaagtgc tatacaaagg cacattcaga ccctccattg catataggtg 4260 gcccctgcaa accccttgcc tgtgtgtgtt ctggaggtgc cactaaactt gggggaagca 4320 tcaggagata cacttgaaaa aactcttttt actaagatta aattattaac taactttcaa 4380 tttcctttaa cttattagag acatctctac ctgtaaatag gtaaagatta cactctccag 4440 tcaacagctg tcattctgtc atatcatcag atacccaggg ctgctgctcc ctgaggcatc 4500 cacagaatca cattttccag tattgaaaga cctgaaagat cacggtgcct tcatttcaac 4560 tgtgagacat gatgtaattt tcacaaatct acaacagtaa gatatagtgc aacaggacca 4620 gattaaggtc tcctggtttg caaccatgtc ccctccatct cctttactcc tgaacacact 4680 cactcctgca aacagttctc ttgtcaagtg ggaaatgaat gctcttacaa ggctcaaact 4740 tgtgaacaca tcactgacca gcacagagct aaaataattg gggctaaaaa taccgcccca 4800 attaaagtgt tttacatgca actggttcaa acctttcaag tactaaaaac aatcctgtaa 4860 agaaggaaat tctgtttcag aagaggacct tcatacagca tctctgacca gcaactgatg 4920 atgctattga actcagatgc tgattcgttc tccaacacta gattacccaa tccaggagca 4980 aggaaatcag taacttactc cctataactt ggaatgtggg tggaggggtt catagttctc 5040 cctgagtgag acttgcctgc tgctctggcc cctggtcctg tcctgttctc cagcatggtg 5100 tgtctgaggc tccctggagg ctcctgcatg gcagttctga cagtgacact gatggtgctg 5160 agctccccac tggctttggc tggggacacc agacgtaagt gcacattgtg ggtgctgagc 5220 tactatgggg tggggaaaat agggagtttt gttaacattg tgcccaggcc atgtacctta 5280 agaaattgtg acgtattttt cagagattgc ccatctttat catatggatc ccaaataatt 5340 tccccaccac aaaaggagct tggctacttg cccactccat gagacttgtg taaggggcct 5400 ccatacaggt catttctact caaatctcca ccaataaaac ctttgcatca catgtcctca 5460 gggtctttag aggatttaga aataaggatg ctaaaataaa ttccccatac agcacttgcc 5520 tttattatgt tgacttatgt cagacaaagg aggttttttc tgaaaatttt gtggaagtca 5580 agggaattta aagggtctct cctaaacgat cctgggttat gtcacccaca ggacctttgg 5640 tgttggcccc tcttcctcat atgtgaggat ggacccagtg gcctccccat tatctacttt 5700 cttttctttc tgaactccaa tgtttataaa gcctgtaccc ctgtagtgta tgtaggttgt 5760 ctgacagaag ttatacttag tgctctttct ttcttgtggg gaaaaatccc tggaactgaa 5820 gctgagatct ttagtacttg gagtcacctt acagatacag agcatttatg aggtattctt 5880 tggtgcctaa agaacttaag gcatcctctg aaaacctggc ccaggttagt gtttattatg 5940 aatctctttt aacctttcta tacttgtttc tcctacatct cctaagtgct ccaactagac 6000 atgacagaag agatttaact aacgtagtat gagttatata aaattctatt tttgtaagtc 6060 aaaaataatc aaatatcaaa aatttaataa tgttcaaact atatactctg tgtggggtta 6120 ccgagacaat gtggacattg ttcacatctc atagggctga aagtcaatgg gcaagtcctg 6180 ggaactcatt gtcttactgg ggtcttgtcc taaatttcat aggttcaccc atcatgccct 6240 caactttcct taattagcca tgtctgctta cctcttcctc cagtttctct cttatttttc 6300 cccagctatg ttgttatcat ttccagaaat ctctaaagct tgcacagatc cttagcacta 6360 tgagatccat tgaaagagat agtttttttc tttttgagat agggcctggc tctgtcaccc 6420 aggctgtagc tcagtggtgc gatcgaggct cactgcaacc tctgcctccc acgctcaagt 6480 gatcctccct cctcaggctc cagagtagct gggaatacag gcaggcaacc acgcccagct 6540 aatttttgta attttggtag aaatgagatt ttgccatgtt gcccaggctg gtcttaaact 6600 gctggactca agcaatccac ctgccttggc ctcccaacat gctaggatta tagatgtgag 6660 ccactgtgcc caggcaaaaa gagatgactc tcaataaaaa aaagtccttt ttcttaaatc 6720 actgtttctt tatctgtgaa ttcttcttcc aactagaagg aggagaaaga agtttgcctg 6780 tatttctcac caggaggaga aggggtctag tgtgacatca gaatgaaaga gtgctggagt 6840 ttgagcccct tcttgctttc caagatcccc acagttatca cttcccatac cctggtttat 6900 tcatgtaaac cacacttatt tttcttagca gctactgtgt actcggctcc attctaggtt 6960 cagatcattc tatttgatta agacagagag ggtcccgact ctcatggaag ttacacaaca 7020 atagaggaga cagacactaa cccaataagc atttaacaaa gaataaaata ttagagagtc 7080 atagtgcact gaagaaaaga catcaggttt gtgaagaaga gagacatgga ttcacctact 7140 ttagttcata tgtttaggga gctctacctg agaaagtgac attcagctga gacaacaaaa 7200 taagtagaca gtcatgaaga tctaatggac gaaagctcca gagagaccaa atggggggaa 7260 agccctggtg tgggaaatta tgtggagaga gagaaagacg gctagagggg ctgatgtata 7320 gaaagtaagg aaatggagag gcagaagatg aggtaggaca cagagagaaa gtcaggagcc 7380 tcatcattat aggctctgat gtccacggta aaaaatttga attttatttt atttatttat 7440 ttatttattt atttatttta tttatttatt tatttatttt tttaagatgg agtctcgctt 7500 tgttgcccag gctggagtgc agtggcgtga tctcagctca ctgcaagctc cacctcctgg 7560 gttcatgcca ttctcctgcc tcagcctccc tagtagctgg gactacaggc acctgccacc 7620 acgcctggct aatttttagt atttttagta gtgagggcat tttgtcatgt taaccagggt 7680 ggtctccatc tcctgacctc gtgatccacc tgcctcagcc tcccaaagtg ctgagactac 7740 aggtgtgagc caccacgcct ggcctatttt tttttttttt gagacggagt ttcgttcttg 7800 ttgcccaggc tggagtgcaa tggtgcaatc tcggctcact gcaaccttcg cctccctggt 7860 tcaagtgatt ctcctgcctc agcttcccaa gtatctgaga ttacaggcac ccaccaccat 7920 acctggctaa tttttatttt tttgtatttt tagtagacat cgggtatcac catgttgacc 7980 atgctggtct cgaactcctg acctcagata atctgtctgc cttggcctcc caaagtgctg 8040 ggattacagg catgagccac cgcggccgga ctgaatttta tttaaataga tacgagaagc 8100 tactgtatgg ttacaaggag agtcaattta tattcaattt atttttattt tattttattt 8160 ttttggtgat ggggtcttgc tctgttgccc aggctagatt gtagtggcac aatctcggct 8220 cactgcaacc tctgccttct gggttcaggc gattctcctg actcagcctc cagagtagct 8280 gggaccacag gtacatgcca ccacacctgg ctaagttttt gtatttttta gtagagacag 8340 gatttcacca tgttagccag gatggtctcg atctcctgat ctcgtgatcc acccaccttg 8400 gcctcccaaa gtgcagggat tacaggcctg agccactgcg cccggcctat attcaatttt 8460 taaaactaat tctagctact ctgtggggat tggaatgttg gggttcacaa gtggtcagga 8520 agactattta ggagcacagc agggaattct ccagcgaaaa caggcttgtg gcttcatgga 8580 gtgcattagt gataaagacg gtgaaaaaga taaagtggac agacttggca tgtatttttc 8640 cttagcttgt taatgaatta ctgtaaaggg ggtagaacaa tcaagcttat tcctaaggat 8700 tttgttttga caaataagtg ggtggtagtg ttgtttattg agataggaaa aactatggga 8760 ggaaattatt tgaagtgggt ggttggaaat aaaagttttg tttaaatttg agatgattta 8820 ttgacattta tgtggagcaa tcagaaggtc aatggcattt aagagactca tggtgaggct 8880 agggcttcaa gtatttatgt tggcggcatc aatacgtgta gtgtgttaaa ttccagggag 8940 tggaagagga tacataggga gatggattgt gtggagaaaa aagaacaggg cacaggccag 9000 caaagggggc tgagaaagag cccagggatg ttggagaaaa atcaagagaa catgatgcgt 9060 gtacgtcaag gaaaatagat ttttttcaag gagaagggag aggccaattg tggtgagtac 9120 cactaagcgg agggggaagt gagaacgtga cagagaagca agtgctgggt ttggtggagt 9180 tgatatttgc agtcagtgga gtatccaggg aggaaactgg attggacaat ttgaagagcg 9240 agtagaagtg aggatgaggt taagattgac tgttttgagt agagagcttc agggaaggac 9300 tgcactctgg gttcagggag ccagctggat caaaaggaaa aggctaaaga ggctgaagag 9360 aagcaggagg acctgtgaac cagagatgct cagtcattat tagcgaggaa atactagaaa 9420 gcccctgtgt gcagtgatga ctactcatgc agaaggtcac acagccaata tttaacacag 9480 ccagtatttc acacagctaa tatttattag tgacatagaa tataccagtt attactctag 9540 gtcatgagaa tggagtgata aataaaatga atccggtcgc catcagtata tgccatgtaa 9600 cattttgcag tgactgtgta ccaggcctgt gaatttcagt atgcaatttc aataatgatc 9660 ctgctgtatc tgtggtgttt aaaaacatat acatctctgg aatctaaaat tgagaggtta 9720 taagtaaaac ccagtattac aaattgagtg ctggaaatca gattgcagtt taaatctgag 9780 catatagaaa gtccctttct tctatgtcag cagatgcctt ttgtgtgagg tttagctgga 9840 ctgcattatt agacataaac cagtgtttct gccctatgtt ttcagaatga caattcttta 9900 tgaaactcat agaagaacag aagacaactg caaaatcatg atgaagatag taattgcttt 9960 agaattaagg aatacaaaaa ataatgtgag ctgtagttat agggatcata aaagtttaaa 10020 tgggaatgta tttgagtatg tgatcagtgc taagaagagt catcatttaa ttttacactt 10080 aacagtaatc tcgtgaggat tacgctatta ttaaatgcat ttgatagatt acaaaaaggc 10140 ttatggttgg taaaaattga cccaagtaga agagatcatg tttttattca ggttttctga 10200 ttctagagtt tgagagtttg tccatcatta gtgagtagtg actatattgt gtctgaatta 10260 ttgacagaat ttctgatatt catatgtacc aggttgtttc ttagagtggg gatagagatg 10320 caagggctgc tagttccgat gtattgggga aactttcatt cattttgcat ttatcatttt 10380 aaaagttctg tatgtctata atggtcatgt gttgaagaac acaaggaagt attaaatcac 10440 tccttcttct aaggtttgac tagcaagttg ggctagagtt accaaataaa atacatgttc 10500 ctagtgaaat ctgaatttca gatacaaaac cataatttat tgaaaatcca aatttaactg 10560 ggcatcctct ggttttattt gccacatctg tcaaccctaa gtgtgacaca tggacatgga 10620 ttacagtgct aaccatgcaa gccacggtga cagcaacttc acacatgttt atttttaact 10680 ttctctgtaa gaaagtgctt agataattta gggataaaaa gatagacatt gcttgatcca 10740 gggtgcacac ctctctgcca ccatttctaa agggcaaagg gagatttctg caggtcttgc 10800 tcacagtctg gggagctgct catttttgta aagtgtctgt atgagaatgt cattttcttg 10860 gtttcctcct ttccgagggg acttgactac aaaaccaaga gttctgcctc tggccaaggc 10920 tggtaatttg atgcctgcta gtattgttgg gagtgggaga ctgaaagaaa tgagttagtt 10980 ggggcattta acgggaataa aatagctgtg gttgtgactc attactacag ataattagtg 11040 gaccagtggc agagaaatta agaaaaaaga tgatgtgaat gataaatgat atgattagtg 11100 actgcttggt aaggcaagga aatcattaaa tcttggttct catcaagttc attttctgga 11160 aagatagcac tgtattggga gcagaattct acaaaacctt ctttttacat aggaccaaga 11220 ttttcaacaa atatttttca atgcaattct cagctgctcc ataactaata gtagcttgtt 11280 caacacagat tttttcagat gattcacacc tgtggtactt acccagggat ggttcaccac 11340 ccctcccttc cctctcatca tcgttgggga acggtgacaa tgtttggaac aatttttggt 11400 tgtcacaaac aggggtttct tctgatattc aatgagtaga agccagggac actgctagag 11460 aacccacaat gttcagaaca gcctctgcca tcaacaagga attatctggt ccaaaatgtc 11520 aatagtgctg aggctaagag cactggttca cactgtgctc tttctgaaaa ttctagactc 11580 acatctgtta tacactcacc acacagttta gtcttttatt tttgcttgtt tcattataaa 11640 caattagaca gttgcataaa ttcaaccact ttcttgttga atccatttag tcaatgcaag 11700 ctcaatattt tcatatttat tttttgcctt atgcaatatt tttcaacatt ttcatgagtt 11760 gtcggtcatc actatctcta ttaactttca acaacttgcc cttgtaagtc acaaatagtg 11820 atgctgctga aattatttct cactaacatg cctcagattt ctgtagtgat tctacatttg 11880 atattattca caatgtaaaa tgcttctatt tattcatttc gcttttaccc aaggattatt 11940 tttaagttat ttttgtcatt ttcacacttc aaacataaag acaaaaacat caaaaatata 12000 gtgttttaca tatgtgcata ttttcacaca tatatgtatg tatatttata tgtattgaaa 12060 gtacagaagc acatgtcacc aataagagct ctgagacacc ttcgaccact tacccttatc 12120 agatgagttg tggaaacaag tttttttaac tgaatttctg agctttgtgg atttagaaat 12180 gcaaaggaag gtttgtggac attcacaggg atcatgattt tattctcctt aaaactcttc 12240 tgtactttcc aattgtcctt agtataaatc caaaatccta acaccaccca agaggctttt 12300 caatacctgg ctcctgtgat ttctccgggc taatctgtta ccctccttcc cctcagcctc 12360 tctgctttag tgaactttct cctagttttt tgaagaagtt catcaattca agcttttgta 12420 catgggattt cctaaacctg aaatgtgcct cccgttttgt ccaaacagac acgggctcca 12480 ctctgccccc tggctcacac ctgcttaacc tgtcaagtca catctgaacc gtcactatta 12540 agagggtcct tctctggcac cctaatgtaa ttgagatcat cctattattc tctgttctag 12600 aactccacac ttccgacatt tctcattcct gtctaagctc ttgtgtgttt ggtgttgggc 12660 catcactttc actgctcttt aagctccccc agcggagtgg agaggtctgt tttccctcgt 