KR101141543B1 - Polynucleotides derived from ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes comprising single nucleotide polymorphisms, microarrays and diagnostic kits comprising the same, and analytic methods using the same - Google Patents
Polynucleotides derived from ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes comprising single nucleotide polymorphisms, microarrays and diagnostic kits comprising the same, and analytic methods using the same Download PDFInfo
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Abstract
본 발명은 1번 또는 2번 염색체 상에 위치하는 ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, 및 MAP2 유전자로부터 유래된 단일염기다형(Single-Nucleotide Polymorphism; SNP)을 포함하는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 제공하며, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드는 장형 위암(Intestinal type of gastric cancer) 의 임상적 진단의 표지 인자로서, 사용될 수 있다.The present invention relates to single-nucleotide polymorphisms (SNPs) derived from ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes located on chromosome 1 or 2. It provides a polynucleotide comprising or a complementary polynucleotide thereof, the polynucleotide or a complementary polynucleotide thereof may be used as a labeling factor of the clinical diagnosis of Intestinal type of gastric cancer.
ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, MAP2, 장형 위암 ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, MAP2, Enteric Gastric Cancer
Description
본 발명은 1번 또는 2번 염색체 상에 위치하는 ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, 및 MAP2 유전자로부터 유래된 단일염기다형을 포함하는 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드; 상기 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드로 이루어진 장형 위암(intestinal type of gastric cancer) 진단을 위한 증폭용 프라이머 또는 장형 위암 진단용 프로브; 상기 프로브를 포함하는 마이크로어레이; 및 상기 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드를 이용한 장형 위암 진단에 필요한 정보를 제공하기 위한 분석 방법에 관한 것이다.The present invention provides polynucleotides or their complements comprising monobasic polymorphisms derived from ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes located on
인간의 게놈은 모두 22쌍의 상동 염색체와 두 개의 성염색체로 이루어져 있다. 그러나 모든 인간이 각기 다른 외모와 성격을 갖는다. 이는 개개인이 같은 수의 염색체를 가지고 있기는 하지만, 그 염색체로부터 발현되는 유전자들에 의한 표현형이 모두 다르기 때문이다. 개개인의 이러한 유전자 발현의 다양성은 곧 유전자를 가지고 있는 게놈의 유전적 다양성 때문이다. 이러한 유전적 다양성은 많은 연구가 수행되어 왔으며, 최근 인간게놈프로젝트의 완성으로 그 구조가 모두 밝혀졌다. The human genome consists of 22 pairs of homologous chromosomes and two sex chromosomes. But every human being has a different appearance and character. This is because each person has the same number of chromosomes, but all of the phenotypes of the genes expressed from that chromosome are different. The diversity of these gene expressions in individuals is due to the genetic diversity of the genome carrying the gene. Much research has been done on this genetic diversity, and the structure of the genetic genome has recently been revealed.
게놈에서의 유전적 다양성을 대표하는 것으로는 Transposable element, STR (short tandem repeats), Microsatellites, STS (sequence tagged site), VNTR (variable number tandem repeat), SNP (single nucleotide polymorphism : 단일염기다형) 등이 알려져 있다. 이중 SNP는 단일염기다형으로서, 인간 게놈 상에서 약 1000개의 뉴클레오티드 중 1개의 빈도로 나타나며 동일한 종의 개체 사이의 단일뉴클레오티드 변이의 형태를 취한다. 이러한 단일염기다형이 나타내는 유전학에서의 의미는 그 위치에 따라 각 개체에 큰 차이를 가져온다. 예를 들면, 단일염기다형이 단백질을 암호화하고 있는 위치에 존재할 경우, 단백질의 구조에 영향을 미칠 수 있게 되어 단백질 기능이 달라질 수 있게 되며, 질병과도 연관될 수 있다. 다른 예로 단일염기다형이 단백질을 암호화하지 않는 다른 유전자상에서 존재할 경우, 즉 프로모터(promoter) 또는 인트론(intron)에 존재할 경우, 각각에 대하여 단백질의 발현 수준에 차이를 가져와 그 단백질의 전체적인 활성이 줄어들 수 있고, 변성적인 인트론 제거 과정(alternative splicing)을 통하여 단백질이 비정상적으로 발현 될 수도 있다. Genetic diversity in the genome is represented by transposable elements, short tandem repeats (STRs), microsatellites, sequence tagged sites (STS), variable number tandem repeats (VNTRs), and single nucleotide polymorphisms (SNPs). Known. Dual SNPs are monobasic, appearing at a frequency of about one thousand nucleotides on the human genome and taking the form of single nucleotide variations between individuals of the same species. The meaning in the genetics represented by these monobasic polymorphisms makes a big difference in each individual depending on its location. For example, when a monobasic polymorph is present at a location that encodes a protein, it may affect the structure of the protein, altering protein function and associated with disease. In another example, if a monobasic polymorph is present on another gene that does not encode a protein, ie, on a promoter or intron, the expression level of the protein may differ for each, resulting in a decrease in the overall activity of the protein. In addition, the protein may be abnormally expressed through alterative splicing.
단일염기다형들은 질병과 같은 특정 표현형(phenotype)의 지표로 사용될 수 있고, 이를 위해서는 가장 우선적으로 인간 유전체에 존재하는 대량의 단일염기다형을 발굴하고 발굴된 단일염기다형은 다수의 인간 유전체 시료에서 전체 인간집단의 1% 이상 존재하는 유전변이형 마커인지를 조사하는 검정작업을 거치게 된다. 검정된 SNP은 특정 질병 또는 약물반응과 같은 유전적 차이에 기인된 원인을 찾기 위한 연관성 연구에 사용되게 된다. 예를 들면, 특정 단일염기다형이 환자군과 대조군 간의 비교에서 유의적인 빈도의 차이가 관측된다면 아주 유용한 단일염기다형으로 선발되어 임상실험을 거치게 될 것이며 임상실험의 결과가 계속적으로 진행되어 그 결과가 좋을 때는 경제적으로 아주 유용한 가치를 지니는 유전지표로 실제 임상에 사용할 수 있게 될 것이다.Single base polymorphisms can be used as an indicator of a specific phenotype such as disease. To do this, first of all, a large number of single base polymorphisms present in the human genome are identified and the single base polymorphism is found in a number of human genome samples. An assay will be conducted to determine whether the genetic marker is present in more than 1% of the human population. Assayed SNPs will be used in association studies to find the cause due to genetic differences such as specific diseases or drug responses. For example, if a single base polymorphism is found to be significantly different in the comparison between the patient and control group, it will be selected as a very useful single base polymorphism and subjected to clinical trials. It is a genetic indicator of economically useful value and will be available for actual clinical use.
이러한 단일염기다형의 발견을 위한 종래 기술로는 제한효소를 이용한 제한 단편화 길이 다형성(Restriction Fragment Length Polymorphism; RFLP), 대립형질 특이적 혼성화(Allele-specific hybridization)를 이용한 TaqManTM 프로브 방법, 용융온도(melting temperature; Tm)을 이용한 역동적 대립형질 특이적 혼성화(Dynamic Allele-Specific Hybridization; DASH)방법, 중합반응을 이용한 pyrosequencing등이 있다. 최근, 마이크로어레이 기술은 단일 염기 신장(Single Base Extension), 또는 대립인자 특이적 프라이머 신장(Allele Specific Primer Extension)이라는 원리를 이용한 프로브들을 조그만 기판위에 집적화시켜 심은 후, 목적 DNA들과의 혼성화와 신장(Extension)을 시킴으로써 단일염기다형을 발견해 내고 있다. Conventional techniques for the discovery of such monobasic polymorphisms include Restriction Fragment Length Polymorphism (RFLP) using restriction enzymes, TaqMan ™ probe method using Allele-specific hybridization, and melting temperature ( dynamic allele-specific hybridization (DASH) using melting temperature (Tm) and pyrosequencing using polymerization. Recently, microarray technology has integrated and planted probes on a small substrate using the principle of Single Base Extension or Allele Specific Primer Extension, and then hybridized and stretched with target DNAs. Single base polymorphisms are found by extension.
한편, 위암의 발생률과 사망률은 감소하고 있으나, 아직도 전 세계에서 두 번째로 많이 발생하는 악성 종양이다. 우리나라의 경우, 남성과 여성에서의 암 발생률은 위암이 1위를 차지하고 사망률의 경우 2위를 차지한다. 위암과 깊게 관련되는 Helicobacter pylori (H. pylori) 감염은 사람에서 가장 흔한 만성 감염으로서 전 세계 인구의 50% 이상이 감염되어 있다. 우리나라의 H. pylori 감염률은 전 국민에서 46.6%, 16세 이상의 성인에서는 69.4%, 40대 에서는 78.5% 라는 높은 감염률을 보인다. 위암은 로렌 분류법(Lauren classification) 에 의해 장형 위암(Intestinal type of gastric cancer) 과 미만형 위암(Diffuse type of gastric cancer)로 분류 된다. 장형 위암은 H. pylori 감염과 관련되어 만성 위염(chronic gastritis), 위축성 위염(atrophic gastritis), 장상피화생(intestinal metaplasia), 이형성증(displasia), 장형 위암(Intestinal type of gastric cancer)의 순서로 진행된다. 반면 미만형 위암은 정상적인 점막으로 부터 H. pylori 감염과 관계없이 유발 될 수 있다. 우리나라에서 H. pylori 감염률이 높다는 것은 장형 위암에 대한 위험이 높다는 것을 의미 한다. The incidence and mortality rate of gastric cancer is decreasing, but it is still the second most common malignancy in the world. In Korea, the incidence of cancer in men and women is ranked first in gastric cancer and second in mortality. Helicobacter pylori (H. pylori) infection, which is closely related to gastric cancer, is the most common chronic infection in humans, affecting more than 50% of the world's population. The prevalence of H. pylori infection in Korea is high at 46.6%, 69.4% in adults over 16 years old, and 78.5% in 40s. Gastric cancer is classified into Intestinal type of gastric cancer and Diffuse type of gastric cancer by Lauren classification. Enteric gastric cancer is associated with H. pylori infection in the order of chronic gastritis, atrophic gastritis, intestinal metaplasia, displasia, and intestinal type of gastric cancer. do. Diffuse gastric cancer, on the other hand, can be induced from normal mucous membranes regardless of H. pylori infection. A high H. pylori infection rate in Korea means a high risk for intestinal gastric cancer.
조기 위암은 5년 생존률이 95～100%로 높지만 증상을 나타내지 않는 경우가 80% 를 차지한다. 이는 조기 진단의 중요성과 함께 적절한 조기 진단법의 개발이 필요함을 뜻한다. H. pylori 감염된 100명 중 1～2명에서만 위암이 발생하기 때문에 H. pylori 감염만으로 위암 발생 위험군으로 판단 내리는 것은 적합하지 않다. 위암의 전 단계에 속하는 만성 위염 환자 사이에서 장형 위암이 발생할 위험성이 있는 사람을 미리 예측하는 것과 위암 발생에 관여하는 인자를 규명하는 것은 국민 보건에 중요하며 위암을 예방하기 위한 검사의 필수 요건이다. 장형 위암에 특이적으로 나타날 수 있는 단일염기다형을 찾아내는 것은 장형 위암을 조기에 진단할 수 있으며, 더 나아가 병태생리학적 경로를 밝히고 치료 방법을 개발하는데까지 이용될 수 있을 것이다.Early gastric cancer has a 5-year survival rate of 95 to 100%, but 80% of the cases show no symptoms. This implies the need for early diagnosis, along with the importance of early diagnosis. Since only 1 or 2 of 100 H. pylori infections develop gastric cancer, it is not appropriate to determine H. pylori infection as a risk group for gastric cancer. Predicting the risk of developing gastrointestinal cancer among patients with chronic gastritis at all stages of gastric cancer and identifying the factors involved in the development of gastric cancer is important for public health and is an essential requirement for tests to prevent stomach cancer. Identifying monobasic polymorphisms that may be specific to enteric gastric cancer can be used to diagnose early gastric cancer and further develop pathophysiological pathways and develop therapeutic methods.
본 발명자들은 한국인의 장형 위암 환자에서 특이적으로 나타나는 단일염기다형을 찾아내고자 연구를 거듭한 결과, 1번 또는 2번 염색체 상에 위치하는 ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, 및 MAP2 유전자로부터 장형 위암환자에 특이적으로 나타나는 단일염기다형 부위를 발견하여 본 발명을 완성하게 되었다. The present inventors conducted a study to find a single nucleotide polymorphism that appears specifically in Korean patients with gastric cancer of the stomach. As a result, ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, and PSME4 located on
따라서, 본 발명은 장형 위암과 관련된 단일염기다형으로서 ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, 및 MAP2 유전자로부터 유래된 단일염기다형을 포함하는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 제공하는 것을 목적으로 한다.Accordingly, the present invention provides polynucleotides or their complements comprising monobasic polymorphisms derived from the ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes as monobasic polymorphisms associated with enteric gastric cancer. It is an object to provide red polynucleotides.
또한, 본 발명은 상기 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드로 이루어진 장형 위암 진단을 위한 증폭용 프라이머 또는 장형 위암 진단용 프로브를 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide an amplification primer for diagnosing enteric gastric cancer or a probe for diagnosing enteric gastric cancer comprising the polynucleotide or its complementary nucleotides.
또한, 본 발명은 상기 프로브를 포함하는 마이크로어레이를 제공하는 것을 목적으로 한다.Another object of the present invention is to provide a microarray including the probe.
또한, 본 발명은 상기 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드를 이용한 장형 위암 진단 방법을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a method for diagnosing enteric gastric cancer using the polynucleotide or its complementary nucleotide.
본 발명의 일 태양에 따라, ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, 및 MAP2 유전자로부터 유래된 특정 단일염기다형을 포함하는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드가 제공된다.According to one aspect of the invention, a polynucleotide comprising a single monopolymorph derived from ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes or complementary polynucleotides thereof Is provided.
또한, 본 발명의 다른 태양에 따라, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진, 장형 위암 진단을 위한 증폭용 프라이머가 제공된다.In addition, according to another aspect of the present invention, an amplification primer for diagnosing enteric gastric cancer, comprising the polynucleotide or a complementary polynucleotide thereof, is provided.
또한, 본 발명의 다른 태양에 따라, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진, 장형 위암 진단용 프로브 및 이를 포함한 마이크로어레이가 제공된다.In addition, according to another aspect of the present invention, there is provided a enteric gastric cancer diagnostic probe and a microarray comprising the polynucleotide or a complementary polynucleotide thereof.
또한, 본 발명의 다른 태양에 따라, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 포함하는 장형 위암 진단용 키트가 제공된다.In addition, according to another aspect of the present invention, there is provided a kit for diagnosing enteric gastric cancer comprising the polynucleotide or a complementary polynucleotide thereof.
또한, 본 발명의 다른 태양에 따라, 장형 위암 진단에 필요한 정보를 제공하기 위하여, (i) 검체로부터 핵산 시료를 얻는 단계; 및 (ii) 상기 핵산 시료로부터, 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 폴리뉴클레오티드로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드의 다형성 부위의 염기 서열을 분석하는 단계를 포함하는, 검체 중의 단일염기다형을 검출하는 방법이 제공된다.In addition, according to another aspect of the invention, to provide information necessary for the diagnosis of enteric gastric cancer, (i) obtaining a nucleic acid sample from a sample; And (ii) at least one polynucleotide selected from the nucleic acid sample from the polynucleotides of SEQ ID NOs: 1 to 3, 10, 14 to 23, 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 Or analyzing a nucleotide sequence of a polymorphic site of the complementary polynucleotide thereof.
또한, 본 발명의 다른 태양에 따라, 장형 위암 진단에 필요한 정보를 제공하기 위하여, (i) 검체로부터 핵산 시료를 얻는 단계 및 (ii) 상기 핵산 시료로부터, 반수체형의 분석을 포함하는 것을 특징으로 하는, 검체 중의 단일염기다형을 검출하는 방법이 제공된다.Further, according to another aspect of the present invention, in order to provide information necessary for diagnosing enteric gastric cancer, (i) obtaining a nucleic acid sample from a sample, and (ii) analyzing the haplotype from the nucleic acid sample A method for detecting a monobasic polymorph in a sample is provided.
본 발명에 따른 폴리뉴클레오티드 (a) 내지 (am)으로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드는 장형 위암의 진단에 유용하게 사용될 수 있다.One or more polynucleotides selected from the group consisting of polynucleotides (a) to (am) according to the present invention or complementary nucleotides thereof may be usefully used for the diagnosis of enteric gastric cancer.
또한, 상기 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드로 이루어진 프라이머 또는 프로브, 및 상기 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드를 포함하는 키트는 장형 위암의 진단에 유용하게 사용될 수 있다.In addition, a primer or probe consisting of the polynucleotide or its complementary nucleotides, and a kit comprising the polynucleotide or the complementary nucleotides thereof, may be usefully used for the diagnosis of enteric gastric cancer.
또한 본 발명의 분석방법은 장형 위암 진단에 필요한 정보를 제공하는데 유용하게 사용될 수 있다.In addition, the analysis method of the present invention can be usefully used to provide information necessary for diagnosing gastric cancer.