12720 ttggattcct agaggcagcg cagaccaggc acaaggtcag cactaaggaa gggttcagag 12780 gatgaacgcg gtgggtgctg tttaaggaac cggtaaacat gtgggatgag agaaggagca 12840 gagtgtcttt ggggtggagg ctcccaggag gaggcggcgc gggctgcggt gctgggcgga 12900 tcctcctcca gctcctgctt ggaggtctcc agaacaggct ggaggtaggg aggggggtcc 12960 caaaagcctg gggatcagac gtggttttcc cgcctggtcc cccaggcccc ctttcgcctc 13020 aggaagacag aggaggagcc cctgggctgc tggtggtggg cgttgcggcg ggggccggtt 13080 aaggttccca gtgcccgcac cccacccagg gagccccgga tggcggcgtc actgtcagtg 13140 tcttctcagg aggccgcctg tgtgactgga tcgttcgtgt ccccacagca cgtttcttgg 13200 agtactctac gtctgagtgt catttcttca atgggacgga gcgggtgcgg tacctggaca 13260 gatacttcca taaccaggag gagaacgtgc gcttcgacag cgacgtgggg gagttccggg 13320 cggtgacgga gctggggcgg cctgatgccg agtactggaa cagccagaag gacctcctgg 13380 agcagaagcg gggccgggtg gacaactact gcagacacaa ctacggggtt gtggagagct 13440 tcacagtgca gcggcgaggt gagcgcggcg cggggcgggg cctgagtccc tgtgagctgg 13500 gaatctgagt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgagagaga gagacagaga 13560 gacagagaga gagagcgcca tctgtgagca tttagaatcc tctctatcct gagcaaggag 13620 ttctgagggc acaggtgtgt gtgtagagtg tggatttgtc tgtgtctgtg aggctgttgt 13680 gggaggggag gcaggagggg gctgcttctt attcttggag gactctgtgg ggaggtgaca 13740 agggaggtgg gtgcgggcgg ctggagagag aggtgacctt gattgtctcg ggtccttaga 13800 gatgcaggga agggaaatgt aaggggtgtg tggttggggt gaaggtttag gggaggagag 13860 ctgaggggta aggaaggttt gggataatgt gaggaggcca gttccagact gtccctggca 13920 cacacccttc atgtaatctc tgaaataaaa gtgtgtgctg tttgtttgta aaagcattag 13980 attaatttct aggggaattg aggagacctc tgaggcatct ctgaagcttc tttaggtcta 14040 aatttcttgc tagttttttg ttttttattg tgtatatttt tacatagtag aaatgactgt 14100 gaaactaact ttttgaatta aagttttaac acagttacta ttttattata atgctaatag 14160 ttttctagta gttacatatt attcttttat atataatagt tgtgacacaa cttacctcac 14220 tttccccttt gttgaccttt attatgacat tcaccaaaat ttgaaaatgt atgtttctgg 14280 ttaattttta atttatattt ttttcattta taattctttt gaattatttt gacctattta 14340 ttggccagtt ttaataactg ctgtaagaat tccctattgt atttggtagg gaatggacaa 14400 tgatctactg cctaatatct cgagggctta gtatttttct cagtgacttt gtgggttctt 14460 tgtactgtga gattattaac actttattga tatttgattc agcatttgct ccagtttgtg 14520 gtttgtatgt tgattttgaa aattcttttc catgttaaga atttgaacat ttttatataa 14580 taaaatatgt tgcaaaattt ttattaatga tttacaatcc atcttaaatc tgccattttg 14640 tggtattgtt gtctccaggt ttctccttac ttctaaaaaa aattgcattt attgagagtc 14700 tgctagtgtt agggattttc ctgggcataa gcaccccaag tgacgagtcc cagacactgc 14760 cttaatccaa atgtgattct ggaaagaaaa atcattttac aatgataggc ctaataataa 14820 ttaagcttgt gttgcatggg agatgcattg atcagctaaa tgtaaatata agaactttca 14880 aaactaaaat gacgttcctt aatccttctc tctgctttat gactcatgct tttctgggaa 14940 agtaaaaatt tggagaatca tttctgtctg tcccaccttc ccaggggcag aaccatttct 15000 gtggtgttct aaggtgtgag tgcatggcgg tagtattcct aaaaattcat attcggtttc 15060 gtcatgtacc caactctgtc ccgttatcta tcaacattgt tttaaatcat atatttctgt 15120 caaggtgtac aaggatgata aataggtgcc aagtggagca cccaagtgtg atgagccccc 15180 tcacagtgga atggagtgtg aagctttatg acctcataaa ttgaaggtta tcttcaggca 15240 ttgttttata tattttacat gcattaatcc tcatataatc ccaagaggta aattagtata 15300 attatccttc attataggtg acaaagttga gacacagaag aatcaaactc ttaaggcaga 15360 ccttggattt gaaccaggca acctggctca gatatcagtt ttaattacta cactctgtac 15420 tttcaaagat ttgtaaacac tttgacaatg catgacaatt tcaagctatg aagaaacaaa 15480 cacaattttt cacaatatct ctcaaatcta ataggtcctc actatcaaga ttaagttcca 15540 ggctgatgac actgtaaggc cacatggcca gctgtgctgg aggcctggtc aaggtcagag 15600 cctgggtttg cagagaagca gacaaacagc caaacaagga gacttactct gtcttcatga 15660 ctcattccct ctaccttttt tctcctagtc catcctaagg tgactgtgta tccttcaaag 15720 acccagcccc tgcagcacca taacctcctg gtctgttctg tgagtggttt ctatccaggc 15780 agcattgaag tcaggtggtt ccggaatggc caggaagaga agactggggt ggtgtccaca 15840 ggcctgatcc acaatggaga ctggaccttc cagaccctgg tgatgctgga aacagttcct 15900 cggagtggag aggtttacac ctgccaagtg gagcacccaa gcgtgacaag ccctctcaca 15960 gtggaatgga gtgagcagct ttctgacttc ataaatttct cacccaccaa gaaggggact 16020 gtgctcatcc ctgagtgtca ggtttctcct ctccgacatc ctattttcat ttgctccatg 16080 ttctcatctc catcagcaca ggtcactggg ggtagccctg taggtgtttc tagaaacacc 16140 tgtacctcct ggagaagcag tctcgcctgc caggcaggag aggctgtccc tcttttgaac 16200 ctccccatga tgtcacaggt cagggtcacc caccctcccc gggctccagg cactgcctct 16260 gggtctgaga ctgagtttct ggtgctgttg atctgagtta tttgttgtga tctgggaaga 16320 ggagaagtgt aggggccttc ctgacatgag gggagtccaa tctcagctct gccttttatt 16380 agctctgtca ctctagacaa actacttagc ctcattgagt ctcaggcttt ctgtggatca 16440 gatgttgaac tcttgcctta catcaaggct gtaatatttg aatgagtttg atgtctgaac 16500 cttgtaactg ttcagtgtga tttgaaatcc tttttttctc cagaaatggc tagttatttt 16560 agttcttgtg ggtcagactt cttccccatt ttcaaagctc tgaatcttag agtctcaatt 16620 aaagaggttc aatttggaat aaacactaaa cctggcttcc tctctcagga gcacggtctg 16680 aatctgcaca gagcaagatg ctgagtggag tcgggggctt tgtgctgggc ctgctcttcc 16740 ttggggccgg gctgttcatc tacttcagga atcagaaagg tgaggagcct ttggtagctg 16800 gctctctcca taggcttttc tggaggagga actatggctt tgctgaggtt agttctcagt 16860 atatgagtgg ccctgaataa agcctttctt tccccaaacg gctctaatgt cctgctaatc 16920 cagaaatcat cagtgcatgg ttactatgtg aaagcataat agcttgtggc ctgcagagac 16980 aagaggaagg ttaacaagta ggggtccttt ggtttgagat cttggagcag attaaggaag 17040 agccactaag actaatggaa ttacactgga tcctgtgaca gacactttac ccttcatggg 17100 tcacatggtc tgtttctgct cctctctgcc ctggctggtg tgggttgtag tgacagagaa 17160 ctctccggtg ggagatctgg ggctgggaca ttgtgttgga agacagattt gcttccataa 17220 attttaagtg tatatatttt cctctttttc ccaggacact ctggacttca gccaagaggt 17280 aatacctttt aatcctcttt tagaaacaga tacggtttcc ctagtgagag gtgaagccag 17340 ctggacttct gggtcgggta gggacttgca gaactttcct gtcttaggag aggtttctaa 17400 atgcaccaat cagtgctctg taaaaacaca ccaattggca ctctgtggct agatagatgt 17460 ttgtaaaatg gactaatcag cactctgtaa aatggagcaa tccacactct gtaaaatgga 17520 ccaatcaatg ctctttaaaa tggaccaatc agcaggacat gggcggggac aaataaggga 17580 atacaagctg gccaccccag ccagcagcag caacccgctc aggtcgcctt ccatgctgtg 17640 gaagctttgt tcttttgctc ttcacaataa atcttgctgt tgctcactct tcgggtctgt 17700 gccaccttta agagctgtaa cactcactgt gaagattcgc ggcttcattc ttgaagtcag 17760 cgaaaccacg aacccaccgg aaggaacaaa ctctggacac actagaattg atggtagagg 17820 tgataaggca tgagacagaa ataataggaa agactttgga tccaaatttc tgatcaggca 17880 atttacacca aaactcctcc tctccactta gaaaaggcct gtgctctgtg ggactattgg 17940 ctctgggaga ctcaggaact tgtttttctt cttcctgcag tgctctcatc tgagtccctg 18000 aaagagagga aaagaaactg ttagtagagt caggttgaaa acaacactct cctctgtctt 18060 ttgcaggatt cctgagctga agtgcagatg acacattcaa agaagaactt tctgccccag 18120 ctttgcagga tgaaaagctt tccctcctgg ctgttattct tccacaagag agggctttct 18180 caggacctgg ttgctactgg ttcagcaact gcagaaaatg tcctcccttg tggcttcctc 18240 agctcctgtt cttggcctga agccccacag ctttgatggc agtgcctcat cttcaacttt 18300 tgtgctcccc tttgcctaaa ccctatggcc tcctgtgcat ctgtactcac cctgtaccac 18360 aaacacatta cattattaaa tgtttctcaa agatggagtt aaatatcatc tggtccattt 18420 ggctccaaag acaaaaaatg aaaagaaaag aaaaagggaa ggaagattat ttcccaatag 18480 aataatgatt ttcatgtata tgtcatgagt atgtgaggta atgcatatgt aaaataactt 18540 gatttagaca ttccacacta taggcatata tcaaaacttc attctgtaca atataaatac 18600 actatacaat ttttacttgt caatcaaaaa agtaatccta atgtttaaaa aggcaatgca 18660 taaaaactga gaacagacta taacaactga aacaaacttg gcaaccatga gatgagaaac 18720 cagctagcaa gtcaatcaga actttttttc accccgtcta caatattttg tatttataac 18780 tgtaaattag tgtatagtgt ttcactccag agacttcaat aatatagtgt tatcaaagga 18840 cttgtacaga tttcagagaa agacaaattt agaagacgga ggattctcta ttatgtgcta 18900 tctgagagtc agtatgaaat gtcaaatcca aaagtacata atttagaggt ctatttcaaa 18960 gtaatcattt gagcatagtt tctccactgt cagagacgac tgttatttta ttttcaatca 19020 aattaaaact tgtttttatg catatcttat ttttagttat atgttacttg tacataagta 19080 gcagcacaat acatacatat aaaccctatg agtataaatc ctatagaaat atattaagtt 19140 gataattatg tctgttctgt ttgatcacag agttgcaaca aagaggcctc atttcctaag 19200 ttgaggaaat gattttctca ttttatatga gactcgtggt gtggaattac aaggtagaac 19260 caaaatgtgt ggaatgagta tttcagtgaa gatgtgttct gctgctaata acaggaaatt 19320 acatctagtg gctttatttt tctttaaccc attatctcac atagccgata gatccaaggc 19380 tgggcatctc cagggatgct caactcagca ggccagtgtc atcaccagtg atcctggaac 19440 ttcgtagctc atctctctat cacacacagc acgtcagctt tcctgagatg gtagggtgac 19500 ccatgcagca gctttaggtt tgttattcat tcacaacaac tcccaaaggc aggaaaagga 19560 tactcctttc tcctgtgtgc ctttataagg agcaactaaa ctgtttccag agtgttccca 19620 gtacccactt tcttatacat tggaatgacc gtgggatcac acaggctcag acaagccagg 19680 attcaacctt tgtagagtgg gcctgatgca catgggaaga aaaggagcaa aatcatatat 19740 ttttaaaaac aaagaaatgg tggatggagt agcagagatt gatttcatca tagggaaatg 19800 atagattgtg gtactatcag gttgtaagta tttgagttaa cttccacacg aaggcctata 19860 gattcctgat aggcaccctc aattcagggc tttgggtctt tatatacata cacacacaca 19920 cacacacaca cacgtatata tgtatatata ggtgtatata cacacacaca tatagagagt 19980 attaaatgtc agccattaac tcaattacaa tcaaacaaaa aagcaaacag aattgttttt 20040 agaactcaat ttatgctgac atgttatttt atgaggtaaa tgtattttcc agggaaattg 20100 aaaaaaaagt agaataagga atgactagct ctataaagct ctaaaacata ctatacattt 20160 acttttaaaa atgcatttgt aactgctttt ttttaaatta aatatgctag taagacagag 20220 tctagaatta gaaacagagt tgagatttag tttcagtttt tgtaagttgt attccaaact 20280 catttctttc actaaataaa tcctggataa ataaaacttg aaacataaag agaaaatata 20340 aaattcacaa gacagatgtt atttctaata ctatcatcat cattataatt atgtttgaag 20400 aca 20403 <110> THE ASAN FOUNDATION University of Ulsan Foundation For Industry Cooperation <120> SNP for asthma diagnosis and asthma diagnosis method using the same <130> MP20-083 <160> 3 <170> KoPatentIn 3.0 <210> 1 <211> 14601 <212> DNA <213> Artificial Sequence <220> <223> HLA-DQB1 (NG_029922.1) <400> 1 tatgtttact gaagcattat tcacaatacc aaaggcatgg aaccaaccca aatgtccatc 60 agtgataggc tggataaaga aaatatggtt catacacacc atggaatact atgcagccat 120 aaaaaggaat gagattatgt cttttgcagg gacatggatg gagctggaag ccattgtcct 180 cagcaaaata atgaaggaac agaaaaccaa atactgcatg ttctcactaa taattgggag 240 ctgaacaatg agaacacat gacacaggga ggggaacaac acacactggg gcctgtgagg 300 ggtaggggca gggacagcat caggataaat agctcatgca tgctgggctt aatacctagg 360 tgatgggttg atagctgcag caaaccgcca tgccacacgt ttacccatgt aacaaacctg 420 catgtcctac acatgtacgc tagaacataa aacaaaataa aataaaataa acaattcaat 480 tcaaaaatgg gattttttag attcctcata taagtaagat catgcattac ttgtctttcc 540 atgtctggct tatttcactt agcttaatgt cctctaggtt catgcatgtt gtcaaaaata 600 acagtgtgaa agaaaaatag aatcttggga ccccaaactc attatgccaa gggaaagtta 660 atcttgagga ctgaggcacc aatactgtct tccttttgtt cccaaacaga taacggtaat 720 ttcacaaccc cgtgtcataa cctcgtttcc tctactcctt cccccttttc aagttccctt 780 aattttatgt aaaatgtaga tttactgagc ataagataat ttataattaa ctttttcttc 840 tactctcttt tcacaggtaa aatgtagatt tacttaagct aatcaaagac tcaggaatgt 900 aaccacttgt atcatggcct actcttcctc cttttttttc tccttcccct cctgcttgct 960 ctttctcttt taaatactga agttctcaaa accctctttg gcaaaagcat ggatcacaga 1020 tgctcctgtg ttttgtgttt ttcccaggtg tattcctcaa ccttggcaaa ataaaccttt 1080 aattgattga gacctacctc agtcactttt tgacttacaa caggatttcc ttctttttaa 1140 agcctgaata ggatttaatt gtgtatatat accacatttt ctttatcttt tcatccactg 1200 aatgacacag gttgattcta taccttgact attgtgaata atgctgcaag gaacatagga 1260 gtataggtat attttcaaca tgctaatttt aaatactttg tctacatcct gcaaatggga 1320 ttactacatc atatgatagt tctattttta actttttgag gaacttccat actgttttcc 1380 ataatggttg tactaatctg catccccacc aacagtgtac aaatgtttcc ttttgtctac 1440 atccttaaca cttgttatct tttatctttt tgataatagc cattctgact gatgtgaggt 1500 gatatgtcat tgtggtttaa atggaatatc ttaagttttc ctatttgatg atataagagt 1560 actctcccca aaatattact gctgatgttg ctgttttgca tgaaccatgg ccttgagctg 1620 agttcttgga cacatgagtt cttgagtact tggatatgga tttaagtact caagaactat 1680 atatattttt atgtggctga acattagggc ctctctttac tggtaagaac ttacagaaaa 1740 aggagacatt ataaagatct cacagagaaa tatttaagtt ttttctggga atgaaggagc 1800 atggtgacta ctaatctaga ggctggggga agagctgtct ctggaaatat cccaggcatc 1860 actagggaac cagaagtaga gacaggcaga ggtgtgttgg aaagagtgac atgtgtaggc 1920 tagctctggg aggtttaatc accagtggtc caactgaggc aatgcgtgga tgaggagact 1980 gacaggaaaa aggaacctga aaagatagat caggaaacaa agcttcattg tacagcatac 2040 ccacagcagg cagcttgggt ttttgtccca gtcttcttcg gtcttcaagg gctattttca 2100 tagagcatga ggagccgtgg gactggtgag gtctgggctt ctgtgccaag atcactcacg 2160 ttcctcattt gccctcaaat gttccaaatg ctttgtatca cctgattttc taccttcctg 2220 ctaaagcttt tcccatactc ctactccttc acgctccatc atcctccaat tctgacatga 2280 cttccaccct ggagtttcac catggccact tgcttgtggg aggcactgtc tgaacacagc 2340 ccctgaatgc tactgatttg gctctttctt cagattctct agactgagat tttaaagaga 2400 taactttgtg ccaagagaaa ggacctagtt tatatgtgcc atgaaaaatt cttatatata 2460 gctggttacc tagaagttga tataagagaa atatgtaaga agcttcacaa agatttttaa 2520 aaatttaagg ataattgctt gataaatttt aattaaagga aaacaatatt ctgggggcag 2580 catttctagt tatattacca ttggcattaa ggaagccaca gaacctttca gaatatacag 2640 tgattcttga ttcctgaagt aaatgcaggg tagggtcctg gatggtcctt ctggtgacag 2700 ggtggctcct atgttcacat tcaattccac tgaccaagca cagattccaa gagatgttga 2760 ccagagaaga tgatttctcc cttgattttc acaaagaagg agtccacaac ttttccttcc 2820 aacctgaagg aagagaggat gtcccttgaa ttgagtctgc ctactgtaac cctgaccgtc 2880 cctactaatg gcagtggctt tttagcccat ttacccacat ggggtaaatg ctctaattgc 2940 tctgcctcca cagaggctgg gcaggcgatt caggtgagac actcggaata aggatgcttg 3000 acctagtttc tttcttctct ggccttcttc tgcctgaatg ccctgaataa tgcagcaggg 3060 atagggccag ggtagtcaac tgtacagaag gctgggccag gcagacacaa ctggcagaag 3120 cccaaagcaa aacctttcca gtgaggtttt agccaatcag aaaaaggctc taaagtgaca 3180 cttgttgcta gctgaaaagt ctgtgcgaag aggcctgtga gactgaggaa tccccaggtc 3240 tggcgtagca gttgcctcag aataaacctg tgggaagttt ttcccttaga caggaaggaa 3300 aggatggatt agaggcctct attctgaggg acactgaggt gggggctgag gaaggacatt 3360 gagggcagct tcaggtctct ctgcctactc ttccttgccc caactccatt ccaggtgtga 3420 gtatggttcc tcctttatgt gtccatcaca gcagtggaga ccatccttag gctgggttta 3480 ccctgatcct gagtaaacca ctgctgctgg acgcccagtg gcaactttcc cagtctcagg 3540 tgctctagaa ttatgctgtg aataatacag aatattggag tggctcaacg ctttcatgtg 3600 ccactattgc aaacctcttg ctgttgcctc ttccctgctt ctttttacct ggtaaactta 3660 tattctgatt ttagattgta ttctctactt taaaagcaga acctaaaatt ttgggaaaag 3720 aaagagagaa agggagagaa gaagagaggt ggagatattt attgtcttgg ttggggtcag 3780 aagtaatgtt tgccaggcat tgttctaatt gctttataac cattagtact gtccctagtc 3840 actgccaaga ggagcttgat aagttatgct tatttataaa aacacattga tgtagatatg 3900 tccatgagga actgttaaat aaaaaataca tagaattgaa aaaaaccaca ttgatacctc 3960 tgccacttgg gatttgatgt ttagggctgg cacagtacaa tctgtgactc taaacatttt 4020 ctccatcatt aatactattc aggacctagg aaatgcttct ccacagcttt tgctctctct 4080 cctcaaatct agacatgact atatctgaat actgtaaagg tttgtgtatt gtgcctttgc 4140 tgatatcaga tgcacctatt tcatggttca gagaggattt aaacagctga agaacttaga 4200 aaaggaatgt caacttaatt aacttttcaa atactttcac tcgaagagta taaatacaat 4260 atattcttgc gtaatgaaga atcatttacc agcagggatg ggtgtcaatt ttttttggct 4320 tgttttcttg ttccacatat taacctgata gttacacata acagttgagg atccttttgt 4380 aacattaaac aagtcatatt aatcttaaat ttgtatatgt gaagatctag atgtaaaatg 4440 catgaaacat gatccacatt ttacaaagag aagcctgggg caaaaataaa ttcagtaatt 4500 tgttgactct cataaagcac attagtggtg gaactgcaac tcaccattat ttccttctaa 4560 gaactttgct cttttcacca aaacttaagg ctcctcaggg tgtgtctaag acaacagcag 4620 taaaaatgtc tatgacagca attttctctc ccctgaaata tgatccccac ttaatttgcc 4680 ctattgaaag aatcccaagt ataagaacaa ctggttttta atcaatatta caaagatgtt 4740 tactgttgaa tcgcattttt ctttggcttc ttaaaatccc ttaggcattc aatcttcagc 4800 tcttccataa ttgagaggaa attttcacct caaatgttca tccagtgcaa ttgaaagacg 4860 tcacagtgcc aggcactgga ttcagaacct tcacaaaaaa aaaatctgcc cagagacaga 4920 tgaggtcctt cagctccagt gctgattggt tcctttccaa gggaccatcc aatcctacca 4980 cgcatggaaa catccacaga tttttattct ttctgccagg tacatcagat ccatcaggtc 5040 cgagctgtgt tgactaccac ttttcccttc gtctcaatta tgtcttggaa aaaggctttg 5100 cggatccccg gaggccttcg ggcagcaact gtgaccttga tgctgtcgat gctgagcacc 5160 ccagtggctg agggcagaga ctctcccggt aagtgcaggg cagctgctct ccagagccgc 5220 tactctggga acaggctctc cttgggctgg ggtacgggga tggtgatctc cataatctcg 5280 gacacaatct tttatcaaca tttcctctgt tttgggaaag agagctatgt tgcatttcca 5340 tttatctttt aatgatgaag tgaggacaat ccaatcccat cctacaggct taagcctgga 5400 agaggaggag agaggagaga aaagaggaga caaagtgttc atttactacc agtgatagga 5460 caaagtgagc atggggttat ttttgaagat atgaatttct ccaaagacac agcaggattt 5520 gccatttagg cgtgtcccaa gacttgcctg gactaaatat tatgatttcc tgcattggga 5580 aatgcaaggc agcaatggtg tctgtagtct ccgtatttgg ggaaaagttg tctgtattcc 5640 tgacccagtg gagcgtttgt ggaggcaaaa tcttggtact gagggaagct gactggctga 5700 ccacagaaag agagccttca ggtttcactg atttatgggc aaatggtgac ctgagtggga 5760 ttcagatacc cgagttgatg atggactaaa tttagtagaa aggaggatgt aaagaaggga 5820 aataacacat actgtgaaac cactcatttc agacacagaa caatacttta cataaattct 5880 ctctcactcc ttctaacatc ctgtgtgtag atatcatgat tttcttttac acaattatac 5940 ttgtgatatg gatattctgt tacataaact gcccgggctg gtgactgcca cagtttaatg 6000 ggaatctagt ttatcaaatt caaaagcttg tgctctttcg gtgaataaat gtttctttct 6060 aggactcaga gatctaggac tcccttcttt ctaacacaga cgtgagtgaa cctcacaggg 6120 cacttgggag ggtaaatcca ggcatgggaa ggaaggtatt ttacccaggg accaagagaa 6180 taggcgtatc ggaagaggac aggtttaatt cctggacctg tctcgtcatt cccttgaact 6240 gtcaggttta tgtggataac tttatctctg aggtacccag gagctccatg gaaaatgaga 6300 tttcatgcga gaacgccctg atccctctaa gtgcagaggt ccatgtaaaa tcagcccgac 6360 tgcctcttca cttggttcac aggccgagac agggacaggg ctttcctccc tttcctgcct 6420 gtaggaaggc ggattcccga agacccccga gagggcgggc agggctgggc agagccgccg 6480 ggaggatccc aggtctgcag cgcgaggcac gggccggcgg gaacttgtgg tcgcgcgggc 6540 tgttccacag ctccgggccg ggtcagggtg gcggctgcgg gggcggacgg gctgggccgc 6600 actgactggc cggtgattcc tcgcagagga tttcgtgtac cagtttaagg gcatgtgcta 6660 cttcaccaac gggacagagc gcgtgcgtct tgtgagcaga agcatctata accgagaaga 6720 gatcgtgcgc ttcgacagcg acgtggggga gttccgggcg gtgacgctgc tggggctgcc 6780 tgccgccgag tactggaaca gccagaagga catcctggag aggaaacggg cggcggtgga 6840 cagggtgtgc agacacaact accagttgga gctccgcacg accttgcagc ggcgaggtga 6900 gcggcgtcgc ccctctgcga ggcccaccct tggccccaag tctctgcgcc aggaggggcg 6960 aagggtcgtg gcctctggaa cctgagcccc gtttgttcca ccccagagga caggaggcag 7020 cggcgagagt ggtgggggca ggtgcatcgg aggtgcgggg acctagggca gagcaggggg 7080 acaggcagag ttggccaggc tgcctagtgt cgccccagcc tacccgttcg tcggccttgt 7140 cctctgctct gcatgttctt gcctcgtgcc ttatgcattt gcctcctttt gccttacctt 7200 tgctaagcag ctctctctgc tcagaatgcc cgccctcttc ccctgcccgc ccgcccgccc 7260 cactagcact gccccaccca gcaaggccca cgtgcacagc tcttgcagca ggaagcttca 7320 ggcttagcct ggtggagtta gggctgttcc acaactgcgc gcaggacatt cagcaattac 7380 agttgtgaaa taagatattt taacttttgg cttcaaatca ttattcatcg taattctgtt 7440 ttcttaaatg gctctcattc atggcagaga tctttgaggt gagggtgttt taatcattgc 7500 atgcctagta cctgacacat tgactggtat gtggtgtgag ctcaatgatc ttctgttaaa 7560 ttaatgaata aatgtactca gctgcccatc cacttaggct caagaaaaaa aaagaggtaa 7620 acagagcctt aaaaatggac tttattaatt attttctata attttgctta atgctttaaa 7680 gtaaactctt attgacttgg atcttaatag agtttgtgaa tacaaaatct gaggaaaaaa 7740 gtttttgcta aaaataaaaa caacgcttga aagatattgt aaggcagttt aaatttcttt 7800 tcttttcttt tttttttttt tttgagacgg attctcactc tgtcgcccag gccggagtgc 7860 agtggcgcga tctcggctca ctgcaagctc cgcctcccgg gttcacgcca ttctcctgcc 7920 tcagcctcct gagtaggtgg gattacaggc gcgtgccacc acgcccggct aatttttttg 7980 tatttttagt agaggcgggg tttcaccgtg ttagccagga tggtctggat ctcctgacct 8040 catgatccgc ccgcctcggc ctcccaaagt gctgggatta caggtgtgag ccacagtgcc 8100 cggccggcac ttttaatttc ttagaaaagc tgaacaaatg gcacaatgca aagagcaaaa 8160 gttttggaat aaatagattg aagccattaa attattggat aaaaatagtt tcgggttgct 8220 tttggcctag gttctcccct ccccccatga ctatccactt caggaataaa cattctgaaa 8280 gtcaatttta cccatttagt gagcatttat ttctagacag ttgccttatc aaataccatc 8340 tatgttacgt catttaatct cacagttact tgtgcatcag agattagcat caccacttta 8400 tatattggta catgataaac actttattgg tcatggatgg ggagatggtc actgtaggct 8460 aatattggta catgataaac actttaagta atcagcccat aattgctcac caagacctta 8520 agcctcccaa agtacacaac attctttgtg ttcttcacta cacatccata gagtctaagg 8580 gacgtaaagc ctcgttaaag ccagttttga ccagaagcag caatgagtct attcctgtgt 8640 gttttccatg ttaatgggac aaaatgatac tttcaaggca ttgaaaattc atgattaatc 8700 aatccctagt ctgaccccag tgttatctat gcaggtttgc aaaaccttta gtttacttaa 8760 tactcccttg ccttcttttg attcacatcc taatgccagc aaatacttat gtttttgcta 8820 tttcagttcc atttccataa aatttatttt atcatctttt ctcataaatt tatgccctct 8880 atttttactc ccaatctgtt taagatgaac aaatcttata aggccacata gctgactgtt 8940 atttctgttg gactccagga aggagaacct aaagaaaagt tcaagtccaa gcagaaaccg 9000 tgatttcttc cagatgatgg ctcatgagtg