본 발명은 장형 위암과 관련된 것으로 새롭게 밝혀진 ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, 및 MAP2 유전자로부터 유래하는 하기 폴리뉴클레오티드 (a) 내지 (am)로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 제공한다. 즉, 본 발명은 서열번호 1의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 C이고, 상기 401번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (a); 서열번호 2의 DNA 서열로 구성된 폴리뉴클레오티드에서, 281번째 염기(다형성 부위)가 C이고, 상기 281번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (b); 서열번호 3의 DNA 서열로 구성된 폴리뉴클레오티드에서, 341번째 염기(다형성 부위)가 T이고, 상기 341번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (c); 서열번호 10의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 A이고, 상기 401번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (d); 서열번호 14의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (e); 서열번호 15의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 T이고, 상기 401번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (f); 서열번호 16의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 T이고, 상기 401번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (g); 서열번호 17의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 C이고, 상기 201번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (h); 서열번호 18의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 T이고, 상기 301번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (i); 서열번호 19의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 A고, 상기 401번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (j); 서열번호 20의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 C이고, 상기 401번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (k); 서열번호 21의 DNA 서열로 구성된 폴리뉴클 레오티드에서, 301번째 염기(다형성 부위)가 C이고, 상기 301번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (l); 서열번호 22의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (m); 서열번호 23의 DNA 서열로 구성된 폴리뉴클레오티드에서, 437번째 염기(다형성 부위)가 T이고, 상기 437번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (n); 서열번호 25의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 C이고, 상기 201번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (o); 서열번호 26의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 T이고, 상기 201번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (p); 서열번호 27의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 A이고, 상기 301번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (q); 서열번호 28의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 T이고, 상기 201번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (r); 서열번호 29의 DNA 서열로 구성된 폴리뉴클레오티드에서, 222번째 염기(다형성 부위)가 G이고, 상기 222번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (s); 서열번호 30의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 A이고, 상기 251번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리 뉴클레오티드 (t); 서열번호 31의 DNA 서열로 구성된 폴리뉴클레오티드에서, 441번째 염기(다형성 부위)가 C이고, 상기 441번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (u); 서열번호 32의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 C이고, 상기 251번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (v); 서열번호 33의 DNA 서열로 구성된 폴리뉴클레오티드에서, 491번째 염기(다형성 부위)가 C이고, 상기 491번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (w); 서열번호 34의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 C이고, 상기 301번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (x); 서열번호 37의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 C이고, 상기 501번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (y); 서열번호 40의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 C이고, 상기 201번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (z); 서열번호 45의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (aa); 서열번호 46의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (ab); 서열번호 48의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번 째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (ac); 서열번호 49의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 T이고, 상기 201번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (ad); 서열번호 50의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 C이고, 상기 301번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (ae); 서열번호 51의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 C이고, 상기 201번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (af); 서열번호 52의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 T이고, 상기 401번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (ag); 서열번호 53의 DNA 서열로 구성된 폴리뉴클레오티드에서, 61번째 염기(다형성 부위)가 T이고, 상기 61번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (ah); 서열번호 55의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 A이고, 상기 251번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (ai); 서열번호 56의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 T이고, 상기 251번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (aj); 서열번호 57의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 A이고, 상기 401번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (ak); 서열번호 58의 DNA 서열로 구성된 폴리뉴클레오티드에서, 101번째 염기(다형성 부위)가 C이고, 상기 101번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (al); 및 서열번호 59의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10개 이상의 연속 DNA 서열로 구성되는 폴리뉴클레오티드 (am)으로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 제공한다.The present invention is from the group consisting of the following polynucleotides (a) to (am) derived from the ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes newly found to be associated with enteric gastric cancer One or more selected polynucleotides or complementary polynucleotides thereof are provided. That is, the present invention provides a polynucleotide consisting of the DNA sequence of SEQ ID NO: 1, wherein the 401th base (polymorphic site) is C, the polynucleotide consisting of 10 or more consecutive DNA sequences comprising the 401th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 2, a polynucleotide (b) consisting of at least 10 consecutive DNA sequences comprising the 281 th base (polymorphic site) is C and comprising the 281 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 3, a polynucleotide (c) consisting of ten or more consecutive DNA sequences comprising the 341th base of T and the 341th base (polymorphic site); A polynucleotide consisting of the DNA sequence of SEQ ID NO: 10, wherein the 401th base (polymorphic site) is A and is composed of 10 or more consecutive DNA sequences comprising the 401th base (d); In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 14, a polynucleotide consisting of ten or more consecutive DNA sequences comprising the 301th base (polymorphic site) G and comprising the 301th base (e); A polynucleotide consisting of the DNA sequence of SEQ ID NO: 15, wherein the 401th base (polymorphic site) is T and the polynucleotide (f) consists of 10 or more consecutive DNA sequences comprising said 401th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 16, a polynucleotide (g) consisting of ten or more consecutive DNA sequences comprising the 401 th base (T polymorphic site) is T and the 401 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 17, a polynucleotide (h) consisting of ten or more consecutive DNA sequences comprising the 201 base, wherein the 201 th base (polymorphic site) is C; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 18, the polynucleotide (i) consisting of ten or more consecutive DNA sequences comprising the 301 th base (polymorphic site) is T and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 19, a polynucleotide (j) consisting of ten or more contiguous DNA sequences comprising the 401 th base, wherein the 401 th base (polymorphic site) is A; In a polynucleotide consisting of a DNA sequence of SEQ ID NO: 20, a nucleotide of base 401 (polymorphism site) is C and a polynucleotide (k) consisting of 10 or more contiguous DNA sequences comprising the 401 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 21, a polynucleotide (l) consisting of 10 or more consecutive DNA sequences comprising the 301 th base (polymorphic site) is C and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 22, a polynucleotide consisting of 10 or more consecutive DNA sequences comprising the 301th base (polymorphic site) G and comprising the 301th base (m); A polynucleotide consisting of the DNA sequence of SEQ ID NO: 23, wherein the 437th base (polymorphic site) is T and the polynucleotide (n) is composed of 10 or more consecutive DNA sequences comprising the 437th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 25, wherein the 201 base (polymorphic site) is C and a polynucleotide (o) consisting of 10 or more consecutive DNA sequences comprising said 201 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 26, a polynucleotide (p) consisting of ten or more contiguous DNA sequences comprising the 201 base, wherein the 20th base (polymorphic site) is T; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 27, the polynucleotide (q) consisting of 10 or more consecutive DNA sequences comprising the 301th base (polymorphic site) is A and the 301th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 28, wherein the 201 base (polymorphic site) is T and the polynucleotide (r) consists of 10 or more consecutive DNA sequences comprising said 201 base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 29, wherein the 222nd base (polymorphic site) is G and the polynucleotide (s) is composed of 10 or more consecutive DNA sequences comprising the 222nd base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 30, wherein the 251 th base (polymorphic site) is A and the poly nucleotide (t) consists of 10 or more consecutive DNA sequences comprising said 251 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 31, a polynucleotide (u) consisting of 10 or more consecutive DNA sequences comprising the 441 th base (polymorphic site) is C and comprising the 441 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 32, a polynucleotide (v) consisting of ten or more consecutive DNA sequences comprising the 251 st base (polymorphic site) C and comprising the 251 st base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 33, wherein the 491th base (polymorphic site) is C and a polynucleotide (w) consisting of 10 or more consecutive DNA sequences comprising said 491th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 34, wherein the 301th base (polymorphic site) is C and the polynucleotide (x) consists of 10 or more consecutive DNA sequences comprising said 301th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 37, wherein the 501th base (polymorphic site) is C, and the polynucleotide (y) is composed of 10 or more consecutive DNA sequences comprising the 501th base; A polynucleotide consisting of a DNA sequence of SEQ ID NO: 40, wherein the 201 base (polymorphic site) is C and a polynucleotide (z) consisting of 10 or more consecutive DNA sequences comprising said 201 base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 45, wherein the 201 base (polymorphic site) is A and is composed of 10 or more consecutive DNA sequences comprising the 201 base (aa); In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 46, the nucleotide 301 (polymorphic site) is G and a polynucleotide (ab) consisting of 10 or more consecutive DNA sequences comprising the 301 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 48, a polynucleotide (ac) consisting of 10 or more consecutive DNA sequences comprising the 301th base (polymorphic site) G and comprising the 301th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 49, wherein the 201 base (polymorphic site) is T and the polynucleotide (ad) consists of 10 or more consecutive DNA sequences comprising said 201 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 50, the polynucleotide (ae) consisting of 10 or more consecutive DNA sequences comprising the 301 th base (polymorphic site) is C and comprising the 301 th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 51, wherein the 201 base (polymorphic site) is C and a polynucleotide (af) consisting of 10 or more consecutive DNA sequences comprising said 201 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 52, a nucleotide of base 401 (polymorphic site) is T, the polynucleotide consisting of 10 or more contiguous DNA sequences comprising the 401 base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 53, wherein the 61 st base (polymorphic site) is T and the polynucleotide (ah) consists of 10 or more consecutive DNA sequences comprising the 61 st base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 55, wherein the 251 st base (polymorphic site) is A and is composed of 10 or more contiguous DNA sequences comprising the 251 st base (ai); A polynucleotide consisting of the DNA sequence of SEQ ID NO: 56, wherein the 251 st base (polymorphic site) is T and the polynucleotide (aj) consists of 10 or more contiguous DNA sequences comprising the 251 st base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 57, wherein the 401th base (polymorphic site) is A and is composed of 10 or more consecutive DNA sequences comprising the 401th base (ak); In a polynucleotide composed of a DNA sequence of SEQ ID NO: 58, a 101 nucleotide (polymorphic site) is C and a polynucleotide (al) composed of 10 or more consecutive DNA sequences comprising the 101 nucleotide; And a polynucleotide consisting of the DNA sequence of SEQ ID NO: 59, wherein the 201 base (polymorphic site) is A and a polynucleotide (am) consisting of 10 or more consecutive DNA sequences comprising the 201 base Provided above is a polynucleotide selected or complementary polynucleotides thereof.
상기 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 DNA 서열은 만성 위염 환자군과 장형 위암 환자군에서 통계학적으로 유의성 있는 차이(유의수준 p value < 0.05)를 보이는 단일염기다형으로서, 이들은 1번 또는 2번 염색체 상에 위치하는 ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, 또는 MAP2 유전자에 존재한다.The DNA sequences of
본 발명자들은 장형 위암과 관련된 후보 유전자군으로서 1번 또는 2번 염색체 상에 위치하는 ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, 및 MAP2 유전자를 선정하여, 장형 위암 진단에 있어서 분자 수준에서의 진단 지표를 개발하고자 다양한 연구를 수행하였다. 본 발명자들은 한국인 만성 위염 환자 326명과 장형 위암 환자 153명을 대상으로 유전자형 분석 및 통계학적 분석을 수행하였으며, 놀랍게도 수많은 단일염기다형 중 극히 일부의 단일염기다형만이 만성 위염 환자군과 장형 위암 환자군에서 통계적으로 유의성 있는 차이를 나타낸다는 것을 발견하였다. 특히, 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 단일염기다형은 하디-와인버 그 평형 (Hardy-Weinberg Equilibrium) 및 로지스틱 회기분석 결과, 각각의 다형성 부위에 위험대립인자가 존재함을 확인하였다.We selected ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes located on
본 발명은 상기 폴리뉴클레오티드 (a) 내지 (am)으로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드와 혼성화하는 폴리뉴클레오티드를 포함하며, 상기 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드의 길이는 10 내지 100 뉴클레오티드, 바람직하게는 20 내지 60 뉴클레오티드, 더욱 바람직하게는 40 내지 60 뉴클레오티드이다. The present invention includes a polynucleotide hybridizing with at least one polynucleotide selected from the group consisting of the polynucleotides (a) to (am) or complementary nucleotides thereof, and the length of the polynucleotide or the complementary nucleotides thereof is 10 to 100. Nucleotides, preferably 20 to 60 nucleotides, more preferably 40 to 60 nucleotides.
본 발명에 따른 상기 폴리뉴클레오티드 (a) 내지 (am)으로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드는 다형성 서열이다. 다형성 서열 (polymorphic sequence)이란 뉴클레오티드 서열 중에 단일염기다형을 나타내는 다형성 부위 (polymorphic site)를 포함하는 서열을 말한다. 다형성 부위 (polymorphic site)란 다형성 서열 중 단일염기다형이 일어나는 부위를 말한다. 상기 폴리뉴클레오티드는 DNA 또는 RNA가 될 수 있다.At least one polynucleotide selected from the group consisting of the polynucleotides (a) to (am) according to the present invention is a polymorphic sequence. A polymorphic sequence refers to a sequence comprising a polymorphic site representing a monobasic polymorphism in a nucleotide sequence. A polymorphic site refers to a site where a monobasic polymorphism occurs in the polymorphic sequence. The polynucleotide can be DNA or RNA.
본 발명은 또한, 상기 폴리뉴클레오티드 (a) 내지 (am)으로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진, 장형 위암 진단을 위한 증폭용 대립형질 특이적 프라이머를 포함한다. 여기서 "프라이머(primer)"란 적절한 버퍼 중의 적절한 조건 (예를 들면, 4개의 다른 뉴클레오시드 트리포스페이트(ATP,GTP,CTP,TTP) 및 DNA 폴리머라제) 및 적당한 온도 하에서 주형-지시 DNA 합성의 시작점으로서 작용할 수 있는 단일가닥 올리고뉴클레오티드를 말한다. 상기 프라이머의 적절한 길이는 사용 목적에 따라 달라질 수 있으나, 통상 10 내지 100, 바람직하게는 10 내지 80 뉴클레오티드이다. 짧은 프라이머 분자는 일반적으로 주형과 안정한 혼성체를 형성하기 위해서는 더 낮은 온도를 필요로 한다. 프라이머 서열은 주형과 완전하게 상보적일 필요는 없으나, 주형과 혼성화 할 정도로 충분히 상보적이어야 한다. 상기 프라이머는 3'-말단이 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 또는 55 내지 59의 단일염기다형과 정렬하는 것이 바람직하다. 상기 프라이머는 다형성 부위를 포함하는 표적 DNA에 혼성화하고, 상기 프라이머가 완전한 상동성을 보이는 대립형질 형태의 DNA에서 증폭을 개시한다. 이 프라이머는 반대편에 혼성화하는 제2 프라이머와 쌍을 이루어 사용된다. 증폭에 의하여 두 개의 프라이머로부터 산물이 증폭되고, 증폭된 산물만을 특이적으로 염색하여 시각화한다. 이는 특정 대립형질 형태가 존재한다는 것을 의미한다. 여기서 사용되는 대립형질 특이적 폴리뉴클레오티드들이 다른 변성화 과정을 거치게 되면, GoldenGate Assay 뿐만 아니라 다른 방법들에 의해서도 사용될 수 있다. The present invention also includes an allele specific primer for amplification for enteric gastric cancer, comprising at least one polynucleotide selected from the group consisting of the polynucleotides (a) to (am) or complementary polynucleotides thereof. “Primer” herein refers to the synthesis of template-directed DNA synthesis under appropriate conditions (eg, four different nucleoside triphosphates (ATP, GTP, CTP, TTP) and DNA polymerase) in a suitable buffer and at a suitable temperature. It refers to a single stranded oligonucleotide that can act as a starting point. The appropriate length of the primer may vary depending on the purpose of use, but is usually 10 to 100, preferably 10 to 80 nucleotides. Short primer molecules generally require lower temperatures to form stable hybrids with the template. The primer sequence need not be completely complementary to the template, but should be sufficiently complementary to hybridize with the template. It is preferred that the primer 3'-end is aligned with a single nucleotide polymorphism of SEQ ID NO: 1-3, 10, 14-23, 25-34, 37, 40, 45, 46, 48-53, or 55-59 . The primer hybridizes to the target DNA comprising the polymorphic site and initiates amplification in allelic form of DNA where the primer exhibits complete homology. This primer is used in pairs with a second primer that hybridizes to the other side. The product is amplified from two primers by amplification, and only the amplified product is specifically stained and visualized. This means that certain allelic forms exist. If the allele specific polynucleotides used herein undergo different denaturation processes, they can be used by other methods as well as GoldenGate Assay.
본 발명은 폴리뉴클레오티드 (a) 내지 (am)으로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진, 장형 위암 진단용 프로브 및 이를 포함하는 장형 위암 진단용 마이크로어레이를 포함한다. 또한, 본 발명은 폴리뉴클레오티드 (a) 내지 (am)으로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 포함하는, 장형 위암 진단용 키트를 포함한다.The present invention includes a probe for diagnosing enteric gastric cancer and a microarray for diagnosing enteric gastric cancer comprising the polynucleotide (a) to at least one selected from the group consisting of (am) or a complementary polynucleotide thereof. The present invention also includes a kit for diagnosing enteric gastric cancer, comprising a polynucleotide selected from the group consisting of polynucleotides (a) to (am) or complementary polynucleotides thereof.
본 발명은 또한 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59로 이루어진 군으로부터 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 주형으로 하는 프라이머 또는 프로브를 이용한 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59로 이루어진 군으로부터 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드의 단일염기다형의 분석방법으로서, 상기 단일염기다형은 폴리뉴클레오티드 (a) 내지 (am)으로 이루어진 군으로부터 선택된 DNA 서열(단, 상기 폴리뉴클레오티드 (a) 내지 (am)은 상기에서 정의한 바와 같다)로 구성되는 것을 특징으로 하는 분석방법을 포함한다. 상기 분석 방법에서 상기 DNA 서열의 길이는 10 내지 100 뉴클레오티드, 바람직하게는 20 내지 60 뉴클레오티드, 더욱 바람직하게는 40 내지 60 뉴클레오티드일 수 있다.The invention also relates to a polynucleotide selected from the group consisting of SEQ ID NOs: 1 to 3, 10, 14 to 23, 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 or complementary polynucleotides thereof. Polynucleotides selected from the group consisting of SEQ ID NOs: 1 to 3, 10, 14 to 23, 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 using primers or probes as templates A method of analyzing monobasic polymorphism of red polynucleotides, wherein the monobasic polymorphism is selected from the group consisting of polynucleotides (a) to (am), provided that the polynucleotides (a) to (am) are defined above. An analysis method characterized in that the configuration). In the analysis method, the length of the DNA sequence may be 10 to 100 nucleotides, preferably 20 to 60 nucleotides, more preferably 40 to 60 nucleotides.
본 발명은 또한 장형 위암 진단에 필요한 정보를 제공하기 위하여, (i) 검체로부터 핵산 시료를 얻는 단계; 및 (ii) 상기 핵산 시료로부터, 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 폴리뉴클레오티드로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드의 다형성 부위의 염기 서열을 분석하는 단계를 포함하는, 검체 중의 단일염기다형을 검출하는 방법을 제공한다. 상기 검출 방법에 있어서, 상기 DNA 서열의 다형성 부위는 다음 표 1과 같다.The present invention also provides a method for diagnosing gastric cancer, comprising: (i) obtaining a nucleic acid sample from a sample; And (ii) at least one polynucleotide selected from the nucleic acid sample from the polynucleotides of SEQ ID NOs: 1 to 3, 10, 14 to 23, 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 Or analyzing the nucleotide sequence of the polymorphic site of the complementary polynucleotide thereof. In the detection method, the polymorphic sites of the DNA sequence are shown in Table 1 below.