ccatttaatt ggggtgccac ctggtgacct 9060 cagcaaatcc cagctatatt tatgtgttca cattacagga tcattaaccc agaccgacca 9120 ctgcacagat ctcagaatat tttctatgga gaacatacat aataatgcct gatttcagaa 9180 gaagaaagta attctcaata gcaaggggat ggagtagggt agacagctgt aattaaactc 9240 acttgtgtga taaaaagaaa ttaaggaaaa aagaaaatga gagaacatat tactaaataa 9300 agaaagcata cattaaatat ttactatagt ttcacactaa gagaataaag gaaatgcaat 9360 aaagtggcct gaaaggtaaa ggatgagatg tgtaaagggg tgtagtattt ttactatgag 9420 cagcaatctg agaagataaa ggaatcgagt tacgggcaaa catgatgttt gatcagtgtt 9480 atttgttttc aaggcctgcc taaatttttt tcaaatatta caaacttttg aaataacatt 9540 ctttttgttt tttgctgtct gttactaggt tgcacatttt ataaaggcag ggaccatggt 9600 atgttgtttg tctttggatt ctcagtgatt gttatattta tatttgttga aggaacctta 9660 atccaagact tggactccaa gtatctttcc actctggttc caaggaggga ccttcctcac 9720 agcaggcatg ctgtgtggtc tcacatctca ctcctatatc tttccctgtc tgttactgcc 9780 ctcagtggag cccacagtga ccatctcccc atccaggaca gaggccctca accaccacaa 9840 cctgctggtc tgctcggtga cagatttcta tccagcccag atcaaagtcc ggtggtttcg 9900 gaatgaccag gaggagacag ctggcgttgt gtccaccccc cttattagga atggtgactg 9960 gaccttccag atcctggtga tgctggaaat gactccccag cgtggagacg tctacacctg 10020 ccacgtggag caccccagcc tccagagccc catcaccgtg gagtggcgta aggggatatt 10080 gagtttctgt tactgtgggc cccacaagac aaaggacaga gctccttctg acccatccct 10140 tcccatctct tatccctgat gtcactgctg agctgggaat cacaggagac tagagcacct 10200 ctagttccat ggcgagtgca tcagaagaat cctgatctca tcacctttcc agatgctagg 10260 gaaattactc tacatactgt tgctctggat cccagtcctg attgctctga ggaactgatt 10320 attagggctg gtgactggga tcttagggtc taagtttatg gatgagttcc tgaggagtgg 10380 agatctgctt ccccactctg tcacctactc actgtatcca aggacctatt ggctggcctt 10440 tccctccctt aggggtggtc tgaatggaga actaggttcc tttgatgcct tcacctcctg 10500 catctcagac tggacttcag ctcctcatca gggaaactat ggggtatggg gacaaacact 10560 gacactcagg ctctgcttct caggggctca atctgaatct gcccagagca agatgctgag 10620 tggcattgga ggcttcgtgc tggggctgat cttcctcggg ctgggcctta tcatccatca 10680 caggagtcag aaaggtgagg aaccccaggg gaaaagggga agatggcctg tgacccagac 10740 cctctgttca gagaggtcct gtctctagat gtagctcttt cctcctgacc ctgagaggaa 10800 gaaagctgag ctggaagtgg aaggagacag gacaaggttg gaggaggcat tggaatctga 10860 ttttactagc tgaagggtag ccctgtcaca gagctgactg atagagctta ttccagggca 10920 tccttaccat tcatcattgt ctcactggct cctttccaaa aacttcctcc attaagaggg 10980 tcagagcctc ggcctccttg ccttctagtg acaatttcct ttattttagg ggattttaaa 11040 ttagggtgct taaggacttg aagaacatga atgggaagag aatataactc taattaagtc 11100 acatgtgtca ttttcctttg gggtgagaga gtggctgttc atgtaatgag acctttctct 11160 gcataacttc cttttgtaag acctcaaggg cctccaccag caggtaatat ttcagccgtg 11220 atccagtgtg gggagggcac aggtgtaaga gggaagagca tgagctgagt gtacctgaca 11280 gtagtggtct ctgttcatgg tatatttgct gctatgagga tcaagactta ggggtgaagt 11340 ttgccagttt ctaggaatct ccagaggttg ttccccagaa ccaagcctta actttggtgg 11400 tatcttcctg ttaaatgtgg agccagaacc acggcttaaa tgttagacac taggatgatg 11460 cccactttgt gccacatgat ggtggctact gcctgtaggc attttccagt gactgaaaga 11520 ggctgctagt ggtagggatg aggtatcatc caatttccta aaaagattga acccttcata 11580 ttcaccagaa gagtaacagc tgttccccca cctcccacac atctgcatca agctgaagtt 11640 ctgtgtcttc atgagctgat ttcacctttg cacagatctt gggggaggtg atgacaatac 11700 actctggacc tcagctttgt ctgtctgaag ctgcaggagg cccctgaggg gtggggaaga 11760 tggcaggccc accagcgtac cctgtgctga tcatccctct tctctcttct tcagggctcc 11820 tgcactgact cctgagacta ttttaactgg gattggttat cacttttctg taacgcctgc 11880 ttgtccctgc ccagaattcc cagctgtctg tgtcagcctg tccccctgag atcagagtcc 11940 tacagtggct gtcacgcagc caccaggtca tctcctttca tccccacctt gaggcggatg 12000 gctgtgaccc tacttcctgc actgacccac agcctctgcc tgtgcacggc cagctgcatc 12060 tactcaggcc ccaaggggtt tctgtttcta ttctctcctc agactgctca agagaagcac 12120 atgaaaacca ttacctgact ttagagcttt tttacataat taaacatgat cctgagttat 12180 ctgtattctg aacttcctta attgagcaga ggcaggaaat cactgcagaa tgaaggaaca 12240 taccttgagg tgacccagcc aacctgtgcc cagaaggagg gttgtacctt gaaaagacac 12300 tgaaagaatt tggggtgcaa agtcatggtg ggcagaggag gtagaaaatc aactcagttg 12360 ttgcatcatt catggttctt tcatattgat gttcagtgca gtggcctgag aatatcccag 12420 cctctcttct ggtttggtga gtgctatata agtaaacatg gtggaattgt ttggggggcag 12480 atatagtgac ccttggtcac tggtgtttca aacattctgg caagtcacat caatcaagaa 12540 taatttttac ttttaagaaa gcataaccag caataaaagt attatttttg attctaaatg 12600 atagaaaccc aaatatattt tgttcatggt gcaaaggaag cctagagtca agttgatttc 12660 agaagtgact agttccagat acacaatgag atcttcacct ctctttctgt tatatctcta 12720 tctgtgaatc tgcctctctt tctgtgtctc tttgtccctg tatagttctt tctgcgtgtc 12780 tctctgcatc tttgtctctg cccccttgtt gtgtctttca ctacattgtt gcctttctat 12840 ttttctaatc catggtcact gtttatctgc attttttcta tctccgtgtt tctttttgca 12900 tctatttttc tgcatttctc ttccttatca cttcatatct tatctcatct ctctctcttg 12960 ctgtgtgtgt gtgtgtgtgt ctgtttgtct gtctctgtta atatatgttt ctagaatgtc 13020 taccagagtt ttaacaactt taggaaagat tctgattggc caagcctggg taacatgcac 13080 acctctcaaa cacatgtcc tgtgcagggg atgctgacag ccagcattgt gtccatcgct 13140 cttattagga aggaggactg gattttccag atccttgtgg tcctggaaat gacttccagt 13200 gtgcagatgt ctacaccagc catgtggagc acctcagcct ccacagcctc ctcacagtgg 13260 aggggtataa ggggcagttt gtttcttgtg gagcccacag gacaaatggc agagctccct 13320 ctggttctag ggtccctcat tgggggtgcc tgttcatagt cattccactc cttgtctgag 13380 ctccctttgt catagacgtt gtaacctgtt gattcctgat gacactcttt tcccggttat 13440 gagggaggtc actacacact gtggcccctt tgatgtgggc ccagccctga agctggtcta 13500 catctcagtc tctgagtttc gtcatgaagc cagagtctgg gagcttctgc gaggttatgt 13560 aaggccatga ccctgaaagc agacatccca tcttcctttc tccctcaccc acacactggg 13620 cgtgaggagt ctttggcagg ctcttccttc ttatggatga ggtcagagtg gagaactagg 13680 tctccttggg accttcatct cctgtactcc aggctgtcat gcaggtcctc agacagggac 13740 actggcgcac aaagaggcac caacacttga gattctgctc cccagggtta tagtctgaat 13800 tttccccaag caaaattctg aatggagtca aaagttttgt gccgattttg tcctcttcct 13860 cagggtgggc actgtcattc accataggga tcaaaaggga gtaacacttt tggggaaatg 13920 gggaaggcat gtgctgggtt gtccagcgtg tcctcagtct ctgtgtgtag ctcctggctt 13980 ttggccctgc aaagggaaga ggcagggcta gggattgaac aagactcaaa gtttagggga 14040 acatcgagat ctgatttttc tagttgaagc ataagcccta taattggggt gggtgataga 14100 ttatattcta ggacattctt acagttcaac attgtcacac tgagcacaca tgctggaaga 14160 ttctttatta acgagagggt caaaatcgtc ttctctttct tccattgaca gtttcataga 14220 aacaactatg ttttgcaccc agatttcatt ggatagtata atctttaatg gataattaat 14280 taaaataata agtacatcgt ctataaataa gtttgctaac acaaagaact gagtcttact 14340 cagcatataa cttggaggaa agcgtgtggg tgttctagag gacaacctac tggtcttgag 14400 catttgtcct taccttagat aataacagta taacttttgg agacagtgat gcttaccagt 14460 attccaaagc tcctgtacat ttctcagtct tttccgctgt taggttgggg acatttgact 14520 aacagtaacc aatggaactt gcaagtaggt gcatggtggt gtatgagatg ctggaaactc 14580 cataatctga gtcatttgaa t 14601 <210> 2 <211> 13247 <212> DNA <213> Artificial Sequence <220> <223> HLA-DQA1 (NG_032876.1) <400> 2 cccttgagaa agcttcactg tgtttttagt gcagattagt aaagataaga tcttgactgg 60 taggtgagtg ggtggaattt atttcaaata tgggggctct ccaatccttg cacaccaaat 120 tcatttacat attgtcaaaa gccagaggat atttatgata agttgcaaaa atagctacaa 180 attctttgta gctcattctg tcaagaaatg caatctatta atccacctct tgatgtgagc 240 tagtactatg acttgctttg aataacagaa tgtaatggaa gtgatgttgt gagttttaag 300 tttcagctca agacacctac tgtttctatc ttgcacagga gagctttcca gcacctgtga 360 taagcctcag cccgcctgcc ggataatgag cccacatgga ttgagagagg cctcctatcc 420 ctgccaaacc tattgatgct acagagatgt gagggagccc acctgagaaa agctgaacct 480 gcccagtaca taaaaaccac tcaggtgggt tgagcacaat ttcctgtctt acagaatcat 540 gaggagacac taaacaatta tttgaagtca ttaagttttg gagtactttg ttacataaaa 600 aaatctgaca gatacaagag tcttcaaaaa aattttgttt ttcagcaatg tcttagtgct 660 tctgtggctc acaggctccc acaggcctgg agtgctacag ggagaaggtt aaatgaatga 720 ggaaaaattg ataggctttc ccagcccaaa gcatgatgtt attatcatta tcattattaa 780 tatttgtctt tatataggag ctaccacttg ggaatagttg ctatgtgtca gacactggat 840 tgtatttaac tttataattg tacttatcta tcatttcatt ttaccatatt aactatcatc 900 taataatttt ccttctgttt tatagaaaat aaccttaagg ctcaggagtt ttgagtagct 960 tgcccaaggt gatgcagctg ataaaatgaa aagcagcatg gaatacatat ttatcttatt 1020 acaaaatctg tattcttttt actttgctac tctagactct cttattattg tgaagcagct 1080 ttaactactg caagacagaa gtcttggcct tcagagtaaa acttcaccag tgcataaagt 1140 cagactaaag caatttgaaa atatacagtc ttagagaatg ttataactgt ttattagaac 1200 taacataaat tctacctaat ttcttagagg gctcttaatg atgtcaatta taatggcaca 1260 tcccattgtt attttagtca tggaatcaat ggcatgtcaa taagtgcttt ctgagaaaat 1320 tgttggacaa agtactattt tgaactccaa attttattcc cactattaat ttatgaagag 1380 ggccttttct ctttctacta gacaaaggta acaaattagc tcttgttaaa atggtatgct 1440 gttcttctga gtctcattta cttattactt taccttacat taaaattatg acctgaagac 1500 ataagcaact ggaacaacgt tcactgtgtt atggccggat gaagcaggaa gaggaaagag 1560 acaaaactag gttaaagata gaaatggcat ctattgggcc agtcgtggcc tcacgcctgt 1620 aattccagca ctttgggagg ccaaggcagg cagatcacga ggtcaggaga tcgagaccat 1680 cctggttaac acagtgaaac cccatctcta ctaaaaatac aaaaaattag ccgggcgtgg 1740 tggcaggtgc ctgtagtccc agctacttgc agtgagccga gattacgcca ctgcactcca 1800 gcctgggcga cagagcaaga ctgtctcaaa aaaagaaaaa aagaaatggc gtctattatc 1860 tcttcaatga ctttgccttg cttggacttt cccttcaccc cacaggatgt gaggtctgaa 1920 acggcaccct caacttccca tccaagatac aattctaatc ctacatttaa caccctaact 1980 tcttaactgg agttgagtta tttaaactgt aattttaata ggtgaaattc tggactacca 2040 tcccaaaaca ttttgctcat ttgccaaagt cctaaggaat ttccatgaga tacaaagcag 2100 gtaagtctgg atacaggaaa aaagataaaa acatgttatt tgctacacag ccagaagggt 2160 attgagtggc aaagggagca catctcaaag gggacctcaa aaaccctctt catccacaat 2220 ggcaggagct agaaagaata aagccaccta tagggtcaaa tatctctcct aatcatgtta 2280 aggcactgga ttctgaattt gcacagaagg agactctcac ccatcactcc tcacaaggac 2340 tcatggcttg ccccatagca tcacatctgt gctgcttacc agctgcgtga ccctgggaaa 2400 agtccttcaa ctctctgggc tttaatgtcc tcctcggaaa atgagaacga tattaaaata 2460 tgacaagtat atgtaaagag tccaggaatt tttcattcca agtgcagtgt atgtacattt 2520 ctcacaactg cctaatgagg tacctcaatg cctccagcca aagaccagca ggagcataca 2580 agcaatgaac aagtcagctt tattgtttat tgcaatgatg gataaaactc accatgagaa 2640 tcatgcagcc cctcagtaag agattgttgg aaccaaagaa gtagaaccac gagaatacat 2700 atattaagag aatgatgcaa ggaattaatt tttgcatctg tgggggtggg ctaggcaagt 2760 cagagatcct ctgggaggta gttatcagga agggcaggct ggaactctca gcacaggctg 2820 acacactgtc cagagtggaa tttctgtttc ctcagagaaa cctcagctct gctcttaagg 2880 cttttcaaca gcttagatta agctcaccca gttttcctag gataaattct taaagtcaac 2940 tgattatgaa cttcaatgac atctacaaaa tatcttcaca gcaacatcta gattattagt 3000 gtttgactga ataactgggg atcacagtct agctgacaca taaaattgac cattaatcag 3060 ttgtaaggtt tgtgcttgtt ttaggtgatt ttggggagga tttaagaaag agggattttg 3120 cttttaattg gattctgaca gaaagtggag ggttggggtg gcaatgttat gattgggtag 3180 cttcataaat cctacctaga gggacagaag actatcctga ggctacagac gtggttggta 3240 aagaagcagt aatcactccc aagagagaga tgtgcctggt catttttgtg gtttggacaa 3300 tatttatgtt ttgtctgggt tcagacatga tgactgagca ttcaggtgtt ctgtctcaat 3360 ccactgtgct cacagagtac ctgtctgatt ctgatgttct atgaaatcct ttatctccaa 3420 caggagaacc aaaaccacct gggagtgcca ggctagctgc tagcaacccc aagcctttgt 3480 taattacatc cagacagctc tcaggtgtca ggacattttt ttttttgttt tacttttttt 3540 ttttacagtc tctgccagta ggaggtaaaa catagtgctg agaatctcag aaggccattt 3600 atcaaggaca gagtgattct aaatagaagc tccattaact tacggtttct atcacataca 3660 gaaaatagat gcatctgaaa aaacataata agtttccctc taaggactaa ctttagctca 3720 atctctagtc ccttgcaaat atttggaatt ttaatggggt aggataacaa gttttaaaag 3780 atctgatagt ttaagaaaag aaaaccattt ttctaaggca gtgcaattct tattctaccc 3840 tcaacttttg acttcatatt cttaattaaa aaaaaaattc ttagagtaat tgagccagcc 3900 aaattttaaa tgtaatcaat gtccctaaat ttcctttaaa cgtactcaag aagcaccaaa 3960 acacagaaca taaggattac tcaatgcaaa gaaaaactgt ataaagtctc atatagttac 4020 tatagacagc cccatctgac attataaccc ctttttattg ccctggccaa aaccacctgg 4080 agcttttgag cacttgagaa gaacttaccc agctggattt atacaagtag aaaaggcaaa 4140 ggtattgctt gggctaccac cagcagagat ccctaggtag gtggggtcag cttaacattt 4200 ggagaattcc atacgcactg tggaagctaa aagaaaaaca gctaacccac atacagaagc 4260 cagagaaagg gcaggggatg gggactgcca gggagggaaa tcaactcagg gaaaaattcc 4320 tggaggttgt aagccagaac atcctgaagg atgccgtata actgatgacc tcatctatcc 4380 acgaggctgc tcagaaatgc ccacccctgg ccaggcgcgg tggctcatgc ctgtaatctg 4440 agtactttgg gaggctgaga cgggcagatc atgaggtcag gagttcaaga ccagcgtggc 4500 caacatagtg aaaccccgtc tctactaaaa atacaaaaat tagctgggcg tggtggcagg 4560 tgcctgcagt cccagctact tgggagggtg agggaggaga atcgcttgaa tccgggaggc 4620 aaaggttgca gtgagccgag accttgccat tgtacctcag cctgggtgac agagtgagac 4680 tacgtctcaa aaaaaaagaa aaagaaaaga aaaaggaaaa aaaagaaaaa cacccatccc 4740 tcttgcgact ggcagacatg cacacaccag agaagattcc aatttaatgt cctcccttta 4800 ttcatagaac aattcctcaa gtccactctg agtagaggct gcatcacaag gggattgccc 4860 cgtctccttc cagggctctt aatacaaact cttcaactag taactgagat gtcaccatag 4920 gggatttttc taattggcca aaacctgact tggcagggtt tggtttgggt gtcttcagat 4980 ttccttgtct tgaggtcctc acaattactc tacagctcag aacaccaact gctgaggctg 5040 ccttgggaag aggatgatcc taaacaaagc tctgctgctg ggggccctcg ctctgaccac 5100 cgtgatgagc ccctgtggag gtgaagacat tgtgggtgag tgcatgagtg agggatgttc 5160 tctggagctg aaaaacagta aattgaagga aaagagataa agcgatttgc agagaaactg 5220 tagagatttc ctaagggccc tttcagtatt aagacaatta aaaattatag ctgttcctcc 5280 ttcaggaaac cagagcccca acctactctt tttgttatct atgctgttgt gttcactaag 5340 gacgctattc tgtttatatt atattcagtg actacggcct ggaggtctct atgtcgttcc 5400 atcatgattg cctcaaaaat tagtgaggtt tccatcagtg gataattttt tattattaaa 5460 aatttatgaa gtgtcattct caaatttccc tgaacaactt ttgaagcttt tcggatgtct 5520 ccggtggtag atcttggggt cattccatca attatgtact ctatagatat ttaaaatgtt 5580 gcccgtttct ttctctcaga cttactcaca tttccacatg ggaactggca caggtgggga 5640 gtgggtaaag gagtccagca ggctgaatgc cttcaacaat cattttacca catggtcctc 5700 acttactctc agctgcctca tatgtgtcac ctcacaagta atcaaataaa atgggcatgt 5760 ggctaagctt tgtaaatagt gaaaacatga atgtcaattt tttttacata tttctattac 5820 agatatagct tcacatttct tttctttagc aaaataaggg atcattttat tttaaaattg 5880 agaagtagaa aaaattggta aaataaatca ttttattctc aaattatcaa cccaaattac 5940 ctgttcttca cctcatctaa taaagtccta taaaaagaaa agtgggccag acaaggtggc 6000 tcatgcctgt aatcccagca ctttgggagg ccgaggcagg aggatcattt gagcctggga 6060 gcttgagacc agcctgggca acatagcaag acctcatctc tacaaaaaaa gaaaaataaa 6120 aattagccag gcatggtggt gtgtgcctgt ggtgccagct actcagaagg ctgccgtggg 6180 aggaccactt gagtccatga ggcggaagct gcagtgagcc atggtggcac cactacactc 6240 cagccagggc aacagagaga ggcgctgtct caaaaagaaa gaggaaagaa agcgaggaag 6300 gaaggaagga aggagaagga aggaaggaag gaaaagaaaa gaaaagggaa gggaggaagg 6360 aagggaaaaa gaaagacaga aagaaagagg aaggaaggaa gaaaggaagc acagattaat 6420 tatttggtct cttactctcc tctgcctttg tcgtccatct ctttccacct ctcttcatgc 6480 atccctttct ccctcttccc tttcaggatc catctctgac tccctgctcc tttatagaga 6540 tggacagtgg gtttgtaaaa caaaagttga aaagtcagat agttaaaagg ggaagtgaac 6600 tggaaggtac tttaaacttt cacaacttta ttaaccgtgg ctgctcccat tatgattttg 6660 ttcggcagtg gaagtttcac ctgcttctcc agagcgcttg gcgtctttgt tccaaatttc 6720 ctttcttcaa cctcacacca gagtgccctg gtcaggcttg gctcattcat taggcacaat 6780 gtgggcagtg caggggaccc tccatactgt aaagccacat gagaaggttt taactccttt 6840 taaaattaga aaaataatgg aatattagag cctaagaaaa tgttttaact tttaattcag 6900 cctagattat attgtcttta taccaattca gtcataaaat ataattttcc atatttttgt 6960 ggaggaagag gcccatacaa gcaagaatgc tcggggctca catgtcagaa tgcagccttg 7020 gtcatgactg atcctggcct tcgtatggtt ctgctacctg tgtgcctgcc cgtcttcccc 7080 aaaatctatg tggtcctcga atatagcaac tgtcattcaa tacacatgtt tgagcacaca 7140 gtgagctaag ttttaaggat tcaaagatga aaagtcatgc tgtcttccct gcagagggtg 7200 ctcagattag tgatggaaac agtatggggt gcaggaaagc agaaggccat tgctgagcag 7260 ggcagtggac ccagcagagg ctgaaacaat acaagtgact tggttccagg tgggccagca 7320 gggtgacgtc ctctagcaaa atttggcacc caagacaagt accagaagaa aagaaagact 7380 gcatgtattc cacatatatt catgtttgaa caaggagtca agatttatgg caaggataag 7440 gaggctttgt tggtgacctg ttaagaccaa ccagggcagt catgctggat agggaagaag 7500 gtgagctgga agaggaacag acaacttgga cagccagatg ttgagacgga ggggttggag 7560 gtcataatgt ggtcaaaaac atgttgatga gaggactcag ctacaaagtt gttaacttaa 7620 gcagaaacct caaggatgga ttttagaatt tctccaggaa gtcctaaaag ataattccat 7680 ttcagggaga aaaacaacag accactgcaa agaccaggga acatgaaagg ataatgtagt 7740 ttgtcttgct tggcagatac ttttgaagga tgttggactg taaggctgtc gatatcctcc 7800 tcagagaact tactacagta cattgtatct gttcccttac ctacctgact cttccactat 7860 tcagtttgtt ccttaatagt agaccatgcc tgattggtgt tttacacatc tccggctatg 7920 tctgacactt gtggatgctc agaaagtggg gaaggaagga aagatacgat ggtaaaaggc 7980 ttacacatgt cttgacaaaa aagtccagtt tggctcattt ggctggagtc gtactgcatg 8040 gctgccattc tgctctggca tcctcagaca agcacactgc ccattagagg aaaaagtgtg 8100 atataagtgt tgagtcagaa tgctgtagac atttagtaat ctccttcaca ggaaaaaaaa 8160 aaaaaaggtg gggggaatga cagaaatcca aaaactagta gagcttccac ttttcatttc 8220 agaagaaatc agttgctctc ctctaaggac cattactatt aacaaaacag agaccttaga 8280 aggaggcatt gtttatttat tatatatttt gtaatgttat taccaatctt gttatactct 8340 ttcttatacc ctacaattgt tagcagaaat tattttaaat taataagatc ctgcatgctt 8400 ttcctttaaa aaaaaaaaaa agaaagatct ctgtgtagag tgtcctattc tgagccagtc 8460 ctgagaggaa aggaagtata atcaatttgt tattaaccaa tgaaagaatt aagtgaaaga 8520 taaatctcag gaagcagagg gaagtaaacc taatttctga ctaagaaagc taaatactat 8580 gataactcat tcattccttc ttttgttcaa ttacattatt taatcataag tccatgacat 8640 gccaggcact caggaaatag taaaaattgg acatgcgata ttctgccctt gtgtagcgca 8700 cactagagtg ggaaagaaag tgcactttta actggacaac taccaacatg aagaggggag 8760 gaagcagggg ctggaaatgt ccacagactg tgccaaaaaa tgaagcccat aatatttgaa 8820 agtcagtttc ttccatcatt ttgtgtatta aggttctttc ttcccctgtt ctccgccttc 8880 ctgcttgtca tcttcactca tcagctgacc acgttgcctc ttgtggtgta aacttgtacc 8940 agttttacgg tccctctggc cagtacaccc atgaatttga tggagatgag cagttctacg 9000 tggacctgga gaggaaggag actgcctggc ggtggcctga gttcagcaaa tttggaggtt 9060 ttgacccgca gggtgcactg agaaacatgg ctgtggcaaa acacaacttg aacatcatga 9120 ttaaacgcta caactctacc gctgctacca atggtatgcg tccaccattc tgcctctctt 9180 tacttaagtt atccctccat accagggttc attattttct tcccaagagg tccccagatc 9240 ttcttatggc aattgctgaa attttatcat ctcccatctc taaaatcaca tattcccatg 9300 taatacaagg gtctttccat tatgcattca gcaaatcctt ctaggagagg tctcatcaac 9360 ctcctacttt attaaacatg cccacagaga gaagggcaca ggaataaagc agaggcaatg 9420 tgtcgttgct cccaagcaga aggtaaataa gacctctttg actatcaggt ggtgaaatgc 9480 tggtaggagg gctcttccag gatgtaatgc agaacttcag ggcagagcta ttcacacttc 9540 acaccagtgc tgtttcctca ccacagaggt tcctgaggtc acagtgtttt ccaagtctcc 9600 cgtgacactg ggtcagccca acaccctcat ttgtcttgtg gacaacatct ttcctcctgt 9660 ggtcaacatc acatggctga gcaatgggca gtcagtcaca gaaggtgttt ctgagaccag 9720 cttcctctcc aagagtgatc attccttctt caagatcagt tacctcacct tcctcccttc 9780 tgctgatgag atttatgact gcaaggtgga gcactggggc ctggaccagc ctcttctgaa 9840 acactggggt aaggatgagt ttcatcattt tttgattctt tcttgtctgt caagttcaga 9900 acttcctgcc ttttactcct atatccaaaa acttgttttc cacacttcat gggtttcttt 9960 tctgtctctc tttttttttt gaaagaataa agcaaaaaaa gcagagattt attgaaaatg 10020 aaagtacact ctacaggatg ggagtgggcc tgccacttca tggttttcta atgatagact 10080 tcactcttct ccctaagcct ggggccttga gtctttgcag agccaaccct ctaccccatc 10140 ccatcccaca cacatgcaca tgagcacact ctgcattctg acctcaacaa cttcacttcc 10200 acagagcctg agattccagc ccctatgtca gagctcacag agactgtggt ctgtgccctg 10260 gggttgtctg tgggcctcat gggcattgtg gtgggcactg tcttcatcat ccaaggcctg 10320 cgttcagttg gtgcttccag acaccaaggg ccattgtgaa tcccatcctg gaagggaagg 10380 taagattgag actggttaca gttgaagcgg cagtatgaaa ggaaggaaag tgggagggcg 10440 ttgtggacat gaatgtggtt gaaagttgta ggggaattgg gaagtggcat gatgatgaca 10500 caggagcccc ctcggaccca ttgatctcat gtctgccctg ttgcaggtgc atcgccatct 10560 acaggagcag aagaatggac ttgctaaatg acctagcact attctctggc ccgatttatc 10620 atatcccttt tctcctccaa atatttctcc tctcaccttt tctctgggac ttaagctgct 10680 atatcccctc agagctcaca aatgccttta cattctttcc ctgacctcct gatttttttt 10740 ttcttttctc aaatgttacc tacaaagaca tgcctggggt aagccacccg gctacctaat 10800 tcctcagtaa cctccatcta aaatctccaa ggaagcaata aattcctttt atgagatcta 10860 tgtcaaattt ttccatcttt catccagggc tgactgaaac tatggctaat aattggggta 10920 ctcttatgtt tcaatccaat ttaacctcat ttcccagatc atttttcatg tccagtaaca 10980 cagaagccac caagtacagt atagcctgat aatatgttga tttcttagct gacattaata 11040 tttcttgctt ccttgtgttc ccacccttgg cactgccacc cacccctcaa ttcaggcaac 11100 aatgaaatta atggataccg tctgcccttg gcccagaatt gttatagcaa aaattttaga 11160 accaaaaaat aagtctgtac taatttcaat gtggctttta aaagtatgac agagaaataa 11220 gttaggataa aggaaatttg aatctcaaaa atatcaaaag taaaaatgta ttctcaaaac 11280 tttaaattta tgaagaatga tgacagtaga agccttcctc ttcccttgtc accttgagat 11340 aaaaattctt