상기 검체는 혈액, 조직, 세포 등을 포함하며, 핵산 시료는 통상의 방법에 따라 얻을 수 있다. 예를 들어 혈액에 경우 다음과 같이 핵산 시료를 얻을 수 있다. 혈액을 원심분리 실험관으로 옮기고 낮은 농도의 염 성분 완충용액(low-salt buffer solution(10mM Tris-HCl [pH 7.6], 10mM KCl, 10mM MgCl2, and 2mM EDTA))을 5ml 첨가한다. 그리고 Nonidet P-40을 첨가한 다음, 얻어진 용액을 잘 섞어준 후, 상온에서 10분간 2,200 rpm으로 원심분리한다. 이때 얻어진 덩어리는 고농도의 염 성분 완충용액(high-salt buffer solution(10mM Tris-HCl [pH 7.6], 10mM KCl, 10mM MgCl2, 0.4M NaCl, and 2mM EDTA))으로 재현탁한다. 게놈 DNA는 50ul의 10% SDS와 섞은 후, 55℃에서 밤새 반응시킨다. 반응 후에, 각 게놈 DNA들은 1.5ml 용량의 원심분리 실험관으로 옮겨, 6M NaCl을 0.3ml 첨가한다. 게놈 DNA들을 잘 섞어준 후, 12,000rpm에서 10분간 원심분리한다. 원심분리 후, 게놈 DNA가 들어있는 상층을 모아서 새로운 시험관으로 옮기고, 상온에서 동량의 100% 에탄올을 첨가한다. 게놈 DNA들이 침전될 때까지 잘 섞어 주고, 침전이 되면 70% 에탄올로 게놈 DNA들을 세척한다. 이 과정이 끝나면 실험관 뚜껑을 열어, 용액성분이 마르도록 놓아둔다. 그리고 TE 완충용액(pH 8.0)을 넣어 게놈 DNA를 재현탁함으로써, 핵산 시료를 얻을 수 있다.The sample includes blood, tissue, cells, and the like, and a nucleic acid sample can be obtained according to a conventional method. For example, in the case of blood, a nucleic acid sample can be obtained as follows. Transfer the blood to a centrifuge tube and add 5 ml of low concentration salt solution (10 mM Tris-HCl [pH 7.6], 10 mM KCl, 10 mM MgCl 2 , and 2 mM EDTA). Then, after adding Nonidet P-40, the resulting solution was mixed well and centrifuged at 2,200 rpm for 10 minutes at room temperature. The obtained mass is resuspended in a high concentration of salt component buffer (10 mM Tris-HCl [pH 7.6], 10 mM KCl, 10 mM MgCl 2 , 0.4M NaCl, and 2 mM EDTA). Genomic DNA is mixed with 50ul of 10% SDS and allowed to react overnight at 55 ° C. After the reaction, each genomic DNA is transferred to a 1.5 ml centrifuge tube and 0.3 ml of 6 M NaCl is added. After mixing the genomic DNA well, centrifuge for 10 minutes at 12,000rpm. After centrifugation, the upper layer containing genomic DNA is collected, transferred to a new test tube, and the same amount of 100% ethanol is added at room temperature. Mix the genomic DNA well until it is settled, and wash the genomic DNA with 70% ethanol when settling. At the end of this process, open the test tube lid and let the solution dry. The nucleic acid sample can be obtained by resuspending genomic DNA by adding TE buffer solution (pH 8.0).
여기에서, 상기 다형성 부위의 염기 서열을 분석하는 단계는 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 폴리뉴클레오티드로 이루어진 군으로부터 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드 서열로서 다형성 부위(단, 상기 다형성 부위는 표 1에서 정의한 바와 같다)를 포함하는 서열을 주형으로 하는 프라이머 또는 프로브를 이용하여 수행될 수 있다. 상기 프라이머 또는 프로브는 상기에서 설명한 바와 같다. Here, the step of analyzing the nucleotide sequence of the polymorphic site is a polynucleotide of SEQ ID NOs: 1 to 3, 10, 14 to 23, 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 A polynucleotide selected from the group consisting of or a complementary polynucleotide sequence thereof may be performed using primers or probes based on a sequence comprising a polymorphic site (wherein the polymorphic site is as defined in Table 1). The primer or probe is as described above.
또한, 상기 다형성 부위의 염기 서열을 분석하는 단계는 폴리뉴클레오티드 (a) 내지 (am)으로 이루어진 군으로부터 선택된 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드가 고정된 마이크로어레이에 상기 핵산 시료를 혼성화 시키는 단계; 및 얻어진 혼성화 결과를 분석하는 단계를 포함하여 수행될 수 있으며, 상기 마이크로어레이에 고정되는 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드의 DNA 서열의 길이는 각각 10 내지 100 뉴클레오티드일 수 있다.In addition, analyzing the nucleotide sequence of the polymorphic site may include hybridizing the nucleic acid sample to a microarray to which a polynucleotide selected from the group consisting of polynucleotides (a) to (am) or a complementary nucleotide thereof is immobilized; And analyzing the obtained hybridization results, wherein the lengths of the DNA sequences of the polynucleotides or complementary nucleotides immobilized on the microarrays may be 10 to 100 nucleotides, respectively.
본 발명의 검체 중의 단일염기다형을 검출하는 방법에 따라 얻어진 결과는 장형 위암 진단에 필요한 정보를 제공할 수 있으며 예를 들어, 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 다형성 부위의 염기가 각각 C, C, T, A, G, T, T, C, T, A, C, C, G, T, C, T, A, T, G, A, C, C, C, C, C, C, A, G, G, T, C, C, T, T, A, T, A, C, A (위험 대립인자)인 것이 하나 이상 존재하는 경우, 장형 위암에 걸릴 확률이 높은 위험군에 속하는 것으로 판정할 수 있다. 상기 위험 대립 인자를 갖는 핵산 서열이 하나의 검체에서 많이 검출되면 될수록 위험군에서 속하는 확률은 더 높은 것으로 판단할 수 있다. Results obtained according to the method for detecting a monobasic polymorphism in a sample of the present invention may provide information necessary for diagnosing gastric cancer, for example, SEQ ID NOs: 1 to 3, 10, 14 to 23, 25 to 34, 37, The bases of the
또한, 상기 다형성 부위의 염기 서열을 분석하는 단계는 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 다형성 부위의 대립인자형(allele) 또는 유전자형(genotype) 분석을 포함할 수 있다. 바람직하게는, 상기 다형성 부위의 염기 서열을 분석하는 단계는 서열번호 1의 DNA 서열의 다형성부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 2의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 3의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 10의 DNA 서열의 다형성 부위의 대립인자형(allele) 분석을 포함하거나, 서열번호 14의 DNA 서열의 다형성 부위의 공우성 유전자형(co-dominant genotype) 분석을 포함하거나, 서열번호 15의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype) 분석을 포함하거나, 서열번호 16의 DNA 서열의 다형성 부위의 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 17의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 18의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 열성 유전자형(recessive genotype) 분석을 포함하거나, 서열번호 19의 DNA 서열의 다형성 부위의 열성 유전자형(recessive genotype) 분석을 포함하거나, 서열번호 20의 DNA 서열의 다형성 부위의 열성 유전자형(recessive genotype) 분석을 포함하거나, 서열번호 21의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 열성 유전자형(recessive genotype) 분석을 포함하거나, 서열번호 22의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 열성 유전자형(recessive genotype) 분석을 포함하거나, 서열번호 23의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 25의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 26의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 열성 유전자형(recessive genotype) 분석을 포함하거나, 서열번호 27의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 열성 유전자형(recessive genotype) 분석을 포함하거나, 서열번호 28의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 열성 유전자형(recessive genotype) 분석을 포함하거나, 서열번호 29의 DNA 서열의 다형성 부위의 열성 유전자형(recessive genotype) 분석을 포함하거나, 서열번호 30의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 31의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 32의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 33의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 34의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 37의 DNA 서열의 다형성 부위의 공우성 유전자형(co-dominant genotype) 분석을 포함하거나, 서열번호 40의 DNA 서열의 다형성 부위의 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 45의 DNA 서열의 다형성 부위의 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 46의 DNA 서열의 다형성 부위의 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 48의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 49의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 50의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 51의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 52의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 53의 DNA 서열의 다형성 부위의 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 55의 DNA 서열의 다형성 부위의 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 56의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 57의 DNA 서열의 다형성 부위의 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 58의 DNA 서열의 다형성 부위의 대립인자형(allele), 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함하거나, 서열번호 59의 DNA 서열의 다형성 부위의 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype) 분석을 포함할 수 있다.In addition, the step of analyzing the nucleotide sequence of the polymorphic site is an allele of the polymorphic sites of SEQ ID NO: 1 to 3, 10, 14 to 23, 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 May include allele or genotype analysis. Preferably, analyzing the nucleotide sequence of the polymorphic site comprises allele, co-dominant genotype, and dominant genotype analysis of the polymorphic region of the DNA sequence of SEQ ID NO: 1. Or allelic, co-dominant genotype, dominant genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 2, or alleles of the polymorphic site of the DNA sequence of SEQ ID NO: 3 Include allele, co-dominant genotype, dominant genotype analysis, or allele analysis of the polymorphic region of the DNA sequence of SEQ ID NO: 10, or Co-dominant genotype analysis of the polymorphic site of the DNA sequence, or allele, co-dominant genot of the polymorphic site of the DNA sequence of SEQ ID NO: 15. ype) analysis, dominant genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 16, or allele, co-dominant genotype (co-) of the polymorphic site of the DNA sequence of SEQ ID NO: 17 includes dominant genotype, dominant genotype analysis, or allele, co-dominant genotype, recessive genotype analysis of the polymorphic region of the DNA sequence of SEQ ID NO: 18. Or include a recessive genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 19, or comprises a recessive genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 20, or the DNA sequence of SEQ ID NO: 21 Allele, co-dominant genotype, recessive genotype analysis of the polymorphic site of Allele, co-dominant genotype, recessive genotype analysis of the sex region, or allele, co-dominant genotype of the polymorphic region of the DNA sequence of SEQ ID NO. co-dominant genotype, dominant genotype analysis, or allele, co-dominant genotype, dominant genotype analysis of polymorphic regions of the DNA sequence of SEQ ID NO: 25 A polymorphic site of the DNA sequence of SEQ ID NO: 26, including allele, co-dominant genotype, recessive genotype analysis of the polymorphic site of SEQ ID NO: 26, or polymorphic site of the DNA sequence of SEQ ID NO: 27 Allele, co-dominant genotype, recessive genotype analysis, or allele, co-expression of the polymorphic region of the DNA sequence of SEQ ID NO: 28 Polymorphic sites of the DNA sequence of SEQ ID NO: 30, including co-dominant genotype, recessive genotype analysis, or recessive genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 29 Allele, co-dominant genotype, dominant genotype analysis, or allele, co-genotype of the polymorphic region of the DNA sequence of SEQ ID NO: 31 include dominant genotype, dominant genotype analysis, or allele, co-dominant genotype, and dominant genotype analysis of the polymorphic region of the DNA sequence of SEQ ID NO. Or allelic, co-dominant genotype, dominant genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 33, or Allele, co-dominant genotype, dominant genotype analysis of the polymorphic site of the DNA sequence of 34, or the co-dominant genotype of the polymorphic site of the DNA sequence of SEQ ID NO: 37 -dominant genotype analysis, co-dominant genotype, dominant genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 40, or polymorphic site of the DNA sequence of SEQ ID NO: 45 Includes dominant genotype analysis, co-dominant genotype, dominant genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 46, or polymorphism of the DNA sequence of SEQ ID NO: 48 Allele, co-dominant genotype, or dominant genotype analysis of the site, or alleles of the polymorphic site of the DNA sequence of SEQ ID NO: 49 Allele, co-dominant genotype, dominant genotype analysis, or allele, co-dominant genotype of the polymorphic region of the DNA sequence of SEQ ID NO: 50 ), Dominant genotype analysis, or allele, co-dominant genotype, dominant genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 51, or Allele, co-dominant genotype, dominant genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 52, or dominant genotype of the polymorphic site of the DNA sequence of SEQ ID NO: 53 includes dominant genotype analysis, co-dominant genotype, dominant genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 55, or SEQ ID NO: 56 Allele, co-dominant genotype, or dominant genotype analysis of the polymorphic region of the DNA sequence of include dominant genotype, dominant genotype analysis, or allele, co-dominant genotype, and dominant genotype analysis of the polymorphic region of the DNA sequence of SEQ ID NO: 58. Or co-dominant genotype, dominant genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 59.
예를 들어, 서열번호 1 내지 3, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 다형성 부위가 각각 유전자형이 C/C(서열번호 1), C/C(서열번호 2), T/T(서열번호 3), A/G와 G/G(서열번호 14), T/T(서열번호 15), T/T(서열번호 16), T/C와 C/C(서열번호 17), T/T(서열번호 18), A/A(서열번호 19), C/C(서열번호 20), C/C(서열번호 21), G/G(서열번호 22), G/T와 T/T(서열번호 23), T/C와 C/C(서열번호 25), T/T와 T/G(서열번호 26), A/A와 A/T(서열번호 27), T/T와 T/C(서열번호 28), G/G와 G/T(서열번호 29), G/A와 A/A(서열번호 30), T/C와 C/C(서열번호 31), T/C와 C/C(서열번호 32), T/C와 C/C(서열번호 33), T/C와 C/C(서열번호 34), C/C(서열번호 37), C/C(서열번호 40), G/A와 A/A(서열번호 45), A/G와 G/G(서열번호 46), A/G와 G/G(서열번호 48), G/T와 T/T(서열번호 49), T/C와 C/C(서열번호 50), T/C와 C/C(서열번호 51), C/T와 T/T(서열번호 52), G/T와 T/T(서열번호 53), G/A와 A/A(서열번호 55), C/T와 T/T(서열번호 56), G/A와 A/A(서열번호 57), T/C와 C/C(서열번호 58), G/A와 A/A(서열번호 59)가 하나 이상 존재하는 경우 장형 위암에 걸릴 위험도가 높은 것으로 판단할 수 있다. 상기 위험 유전자형을 갖는 핵산 서열이 하나의 검체에서 많이 검출되면 될수록 위험군에서 속하는 확률은 더 높은 것으로 판단할 수 있다.For example, the polymorphic sites of SEQ ID NOs 1 to 3, 14 to 23, 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 are each genotype C / C (SEQ ID NO: 1), C / C (SEQ ID NO: 2), T / T (SEQ ID NO: 3), A / G and G / G (SEQ ID NO: 14), T / T (SEQ ID NO: 15), T / T (SEQ ID NO: 16), T / C and C / C (SEQ ID NO: 17), T / T (SEQ ID NO: 18), A / A (SEQ ID NO: 19), C / C (SEQ ID NO: 20), C / C (SEQ ID NO: 21), G / G (SEQ ID NO: 22), G / T and T / T (SEQ ID NO: 23), T / C and C / C (SEQ ID NO: 25), T / T and T / G (SEQ ID NO: 26), A / A and A / T (SEQ ID NO: 27), T / T and T / C (SEQ ID NO: 28), G / G and G / T (SEQ ID NO: 29), G / A and A / A (SEQ ID NO: 30), T / C and C / C (SEQ ID NO: 31), T / C and C / C (SEQ ID NO: 32), T / C and C / C (SEQ ID NO: 33), T / C and C / C (SEQ ID NO: 34), C / C (SEQ ID NO: 37), C / C (SEQ ID NO: 40), G / A and A / A (SEQ ID NO: 45), A / G and G / G (SEQ ID NO: 46), A / G and G / G (SEQ ID NO: 48), G / T and T / T (SEQ ID NO: 49), T / C and C / C (SEQ ID NO: 50), T / C and C / C (SEQ ID NO: 51), C / T and T / T (SEQ ID NO: 52) , G / T and T / T (SEQ ID NO: 53), G / A and A / A (SEQ ID NO: 55), C / T and T / T (SEQ ID NO: 56), G / A and A / A (SEQ ID NO: 57) If one or more of T / C and C / C (SEQ ID NO: 58), G / A, and A / A (SEQ ID NO: 59) are present, the risk of developing gastrointestinal cancer may be high. The more the nucleic acid sequence having the risk genotype is detected in one sample, the higher the probability of belonging to the risk group can be determined.
본 발명은 또한, 장형위암 진단에 필요한 정보를 제공하기 위하여, 상기 핵산 시료로부터 반수체형(haplotype)을 분석하는 단계를 포함하는, 검체 중의 단일염기다형을 검출하는 방법을 포함한다. 구체적으로, 상기 반수체형 분석은 상기 핵산 시료로부터, 서열번호 1 내지 3의 DNA 서열의 다형성 부위로부터 결정되는 반수체형; 서열번호 4 내지 13의 DNA 서열의 다형성 부위로부터 결정되는 반수체형; 서열번호 18 내지 20의 DNA 서열의 다형성 부위로부터 결정되는 반수체형; 서열번호 24 내지 26의 DNA 서열의 다형성 부위로부터 결정되는 반수체형; 서열번호 27, 28, 31 내지 35의 DNA 서열의 다형성 부위로부터 결정되는 반수체형; 서열번호 36 내지 37의 DNA 서열의 다형성 부위로부터 결정되는 반수체형; 서열번호 38 내지 44의 DNA 서열의 다형성 부위로부터 결정되는 반수체형; 및 서열번호 45 내지 59의 DNA 서열의 다형성 부위로부터 결정되는 반수체형으로 이루어진 군으로부터 선택된 반수체형을 분석함으로써 수행될 수 있다. 단, 반수체형 분석에 있어서, 상기 DNA 서열의 다형성 부위는 다음 표 2와 같다.The present invention also includes a method for detecting a monobasic polymorph in a sample, comprising analyzing a haplotype from the nucleic acid sample to provide information necessary for diagnosing gastric cancer. Specifically, the haplotype analysis is a haplotype determined from the polymorphic site of the DNA sequence of SEQ ID NOS: 1 to 3 from the nucleic acid sample; Haplotype determined from the polymorphic site of the DNA sequence of SEQ ID NOs: 4 to 13; Haplotype determined from the polymorphic site of the DNA sequence of SEQ ID NOs: 18-20; Haplotype determined from the polymorphic site of the DNA sequence of SEQ ID NOs: 24-26; Haplotype determined from the polymorphic site of the DNA sequence of SEQ ID NOs: 27, 28, 31-35; Haplotype determined from the polymorphic site of the DNA sequence of SEQ ID NOs: 36 to 37; Haplotype determined from the polymorphic site of the DNA sequence of SEQ ID NOs: 38-44; And haplotypes selected from the group consisting of haplotypes determined from the polymorphic sites of the DNA sequences SEQ ID NOs: 45-59. However, in haplotype analysis, the polymorphic sites of the DNA sequence are shown in Table 2 below.