taggcaggaa aagaaatgga agtcagaaaa acattagaat aagacaataa 11400 tgtgggtgtc tgaaaaggaa caaatactta ttcctcacat agggttagtg acaatgggaa 11460 aagggacggg agtagaagcc acagacatat ctaggagccc tgaatagagg cgcagtctgc 11520 ctcacctcct gaatgaagct gtactagata accatgtagc tttccctgtg ccactctggc 11580 atgaaggaga cagtatagtg aatatggcta caggatgttt cttggaaaca tgccaatatc 11640 ttcagaaatc cccagccctt tcccctaacc cctcctgact aaggaaagca tgagcttatg 11700 agagaaaccc taggaagaac aacacagttg agacaatgta gcagcagcag tgggtgctgt 11760 gtcctccact ggattcgcca tctccgagga gaaactctca cagaggaaat gggtcagcag 11820 cgacctcatg gctctaaaca gctatgaaat ccatgaggat atttctaacc atgctacctg 11880 catcagtgag tttaaatttt aattggagaa aaaatacaaa acattaatgc aataattgat 11940 acagtatagt ttggtgcaaa gaaccctaaa tccaaatcca ggactcagta ctttgaagct 12000 agtattttaa actttataaa tgtgtgaagt ctctaacatt tctggcctta cttttctcat 12060 ccacaatgta ggagtaataa tactttcctt gcagagttat tgataaaatt tgaataattt 12120 tgatatttag tcaatgcctt acacatagta catgaacaca taagaaaaca ttgtggttat 12180 atttataatt aatttattta aaagaatgga tcatattata tgaaaagcac ttttgttttt 12240 ctcagcctct taatgattta ggagattcaa atgtagagct atgggtgaat ttcttttcat 12300 atgataattg aaggatattt ttctttttcc agaatgagag aggctgagat tggattggta 12360 agagaactct tagcactaga agttgtaata tttgactttg gttttcaact ctctaagagg 12420 gaatatattc cctccttatg gcccataagt gtttattcaa ggtatatcat atacaacaga 12480 tctttatgcc tgtttacttt ggggaagaag tgaagatagt tcaaggagaa aataatttaa 12540 aacacagact gggaatcagt aagcacagga aatctgaacc agtgatgatc atgaaaatgt 12600 ccatcacaga gcacagatga ttttcagggc aataaaacta ttctgtttga taccacaatg 12660 gtgaaaaatg tcattataca tttgctcaaa tccacagaat atataacacc aagagttaga 12720 cttaatgtaa actatggact ttgggtgata atgatgtgcc aatgtaagtt cataaattat 12780 agcaaatgta ccactcagat gggagatgtt gctaatgggg gaggctatgc atgtgtggga 12840 gcagagtgta tctggcagca gtccccagcc tttttggcag cagggaccag ttttatggaa 12900 gacaattttt ccacagatag ttgggggaat gggggtatga tctggggatg aaactgtgaa 12960 actattccac ctcagatcaa caagcattag ttagattctc ataaggaaca tgcaacctag 13020 atctcttgca tgcacagtta aaaatagggt tcgcactcct atgagaatct aatgccacca 13080 ctgatctgac ggaaggcggg gctcagttgg taatgctggc tcacccactg cgtggtccag 13140 tttctaacag gccaccaact ggtactggtc catggcccgg gggttgggga cctctgggat 13200 acctctgcac cttctgctca gtttttctgt gaacctacaa ccgcttt 13247 <210> 3 <211> 20403 <212> DNA <213> Artificial Sequence <220> <223> HLA-DRB1 (NG_029921.1) <400> 3 gaggttgcag ttagacaaga tcacgccact gcactccagc ctggcaacag agtgagactc 60 tgtctcaaaa aaaataaaag aaaaaaagaa aagaaaaaaa aagaattaag tgtttaagtc 120 ctgttctgga gagaaaataa acccatgtct atgtattttg cctcagtgga agaaccagtt 180 gcttttagaa ctgattcttg ttatgctttt ttgtttttca tagctttaga acttgtaata 240 gcaataaaga ttcctcactt ctggaaaaac tcaaaaattt cgaataatcc ttatattatc 300 ttctgctgtg gttattataa agtattttct tctggttaat tatatagcta tggcttagat 360 tattttttac tagctgatac cttttttctt attctaacaa ttgactagac acctccttaa 420 ggtcaaatcc aaaattctga actgtggata ctgacaggct tttgtttgca cccagatcat 480 ctttagcatc tctagattga tacgtagtag taccaagttt tccaccttta tcttgctagt 540 gtaccccttg aatgaacaca agaccaaaac agggatgcta gcaatagtta gtgtggttct 600 tatgctttat ttttctcaaa actgctgtat gatactgaga gttgctttgt ttgacaggca 660 cacagggtag gaagagatgt catgacaaaa ggaatcgtta atttttttgc acatatataa 720 gttgatttta tttaggtaaa atattgttaa cataaataag tactagtaag tttacttttt 780 caagataata aattgtctac aaggatgaac tgttagaaaa ataactgcta aaagatttta 840 ttatttattt taaataaaat aagcaacaaa ccaggcacac actttatagg acagattgag 900 aagttggtac agttcaacag gttcatcaat ttcttcactg tccacactgc agtcactggg 960 gagtgggcta gtggagcacc aaaatgaaat tttgaaaaat aatctggcct attttggact 1020 ggatagatag gtggatactt accgcagtac aattaacata agatctagaa acagaaataa 1080 aaagaaaatt ctttgtactt acaatattag tacaaaggcc tatgggaatt ctagttgttc 1140 tctctatta ctatgcaatg gcaagcattc tgttataaaa cagctaagtt gagtcaaaga 1200 atgacatttg gaagttgaag aagtcctgtc aactgaccta gatagtgtca tggtgtaatg 1260 attggcacta ccaaagttcc tcaatggagg acattgctga aattttactg gaaagggtcc 1320 tgtcaagtgt gatgaatact agtaaggcct ttaaatggca ccgttttctg tttcaggata 1380 catatcttcc atgctaagaa gaaactggtc ctgtttatcc atttattgtt attatcattt 1440 tttctttaga tataaggatt agtaacctgc tttttacttt aaattccaga ttagtggtgg 1500 ttgctttctg aaaacccctg agaacatttt gagactactt ggacaagtgg cagacattct 1560 atgataacta aggcttgctg atagccaaaa gagcctattt ttccaaaatg tgttgcaagc 1620 tttcaggctt actacaagtg agccccattc tgtgacaatc agtaggactc aagacatgct 1680 gtaatcctac caatgtcaac ctgcctgttg ttcaacaaaa gtctgtgctt ccgattttac 1740 ctgtttagtc ctgggaatgt tgggatttat ttcccgtaaa accaaaccta tggtttcatg 1800 catcaagacc agagaccat gaagttccgt actgaaagcc actttcttcc agaaaccaat 1860 ttaattgtca tttcctcagg aaataagctc tcatatttga cacctctcac agccagctga 1920 gttgagagga ttattctctt ttttccgtga aaaagttcag cctattagac cacctatgtg 1980 actgatggtt tggtgagagt tgctacattg tttagcctga actatcctta tattgaatat 2040 tgaaggaaag tgtgagatat ataatttaaa gaagcacatc tgttgtagta taagtgtgtc 2100 tcctttaaaa ttcaggtagg gctcctcact catgaatggg attaaggccc ttgtaaaaca 2160 cgcttcacac agtttttagc ctctcatcct tccaccttct acaatgtaag tacacagcgt 2220 tcatcccctc tggaggatgc aagacgccat cttggaagtg gcgaccatgc cctttgccag 2280 acattgaacc tgttggtgcc ttaatcttgg acttctcagc ctccatgtgt tctttataaa 2340 ttacccagtc tactgtattt tatcacagca caaataaact aagacaacat ctttgttact 2400 cataaatgta taaaacatac agaatttagt tcattgccat tggccatctt tttaaatata 2460 aatttgtatg atttataaat agtgtgtcaa atttatataa acaagttttg aaagtttcct 2520 tttaactgta ttttagtaca ttcttgatgt agaattactt atttttgcct aattaactaa 2580 ttaactaatt gtgatgtggt gacctaggaa aggaagctaa ggttcacctt agtattacag 2640 gataaaagca ggagctatgg atgtccttac gtaacataaa cgcaaattgt gtcatttcca 2700 gaggagagta accatggtga tgaggggaat cttttgaaat aactagaatt gctacaaagt 2760 atctacccca aggtctataa aatgttgcca ttcattaaaa gaagtagtct tactgatttg 2820 cacagccatg aattaaagtg ataaaaataa ttttagtata atggacataa ttctctttag 2880 aaattgaatg tgaggtagta taatataacg acagagcttg aggggtttgg aattacatat 2940 ataataactt ggttcaatag aattgacaga acaactctgc tttaaaataa ttaatatttt 3000 atgtgaagag tgttcagtct cttactcctg gttcccatta tgatttcctc atttgtttga 3060 ggctatggcc ctttactatt ccacttctct ggttttatcg taagggaaga tataagaaga 3120 ttttgcaggc cagacgtggt ggctcacgcc tgtaatccca gcactttggg aggccgagtt 3180 actgtttact agccttgcat ctttgcaaaa gttgtttaat ctccatcatt ttattctctt 3240 cacttgtagg gatgaaaagg ttatatccct cattcagcta atgtgagaat tgattaaaaa 3300 tatgatgtat ggaaagctct gtacaattct gagtacaaag caaaatgctc aaaaattgct 3360 aagaaatttt agtcattttt attgcagcat ggtgagtatc ccattcctag aaacactaag 3420 gcacataagg aatgactgcc tatcagaact gtggtagggt gtgaattaat gcagaacttt 3480 atctgcatag ttatactttg aagtccgttc tgaatcttag atgctacatt tatataaata 3540 caaagcataa tagctatcta aatgtagaat tgtatgttta aaattatatg attacatcaa 3600 ctgatgtaaa tcacagattt tccctagggt tctgtttcct gaacattctg taacgtatta 3660 gttagcaaag tctttttttt ttaaaactga gtctcgccgc atcaaccaga ccggagtgca 3720 gtggcgtgct cccaactcac tgcaacctct acctcccaga atcaagcaat tcttgtgcct 3780 cagcctcccg agaagctggg attacaggca tgcaccacca agaccagctg atttttctat 3840 tttttttttt tagtagagac ggggtttcac catcttggcc aggctggtct tgaactcctg 3900 acctcaagtg atctgcccac ctcagcctcc caaagtgctg ggattatagg catgacccac 3960 cacgtcctgc cagcaaagtc ttcttatata ttcccttacg ataaaacaag agaagtggaa 4020 tagtaaaggg ccatagtctc aatcaaatga ggaaatccta atgggaacca ggaatgaggg 4080 attgaacact cttcacataa aatattattt taaaacaaaa ttgttctgtc aacagctgac 4140 tttgagtcct tgatcgatct ctcagaccca tgaatacttg gattgcacag ttgaccttat 4200 cgcattgtta gggtaagtgc tatacaaagg cacatcaga ccctccattg catataggtg 4260 gcccctgcaa accccttgcc tgtgtgtgtt ctggaggtgc cactaaactt gggggaagca 4320 tcaggagata cacttgaaaa aactcttttt actaagatta aattattaac taactttcaa 4380 tttcctttaa cttattagag acatctctac ctgtaaatag gtaaagatta cactctccag 4440 tcaacagctg tcattctgtc atatcatcag atacccaggg ctgctgctcc ctgaggcatc 4500 cacagaatca cattttccag tattgaaaga cctgaaagat cacggtgcct tcatttcaac 4560 tgtgagacat gatgtaattt tcacaaatct acaacagtaa gatatagtgc aacaggacca 4620 gattaaggtc tcctggtttg caaccatgtc ccctccatct cctttactcc tgaacacact 4680 cactcctgca aacagttctc ttgtcaagtg ggaaatgaat gctcttacaa ggctcaaact 4740 tgtgaacaca tcactgacca gcacagagct aaaataattg gggctaaaaa taccgcccca 4800 attaaagtgt tttacatgca actggttcaa acctttcaag tactaaaaac aatcctgtaa 4860 agaaggaaat tctgtttcag aagaggacct tcatacagca tctctgacca gcaactgatg 4920 atgctattga actcagatgc tgattcgttc tccaacacta gattacccaa tccaggagca 4980 aggaaatcag taacttactc cctataactt ggaatgtggg tggaggggtt catagttctc 5040 cctgagtgag acttgcctgc tgctctggcc cctggtcctg tcctgttctc cagcatggtg 5100 tgtctgaggc tccctggagg ctcctgcatg gcagttctga cagtgacact gatggtgctg 5160 agctccccac tggctttggc tggggacacc agacgtaagt gcacattgtg ggtgctgagc 5220 tactatgggg tggggaaaat agggagtttt gttaacattg tgcccaggcc atgtacctta 5280 agaaattgtg acgtattttt cagagattgc ccatctttat catatggatc ccaaataatt 5340 tccccaccac aaaaggagct tggctacttg cccactccat gagacttgtg taaggggcct 5400 ccatacaggt catttctact caaatctcca ccaataaaac ctttgcatca catgtcctca 5460 gggtctttag aggatttaga aataaggatg ctaaaataaa ttccccatac agcacttgcc 5520 tttattatgt tgacttatgt cagacaaagg aggttttttc tgaaaatttt gtggaagtca 5580 agggaattta aagggtctct cctaaacgat cctgggttat gtcacccaca ggacctttgg 5640 tgttggcccc tcttcctcat atgtgaggat ggacccagtg gcctccccat tatctacttt 5700 cttttctttc tgaactccaa tgtttataaa gcctgtaccc ctgtagtgta tgtaggttgt 5760 ctgacagaag ttatacttag tgctctttct ttcttgtggg gaaaaatccc tggaactgaa 5820 gctgagatct ttagtacttg gagtcacctt acagatacag agcatttatg aggtattctt 5880 tggtgcctaa agaacttaag gcatcctctg aaaacctggc ccaggttagt gtttattatg 5940 aatctctttt aacctttcta tacttgtttc tcctacatct cctaagtgct ccaactagac 6000 atgacagaag agatttaact aacgtagtat gagttatata aaattctatt tttgtaagtc 6060 aaaaataatc aaatatcaaa aatttaataa tgttcaaact atatactctg tgtggggtta 6120 ccgagacaat gtggacattg ttcacatctc atagggctga aagtcaatgg gcaagtcctg 6180 ggaactcatt gtcttactgg ggtcttgtcc taaatttcat aggttcaccc atcatgccct 6240 caactttcct taattagcca tgtctgctta cctcttcctc cagtttctct cttatttttc 6300 cccagctatg ttgttatcat ttccagaaat ctctaaagct tgcacagatc cttagcacta 6360 tgagatccat tgaaagagat agtttttttc tttttgagat agggcctggc tctgtcaccc 6420 aggctgtagc tcagtggtgc gatcgaggct cactgcaacc tctgcctccc acgctcaagt 6480 gatcctccct cctcaggctc cagagtagct gggaatacag gcaggcaacc acgcccagct 6540 