즉, 반수체형 분석결과, 서열번호 1 내지 3의 DNA 서열이 C-C-T 반수체형을 둘 다 가지는 경우(즉, 이배체형(diplotype)을 가지는 경우), 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있으며, T-T-C 반수체형을 하나라도 나타내는 경우 장형 위암에 저항성을 갖는 것으로 판정할 수 있다 (표 8, 도 1a 및 1b 참조). 서열번호 4 내지 13의 DNA 서열이 G-T-C-A-T-T-C-G-G-G 반수체형을 하나도 갖지 않는 경우, 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있다 (표 8, 도 2a 및 2b 참조). 서열번호 18 내지 20 의 DNA 서열이 T-A-C 반수체형을 둘 다 갖는 경우, 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있으며, G-G-T 반수체형을 하나라도 나타내는 경우 장형 위암에 저항성을 갖는 것으로 판정할 수 있다 (표 8, 도 3a 및 3b 참조). 서열번호 24 내지 26의 DNA 서열이 C-C-T 반수체형을 하나라도 갖는 경우, 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있고, C-T-G 반수체형을 둘 다 가지는 경우 장형 위암에 저항성을 갖는 것으로 판정할 수 있다 (표 8, 도 4a 및 4b 참조). 서열번호 27, 28, 31 내지 35의 DNA 서열이 A-T-C-C-C-C-A 반수체형을 하나라도 갖는 경우, 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있으며, T-C-T-T-T-T-A 반수체형을 둘 다 갖는 경우, 장형 위암에 저항성을 갖는 것으로 판정할 수 있다 (표 8, 도 5a 및 5b 참조). 서열번호 36 내지 37 의 DNA 서열이 T-T를 하나라도 갖는 경우 장형 위암에 저항성을 갖는 것으로 판정할 수 있으며(표 8, 도 6a 및 6b 참조), 서열번호 38 내지 44 의 DNA 서열이 G-G-T-A-A-C-C 반수체형을 하나라도 갖는 경우 장형 위암에 저항성을 갖는 것으로 판정할 수 있고(표 8, 도 7a 및 7b 참조), 서열번호 45 내지 59의 DNA 서열이 A-G-G-G-T-C-C-T-T-A-A-T-A-C-A 반수체형을 하나라도 갖는 경우, 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있다(표 8, 도 8a 및 8b 참조). In other words, the haplotype analysis revealed that the DNA sequences of SEQ ID NOs: 1 to 3 had both CCT haplotypes (ie, having a diplotype), and were found to have a higher risk of developing gastric cancer than those who did not. In the case where any one of the TTC haplotypes is shown, it can be determined to be resistant to enteric gastric cancer (see Table 8, FIGS. 1A and 1B). If the DNA sequences of SEQ ID NOs: 4 to 13 do not have any G-T-C-A-T-T-C-G-G-G haplotypes, it can be determined that the risk of developing gastrointestinal cancer is higher than that of humans (see Table 8, Figures 2A and 2B). If the DNA sequences of SEQ ID NOs: 18 to 20 have both TAC haplotypes, they may be determined to have a higher risk of gastrointestinal cancer than those who do not, and if any of the GGT haplotypes are present, they are resistant to enteric gastric cancer. Can be determined (see Table 8, FIGS. 3A and 3B). If the DNA sequences of SEQ ID NOs: 24-26 have any CCT haplotype, they may be determined to have a higher risk of gastric cancer than those who do not, and if they have both CTG haplotypes, they may be resistant to gastric gastric cancer. Can be determined (see Table 8, FIGS. 4A and 4B). If the DNA sequences of SEQ ID NOs: 27, 28, 31 to 35 have any one ATCCCCA haplotype, they may be determined to have a higher risk of gastric cancer than those who do not, and if they have both TCTTTTA haplotypes, It can be determined to have resistance to (see Table 8, Figs. 5A and 5B). When the DNA sequences of SEQ ID NOs: 36 to 37 have any TT, it can be determined that they are resistant to enteric gastric cancer (see Table 8, FIGS. 6A and 6B), and the DNA sequences of SEQ ID NOs: 38 to 44 show the GGTAACC haplotype. If there is any one can be determined to have resistance to enteric gastric cancer (see Table 8, Figures 7a and 7b), and if the DNA sequence of SEQ ID NO: 45 to 59 has at least one AGGGTCCTTAATACA haplotype, entero gastric cancer than those who do not It can be determined that the risk of getting high is high (see Table 8, FIGS. 8A and 8B).
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.
실시예Example
1. 피검자 선정1. Selection of subjects
본 실험은 한국 아주대 병원으로부터 임상적으로 장형 위암으로 진단받은 153명의 환자들과 만성 위염으로 진단받은 326명의 환자들로부터 동의를 받아서 실험과 연관성 분석이 수행되었다. 479명의 환자 모두가 Helicobacter pylori에 감염된 환자이다. 사용된 군집의 크기는 다음 표 3과 같다.This study was performed with the consent of 153 patients who were clinically diagnosed as enteric gastric cancer and 326 patients who were diagnosed with chronic gastritis. All 479 patients were infected with Helicobacter pylori. The size of the clusters used is shown in Table 3 below.
2. 게놈 DNA의 준비2. Preparation of Genomic DNA
게놈 DNA(genomic DNA; gDNA)를 준비하기 위하여 장형 위암 환자와 만성 위염 환자들로부터 혈액을 채취하였다. 전체 정맥혈의 5ml은 각 지원자들의 전주정맥으로부터 얻었고 15% EDTA가 들어있는 Vacutainer tube로 옮겨졌다. 게놈 DNA를 추출하기 위하여, 혈액을 원심분리 실험관으로 옮기고 낮은 농도의 염 성분 완충용액(low-salt buffer solution(10mM Tris-HCl [pH 7.6], 10mM KCl, 10mM MgCl2, and 2mM EDTA))을 5ml 첨가 하였다. 그리고 Nonidet P-40을 첨가하였다. 얻어진 용액을 잘 섞어준 후, 상온에서 10분간 2,200 rpm으로 원심분리 하였다. 이 때 얻어진 덩어리는 고농도의 염 성분 완충용액(high-salt buffer solution(10mM Tris-HCl [pH 7.6], 10mM KCl, 10mM MgCl2, 0.4M NaCl, and 2mM EDTA))으로 재현탁 하였다. 이 게놈 DNA는 50ul의 10% SDS와 섞은 후, 55℃에서 밤새 반응시켰다.Blood was collected from enteric gastric cancer patients and chronic gastritis patients to prepare genomic DNA (gDNA). 5 ml of total venous blood was obtained from each volunteer's anterior venous vein and transferred to a Vacutainer tube containing 15% EDTA. To extract genomic DNA, the blood is transferred to a centrifuge tube and a low concentration of salt buffer solution (10 mM Tris-HCl [pH 7.6], 10 mM KCl, 10 mM MgCl 2 , and 2 mM EDTA) is added. 5 ml was added. And Nonidet P-40 was added. The resulting solution was mixed well and centrifuged at 2,200 rpm for 10 minutes at room temperature. The obtained mass was resuspended in a high concentration salt buffer solution (10 mM Tris-HCl [pH 7.6], 10 mM KCl, 10 mM MgCl 2 , 0.4M NaCl, and 2 mM EDTA). The genomic DNA was mixed with 50ul of 10% SDS and reacted overnight at 55 ° C.
반응 후에, 각 게놈 DNA들은 1.5ml 용량의 원심분리 실험관으로 옮겨, 6M NaCl을 0.3ml 첨가하였다. 게놈 DNA들을 잘 섞어준 후, 12,000rpm에서 10분간 원심분리하였다. 원심분리 후, 게놈 DNA가 들어있는 상층을 모아서 새로운 시험관으로 옮기고, 상온에서 동량의 100% 에탄올을 첨가하였다. 게놈 DNA들이 침전될 때까지 잘 섞어 주고, 침전이 되면 70% 에탄올로 게놈 DNA들을 세척하였다. 이 과정이 끝나면 실험관 뚜껑을 열어, 용액성분이 마르도록 놓아둔다. 그리고 TE 완충용액(pH 8.0)을 넣어 게놈 DNA를 재현탁하였다.After the reaction, each genomic DNA was transferred to a 1.5 ml centrifuge tube and 0.3 ml of 6 M NaCl was added. After mixing the genomic DNA well, it was centrifuged for 10 minutes at 12,000rpm. After centrifugation, the upper layer containing genomic DNA was collected and transferred to a new test tube, and the same amount of 100% ethanol was added at room temperature. Mix well until genomic DNA precipitates and wash genomic DNA with 70% ethanol when precipitated. At the end of this process, open the test tube lid and let the solution dry. Then, TE buffer solution (pH 8.0) was added to resuspend the genomic DNA.
준비된 게놈 DNA는 GoldenGate Assay를 위해 Quant-iTTM PicoGreen dsDNA reagent (Molecular Probes, Invitrogen)을 사용하여 250ng/5uL의 농도로 조정하였다. Prepared genomic DNA using the Quant-iT TM PicoGreen dsDNA reagent ( Molecular Probes, Invitrogen) for GoldenGate Assay was adjusted to a concentration of 250ng / 5uL.
3. 게놈 DNA의 증폭 및 유전자형 분석 - Goldengate assay 3. Amplification and Genotyping of Genomic DNA-Goldengate assay
Goldengate assay 방법에 따라, Sentrix array matrix chip을 사용하여 유전자형을 분석하였다. 일루미나사(Illumina Inc.)로부터 GoldenGate assay를 위한 모든 시약과 Sentrix array matrix chip을 구입하여 사용하였다. 모든 과정은 일루미나사의 GoldenGate assay 방법에 따라 시행하였다. According to the Goldengate assay method, genotyping was performed using a Sentrix array matrix chip. All reagents and Sentrix array matrix chips for GoldenGate assay were purchased from Illumina Inc. All procedures were performed according to Illumina's GoldenGate assay method.
게놈 DNA 시료(250 ng/5 ㎕)는 96웰 플레이트에서 5 ul의 GS#-MS1 시약과 혼합하였다. 플레이트를 밀봉하고 250×g에서 1 분 동안 원심분리하고, 95 ℃ heat block에서 30 분간 반응시켰다. 여기에 5 ul GS#-SUD를 넣고 혼합한 후 5 ul 2-프로판올을 넣고, 다시 혼합한 후에 3,000×g에서 20분 동안 원심분리한 후 상등액을 제거하고 펠렛을 건조시켰다. 건조된 DNA는 10 ul의 GS#-RS1 시약을 넣고 잘 풀어주었다. 여기에 10 ul의 GS#-OPA와 30 ul의 GS#-OB1를 넣고, 잘 혼합한 후 70℃ heat block에 넣고 30℃가 될 때까지 천천히 식혔다. GS#-ASE 플레이트를 마그네틱 플레이트 위에 올리고 2분간 방치하였다. 상등액을 제거하고, 50 ul GS#-AM1을 넣어주고 잘 혼합하였다. 마그네틱 플레이트 위에 올리고 2분간 방치한 후 상등액을 제거하고, 50 ul GS#-AM1을 넣어주고 잘 혼합하였다. 위와 동일한 방법으로 50 ul GS#-UB1로 세척 후, 상등액을 제거하고, 37 ul GS#-MEL을 넣어주고 잘 혼합한 후에 45℃에서 15분간 배양하였다. 위 플레이트를 다시 마그네틱 플레이트 위에 올리고 2분간 방치한 후 상등액을 제거하고, 50 ul GS#-UB1을 넣어주었다. 다시 위 과정을 반복하고, 35 ul GS#-IP1을 넣어주고 잘 혼합한 후 95℃ heat block에서 1분간 배양(incubation)하였다. 플레이트를 마그네틱 플레이트 위에 올리고 2분간 방치하였다. 상등액 30 ul를 GS#-PCR 플레이트에 옮긴 후 64 ul의 illumina-recommended DNA polymerase와 100 ul UDG를 GS#-MMP tube에 넣어준후 잘 섞어주고, 표 4에 나타낸 조건으로 증폭시켰다. Genomic DNA samples (250 ng / 5 μl) were mixed with 5 ul of GS # -MS1 reagent in 96 well plates. The plate was sealed and centrifuged for 1 minute at 250 × g, and reacted for 30 minutes in a 95 ° C. heat block. 5 ul GS # -SUD was added thereto and mixed, 5 ul 2-propanol was added thereto, and mixed again, followed by centrifugation at 3,000 × g for 20 minutes, and then the supernatant was removed and the pellet was dried. The dried DNA was added well with 10 ul of GS # -RS1 reagent. 10 ul of GS # -OPA and 30 ul of GS # -OB1 were added thereto, mixed well, and placed in a 70 ° C. heat block and slowly cooled down to 30 ° C. The GS # -ASE plate was placed on the magnetic plate and left for 2 minutes. The supernatant was removed and 50 ul GS # -AM1 was added and mixed well. After placing on a magnetic plate and left for 2 minutes, the supernatant was removed, 50 ul GS # -AM1 was added and mixed well. After washing with 50 ul GS # -UB1 in the same manner as above, the supernatant was removed, 37 ul GS # -MEL was added and well mixed and incubated for 15 minutes at 45 ℃. The upper plate was placed again on the magnetic plate, left for 2 minutes, the supernatant was removed, and 50 ul GS # -UB1 was added thereto. Repeat the above process again, put 35 ul GS # -IP1 and mix well and incubated for 1 minute in a 95 ℃ heat block. The plate was placed on a magnetic plate and left for 2 minutes. 30 ul of the supernatant was transferred to the GS # -PCR plate, 64 ul of illumina-recommended DNA polymerase and 100 ul UDG were added to the GS # -MMP tube, mixed well, and amplified under the conditions shown in Table 4.
반응 후에 20 ul의 GS#MPB를 넣고 잘 혼합한 후, 96웰 필터 플레이트에 옮기고, 암실에서 60분 동안 방치하였다. 필터 플레이트 어댑터를 96웰 V-bottom에 놓고, 원심 분리하여 상등액을 제거하였다. 다시 필터 플레이트에 50 ul GS#-UB2를 넣고 1000 x g에서 5 분간 원심 분리하였다. 30 ul의 GS#_MH1가 들어있는 GS#-INT 플레이트를 필터 플레이트위에 놓고, 30 ul의 0.1N NaOH를 필터 플레이트에 넣었다. 1000 xg에서 5 분간 원심 분리하여 PCR 생산물을 수거하였다.After the reaction, 20 ul of GS # MPB was added and mixed well, and then transferred to a 96 well filter plate, and left in the dark for 60 minutes. The filter plate adapter was placed in a 96 well V-bottom and centrifuged to remove the supernatant. 50 ul GS # -UB2 was put back into the filter plate and centrifuged at 1000 x g for 5 minutes. A GS # -INT plate containing 30 ul of GS # _MH1 was placed on the filter plate and 30 ul of 0.1N NaOH was placed in the filter plate. PCR products were harvested by centrifugation at 1000 xg for 5 minutes.
칩을 GS#-UB2와 NaOH에서 전 처리하고, 수거한 PCR 산물을 384웰에 옮기고 여기에 전처리한 칩을 올렸다. 60 ℃에서 30 분 동안 혼성화시키고 다시 온도를 45℃로 바꾸고 14시간 이상 혼성화시켰다. GS#UB2, GS#IS1에서 세척한 후에 상온에서 건조시킨 후, 분석을 위해서 이미지 스캐닝(image scanning)을 실시하였다.The chips were pretreated in GS # -UB2 and NaOH, and the collected PCR products were transferred to 384 wells and the pretreated chips were loaded thereon. Hybridization was performed at 60 ° C. for 30 minutes and again the temperature was changed to 45 ° C. and hybridized for at least 14 hours. After washing in GS # UB2, GS # IS1, and dried at room temperature, image scanning was performed for analysis.
유전자형 분석 이미지 파일로부터의 유전자형의 분석은 Illumina사의 Beadstudio를 사용하여 각 다형성에 대한 유전자형를 확인하였다. Beadstudio는 두 개의 대립인자를 인식하는 프로브들 사이의 발색의 세기에 대한 비율을 가지고 전형적인 유전자형의 패턴을 나타낸다.Genotyping Analysis of genotypes from image files confirmed the genotype for each polymorphism using Illumina's Beadstudio. Beadstudio exhibits a typical genotype pattern with a ratio of the intensity of color development between probes recognizing two alleles.