aatttttgta attttggtag aaatgagatt ttgccatgtt gcccaggctg gtcttaaact 6600 gctggactca agcaatccac ctgccttggc ctcccaacat gctaggatta tagatgtgag 6660 ccactgtgcc caggcaaaaa gagatgactc tcaataaaaa aaagtccttt ttcttaaatc 6720 actgtttctt tatctgtgaa ttcttcttcc aactagaagg aggagaaaga agtttgcctg 6780 tatttctcac caggaggaga aggggtctag tgtgacatca gaatgaaaga gtgctggagt 6840 ttgagcccct tcttgctttc caagatcccc acagttatca cttcccatac cctggtttat 6900 tcatgtaaac cacacttatt tttcttagca gctactgtgt actcggctcc attctaggtt 6960 cagatcattc tatttgatta agacagagag ggtcccgact ctcatggaag ttacacaaca 7020 atagaggaga cagacactaa cccaataagc atttaacaaa gaataaaata ttagagagtc 7080 atagtgcact gaagaaaaga catcaggttt gtgaagaaga gagacatgga ttcacctact 7140 ttagttcata tgtttaggga gctctacctg agaaagtgac attcagctga gacaacaaaa 7200 taagtagaca gtcatgaaga tctaatggac gaaagctcca gagagaccaa atgggggggaa 7260 agccctggtg tgggaaatta tgtggagaga gagaaagacg gctagagggg ctgatgtata 7320 gaaagtaagg aaatggagag gcagaagatg aggtaggaca cagagagaaa gtcaggagcc 7380 tcatcattat aggctctgat gtccacggta aaaaatttga attttatttt atttatttat 7440 ttatttattt atttatttta tttatttatt tatttatttt tttaagatgg agtctcgctt 7500 tgttgcccag gctggagtgc agtggcgtga tctcagctca ctgcaagctc cacctcctgg 7560 gttcatgcca ttctcctgcc tcagcctccc tagtagctgg gactacaggc acctgccacc 7620 acgcctggct aatttttagt atttttagta gtgagggcat tttgtcatgt taaccagggt 7680 ggtctccatc tcctgacctc gtgatccacc tgcctcagcc tcccaaagtg ctgagactac 7740 aggtgtgagc caccacgcct ggcctatttt tttttttttt gagacggagt ttcgttcttg 7800 ttgcccaggc tggagtgcaa tggtgcaatc tcggctcact gcaaccttcg cctccctggt 7860 tcaagtgatt ctcctgcctc agcttcccaa gtatctgaga ttacaggcac ccaccaccat 7920 acctggctaa tttttatttt tttgtatttt tagtagacat cgggtatcac catgttgacc 7980 atgctggtct cgaactcctg acctcagata atctgtctgc cttggcctcc caaagtgctg 8040 ggattacagg catgagccac cgcggccgga ctgaatttta tttaaataga tacgagaagc 8100 tactgtatgg ttacaaggag agtcaattta tattcaattt atttttattt tattttattt 8160 ttttggtgat ggggtcttgc tctgttgccc aggctagatt gtagtggcac aatctcggct 8220 cactgcaacc tctgccttct gggttcaggc gattctcctg actcagcctc cagagtagct 8280 gggaccacag gtacatgcca ccacacctgg ctaagttttt gtatttttta gtagagacag 8340 gatttcacca tgttagccag gatggtctcg atctcctgat ctcgtgatcc acccaccttg 8400 gcctcccaaa gtgcagggat tacaggcctg agccactgcg cccggcctat attcaatttt 8460 taaaactaat tctagctact ctgtggggat tggaatgttg gggttcacaa gtggtcagga 8520 agactattta ggagcacagc agggaattct ccagcgaaaa caggcttgtg gcttcatgga 8580 gtgcattagt gataaagacg gtgaaaaaga taaagtggac agacttggca tgtatttttc 8640 cttagcttgt taatgaatta ctgtaaaggg ggtagaacaa tcaagcttat tcctaaggat 8700 tttgttttga caaataagtg ggtggtagtg ttgtttattg agataggaaa aactatggga 8760 ggaaattatt tgaagtgggt ggttggaaat aaaagttttg tttaaatttg agatgattta 8820 ttgacattta tgtggagcaa tcagaaggtc aatggcattt aagagactca tggtgaggct 8880 agggcttcaa gtatttatgt tggcggcatc aatacgtgta gtgtgttaaa ttccagggag 8940 tggaagagga tacataggga gatggattgt gtggagaaaa aagaacaggg cacaggccag 9000 caaagggggc tgagaaagag cccagggatg ttggagaaaa atcaagagaa catgatgcgt 9060 gtacgtcaag gaaaatagat ttttttcaag gagaagggag aggccaattg tggtgagtac 9120 cactaagcgg agggggaagt gagaacgtga cagagaagca agtgctgggt ttggtggagt 9180 tgatatttgc agtcagtgga gtatccaggg aggaaactgg attggacaat ttgaagagcg 9240 agtagaagtg aggatgaggt taagattgac tgttttgagt agagagcttc agggaaggac 9300 tgcactctgg gttcagggag ccagctggat caaaaggaaa aggctaaaga ggctgaagag 9360 aagcaggagg acctgtgaac cagagatgct cagtcattat tagcgaggaa atactagaaa 9420 gcccctgtgt gcagtgatga ctactcatgc agaaggtcac acagccaata tttaacacag 9480 ccagtatttc acacagctaa tatttattag tgacatagaa tataccagtt attactctag 9540 gtcatgagaa tggagtgata aataaaatga atccggtcgc catcagtata tgccatgtaa 9600 cattttgcag tgactgtgta ccaggcctgt gaatttcagt atgcaatttc aataatgatc 9660 ctgctgtatc tgtggtgttt aaaaacatat acatctctgg aatctaaaat tgagaggtta 9720 taagtaaaac ccagtattac aaattgagtg ctggaaatca gattgcagtt taaatctgag 9780 catatagaaa gtccctttct tctatgtcag cagatgcctt ttgtgtgagg tttagctgga 9840 ctgcattatt agacataaac cagtgtttct gccctatgtt ttcagaatga caattcttta 9900 tgaaactcat agaagaacag aagacaactg caaaatcatg atgaagatag taattgcttt 9960 agaattaagg aatacaaaaa ataatgtgag ctgtagttat agggatcata aaagtttaaa 10020 tgggaatgta tttgagtatg tgatcagtgc taagaagagt catcatttaa ttttacactt 10080 aacagtaatc tcgtgaggat tacgctatta ttaaatgcat ttgatagatt acaaaaaggc 10140 ttatggttgg taaaaattga cccaagtaga agagatcatg tttttattca ggttttctga 10200 ttctagagtt tgagagtttg tccatcatta gtgagtagtg actatattgt gtctgaatta 10260 ttgacagaat ttctgatatt catatgtacc aggttgtttc ttagagtggg gatagagatg 10320 caagggctgc tagttccgat gtattgggga aactttcatt cattttgcat ttatcatttt 10380 aaaagttctg tatgtctata atggtcatgt gttgaagaac acaaggaagt attaaatcac 10440 tccttcttct aaggtttgac tagcaagttg ggctagagtt accaaataaa atacatgttc 10500 ctagtgaaat ctgaatttca gatacaaaac cataatttat tgaaaatcca aatttaactg 10560 ggcatcctct ggttttattt gccacatctg tcaaccctaa gtgtgacaca tggacatgga 10620 ttacagtgct aaccatgcaa gccacggtga cagcaacttc acacatgttt atttttaact 10680 ttctctgtaa gaaagtgctt agataattta gggataaaaa gatagacatt gcttgatcca 10740 gggtgcacac ctctctgcca ccatttctaa agggcaaagg gagatttctg caggtcttgc 10800 tcacagtctg gggagctgct catttttgta aagtgtctgt atgagaatgt cattttcttg 10860 gtttcctcct ttccgagggg acttgactac aaaaccaaga gttctgcctc tggccaaggc 10920 tggtaatttg atgcctgcta gtattgttgg gagtgggaga ctgaaagaaa tgagttagtt 10980 ggggcattta acgggaataa aatagctgtg gttgtgactc attactacag ataattagtg 11040 gaccagtggc agagaaatta agaaaaaaga tgatgtgaat gataaatgat atgattagtg 11100 actgcttggt aaggcaagga aatcattaaa tcttggttct catcaagttc attttctgga 11160 aagatagcac tgtattggga gcagaattct acaaaacctt ctttttacat aggaccaaga 11220 ttttcaacaa atatttttca atgcaattct cagctgctcc ataactaata gtagcttgtt 11280 caacacagat tttttcagat gattcacacc tgtggtactt acccagggat ggttcaccac 11340 ccctcccttc cctctcatca tcgttgggga acggtgacaa tgtttggaac aatttttggt 11400 tgtcacaaac aggggtttct tctgatattc aatgagtaga agccagggac actgctagag 11460 aacccacaat gttcagaaca gcctctgcca tcaacaagga attatctggt ccaaaatgtc 11520 aatagtgctg aggctaagag cactggttca cactgtgctc tttctgaaaa ttctagactc 11580 acatctgtta tacactcacc acacagttta gtcttttatt tttgcttgtt tcattataaa 11640 caattagaca gttgcataaa ttcaaccact ttcttgttga atccatttag tcaatgcaag 11700 ctcaatattt tcatatttat tttttgcctt atgcaatatt tttcaacatt ttcatgagtt 11760 gtcggtcatc actatctcta ttaactttca acaacttgcc cttgtaagtc acaaatagtg 11820 atgctgctga aattatttct cactaacatg cctcagattt ctgtagtgat tctacatttg 11880 atattattca caatgtaaaa tgcttctatt tattcatttc gcttttaccc aaggattatt 11940 tttaagttat ttttgtcatt ttcacacttc aaacataaag acaaaaacat caaaaatata 12000 gtgttttaca tatgtgcata ttttcacaca tatatgtatg tatatttata tgtattgaaa 12060 gtacagaagc acatgtcacc aataagagct ctgagacacc ttcgaccact tacccttatc 12120 agatgagttg tggaaacaag tttttttaac tgaatttctg agctttgtgg atttagaaat 12180 gcaaaggaag gtttgtggac attcacaggg atcatgattt tattctcctt aaaactcttc 12240 tgtactttcc aattgtcctt agtataaatc caaaatccta acaccaccca agaggctttt 12300 caatacctgg ctcctgtgat ttctccgggc taatctgtta ccctccttcc cctcagcctc 12360 tctgctttag tgaactttct cctagttttt tgaagaagtt catcaattca agcttttgta 12420 catgggattt cctaaacctg aaatgtgcct cccgttttgt ccaaacagac acgggctcca 12480 ctctgccccc tggctcacac ctgcttaacc tgtcaagtca catctgaacc gtcactatta 12540 agagggtcct tctctggcac cctaatgtaa ttgagatcat cctattattc tctgttctag 12600 aactccacac ttccgacatt tctcattcct gtctaagctc ttgtgtgttt ggtgttgggc 12660 catcactttc actgctcttt aagctccccc agcggagtgg agaggtctgt tttccctcgt 12720 ttggattcct agaggcagcg cagaccaggc acaaggtcag cactaaggaa gggttcagag 12780 gatgaacgcg gtgggtgctg tttaaggaac cggtaaacat gtgggatgag agaaggagca 12840 gagtgtcttt ggggtggagg ctcccaggag gaggcggcgc gggctgcggt gctgggcgga 12900 tcctcctcca gctcctgctt ggaggtctcc agaacaggct ggaggtaggg aggggggtcc 12960 caaaagcctg gggatcagac gtggttttcc cgcctggtcc cccaggcccc ctttcgcctc 13020 aggaagacag aggaggagcc cctgggctgc tggtggtggg cgttgcggcg ggggccggtt 13080 aaggttccca gtgcccgcac cccacccagg gagccccgga tggcggcgtc actgtcagtg 13140 tcttctcagg aggccgcctg tgtgactgga tcgttcgtgt ccccacagca cgtttcttgg 13200 agtactctac gtctgagtgt catttcttca atgggacgga gcgggtgcgg tacctggaca 13260 gatacttcca taaccaggag gagaacgtgc gcttcgacag cgacgtgggg gagttccggg 13320 cggtgacgga gctggggcgg cctgatgccg agtactggaa cagccagaag gacctcctgg 13380 agcagaagcg gggccgggtg gacaactact gcagacacaa ctacggggtt gtggagagct 13440 tcacagtgca gcggcgaggt gagcgcggcg cggggcgggg cctgagtccc tgtgagctgg 13500 gaatctgagt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgagagaga gagacagaga 13560 gacagagaga gagagcgcca tctgtgagca tttagaatcc tctctatcct gagcaaggag 13620 ttctgagggc acaggtgtgt gtgtagagtg tggatttgtc tgtgtctgtg aggctgttgt 13680 gggaggggag gcaggagggg gctgcttctt attcttggag gactctgtgg ggaggtgaca 13740 agggaggtgg gtgcgggcgg ctggagagag aggtgacctt gattgtctcg ggtccttaga 13800 gatgcaggga agggaaatgt aaggggtgtg tggttggggt gaaggtttag gggaggagag 13860 ctgaggggta aggaaggttt gggataatgt gaggaggcca gttccagact gtccctggca 13920 cacacccttc atgtaatctc tgaaataaaa gtgtgtgctg tttgtttgta aaagcattag 13980 attaatttct aggggaattg aggagacctc tgaggcatct ctgaagcttc tttaggtcta 14040 aatttcttgc tagttttttg ttttttattg tgtatatttt tacatagtag aaatgactgt 14100 gaaactaact ttttgaatta aagttttaac acagttacta ttttattata atgctaatag 14160 ttttctagta gttacatatt attcttttat atataatagt tgtgacacaa cttacctcac 14220 tttccccttt gttgaccttt attatgacat tcaccaaaat ttgaaaatgt atgtttctgg 14280 ttaattttta atttatattt ttttcattta taattctttt gaattatttt gacctattta 14340 ttggccagtt ttaataactg ctgtaagaat tccctattgt atttggtagg gaatggacaa 14400 tgatctactg cctaatatct cgagggctta gtatttttct cagtgacttt gtgggttctt 14460 tgtactgtga gattattaac actttattga tatttgattc agcatttgct ccagtttgtg 14520 gtttgtatgt tgattttgaa aattcttttc catgttaaga atttgaacat ttttatataa 14580 taaaatatgt tgcaaaattt ttattaatga tttacaatcc atcttaaatc tgccattttg 14640 tggtattgtt gtctccaggt ttctccttac ttctaaaaaa aattgcattt attgagagtc 14700 tgctagtgtt agggattttc ctgggcataa gcaccccaag tgacgagtcc cagacactgc 14760 cttaatccaa atgtgattct ggaaagaaaa atcattttac aatgataggc ctaataataa 14820 ttaagcttgt gttgcatggg agatgcattg atcagctaaa tgtaaatata agaactttca 14880 aaactaaaat gacgttcctt aatccttctc tctgctttat gactcatgct tttctgggaa 14940 agtaaaaatt tggagaatca tttctgtctg tcccaccttc ccaggggcag aaccatttct 