4. 통계학적 분석4. Statistical Analysis
단일염기다형들을 구성하는 대립인자들에 대한 집단내의 유전학적 분포여부에 대하여 하아디-와인버그 평형 검정을 하였다. 여기에서 단일염기다형의 기준이 되는 HWE p value > 0.05와 작은 대립인자 빈도(Minor Allele Frequency; MAF) > 0.1의 기준을 적용하였다. 장형 위암 환자군과 만성 위염 환자군간의 출현빈도를 이용하여 질병에 대한 각 단일염기다형들의 연관성분석은 유의수준을 < 0.05로 정하였으며, SAS software version 9.1.3를 사용하여 분석하였다. 연관성분석은 대립인자들 간의 장형 위암 환자군과 만성 위염 환자군에서의 출현빈도로 나누어 유의성 있는 차이를 비교하였으며, 유의수준을 < 0.05로 하였다. 오즈 비(Odds Ratio)는 로지스틱 회귀모형을 통하여 산출하였으며 대립인자(Allele), 우성 (Dominant), 열성 (Recessive) 및 공우성(Co-Dominant) 모형을 적용하였다. 각 모형에 따른 질병과의 유의성을 분석함에 있어 다수 대립인자를 A1이라 하고 소수 대립인자를 A2라 하면 대립인자(Allele) 모형은 A1의 빈도와 A2의 빈도를 비교하는 것이고, 우성 (Dominant) 모형은 A1A1의 빈도와 A1A2와 A2A2의 빈도에 대한 합을 비교하는 것이고, 열성 (Recessive) 형질 모형은 A1A1과 A1A2의 합과 A2A2의 빈도를 비교하는 것이고, 공우성 (Co-Dominant) 형질 모형은 A1A1, A1A2 및 A2A2에 대한 각각의 빈도를 비교하는 것이다. The Hardy-Weinberg equilibrium test was performed to determine the genetic distribution of the alleles that make up the monobasic polymorphisms. In this case, the criteria of HWE p value> 0.05 and Minor Allele Frequency (MAF)> 0.1, which are the criteria for polybasic polymorphism, were applied. Using the frequency of incidence between intestinal gastric cancer patients and chronic gastritis patients, the significance level of each polybasic polymorphism was set to <0.05 and analyzed using SAS software version 9.1.3. Correlation analysis was performed to compare significant differences between alleles in the incidence of intestinal gastric cancer and in patients with chronic gastritis. The significance level was <0.05. Odds Ratio was calculated by logistic regression model and allele, dominant, recessive and co-dominant models were applied. In analyzing the significance of each model, the majority allele is A1 and the minor allele is A2. The allele model compares the frequency of A1 with the frequency of A2, and the dominant model. Is comparing the sum of the frequency of A1A1 with the sum of the frequencies of A1A2 and A2A2, the recessive trait is comparing the sum of A1A1 and A1A2 with the frequency of A2A2, and the co-dominant trait is A1A1. , To compare the respective frequencies for A1A2 and A2A2.
단일염기다형들 간의 연관비평형 검정을 하였다. 이는 Haploview (ver. 4.1)을 사용하였다. 장형 위암 환자군과 만성 위염 환자군 모두에서 형성되는 각 단일염기다형들간의 상호연관성에 대한 분석에서 형성된 연관비평형블록으로부터 반수체형이 형성되었으며, 이들을 장형 위암 환자군과 만성 위염 환자군으로 나누어 장형 위암 환자군 특이적인 반수체형을 분석하였다. Associative non-equilibrium tests between monobasic polymorphs were performed. It used Haploview (ver. 4.1). The haplotype was formed from the association non-equilibrium block formed in the analysis of the correlation between the monobasic polymorphisms in both the gastric cancer patients and the chronic gastritis patients, and divided into the gastric cancer patients and the chronic gastritis patients. Haploid type was analyzed.
5. 결과5. Results
(1) ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, 및 MAP2 유전자에 존재하는 유의성을 나타내는 단일염기다형(1) Monobasic polymorphisms showing significance in the ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes
하기 표 5a 및 5b는 상기 만성 위염 환자군과 장형 위암 환자군이 참여하여 장형 위암과의 연관성을 분석한 결과 유의성 있는 차이를 나타낸 서열의 목록으로서, 이 중 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 다형성 서열은 통계학적으로 유의성 있는 차이를 나타내는 것을 분석되었다.Table 5a and 5b is a list of sequences showing significant differences as a result of analyzing the association between the gastric gastritis patient group and the gastrointestinal gastric cancer patient group to analyze the association between gastric gastric cancer, SEQ ID NOs: 1 to 3, 10, 14 to 23, Polymorphic sequences of 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 were analyzed to show statistically significant differences.
ㆍ서열번호는 각 단일염기다형을 나타내는 서열번호이다.Sequence number is a sequence number which represents each monobasic polymorphism.
ㆍReference SNP ID는 표준단일염기다형의 명칭 (Reference SNP ID; rs)을 의미하며, 이는 인간게놈프로젝트 후, 미국 국립보건원 산하 생물공학정보연구소 (NCBI)의 데이터베이스에서 각 단일염기다형을 구분하기 위하여 붙인 이름이다. Reference SNP ID refers to the name of the standard single nucleotide polymorphism (Reference SNP ID; rs), which is used to distinguish each single nucleotide polymorphism from the database of the National Institute of Biotechnology Information (NCBI) under the National Institute of Health. Name given.
ㆍ대립인자는 각 단일염기다형에서의 Major allele과 Minor allele을 나타낸다.Alleles represent major and minor alleles in each monobasic polymorph.
ㆍ염색체는 각 단일염기다형들이 몇 번 염색체에 위치하고 있는지를 나타내주고 있다.The chromosome shows how many times each single base polymorph is located on the chromosome.
ㆍ위치는 염색체상에서 표준염기서열의 위치를 의미한다(NCBI Genome build 36.3).Position refers to the position of the standard base sequence on the chromosome (NCBI Genome build 36.3).
ㆍSNP 역할은 상기 단일염기다형들이 유전자상에서 어디에 위치하고 있는지를 나타내주고 있다. 따라서 각각의 단일염기다형들이 유전자의 발현과 기능에 있어서 어떻게 작용하는지를 알 수 있다. The SNP role indicates where the single base polymorphisms are located on the gene. Thus, it can be seen how each monobasic polymorphism works in gene expression and function.
ㆍ아미노산의 변화는 상기 단일염기다형들이 유전자가 발현되어 단백질을 생성할 때, 그 단백질을 이루는 아미노산에 변화를 주고 있는지에 대한 설명이다.A change in amino acid is a description of whether the monobasic polymorphs are changing the amino acids constituting the protein when the gene is expressed to produce a protein.
(2) 유전자형(genotype) 및 위험대립인자 분석(2) Genotype and Risk Allele Analysis
하기 표 6a 내지 표 6d는 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 DNA 서열의 대립인자 빈도와 각 유전자형에 대한 만성 위염 환자군과 장형 위암 환자군 각각의 빈도를 나타내며 표 7a 내지 표 7e는 표 6a 내지 표 6d의 유전자형 빈도를 토대로 진행한 하아디-와인버그 평형 검정(Hardy-Weinberg Equilibrium Test) 결과와 장형 위암 연관성 분석[즉, 케이스-컨트롤 연관 분석(Case-control association study)] 결과로서, 하기 연관성 분석에 의해 장형 위암에 영향을 미칠 수 있는 단일염기다형들과 이들의 유전자형을 확인할 수 있다. Tables 6a to 6d below show allelic frequencies of DNA sequences of SEQ ID NOs: 1 to 3, 10, 14 to 23, 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 and their respective genotypes. Correlation between Chronic Gastritis Patients and Gastrointestinal Gastric Cancer Patients, and Tables 7a to 7e show the results of the Hardy-Weinberg Equilibrium Test and the analysis of intestinal gastric cancer based on genotype frequencies in Tables 6a to 6d. That is, as a result of case-control association study], the following association analysis can confirm the single base polymorphisms and genotypes thereof that may affect bowel gastric cancer.
ㆍ서열번호는 각 단일염기다형을 나타내는 서열번호이다.Sequence number is a sequence number which represents each monobasic polymorphism.
ㆍReference SNP ID는 표준단일염기다형의 명칭 (Reference SNP ID; rs)을 의미하며, 이는 인간게놈프로젝트 후, 미국 국립보건원 산하 생물공학정보연구소 (NCBI)의 데이터베이스에서 각 단일염기다형을 구분하기 위하여 붙인 이름이다. Reference SNP ID refers to the name of the standard single nucleotide polymorphism (Reference SNP ID; rs), which is used to distinguish each single nucleotide polymorphism from the database of the National Institute of Biotechnology Information (NCBI) under the National Institute of Health. Name given.
ㆍ 대립인자형 빈도(allele frequency) 란에서는 집단 내에서 관찰되는 각각의 대립인자들의 빈도를 나타내고 있다. 여기서 대립인자란 단일염기다형 부위에 실제로 존재하고 있는 뉴클레오티드의 염기서열을 뜻하며, 하나의 단일염기다형은 그 특성상 두 개의 대립인자를 가질 수 있다. 이들 대립인자 빈도의 고저에 따라 다수 대립인자(Major allele)와 소수 대립인자(Minor allele)로 나뉜다. 특히 소수 대립인자의 빈도(Minor allele frequency; MAF)는 0.1을 기준으로 하여 단일염기다형과 단일염기변이(point mutation)을 나누는 유전학적 기준으로 사용된다. 이러한 기준은 다형성 자체의 안정성을 뜻하기 때문에(즉, 단일염기다형이 일어나는 부위는 일정하다라는 의미), 유전적 표지인자로써의 사용 가능성을 대변해 준다. The allele frequency column shows the frequency of each allele observed in the population. Here, an allele means a nucleotide sequence of nucleotides actually present at a single nucleotide polymorphism site, and a single nucleotide polymorphism may have two alleles due to its characteristics. According to the high and low frequency of these alleles, they are divided into major alleles and minor alleles. In particular, the minor allele frequency (MAF) is used as a genetic reference for dividing a single base polymorphism and a point mutation based on 0.1. This criterion represents the stability of the polymorphism itself (that is, the site where a monobasic polymorphism occurs is constant), thus representing its potential use as a genetic marker.
ㆍ 유전자형은 각 단일염기다형을 형성하는 각각의 대립인자들로 이루어지며, 단일염기다형 부위가 존재하는 유전자좌(locus)에 어떠한 대립인자들이 있는지를 나타내 주고 있다. Genotype consists of alleles that form each monobasic polymorphism, and shows what alleles are in the locus where the monobasic polymorphic site exists.
ㆍ 유전자형 빈도수(genotype frequency)와 유전자형 빈도 % 란은 각각의 유전자형에 해당하는 사람들의 수를 만성 위염 환자군과 장형 위암 환자군으로 나누어 나타낸다. 이를 관측치라고 할 수 있다. The genotype frequency and% genotype frequency column shows the number of people corresponding to each genotype divided into the group of patients with chronic gastritis and the patients with type gastric cancer. This can be called an observation.
표 7a 내지 표 7e는 하나의 단일염기다형을 이루는 두 개의 대립인자와 이로 인하여 형성되는 3가지 형태의 유전자형에 대한 만성 위염 환자군-장형 위암 환자군 간의 빈도차이를 비교하여 어떠한 대립인자가 또는 어떠한 유전자형이 질병과 연관되어 있는지를 분석한 결과이다. 이러한 연관성 분석은 대립인자형(allele model), 공동-우성 유전자형(Co-dominant model), 우성 유전자형(Dominant model), 그리고 열성 유전자형(Recessive model)이라는 네 가지 항목에서 실시하였다. 표 7a 내지 표 7e에 있어서 각 칼럼이 의미하는 바는 다음과 같다. Table 7a to table 7e compare the frequency differences between the two alleles that form a single base polymorphism and the three types of genotypes resulting from chronic gastritis patients and gastrointestinal cancer patients, and which alleles or genotypes It is the result of analyzing whether it is related to the disease. This association analysis was carried out in four categories: the allele model, the co-dominant genotype, the dominant genotype, and the recessive model. In Tables 7a to 7e, the meaning of each column is as follows.
ㆍ서열번호는 각각의 단일염기다형을 나타내는 번호이다. The sequence number is a number representing each monobasic polymorphism.
ㆍReference SNP ID는 표준단일염기다형의 명칭 (Reference SNP ID; rs)을 의미하며, 이는 인간게놈프로젝트 후, 미국 국립보건원 산하 생물공학정보연구소 (NCBI)의 데이터베이스에서 각 단일염기다형을 구분하기 위하여 붙인 이름이다. Reference SNP ID refers to the name of the standard single nucleotide polymorphism (Reference SNP ID; rs), which is used to distinguish each single nucleotide polymorphism from the database of the National Institute of Biotechnology Information (NCBI) under the National Institute of Health. Name given.
ㆍHWE는 하아디-와인버그 평형 (Hardy-Weinberg Equilibrium)의 상태를 나타내는 것이다. 카이제곱 (df=1) 검정에서 chi-value = 3.84(p-value=0.05, df=1)을 기준으로, 3.84보다 큰 경우에는 하아디-와인버크 평형 HWE (Hardy-Weinberg Equilibrium)으로 판단하고, 3.84보다 작은 경우에는 하아디-와인버그 비평형 (Hardy-Weinberg Disequilibrium)으로 판단하였다. 이는 만성 위염 환자군과 장형 위암 환자군 모두에서 관찰된 각 단일염기다형들의 유전적 표지인자로서의 기능과 이들로 이루어지는 유전자형의 분포가 일반적인 것들인지를 나타낸다.HWE represents the state of the Hardy-Weinberg Equilibrium. Based on chi-value = 3.84 (p-value = 0.05, df = 1) in the chi-square (df = 1) test, it is judged by Hardy-Weinberg equilibrium HWE (Hardy-Weinberg Equilibrium) if it is greater than 3.84, If less than 3.84, it was judged as Hardy-Weinberg Disequilibrium. This indicates that the genotype and distribution of genotypes of the individual monobasic polymorphisms observed in both patients with chronic gastritis and intestinal gastric cancer are common.
ㆍ오즈 비율 (odds ratio, OR)은 장형 위암 환자 중에서 위험 대립인자를 가질 오즈에 대한 만성 위염 환자군 중에서 위험 대립인자를 가질 오즈의 비율을 나타낸다. 95% 신뢰하한과 95% 신뢰상한은 오즈 비율의 95% 신뢰구간을 나타낸다. 신뢰구간은 1을 포함하는 경우에는 질병과의 연관성을 유의하다고 판단할 수 없다. 오즈비율이 1보다 크고 95%신뢰구간에 1이 포함되어 있지 않은 경우 소수 대립인자가 질환군에서 더 높은 빈도를 가지며, 오즈비율이 1보다 작은 경우에는 다수 대립인자가 질환군에서 더 높은 빈도를 가진다. The odds ratio (OR) represents the ratio of odds of risk allele among the group of chronic gastritis patients to odds of risk allele among patients with gastric cancer. The 95% confidence bounds and 95% confidence bounds represent the 95% confidence intervals for the odds ratio. Confidence intervals with a value of 1 cannot be considered significant for association with disease. If the odds ratio is greater than 1 and does not include 1 in the 95% confidence interval, minor alleles have a higher frequency in the disease group. If the odds ratio is less than 1, the majority allele has a higher frequency in the disease group. Have
ㆍ연관성 분석에서 Logit p value는 오즈비에 대한 통계적 유의성을 나타낸다. 이는 오즈비 만큼 만성 위염 환자군과 장형 위암 환자군간에 차이에 대한 유의성을 뜻한다. 여기서 유의성있는 차이가 있다고 판단하는 기준은 Logit_p value가 0.05 이하의 값을 나타낼 경우이다. 이러한 값은 로지스틱 회귀(logistic regression) 분석을 통하여 얻었다. In the correlation analysis, the logit p value represents the statistical significance of the odds ratio. This means that the difference between the patients with chronic gastritis and the patients with gastrointestinal cancer is as significant as the odds ratio. The criterion for determining that there is a significant difference is when the Logit_p value indicates a value of 0.05 or less. These values were obtained through logistic regression analysis.
ㆍ위험 대립 인자 (risk allele)는 p-value에 유의성이 있는 경우 오즈비가 1 보가 크면 소수 대립인자, 오즈비가 1 보다 작으면 다수 대립인자로 하였다.The risk allele was a small allele if the odds ratio was greater than 1 when the p-value was significant and a majority allele if the odds ratio was less than 1.
ㆍ각 네가지 분석모델에 따른 질병과의 유의성을 분석함에 있어 다수 대립인자를 A1이라 하고 소수 대립인자를 A2라 하면 우성 (Dominant) 모형은 A1A1의 빈도와 A1A2와 A2A2의 빈도에 대한 합을 비교하는 것이고, 열성 (Recessive) 형질 모형은 A1A1과 A1A2의 합과 A2A2의 빈도를 비교하는 것이고, 공우성 (Co-Dominant) 형질 모형은 A1A1, A1A2 및 A2A2에 대한 각각의 빈도를 비교하는 것이다. In analyzing the significance of the disease according to the four analysis models, if the majority allele is A1 and the minor allele is A2, the dominant model compares the sum of the frequency of A1A1 with the frequency of A1A2 and A2A2. The recessive trait model compares the sum of A1A1 and A1A2 with the frequency of A2A2, and the co-dominant trait model compares the respective frequencies for A1A1, A1A2 and A2A2.
각 네가지 분석모델에 대한 연관성 분석은 대립형질들이 만성 위염 환자군과 장형 위암 환자군 사이에서 출현되는 빈도수의 비율을 통하여 위험 대립인자가 장형 위암에 어느 정도의 연관성 (위험도)를 가지고 있는지 확인할 수 있다. 95% 신뢰구간에 1을 포함하고 있을 경우 유의성이 없기 때문에, 상기 표 7a 내지 표 7e로부터 확인할 수 있는 바와 같이, 서열번호 1 내지 3, 10, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 다형성 부위의 염기가 각각 C, C, T, A, G, T, T, C, T, A, C, C, G, T, C, T, A, T, G, A, C, C, C, C, C, C, A, G, G, T, C, C, T, T, A, T, A, C, A (위험 대립인자)인 것이 하나 이상 존재하는 경우, 장형 위암에 걸릴 가능성이 높은 것으로 판단할 수 있다. Correlation analysis for each of the four analytical models shows how risk alleles have an association (risk) with intestinal gastric cancer, based on the ratio of the frequencies of alleles between the patients with chronic gastritis and those with gastric cancer. Since there is no significance when 1 is included in the 95% confidence interval, as can be seen from Tables 7a to 7e, SEQ ID Nos. 1 to 3, 10, 14 to 23, 25 to 34, 37, 40, 45 Bases of the polymorphic sites of, 46, 48 to 53, and 55 to 59 are C, C, T, A, G, T, T, C, T, A, C, C, G, T, C, T, A, T, G, A, C, C, C, C, C, C, A, G, G, T, C, C, T, T, A, T, A, C, A (risk allele) If more than one is present, it may be determined that there is a high possibility of developing intestinal gastric cancer.
서열번호 22는 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype), 열성 유전자형(recessive genotype)에서 유의성을 나타내며, 서열번호 1 내지 3, 17, 23, 25, 30 내지 34, 40, 46, 48 내지 52, 및 55 내지 59는 공우성 유전자형(co-dominant genotype), 우성 유전자형(dominant genotype)에서 유의성을 보이며, 서열번호 18, 21, 및 26 내지 28은 공우성 유전자형(co-dominant genotype), 열성 유전자형(recessive genotype)에서 유의성을 나타내며, 서열번호 16, 45, 및 53은 우성 유전자형(dominant genotype)에서 유의성을 보이며, 서열번호 19, 20, 및 29는 열성 유전자형(recessive genotype)에서 유의성을 나타내고, 서열번호 14, 15, 및 37은 공우성 유전자형(co-dominant genotype)에서 유의성을 나타내었다. 상기 결과로부터 서열번호 1 내지 3, 14 내지 23, 25 내지 34, 37, 40, 45, 46, 48 내지 53, 및 55 내지 59의 다형성 부위가 각각 유전자형이 C/C(서열번호 1), C/C(서열번호 2), T/T(서열번호 3), A/G와 G/G(서열번호 14), T/T(서열번호 15), T/T(서열번호 16), T/C와 C/C(서열번호 17), T/T(서열번호 18), A/A(서열번호 19), C/C(서열번호 20), C/C(서열번호 21), G/G(서열번호 22), G/T와 T/T(서열번호 23), T/C와 C/C(서열번호 25), T/T와 T/G(서열번호 26), A/A와 A/T(서열번호 27), T/T와 T/C(서열번호 28), G/G와 G/T(서열번호 29), G/A와 A/A(서열번호 30), T/C와 C/C(서열번호 31), T/C와 C/C(서열번호 32), T/C와 C/C(서열번호 33), T/C와 C/C(서열번호 34), C/C(서열번호 37), C/C(서열번호 40), G/A와 A/A(서열번호 45), A/G와 G/G(서열번호 46), A/G와 G/G(서열번호 48), G/T와 T/T(서열번호 49), T/C와 C/C(서열번호 50), T/C와 C/C(서열번호 51), C/T와 T/T(서열번호 52), G/T와 T/T(서열번호 53), G/A와 A/A(서열번호 55), C/T와 T/T(서열번호 56), G/A와 A/A(서열번호 57), T/C와 C/C(서열번호 58), G/A와 A/A(서열번호 59)가 하나 이상 존재하는 경우 장형 위암에 걸릴 위험도가 높은 것으로 판단할 수 있다. 상기 위험 유전자형을 갖는 핵산 서열이 하나의 검체에서 많이 검출되면 될수록 위험군에서 속하는 확률은 더 높은 것으로 판단할 수 있다. SEQ ID NO: 22 shows significance in co-dominant genotype, dominant genotype, recessive genotype, and SEQ ID NOs: 1 to 3, 17, 23, 25, 30 to 34, 40, 46, 48-52, and 55-59 show significance in co-dominant genotype, dominant genotype, and SEQ ID NOs: 18, 21, and 26-28 are co-dominant genotypes. genotype, recessive genotype, and SEQ ID NOs: 16, 45, and 53 show significance in the dominant genotype, and SEQ ID NOs: 19, 20, and 29 in the recessive genotype. Significance was shown, and SEQ ID NOs: 14, 15, and 37 showed significance in the co-dominant genotype. From the above results, the polymorphic sites of SEQ ID NOs: 1 to 3, 14 to 23, 25 to 34, 37, 40, 45, 46, 48 to 53, and 55 to 59 are genotypes C / C (SEQ ID NO: 1), C, respectively. / C (SEQ ID NO: 2), T / T (SEQ ID NO: 3), A / G and G / G (SEQ ID NO: 14), T / T (SEQ ID NO: 15), T / T (SEQ ID NO: 16), T / C and C / C (SEQ ID NO: 17), T / T (SEQ ID NO: 18), A / A (SEQ ID NO: 19), C / C (SEQ ID NO: 20), C / C (SEQ ID NO: 21), G / G (SEQ ID NO: 22), G / T and T / T (SEQ ID NO: 23), T / C and C / C (SEQ ID NO: 25), T / T and T / G (SEQ ID NO: 26), A / A and A / T (SEQ ID NO: 27), T / T and T / C (SEQ ID NO: 28), G / G and G / T (SEQ ID NO: 29), G / A and A / A (SEQ ID NO: 30), T / C And C / C (SEQ ID NO: 31), T / C and C / C (SEQ ID NO: 32), T / C and C / C (SEQ ID NO: 33), T / C and C / C (SEQ ID NO: 34), C / C (SEQ ID NO: 37), C / C (SEQ ID NO: 40), G / A and A / A (SEQ ID NO: 45), A / G and G / G (SEQ ID NO: 46), A / G and G / G (SEQ ID NO: 48), G / T and T / T (SEQ ID NO: 49), T / C and C / C (SEQ ID NO: 50), T / C and C / C (SEQ ID NO: 51), C / T and T / T (sequence 52), G / T and T / T (SEQ ID NO: 53), G / A and A / A (SEQ ID NO: 55), C / T and T / T (SEQ ID NO: 56), G / A and A / A (SEQ ID NO: 57), one or more of T / C and C / C (SEQ ID NO: 58), and G / A and A / A (SEQ ID NO: 59) may be considered to be at high risk for gastric cancer. The more the nucleic acid sequence having the risk genotype is detected in one sample, the higher the probability of belonging to the risk group can be determined.
(3) 반수체형 분석(3) haploid analysis
표 8a 내지 표 8c 및 도 1a 내지 도 8a는 서열번호 1 내지 3, 서열번호 4 내지 13, 서열번호 18 내지 20, 서열번호 24 내지 26, 서열번호 27, 28, 31 내지 35, 서열번호 36 내지 37, 서열번호 38 내지 44, 서열번호 45 내지 59에 대한 다형성 부위간의 연관성을 나타내며, 도 1b 내지 도 8b는 이를 토대로, 도 1a 내지 도 8a로부터 형성된 연관 비평형 블록(Linkage Disequilibrium Block)으로부터 유전자형의 분석결과와 대비하여 형성된 반수체형(Haplotype)을 나타낸다. 표 9a 내지 표 9d는 각 블록의 반수체형에 대한 장형 위암과의 연관성 검정 결과이다.Tables 8a to 8c and FIGS. 1a to 8a are SEQ ID NOs: 1 to 3, SEQ ID NOs: 4 to 13, SEQ ID NOs: 18 to 20, SEQ ID NOs: 24 to 26, SEQ ID NOs: 27, 28, 31 to 35, and SEQ ID NOs: 36 to 37, SEQ ID NOs: 38-44, shows the association between polymorphic sites for SEQ ID NOs: 45-59, and FIGS. 1B-8B show genotypes from the Linkage Disequilibrium Block formed from FIGS. 1A-8A based on this. The haplotype formed in comparison with the analysis result is shown. Tables 9a to 9d show the results of the association test with enteric gastric cancer for the haplotype of each block.
표 8a 내지 표 8c는 도 1a 내지 도 8a에 나타난 각 단일염기다형들 사이의 연관비평형 블록의 조밀함을 수치화하여 나타낸 것으로 D' 값과 r2값을 나타내고 있다. D' 값이 0.8 이상이 될 때, 각 단일염기다형들은 연관비평형 관계에 있다고 판단하며, 도 1a 내지 도 8a에서 보듯이 붉은 색으로 표시된다. 이러한 D' 값의 범위는 0 ～ 1까지 이며, 각 단일염기다형들 사이의 게놈 DNA 상에서의 떨어져 있는 거리에 대한 계산이 포함되어 있다. 또한 r2 값은 각 단일염기다형들 간의 상관관계를 나타내는 것으로 r2 값이 0.3 이상이면 그 값에 해당하는 단일염기다형들이 매우 조밀하게 묶여있다는 것을 뜻한다. 이는 앞서 언급한 도 1a 내지 도 8a와 표 8a 내지 8c에서 뜻하는 바는 서열번호 1 내지 3, 서열번호 4 내지 13, 서열번호 18 내지 20, 서열번호 24 내지 26, 서열번호 27, 28, 31 내지 35, 서열번호 36 내지 37, 서열번호 38 내지 44, 및 서열번호 45 내지 59의 단일염기다형들이 서로 밀접하게 연관되어 있어 유전적 단위체를 형성한다는 것이다. 또한 이렇게 형성된 단위체들은 다음 세대로 유전될 때, 같이 묶여서 전달 되게 된다. 따라서 연관비평형 블록들이 환자군 특이적으로 나타나 질병을 일으키는데, 많은 영향을 미칠 경우, 그 블록 자체가 다음 세대로 전달되기 때문에, 다음 세대의 자손에 대한 질병이 일어날 수 있는 빈도를 예측할 수 있다. Tables 8a to 8c quantify the compactness of associative non-equilibrium blocks between the respective monobasic polymorphs shown in FIGS. 1a to 8a, and show the values of D 'and r 2 . When the D 'value is 0.8 or more, each of the single base polymorphisms is determined to be in an associative non-equilibrium relationship, and is shown in red as shown in FIGS. 1A to 8A. These D 'values range from 0 to 1, and include calculations of the distance on genomic DNA between each monobasic polymorph. In addition, the r 2 value represents the correlation between the single polymorphic polymorphisms. If the r 2 value is 0.3 or more, it means that the single polymorphisms corresponding to the value are closely packed. This means in the aforementioned FIGS. 1A to 8A and Tables 8A to 8C, SEQ ID NOs: 1 to 3, SEQ ID NOs: 4 to 13, SEQ ID NOs: 18 to 20, SEQ ID NOs: 24 to 26, SEQ ID NOs: 27, 28, 31 To 35, SEQ ID NOs: 36 to 37, SEQ ID NOs: 38 to 44, and SEQ ID NOs: 45 to 59 are closely related to each other to form a genetic unit. In addition, these formed units are bundled together and transferred when passed to the next generation. Thus, non-equilibrium blocks appear to be patient-specific and cause disease, and if so affected, the block itself is passed on to the next generation, thus predicting the frequency of disease in the offspring of the next generation.
연관비평형 블록들로부터 형성되는 유전적 단위체는 각 단일염기다형의 대립인자형 분석으로부터 그 유형이 결정되는데, 이를 반수체형(haplotype)이라고 한다 (도 1b 내지 도 8b). 도 1b 내지 도 8b는 각각 도 1a 내지 도 8a로부터 형성된 연관비평형 블록으로부터 유전자형의 분석결과와 대비하여 형성된 반수체형이다. 도 1a 내지 도 8a에서 나타난 한 개의 연관비평형 블록으로부터 각각 도 1b 내지 도 8b에 상응하는 반수체형이 나타나며, 각각의 블록에서 환자군에서 특이적으로 많이 나타나는 반수체형과 정상인군에서 특이적으로 많이 나타나는 반수체형이 관찰 되었다(표 9a 내지 표 9d). 반수체형은 다음 세대로 유전되기 때문에, 이러한 반수체형이 질병과 연관되는지를 분석할 필요가 있다. 총체적으로 연관비평형블록과 반수체형에 대한 질병관련 분석은 지금 세대에서의 질병의 예측 뿐 만아니라, 그 질병의 다음 세대로의 전달까지 예측할 수 있게 한다. 표 9a 내지 표 9d는 도 1b 내지 도 8b의 반수체형들의 빈도수가 환자군과 정상인군 사이에서 나타나는 빈도에 유의성 있는 차이를 조사한 표이다. Genetic units formed from associative non-equilibrium blocks are determined from an allele analysis of each monobasic polymorph, which is called a haplotype (FIGS. 1B-8B). 1b to 8b are haplotypes formed in comparison to genotyping results from associative non-equilibrium blocks formed from FIGS. 1a to 8a, respectively. The haplotypes corresponding to FIGS. 1B to 8B are shown from one of the associative non-equilibrium blocks shown in FIGS. 1A to 8A, respectively. Haploid forms were observed (Tables 9A-9D). Since haplotypes are passed down to the next generation, it is necessary to analyze whether these haplotypes are associated with disease. Overall, disease-related analyzes of associative non-equilibrium blocks and haplotypes allow us to predict not only the disease in the current generation, but also the transmission of the disease to the next generation. Tables 9a to 9d are tables that examine the significant difference in the frequency of the haplotypes of FIGS. 1b to 8b between the patient group and the normal group.
서열번호 1 내지 3, 서열번호 4 내지 13, 서열번호 18 내지 20, 서열번호 24 내지 26, 서열번호 27, 28, 31 내지 35, 서열번호 36 내지 37, 서열번호 38 내지 44, 서열번호 45 내지 59의 DNA 서열의 다형성 부위로부터 결정된 반수체형 분석결과, 서열번호 1 내지 3의 DNA 서열이 C-C-T 반수체형을 둘 다 가지는 경우(즉, 이배체형을 가지는 경우), 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있으며, T-T-C 반수체형을 하나라도 나타내는 경우 장형 위암에 저항성을 갖는 것으로 판정할 수 있고, 서열번호 4 내지 13의 DNA 서열이 G-T-C-A-T-T-C-G-G-G 반수체형을 하나도 갖지 않는 경우, 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있고, 서열번호 18 내지 20 의 DNA 서열이 T-A-C 반수체형을 둘 다 갖는 경우, 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있으며, G-G-T 반수체형을 하나라도 나타내는 경우 장형 위암에 저항성을 갖는 것으로 판정할 수 있고, 서열번호 24 내지 26의 DNA 서열이 C-C-T 반수체형을 하나라도 갖는 경우, 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있고, C-T-G 반수체형을 둘 다 가지는 경우 장형 위암에 저항성을 갖는 것으로 판정할 수 있고, 서열번호 27 내지 28과 서열번호 31 내지 35 의 DNA 서열이 A-T-C-C-C-C-A 반수체형을 하나라도 갖는 경우, 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있으며, T-C-T-T-T-T-A 반수체형을 둘 다 갖는 경우, 장형 위암에 저항성을 갖는 것으로 판정할 수 있고, 서열번호 36 내지 37 의 DNA 서열이 T-T를 하나라도 갖는 경우, 장형 위암에 저항성을 갖는 것으로 판정할 수 있고, 서열번호 38 내지 44 의 DNA 서열이 G-G-T-A-A-C-C 반수체형을 하나라도 갖는 경우, 장형 위암에 저항성을 갖는 것으로 판정할 수 있고, 서열번호 45 내지 59의 DNA 서열이 A-G-G-G-T-C-C-T-T-A-A-T-A-C-A 반수체형을 하나라도 갖는 경우, , 그렇지 않은 사람보다 장형위암에 걸릴 위험이 높은 것으로 판정할 수 있다.SEQ ID NOs: 1 to 3, SEQ ID NOs: 4 to 13, SEQ ID NOs: 18 to 20, SEQ ID NOs: 24 to 26, SEQ ID NOs: 27, 28, 31 to 35, SEQ ID NOs: 36 to 37, SEQ ID NOs: 38 to 44, SEQ ID NOs: 45 to Haplotype analysis determined from the polymorphic site of the DNA sequence of 59 shows that if the DNA sequences of SEQ ID NOs: 1 to 3 have both CCT haplotypes (ie, diploid), they are more likely to develop gastric cancer than those who do not. Can be judged to be high, and if any of the TTC haplotypes are shown, it can be determined to be resistant to enteric gastric cancer, and if the DNA sequences of SEQ ID NOs: 4 to 13 do not have any GTCATTCGGG haplotypes, If the DNA sequence of SEQ ID NOs: 18-20 has both TAC haplotypes, it can be determined that the risk of developing gastric cancer is higher than that of those who do not. It can be determined that the risk of getting a high risk is high, and if any of the GGT haplotypes is shown, it can be determined to be resistant to enteric gastric cancer, and if the DNA sequence of SEQ ID NOs. 24-26 has any CCT haplotype, It may be determined that the risk of developing gastrointestinal cancer is higher than that of the non-human, and if both have CTG haplotypes, it may be determined to be resistant to enteric gastric cancer, and the DNA sequences of SEQ ID NOs: 27 to 28 and SEQ ID NOs: 31 to 35 may be determined. If you have any of these ATCCCCA haplotypes, you may be determined to be at higher risk for gastric cancer than those who do not. If you have both TCTTTTA haplotypes, you may be determined to be resistant to gastric cancer. If the DNA sequence of 36 to 37 has any TT, it can be determined that it is resistant to enteric gastric cancer. When the DNA sequences of SEQ ID NOs: 38 to 44 have at least one GGTAACC haplotype, it can be determined that they are resistant to enteric gastric cancer, and when the DNA sequences of SEQ ID NOs: 45 to 59 have at least one AGGGTCCTTAATACA haplotype, The risk of developing gastric cancer is higher than that of those who do not.
도 1a 및 1b는 각각 서열번호 1 내지 3의 단일염기다형들 간의 연관비평형블록 및 상기 연관비평형블록으로부터 형성된 반수체형을 나타낸다.1A and 1B show associative non-equilibrium blocks between the monobasic polymorphs of SEQ ID NOs: 1 to 3 and haplotypes formed from the associative non-equilibrium blocks, respectively.
도 2a 및 2b는 각각 서열번호 4 내지 13의 단일염기다형들 간의 연관비평형블록 및 상기 연관비평형블록으로부터 형성된 반수체형을 나타낸다.2A and 2B show associative non-equilibrium blocks between the monobasic polymorphs of SEQ ID NOs: 4 to 13 and haplotypes formed from the associative non-equilibrium blocks, respectively.
도 3a 및 3b는 각각 서열번호 18 내지 20의 단일염기다형들 간의 연관비평형블록 및 상기 연관비평형블록으로부터 형성된 반수체형을 나타낸다.3A and 3B show associative non-equilibrium blocks between the monobasic polymorphs of SEQ ID NOs: 18-20, and haplotypes formed from the associative non-equilibrium blocks, respectively.
도 4a 및 5b는 각각 서열번호 24 내지 26의 단일염기다형들 간의 연관비평형블록 및 상기 연관비평형블록으로부터 형성된 반수체형을 나타낸다.4A and 5B show associative non-equilibrium blocks between the monobasic polymorphs of SEQ ID NOs: 24-26 and haplotypes formed from the associative non-equilibrium blocks, respectively.
도 5a 및 5b는 각각 서열번호 27, 28, 31 내지 35의 단일염기다형들 간의 연관비평형블록 및 상기 연관비평형블록으로부터 형성된 반수체형을 나타낸다.5A and 5B show associative non-equilibrium blocks between the monobasic polymorphs of SEQ ID NOs: 27, 28, 31 to 35 and haplotypes formed from the associative non-equilibrium blocks, respectively.