15000 gtggtgttct aaggtgtgag tgcatggcgg tagtattcct aaaaattcat attcggtttc 15060 gtcatgtacc caactctgtc ccgttatcta tcaacattgt tttaaatcat atatttctgt 15120 caaggtgtac aaggatgata aataggtgcc aagtggagca cccaagtgtg atgagccccc 15180 tcacagtgga atggagtgtg aagctttatg acctcataaa ttgaaggtta tcttcaggca 15240 ttgttttata tattttacat gcattaatcc tcatataatc ccaagaggta aatttagtata 15300 attatccttc attataggtg acaaagttga gacacagaag aatcaaactc ttaaggcaga 15360 ccttggattt gaaccaggca acctggctca gatatcagtt ttaattacta cactctgtac 15420 tttcaaagat ttgtaaacac tttgacaatg catgacaatt tcaagctatg aagaaacaaa 15480 cacaattttt cacaatatct ctcaaatcta ataggtcctc actatcaaga ttaagttcca 15540 ggctgatgac actgtaaggc cacatggcca gctgtgctgg aggcctggtc aaggtcagag 15600 cctgggtttg cagagaagca gacaaacagc caaacaagga gacttactct gtcttcatga 15660 ctcattccct ctaccttttt tctcctagtc catcctaagg tgactgtgta tccttcaaag 15720 acccagcccc tgcagcacca taacctcctg gtctgttctg tgagtggttt ctatccaggc 15780 agcattgaag tcaggtggtt ccggaatggc caggaagaga agactggggt ggtgtccaca 15840 ggcctgatcc acaatggaga ctggaccttc cagaccctgg tgatgctgga aacagttcct 15900 cggagtggag aggtttacac ctgccaagtg gagcacccaa gcgtgacaag ccctctcaca 15960 gtggaatgga gtgagcagct ttctgacttc ataaatttct cacccaccaa gaaggggact 16020 gtgctcatcc ctgagtgtca ggtttctcct ctccgacatc ctattttcat ttgctccatg 16080 ttctcatctc catcagcaca ggtcactggg ggtagccctg taggtgtttc tagaaacacc 16140 tgtacctcct ggagaagcag tctcgcctgc caggcaggag aggctgtccc tcttttgaac 16200 ctccccatga tgtcacaggt cagggtcacc caccctcccc gggctccagg cactgcctct 16260 gggtctgaga ctgagtttct ggtgctgttg atctgagtta tttgttgtga tctgggaaga 16320 ggagaagtgt aggggccttc ctgacatgag gggagtccaa tctcagctct gccttttatt 16380 agctctgtca ctctagacaa actacttagc ctcattgagt ctcaggcttt ctgtggatca 16440 gatgttgaac tcttgcctta catcaaggct gtaatatttg aatgagtttg atgtctgaac 16500 cttgtaactg ttcagtgtga tttgaaatcc tttttttctc cagaaatggc tagttatttt 16560 agttcttgtg ggtcagactt cttccccatt ttcaaagctc tgaatcttag agtctcaatt 16620 aaagaggttc aatttggaat aaacactaaa cctggcttcc tctctcagga gcacggtctg 16680 aatctgcaca gagcaagatg ctgagtggag tcgggggctt tgtgctgggc ctgctcttcc 16740 ttggggccgg gctgttcatc tacttcagga atcagaaagg tgaggagcct ttggtagctg 16800 gctctctcca taggcttttc tggaggagga actatggctt tgctgaggtt agttctcagt 16860 atatgagtgg ccctgaataa agcctttctt tccccaaacg gctctaatgt cctgctaatc 16920 cagaaatcat cagtgcatgg ttactatgtg aaagcataat agcttgtggc ctgcagagac 16980 aagaggaagg ttaacaagta ggggtccttt ggtttgagat cttggagcag attaaggaag 17040 agccactaag actaatggaa ttacactgga tcctgtgaca gacactttac ccttcatggg 17100 tcacatggtc tgtttctgct cctctctgcc ctggctggtg tgggttgtag tgacagagaa 17160 ctctccggtg ggagatctgg ggctgggaca ttgtgttgga agacagattt gcttccataa 17220 attttaagtg tatatatttt cctctttttc ccaggacact ctggacttca gccaagaggt 17280 aatacctttt aatcctcttt tagaaacaga tacggtttcc ctagtgagag gtgaagccag 17340 ctggacttct gggtcgggta gggacttgca gaactttcct gtcttaggag aggtttctaa 17400 atgcaccaat cagtgctctg taaaaacaca ccaattggca ctctgtggct agatagatgt 17460 ttgtaaaatg gactaatcag cactctgtaa aatggagcaa tccacactct gtaaaatgga 17520 ccaatcaatg ctctttaaaa tggaccaatc agcaggacat gggcggggac aaataaggga 17580 atacaagctg gccaccccag ccagcagcag caacccgctc aggtcgcctt ccatgctgtg 17640 gaagctttgt tcttttgctc ttcacaataa atcttgctgt tgctcactct tcgggtctgt 17700 gccaccttta agagctgtaa cactcactgt gaagattcgc ggcttcattc ttgaagtcag 17760 cgaaaccacg aacccaccgg aaggaacaaa ctctggacac actagaattg atggtagagg 17820 tgataaggca tgagacagaa ataataggaa agactttgga tccaaatttc tgatcaggca 17880 atttacacca aaactcctcc tctccactta gaaaaggcct gtgctctgtg ggactattgg 17940 ctctgggaga ctcaggaact tgtttttctt cttcctgcag tgctctcatc tgagtccctg 18000 aaagagagga aaagaaactg ttagtagagt caggttgaaa acaacactct cctctgtctt 18060 ttgcaggatt cctgagctga agtgcagatg acacattcaa agaagaactt tctgccccag 18120 ctttgcagga tgaaaagctt tccctcctgg ctgttattct tccacaagag agggctttct 18180 caggacctgg ttgctactgg ttcagcaact gcagaaaatg tcctcccttg tggcttcctc 18240 agctcctgtt cttggcctga agccccacag ctttgatggc agtgcctcat cttcaacttt 18300 tgtgctcccc tttgcctaaa ccctatggcc tcctgtgcat ctgtactcac cctgtaccac 18360 aaacacatta cattattaaa tgtttctcaa agatggagtt aaatatcatc tggtccattt 18420 ggctccaaag acaaaaaatg aaaagaaaag aaaaagggaa ggaagattat ttcccaatag 18480 aataatgatt ttcatgtata tgtcatgagt atgtgaggta atgcatatgt aaaataactt 18540 gatttagaca ttccacacta taggcatata tcaaaacttc attctgtaca atataaatac 18600 actatacaat ttttacttgt caatcaaaaa agtaatccta atgtttaaaa aggcaatgca 18660 taaaaactga gaacagacta taacaactga aacaaacttg gcaaccatga gatgagaaac 18720 cagctagcaa gtcaatcaga actttttttc accccgtcta caatattttg tatttataac 18780 tgtaaattag tgtatagtgt ttcactccag agacttcaat aatatagtgt tatcaaagga 18840 cttgtacaga tttcagagaa agacaaattt agaagacgga ggattctcta ttatgtgcta 18900 tctgagagtc agtatgaaat gtcaaatcca aaagtacata atttagaggt ctatttcaaa 18960 gtaatcattt gagcatagtt tctccactgt cagagacgac tgttatttta ttttcaatca 19020 aattaaaact tgtttttatg catatcttat ttttagttat atgttacttg tacataagta 19080 gcagcacaat acatacatat aaaccctatg agtataaatc ctatagaaat atattaagtt 19140 gataattatg tctgttctgt ttgatcacag agttgcaaca aagaggcctc atttcctaag 19200 ttgaggaaat gattttctca ttttatatga gactcgtggt gtggaattac aaggtagaac 19260 caaaatgtgt ggaatgagta tttcagtgaa gatgtgttct gctgctaata acaggaaatt 19320 acatctagtg gctttatttt tctttaaccc attatctcac atagccgata gatccaaggc 19380 tgggcatctc cagggatgct caactcagca ggccagtgtc atcaccagtg atcctggaac 19440 ttcgtagctc atctctctat cacacacagc acgtcagctt tcctgagatg gtagggtgac 19500 ccatgcagca gctttaggtt tgttattcat tcacaacaac tcccaaaggc aggaaaagga 19560 tactcctttc tcctgtgtgc ctttataagg agcaactaaa ctgtttccag agtgttccca 1920 gtacccactt tcttatacat tggaatgacc gtgggatcac acaggctcag acaagccagg 1980 attcaacctt tgtagagtgg gcctgatgca catgggaaga aaaggagcaa aatcatatat 197440 ttttaaaaac aaagaaatgg tggatggagt agcagagatt gatttcatca tagggaaatg 1800 atagattgtg gtactatcag gttgtaagta tttgagttaa cttccacacg aaggcctata 19860 gattcctgat aggcaccctc aattcagggc tttgggtctt tatacata cacacacaca 19920 cacacacaca cacgtatata tgtatatata ggtgtatata cacacacaca tatagagagt 19980 attaaatgtc agccattaac tcaattacaa tcaaacaaaa aagcaaacag aattgttttt 20040 agaactcaat ttatgctgac atgttatttt atgaggtaaa tgtattttcc agggaaattg 20100 aaaaaaaagt agaataagga atgactagct ctataaagct ctaaaacata ctatacattt 20160 acttttaaaa atgcatttgt aactgctttt ttttaaatta aatatgctag taagacagag 20220 tctagaatta gaaacagagt tgagatttag tttcagtttt tgtaagttgt attccaaact 20280 catttctttc actaaataaa tcctggataa ataaaacttg aaacataaag agaaaatata 20340 aaattcacaa gacagatgtt atttctaata ctatcatcat cattataatt atgtttgaag 20400 aca 20403
Claims (11)
A composition for diagnosing asthma comprising a detection agent of GeneBank SNP database rs1770, which is a single nucleotide polymorphism (SNP) site on chromosome 6.
상기 천식은 한국인에 대한 천식인 것을 특징으로 하는, 진단용 조성물.
According to claim 1,
The asthma is a composition for diagnosis, characterized in that the asthma for Koreans.
상기 검출 제제는 rs1770을 검출할 수 있는 프로브인 것을 특징으로 하는, 진단용 조성물.
According to claim 1,
The detection agent is a probe capable of detecting rs1770, a diagnostic composition.
상기 검출 제제는 rs1770을 검출할 수 있는 프라이머인 것을 특징으로 하는, 진단용 조성물.
According to claim 1,
The detection agent is a diagnostic composition, characterized in that the primer capable of detecting rs1770.
A kit for predicting or diagnosing asthma, comprising the composition of claim 1.
상기 키트는 RT-PCR 키트 또는 마이크로어레이 칩 키트인 것을 특징으로 하는, 키트.
6. The method of claim 5,
The kit is an RT-PCR kit or a microarray chip kit, characterized in that the kit.
If the GeneBank SNP database rs1770, a single nucleotide polymorphism (SNP) site on chromosome 6, exists in the nucleotide sequence of the SNP site in the sample obtained from the subject, the step of determining that the subject is an asthma patient or has a high risk of contracting asthma A method of providing information necessary for diagnosing or predicting asthma, including
상기 방법은 시퀀싱(sequencing), 엑솜 시퀀싱(exome sequencing), 마이크로어레이에 의한 혼성화(microarray hybridization), 대립유전자 특이적인 PCR(allele specific PCR), 다이나믹대립유전자 혼성화 기법(dynamic allele-specific hybridization), PCR 연장 분석 및 Taqman 기법으로 이루어진 군으로부터 선택되는 하나 이상의 방법으로 수행되는 것을 특징으로 하는, 방법.
8. The method of claim 7,
The method includes sequencing, exome sequencing, microarray hybridization, allele specific PCR, dynamic allele-specific hybridization, and PCR. Method according to any one of the preceding claims, characterized in that it is performed by at least one method selected from the group consisting of extension analysis and Taqman technique.
상기 조성물은 rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593으로 이루어진 군으로부터 선택된 하나 이상의 SNP의 검출 제제를 추가로 포함하는 것을 특징으로 하는, 진단용 조성물.
According to claim 1,
The composition further comprises an agent for detecting one or more SNPs selected from the group consisting of rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 and rs17426593.
상기 키트는 rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593으로 이루어진 군으로부터 선택된 하나 이상의 SNP의 검출 제제를 추가로 포함하는 것을 특징으로 하는, 키트.
6. The method of claim 5,
The kit further comprises a detection agent for one or more SNPs selected from the group consisting of rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 and rs17426593.
상기 방법은 rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 및 rs17426593로 이루어진 군으로부터 선택된 하나 이상의 단일염기다형성이 존재하는 경우, 피검체가 천식 환자이거나 천식에 걸릴 위험이 높은 것으로 결정하는 단계를 추가로 포함하는 것을 특징으로 하는, 방법.
8. The method of claim 7,
The method comprises a method comprising at least one mononucleotide polymorphism selected from the group consisting of rs9273508, rs9272998, rs9271469, rs9272221, rs9272254, rs118008956, rs117477741, rs117552038, rs11545686, rs117316263, rs35789108 and rs17426593 when the subject has asthma or has asthma. and determining that the risk is high.
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Non-Patent Citations (5)
| Title |
|---|
| Advances in Genomics and Genetics (2015) 5:107-119* * |
| Allergy Asthma and Immunology Research (2021) 13(4):609-622 * |
| American Journal of Respiratory Cell and Molecular Biology (2006) 35:488-495* * |
| G3 Genes|Genomes|Genetics (2016) 6:2043-2050* * |
| Korean Journal of Internal Medicine (2016) 31(2):375-385 * |
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