도 6a 및 6b는 각각 서열번호 36 내지 37의 단일염기다형들 간의 연관비평형블록 및 상기 연관비평형블록으로부터 형성된 반수체형을 나타낸다.6A and 6B show associative non-equilibrium blocks between the monobasic polymorphs of SEQ ID NOs: 36 to 37 and haplotypes formed from the associative non-equilibrium blocks, respectively.
도 7a 및 7b는 각각 서열번호 38 내지 44의 단일염기다형들 간의 연관비평형블록 및 상기 연관비평형블록으로부터 형성된 반수체형을 나타낸다.7A and 7B show associative non-equilibrium blocks between the monobasic polymorphs of SEQ ID NOs: 38 to 44 and haplotypes formed from the associative non-equilibrium blocks, respectively.
도 8a 및 8b는 각각 서열번호 45 내지 59의 단일염기다형들 간의 연관비평형블록 및 상기 연관비평형블록으로부터 형성된 반수체형을 나타낸다.8A and 8B show associative non-equilibrium blocks between the monobasic polymorphs of SEQ ID NOs: 45-59 and haplotypes formed from the associative non-equilibrium blocks, respectively.
<110> College of Medicine Pochon CHA University Industry-Academic Cooperation Foundation <120> Polynucleotides derived from ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes comprising single nucleotide polymorphisms, microarrays and diagnostic kits comprising the same, and analytic methods using the same <130> PN0304 <160> 59 <170> KopatentIn 1.71 <210> 1 <211> 801 <212> DNA <213> Homo sapiens <400> 1 ggaaccatga acccttctgg agggaatggt atctctgggc aactctcatg ccagctgctg 60 ctggaagcct ctgggacctg gacccttagt tctccgggtg tgggtttggc agggagagcc 120 agaaaatgtt tgcatctttt gccggcttgt ggtgggatgg acaggacagg gagctgggca 180 cgttgctgtc ctggagggaa cccaggagga ggcgacacct gacccttctt gcagacactg 240 aagtgtaaac tgaggcccag ggactgggga gagggtgagc cagagcaggg gcactgggag 300 ggctcagggc cctggtccct ggtcccgtgg agggtctgac gccggggcct ctctcctagg 360 agatcttcgg gcctgtactg tctgtgtacg tctacccgga ygacaagtac aaggagacgc 420 tgcagctggt tgacagcacc accagctatg gcctcacggg ggcagtgttc tcccaggata 480 agtgagtggc caggccgcag ccctggtgct gtgctccggg tgtcctgtcc gtgtccccat 540 ccccacctcc tggacgtggt tcccagtaat aatgctgccc ctaccttctc tctgtcccct 600 cccctcagcc cagacaggca gccagggctc gccacatggg cccacagcag caggctcttt 660 gttgccggta ctggtggtgc cggtgccagg gtgccactgg ggaccagtgg atctgaacct 720 ctaggggcag ggctaggaat tggtgtcttc gactggctct gcgggatctg gtgttgcccc 780 actgagtgag gtgattgtcc c 801 <210> 2 <211> 626 <212> DNA <213> Homo sapiens <400> 2 aacattttct ggctctccct gccaaaccca cacccggaga actaagggtc caggtcccag 60 aggcttccag cagcagctgg catgagagtt gcccagagat accattccct ccagaagggt 120 tcatggttcc ctctgccacc aaggggctgg ggggaagatc ttctcaggca cactccagcc 180 ctgcactacc aacttgggca agtgccttga cctcagtttc tcatctgtaa aatgggaaca 240 gtaacaccca cgtcatctca gccaagtgct cagccacagc yggccccaca gtaaaagtct 300 atcagtgtca gccattatga tggctgcagt ggacgtggtt gctgagggca ctggaaatgc 360 tcagacccca gccagggtca aggacacagc cccggatttg gagttaggca gcctgagctc 420 aaaacctggc tctactctct cccggtcgga ggcattccct tttagggtct ccctttaggg 480 cctcatctgt gaaatgggag aatgtctcca ggagaactgt gtgtgtgctg tgctccggtg 540 ggattgtcct cctctggacc ccaggctgcc caccccagtc acctccttca tgatgggctc 600 ctgagggtcc ttgctctcca cgatgc 626 <210> 3 <211> 641 <212> DNA <213> Homo sapiens <400> 3 acacacrtac acttgtgtgt gnnnnnnnnn nnnnnnnnnn ntnnnnnnnn nnnnnnnnnn 60 nnacacacac acacacacac agtgttcatg tctgtccttg tctctkctgt ggctcagcca 120 gaccctggct tttgcccttg gcgtccccta cccctgcccc tgtttcagga gttgggccct 180 tcagntgcag gtgtttcggg gtgagtgtgt tgtgggggct gccgcaggga tgccttccca 240 gcctcttaga cctccctcct ccctgcccac cccagtcctt tgcccgtatc aagaagtggc 300 tggagcacgc rcgctcctcr cccagcctca ccatcctggc ygggggcaag tgtgatgact 360 ccgtgggcta ctttgtggag ccctgcatcg tggagagcaa ggaccctcag gagcccatca 420 tgaaggaggt gactggggtg ggcagcctgg ggtccagagg aggacartcc caccggagca 480 cagcacacac acagttctcc tggagacatt ctcccatttc acagatgagg ccctaaaggg 540 agaccctaaa agggaatgcc tccgaccggg agagagtaga gccaggtttt gagctcaggc 600 tgcctaactc caaatccggg gctgtgtcct tgaccctggc t 641 <210> 4 <211> 924 <212> DNA <213> Homo sapiens <400> 4 cggccaacca agttgacttc tgattaacca gcttttaggg aaggcctcta agatttccag 60 tttatctatt gttccttgtg taaaagtatg tacttaccat aaatcctgcc cttaggcaga 120 ttcacacagc attcttgcct ttccctgggg gactgacttc aaatgtccgt cacattcctt 180 tcctatagca tataggccct gggtcttggg ggtaatggca tggggatcca ccatcttgtc 240 tccctgccgc tgaagccaga gactatggct tctgttcata aatccctttc tccttaaata 300 tgaagtcaaa ggtcatgtag ataggagctg ctgctgaaga agggattttt tgtctgaaga 360 gttctgtccc ctgggcttac ttggctatgg ggtggacccc tggccaggag acagcaaact 420 gtttcagtaa tgtgcgtgtc gtgcgtgtgt gtgttctgtg gtgagcaggc ctatgccatt 480 aaacaaacgg tgtggctttg rgcaagctgc tatcttggga cctcagcaca ctcattcata 540 aattgtgtct tttgggtgag atttgtcttg gggtcttcaa aacccctgag actgtggaca 600 catacagcag cctaacggca ttgaggaggg caagcattca acagttagga caatgtgaac 660 tgtagctcag ctctgctagg taccttcaca agacctcgaa tgctgcccct tactatgcct 720 cggttttctt atctataaaa acggcatttt tatcttgttg gtggagctgt taaataaatt 780 aaaagacgta aagggtctgg caccatggtt ggcaaaaaat atcagtttcc cttctcgact 840 tctcgatttt gcccaggacc agtgatgttc acattcagga cctgcctgaa ccggcaagcc 900 ctccacgtgg gtccaaagtg caaa 924 <210> 5 <211> 677 <212> DNA <213> Homo sapiens <400> 5 tgggcttact tggctatggg gtggacccct ggccaggaga cagcaaactg tttcagtaat 60 gtgcgtgtcg tgcgtgtgtg tgttctgtgg tgagcaggcc tatgccatta aacaaacggt 120 gtggctttgg gcaagctgct atcttgggac ctcagcacac tcattcataa attgtgtctt 180 ttgggtgaga tttgtcttgg ggtcttcaaa acccctgaga ctgtggacac atacagcagc 240 ctaacggcat tgaggagggc aagcattcaa cagttaggac aatgtgaact gtagctcagc 300 tctgctaggt accttcacaa gacctcgaat gctgcccctt actatgcctc ggttttctta 360 tctataaaaa cggcattttt atcttgttgg tggagctgtt aaataaatta aaagacgtaa 420 agggtctggc accatggttg gcaaaaaata tcagyttccc ttctcgactt ctcgattttg 480 cccaggacca gtgatgttca cattcaggac ctgcctgaac cggcaagccc tccacgtggg 540 tccaaagtgc aaagggaaag tcactgctag aggcgccagt accagcatag cgcccccacg 600 cgccgagtcg gggaactgcc gcgggggccg gccccgccca ccagcgcctg cgcctgcgca 660 gaggcaccgc cccaagt 677 <210> 6 <211> 601 <212> DNA <213> Homo sapiens <400> 6 agagaagcct ggcacattcg gggaaggagc tatgaagcca gcgtggtgga gtgtagggtg 60 ctgatgagaa gggtgagaga taaggcggga gacgtggtga gatgagcagg ttaagcgcct 120 tcaatctctg ggccccagga gagcagaggc taggaggaaa tgaacccagg gtgttcttgg 180 gaaagcttct cccaaggtgt accagaagtt gaggtaatgt acctgctgcc acatctatcc 240 ggtcattcaa caggtattta ctgagggtat gcagtaaaca aagagtgttt acagtacagc 300 yggagcaaaa aggaaccaac agaaaaagac gtgttatttg aggccagaca gtgagaactg 360 ctaaaggaac aaagtccctg aagagggaca gggactatgt cagatgggag gtctcagcag 420 cagacatcat ggtgctccgg cagcaggaca gcaccacgtc ggccggctgc cactcatgcc 480 acaaaaggag gcatcaagga tcatgttagc cccaaagcag ctgacattca ggtgtccact 540 ttctccaaaa aggcctcagg agaagcagca gccacttgag cagctacctc caccggcctg 600 c 601 <210> 7 <211> 699 <212> DNA <213> Homo sapiens <400> 7 tgaatatagg gagccccaac tcttacttcc taatttgagg atggtgagtg ggagggaaca 60 gaaaggatgc tggggaaaag tgggaatcaa agtgctcctg gaaggggaag aggaacggcc 120 taaccctaac agtgattaag gttattagga ggccgggaat ggtggctgac gcctgtaatc 180 ccagcacttt ggaaggcgga ggtgggtaga tcacttgagg tcaggagttt gagaccagcc 240 tggccaacat gatgaaaccc tgtatctact aaacatacaa aaattagcct ggtgtggtgg 300 cgggcaccta taatcccagc tactcgggag gctgaggtag gagaattgct tgaacctgga 360 aggtggaggt tgcagtgagc caagatcgtg ctactgcact ccagcttggc gacagagtga 420 gactccatct caaaaaaaaa aaaaaaaacg tattgggagt cgtcgatgtg tggtagccag 480 aggccctctc ccctctccrc cagctatccc tgtaccctgc gccagtacct ttgtgtgaac 540 acacccagcc cccgcctcgc cgccatgatg ctgctgcagc tgctggaagg cgtggaccat 600 ctggttcaac agggcatcgc gcacagagac ctgaaatccg acaacatcct tgtggagctg 660 gacccaggta ggaacctgct gcaccatcag agctctcca 699 <210> 8 <211> 601 <212> DNA <213> Homo sapiens <400> 8 gagagagaaa aggaggcatt tttgagaaat gtttaatgga gatgtagctc atggaagcag 60 ctgagaactg atcagagaga gatggaaaac atctcctgag agcagatctg gacattgtga 120 aattaatata aaggaatgca aaggcagacc tatccgaagc cataattgga gtggcagctg 180 gctcaggggc aggcttagtg caaagagctg agccatacct gcatcccagc actgttctgc 240 cactccgtta actgctctct gtacgtggcc tgctatcttg gtgcgcagtg aaggttagaa 300 yaacagctgc aaccagttat gaaatgatag aggagactac ttacctggtt caagggacca 360 gatagctgtg cacaagaggc actaggcttt ccacccaggg ggaaaggcta tttcaacaat 420 gcatgctgcc ccatgcagag gtgtacacat ggaaaagctt ggagcacggg taggggacag 480 gcagtatttg tcacctgagt gaagggcatc agtaggagat agggtagagg aagaattggg 540 ttgggaccag agaagggaag accctcacta acaaagcagg ctttgggttg agactgtgtt 600 a 601 <210> 9 <211> 801 <212> DNA <213> Homo sapiens <400> 9 atcagagaga gatggaaaac atctcctgag agcagatctg gacattgtga aattaatata 60 aaggaatgca aaggcagacc tatccgaagc cataattgga gtggcagctg gctcaggggc 120 aggcttagtg caaagagctg agccatacct gcaccccagc actgttctgc cactccgtta 180 actgctctct gtacgtggcc tgctatcttg gtgcgcagtg aaggttagaa caacagctgc 240 aaccagttat gaaatgatag aggagactac ttacctggtt caagggacca gatagctgtg 300 cacaagaggc actaggcttt ccacccaggg ggaaaggcta tttcaacaat gcatgctgcc 360 ccatgcagag gtgtacacat ggaaaagctt ggagcacggg yaggggacag gcagtatttg 420 tcacctgagt gaagggcatc agtaggagat agggtagagg aagaattggg ttgggaccag 480 agaagggaag accctcacta acaaagcagg ctttgggttg agactgtgtt aacagatgtt 540 ctagctacag cttcccttcc tgttgcagag accatctgcc cgagtagccg caaatgtgct 600 tcatctaagc ctctggggtg aacatattct agccctgaag aatctgaagt tagacaagat 660 ggttggctgg ctcctccaac aatcggccgc cactttgttg gccaacaggc tcacagagaa 720 gtgttgtgtg gaaacaaaaa tgaagatgct ctttctggct aacctggagt gtgaaacgct 780 ctgccaggca gccctcctcc t 801 <210> 10 <211> 801 <212> DNA <213> Homo sapiens <400> 10 accagttatg aaatgataga ggagactact tacctggttc aagggaccag atagctgtgc 60 acaagaggca ctaggctttc cacccagggg gaaaggctat ttcaacaatg catgctgccc 120 catgcagagg tgtacacatg gaaaagcttg gagcacgggc aggggacagg cagtatttgt 180 cacctgagtg aagggcatca gtaggagata gggtagagga agaattgggt tgggaccaga 240 gaagggaaga ccctcactaa caaagcaggc tttgggttga gactgtgtta acagatgttc 300 tagctacagc ttcccttcct gttgcagaga ccatctgccc gagtagccgc aaatgtgctt 360 catctaagcc tctggggtga acatattcta gccctgaaga mtctgaagtt agacaagatg 420 gttggctggc tcctccaaca atcggccgcc actttgttgg ccaacaggct cacagagaag 480 tgttgtgtgg aaacaaaaat gaagatgctc tttctggcta acctggagtg tgaaacgctc 540 tgccaggcag ccctcctcct ctgctcatgg agggcagccc tgtgatgtcc ctgcatggag 600 ctggtgaatt actaaaagaa catggcatcc tctgtgtcgt gatggtctgt gaatggtgag 660 ggtgggagtc aggagacaag acagcgcaga gagggctggt tagccggaaa aggcctcggg 720 cttggcaaat ggaagaactt gagtgagagt tcagtctgca gtcctctgct cacagacatc 780 tgaaaagtga atggccaagc t 801 <210> 11 <211> 801 <212> DNA <213> Homo sapiens <400> 11 tctggaccag ctactgaatt attaatctca cttagcgaaa gtgacggatg agcagtaagt 60 aagtaagtgt ggggatttaa acttgagggt ttccctcctg actagcctct cttacaggaa 120 ttgtgaaata ttaaatgcaa atttacaact gcagatgacg tatgtgcctt gaactgaata 180 tttggcttta agaatgattc ttatactctg aaggtgagaa tattttgtgg gcaggtatca 240 acattgggga agagatttca tgtctaacta actaacttta tacatgattt ttaggaagct 300 attgcctaaa tcagcgtcaa catgcagtaa aggttgtctt caactgagct gttctagttt 360 tctcttcccc agcactgtca tctagatttt ccatttcagt rattcccacc cctcggtcta 420 ctagcaacaa caactttctt gtatcctttg aggagacgtt agggagaacc atcatttcac 480 agttaaaaga aagacagtcc agtcctaggc aaaatttcat gaagccactt aggattttgt 540 atccagtcag tcatcaccca cagcaacccc cacccacagc cattagcaaa ccaggaccgg 600 ggccaggtga agtttgaggg caacatctcg ctttattttt atttatttat ttatttattt 660 atttatttat ttatatttga gacagagtct taacactgtt gcccaggctg gagtgcaatg 720 gcgtgatctc agctcactgc aagctctgcc tcttggattc atgcctttct cctgcctcag 780 cctcccgagt agctgggact a 801 <210> 12 <211> 801 <212> DNA <213> Homo sapiens <400> 12 ttctaaaagg aacggtggag gttagggatc tctagataag tcactactac cttaaaaaat 60 tggaagtgcc aataccagca atatagcaat aaagccctga aataatctga cagcacctga 120 aacactcagc ctctgacact tttagctaaa agcctccttc ttccccttct gagtcctccc 180 catatacaca cactgcacca cccggatccc cggcccctaa gcctcctggc agctacctct 240 gggagccggg cgccgccttc tgcactgctg agttgaagaa ggagtcgctg aagaagtcga 300 gggagccgct gaagatgacg cgggcattgt tcctggcctg gagcccagca atgaggaggg 360 tgttcttccc caccgcatgt ggatactggg aacaaaacga rgctgtgacc caagcagttc 420 caagtaaggg aaaagctgcc acgcctcccg aacaagagga cagcaggcca gaccaaaacg 480 accctggccc tacctgaagg gggagcctga gaccacaccg cttctgccca tgccccaccc 540 caccaactag tcatttcctt cgcctcagcc aaatgtgctg ttctgcttca tttttatttc 600 gaagcctcaa ggttgtgaag cccttacctg ggtgataggc ttgtccggga agaaggagta 660 agaggtggaa gagcccgtca ggatgtccag caccaaaggg ttatcaggat cggccaccat 720 cctgcagcag gacgagagca gcccagcact ggccccagga actgagccca aggacatggg 780 atccccgaga gccagttctt c 801 <210> 13 <211> 635 <212> DNA <213> Homo sapiens <400> 13 atcataccta gccttttctt tttttttttt ttaagcaggt caatttgaag aaaaatatta 60 ggtagttatt agcacaggag atacgtaaca tggtaaaaac catgaaggac gtgtgcaaat 120 gactaaagtt tgggaaacac tgttttacac tctctgtcgt ttctcccacc aacagtatcc 180 tctctcagcc ctctcccgag cagtctcatt cactgctttt ttccttctga cctatacaag 240 ctgacagtgc ctccgcttca tcttacatcc tgacacaggg tttggtaact catttcaggt 300 ctttatttcc tcaaaaacag actgaaaaaa ctcctccagg gcagactccc tatccttaag 360 atctcaccca gtccactgta aggtacctat ttcaaagttt caaacacagc aaaaacttgg 420 caaacaccag ttactgcacc raagcccagt catcagaaga tttcaacttc taccaatttg 480 gggtgacatc cgcctaacta atcttgcctc caaaaagcca attccaaaag cacatgttgc 540 aagggagttg ggagtgacac agtaagtaac agaagcctag ggaaagtact tgagggattc 600 ggtggaactg aatctcgcat gaactacaga gaata 635 <210> 14 <211> 601 <212> DNA <213> Homo sapiens <400> 14 cagacttgtc gtcggctgct gggggacaga ctcctcccca ccctgactgc ctcgcctctg 60 cacaggccat ttccacagcc agggatgcct tttctgcttc catcaatgca cagccacccc 120 ttccttcaaa acggagggga gaccacgccc ctggagacac ctccacaccc ctctgttctc 180 accacgcagg ccctaaggcg gcattgaatg cagtctggag tcaagaactc aagttcaaat 240 cctggctcag actctttgct gtgtgacctt gggcaagtcc tggcatctct ttgagcttca 300 rctttctcag gaccaaaccc acggtgaagg tacggtgata tcgcgttgga ccccagcggc 360 agccctgccc ttcccgctgg gccccacctg cctgtccctt ctccatgttc ccacccgctt 420 gggtctcacc tcccggatca gctgcttctc ggcctccatg tcatgctgga tcacaggttg 480 gggcaacagc ttctcctcca cctgcacagg gtctgggggc acctgcctgg acagcagggc 540 tgggggagaa acagaaatta gcagccagga tgaggggcac attgtgtgca ggaactaagc 600 a 601 <210> 15 <211> 801 <212> DNA <213> Homo sapiens <400> 15 tgcacaggcc atttccacag ccagggatgc cttttctgct tccatcaatg cacagccacc 60 ccttccttca aaacggaggg gagaccacgc ccctggagac acctccacac ccctctgttc 120 tcaccacgca ggccctaagg cggcattgaa tgcagtctgg agtcaagaac tcaagttcaa 180 atcctggctc agactctttg ctgtgtgacc ttgggcaagt cctggcatct ctttgagctt 240 cagctttctc aggaccaaac ccacggtgaa ggtacggtga tatcgcgttg gaccccagcg 300 gcagccctgc ccttcccgct gggccccacc tgcctgtccc ttctccatgt tcccacccgc 360 ttgggtctca cctcccggat cagctgcttc tcggcctcca ygtcatgctg gatcacaggt 420 tggggcaaca gcttctcctc cacctgcaca gggtctgggg gcacctgcct ggacagcagg 480 gctgggggag aaacagaaat tagcagccag gatgaggggc acattgtgtg caggaactaa 540 gcagaaatct ataaaaagac gacctcatgg tcattcaaga agactttaaa gtattcagct 600 tatttcaaac acatctccat gtaaaaggct gttagtcatc caacaaatat ttatggagca 660 cctcgatgtt ccagactctg aggatgcggc attgaacaaa gacaaaaact ccacacccac 720 gctgagtttt ccactgggaa aaagaggaga aaagcagatg gacaaggtga aatgcctcgt 780 ggtggtgttc gaggccctct c 801 <210> 16 <211> 801 <212> DNA <213> Homo sapiens <400> 16 ggtggggggt gtggtggggg tgggggggat aatggatgag cagatgagag gcggggagtg 60 ggcaacagcc tgcgtcagat gggacaggcc agacggactg ccctcctccc aggacactga 120 caagcagata ccatctgggc cgtctccaac cagggccctg cgctcacatg gggctgaggg 180 gtgggaggat gctgctccca ctgtctttta ggtgggaagt tggaggcgag aagacagagg 240 gaaggaagct ttctcctggg gacctggccc tcccgccact accccaacgt ggtcccacct 300 gacaggctgc tggggctcat ctgctgtgtc aggatggcct tgagcttctt gatctcctcc 360 tggtactcgc gaagcagcgc atccttgggg tcctcattga ygcgcggctt gttcctgatg 420 ttcttggccc ggttggcgta gcgcagcgtg ctgagtgtct catcgtagtt gttgtccgca 480 ggcgacaggc aggccaccat gagcgtcttg gtgttgccgc ccagtgagtc ctgcagcagc 540 cgcgtcagct tcgagtcacg gtaggggacg tgcttacagc gcccgtccac cagcgccgag 600 atgacattgc ccagtgccga gagcgacagg ttgatcttgg tggcctcctt gagccgctcg 660 cccgtggccc cggtcttgga ctgccgctcg ctgcccgcca ggtccaccag gttcagcttg 720 cccgcccgga ggtggtcctt gccccgctca tctgcacaca gaccaggcaa agtggcgagg 780 gcctcgggtg agccctatgt a 801 <210> 17 <211> 401 <212> DNA <213> Homo sapiens <400> 17 tcagatgttt ggggctcaga gctcagtcta gataaaagct cattaatcca gcttccctat 60 ggttcactag gcttggagta ttatatgcat gacattgtat taggttcaaa tgaataaggt 120 ttgagtgtgt ttgtcctaat ttgggaagta acttaagtgg atcgaatacc atctctcttt 180 ggagtagtcc aattctgcta yattaattac tagtcttttg aaggataaat tatctgagaa 240 aattaaattg tttctaggca agggttggaa gacaaagggt taattatctc tccaaattga 300 aaaagaccaa gacaacaatc ctgtaggtgg ttaggaaggt gcggtaagtt gactaacact 360 caaaatgttc tcattgcaaa agtgagtcct cattggtcaa a 401 <210> 18 <211> 601 <212> DNA <213> Homo sapiens <400> 18 tcccctttga aaaccaggaa tgaattcaca tagagaatca gaccttgagg agttgagttg 60 ttctctattt tctaaagaat ttagtttata ccttcaaaag ggcttccctt tgtcttgaga 120 tattctaagt tccaagtagt ctcaagtggt ttttgtagca ggagctagac tggaaaaact 180 ctagagcttt gtatttcatt ataagcattt gtctattgtg tgcagttagg atatagagag 240 cataagatgg attcagtgcc ctcgcgccag ggaggctgta tgaaggggaa gacaagaatt 300 ktatgagcac atgttaatgt ccctgtcact cttgcttctg ttgcagtgat agccctcatg 360 gagagactac ctcggttgaa gactcaaccc aggatgtgac cgcagagcac cacacgagcg 420 atgacggtac gaggccctgc ttcctggtca gtggggacgc caggggtgag gcagaaggaa 480 gcgattatat atcctgtgca tctgatgaac ctgtctgccc agcggtcccc tgagggcagg 540 cagagagctc cctgtctcaa tttcattccc ttccttcctt ggagaggtag cccaccttct 600 c 601 <210> 19 <211> 801 <212> DNA <213> Homo sapiens <400> 19 gcgacagagt aagactccat cccaaaaaaa aaaaaaaaaa aaaaaaaaaa gggatgcttg 60 agttgtgttt tgatgtgctt catcaggcag ataagagaga agaagattcc tggtggaggg 120 aacagtgtga gcaaaggcag gtaaaaggtg ataccagtgc tttcaggata atggtatagt 180 ctgcgtgaga attacttgct ttatagatca tccatggctt cgttttccca ctaagtaatt 240 tcctaccact gtaagttcag ctaattcagc ttttccaccc agtttcctga gtctgcaggt 300 cccaagaaca tgtgtttact tcttttccac ccttctcaga atgtgagccc atcgaggcca 360 ttgccaagtt tgactacgtg ggccggacag cccgagagct rtcctttaag aagggagcat 420 ccctgctgct ttaccagcgg gcttccgacg actggtggga aggccggcac aatggcatcg 480 acggactcat cccccatcag tacatcgtgg tccaagacac gtacgttggg cccatggcat 540 ctttgggggt ggtccccagc tgctctatgg gaatgagact tcatttctgg agccatagga 600 ctatgaggga ggccaacccc tcgggggtcc agtgcagtcc tgaggctcac acagttcctt 660 gaagagcagc ccccccaccc cccgccccac tccctgcact cagtggagaa tttttttaaa 720 tctctccact atctgtgccc cctgcaaatc accccctaat ccagtcattt tagaaacctg 780 ccagccagcc agcactcatc c 801 <210> 20 <211> 801 <212> DNA <213> Homo sapiens <400> 20 aaccagtcat tttaatttgc aagtggaaga gtggctcaac aggttggggt gagcatagtt 60 gtttaaaaaa aaaagagagt aacaaaaatg ttttcccagc ctgatctttc gagaaaagaa 120 atataggtgg tcaaataaaa accccttgtt atcactcatc aggtataaat atggatgagt 180 gctggctggc tggcaggttt ctaaaatgac tggattaggg ggtgatttgc agggggcaca 240 gatagtggag agatttaaaa aaattctcca ctgagtgcag ggagtggggc ggggggtggg 300 ggggctgctc ttcaaggaac tgtgtgagcc tcaggactgc actggacccc cgaggggttg 360 gcctccctca tagtcctatg gctccagaaa tgaagtctca ytcccataga gcagctgggg 420 accaccccca aagatgccat gggcccaacg tacgtgtctt ggaccacgat gtactgatgg 480 gggatgagtc cgtcgatgcc attgtgccgg ccttcccacc agtcgtcgga agcccgctgg 540 taaagcagca gggatgctcc cttcttaaag gacagctctc gggctgtccg gcccacgtag 600 tcaaacttgg caatggcctc gatgggctca cattctgaga agggtggaaa agaagtaaac 660 acatgttctt gggacctgca gactcaggaa actgggtgga aaagctgaat tagctgaact 720 tacagtggta ggaaattact tagtgggaaa acgaagccat ggatgatcta taaagcaagt 780 aattctcacg cagactatac c 801 <210> 21 <211> 601 <212> DNA <213> Homo sapiens <400> 21 atatgttttt ctagtctctg gcatgggtag cctctcctgg tcatagacca gtctctttgt 60 aagttattgt ggcagttcac acagtagcca ccaggggtct ctgtttccat tacaaacttt 120 gttctgtctg ggccagagaa cctagccttt gaaatctctc catcatatga aacataacgg 180 gatgggacaa tcccgtaacc tgtttggggt tgggggcttt ctctctgtgt tctttccatt 240 gatgtgaatt ggtcattggt gtttgctctt gcctctcctc catcccctag aagtacaccc 300 ycgtcttatt aaggagcttt taaagttttt ctgaatgtat agacatttct cgggttccta 360 cctttgtctc tgatggacca ttttccattt aagacatttt cctgtataag acagttttat 420 agctggttcc ttttagggta aagagtctta agagagtttt attgtgtcta tggcaggttt 480 gggaaaggta agaaatgggt cctttttcct cctaatgttt ttggcactta aaacataaaa 540 ttcattatcc tattaaaaaa ttaaattcag ctttgctaat ccagaaattg ttcccaaatg 600 a 601 <210> 22 <211> 601 <212> DNA <213> Homo sapiens <400> 22 agagaacata actccacaga cattccaaag agaaaaatta agtttagcat ttttctgacc 60 acaaagtaca gaataagcag atttttagga cctacttttg tgtatataat ccttattaaa 120 aataaaagga tatcataaaa ttaaaatatc agtaaacatc tgcttttctt tatatgttcc 180 ttaggctaag attataaaat caaatatgat ttttactgaa gggaattact agccatcccc 240 taacaacccc atcttttcct cacataagaa aatgcaaatt atgtctaatt tgtgttcacc 300 ratgaatctt atcacttaaa attacaacac agctagagaa gcaagagaag gaaaagtagt 360 gaagtgtgtt taaaagttat tctttcttac caatatgttg ctgtagaatc caagcgtttg 420 aggcacgagc agagagcatc ctttcaacag ctggtgcaag tgtcttccaa ttagtaaact 480 ccaaagtgaa gataagggtg tcaatgctga ctgagtcaat cctatgttag caagatgtta 540 atataatatt agaaacaaaa catgccaagg gttcgtactt gaaacaaaca ccacatacct 600 a 601 <210> 23 <211> 611 <212> DNA <213> Homo sapiens <400> 23 gaattcttta tctgtcattt ctgagtttcc atttgggtca ggaaccattg tgggaacacg 60 actgtgatcc ttcagtggtg tcactatatt tagatttttc acaaatccaa aattcttggg 120 gtagttcctt ttcatctgga gatgttcaca cttctaattt ttgtaattat tttcatgcag 180 gtgggatttt tttctttttc tttctttcac tataatatta ttgtttttcc ctttcacatt 240 tatgatttta aatatcaact cagaaacctg ttgaaagaga ccctttttct ctgattgtag 300 gcattattta tcatgcagtg gttatgaaga aagagatgta atagagagta tagtcaatat 360 tagttttaag gcgtggctcc catatatgtc atatctactg ataatttttc ataaatctta 420 gcctgaatca attagtkgca taatttggat tttatctttt tcagcagtta tcagaaatat 480 tatccatgtt tgatagtttg tatttttctt tttaaatgtt tacttattgg gccccagaat 540 gcttgttgga ggagggattg gaatgaaatg tatccttcat tgaataggat nttttgtttt 600 agcttaaaaa t 611 <210> 24 <211> 601 <212> DNA <213> Homo sapiens <400> 24 aaactgctca agtccctaca ggaaaggaca gccccatcat tcaacttgcc aataaacctg 60 ctttagtgat agatcattat gttcctactc agataaatta gtagctgtgc actgcattgt 120 tagtaataga tacttaataa ccaggtttat aaatcaattt gtatttactc ttatttacca 180 cttacataaa accataaatt tcacaacctg atttatattt gagacaagaa ttattcctct 240 aggaaatata gtttaaagct catgatctta acagtacaaa ggctaatgga taatcttacc 300 ygatgaaata agtatgctca agctttctag cttgccatac tgagcagcca caaataaagg 360 tgtgattcca aagtcatcct ggcattcctt gtttgctcct tttctaagaa gcaattttat 420 gatctcagca ttttcctaaa gcacagattc acattttaaa taagaaaaaa acaaagaaaa 480 tagaaggtat ctttcttctt actgtgtttt ttttttcttt tttatcctct cactaaagga 540 taacttgaag gaaaaaacaa aacagtatac tgctgtatta gttggaaaga aattggccaa 600 a 601 <210> 25 <211> 701 <212> DNA <213> Homo sapiens <400> 25 ataagatttt tttttcattt caatcataca gttattctgt atctcccact atagtaggag 60 gcaggaagtg ggaatcaaca cttctcagtc acaaaattag aaaggcacat ttggataatg 120 agtcacatta gaaaacacta atacacatga aacaatggga atataaaaat ccttaaaagt 180 gtaaaacaag aaatgataag ygtgcttatt actgaagaca agtaacatgc cattgatatt 240 gtactagttt tatatattga atttatacca aagcttattt cccctataag acactcagaa 300 gttctttaat aaaaaattct ccaccgagtg tggtggctcc cgcctgtaat cccagcactt 360 tgggaggcta aggcgggtgg accacgagtt caggagatcg agaccatcct ggctaacatg 420 gtgaaacccc gtctctacta aaaatacaaa aaaattagct gggcatggtg gcacgcacct 480 gtaatcctag ctacttgaga ggctgaggca ggagaatcgc ttaaacctgg gaggtggagg 540 ttgcactgca ctccacctgg gttgctgcac tgcactccag cctgggcgac agagcaagac 600 tccatctcaa aaaacaaaac aaaacaaaac aaaaaaccaa aactcttact ctgaagggtt 660 tcagaaatgt aaccaatggc tgtgacagta ccactgaggt a 701 <210> 26 <211> 696 <212> DNA <213> Homo sapiens <400> 26 cttagtcaat acaaatttac catttacaaa atggtaaatt cactgccaca gaaacaaaat 60 aaatcctact actaaaaata agtgatttaa agttatttac tggtttgaat tatctcccat 120 cccttgcttc attaacataa aaaagtacaa gttaactaca tgttgaaata taaaccccta 180 aaaactatgc atctctaatt ktctccaaat actaataaaa gtaggcacaa tactgaattt 240 cataaatggg actctaataa taataataat aatttgaaac tgtaaactat gtggccagaa 300 tagcatttct caaatagtcc catggaatat caatgtttct ggaggtattc ctaaatgttc 360 cataaagaaa aagaatacag ctgggcacag tggctcatgc ctgtaatccc agcacttaga 420 gaggctgagg caggcagatc gcctgaggtc aggagttcca gattagcctg gccaacatgg 480 tgaaacccca tctctactaa aaatataaaa attagccagg cgtggtggcg ggggcttgta 540 atcccagcta ctcgggaggc tgaggcagga gaaacacttg aacccgggag gcagaggttg 600 cagtgagccg agattgtgcc attgcactcc aggctggaca acgagactga aagaacagta 660 cagtcaaata cgtttcaaag ctctgcgata aacaaa 696 <210> 27 <211> 601 <212> DNA <213> Homo sapiens <400> 27 ccagacagag gcacttccgt ataagatgtc caactagagt atcatactaa ttgaatccaa 60 ggcaggcaat cttactatcc ttaataaata aattcaggca gttattttat gactatagaa 120 agggaaacaa atactactgt taataagtta tgtattatac ttttttatgt tttattaatc 180 cagcttgtag gcaaagcctc cataccttga atttacttta cctgcattaa ttaacatttg 240 caaacattct acagagttgt gataagctgc ttcatgaatt ggcatccatc ccctgttatc 300 wgcaacatcg acacttcggc cctttttgag cagtttcctt aagactttaa cattgccttc 360 cctggcagca agtccaactg tagagcacgt gtccgcgtaa gcctctgtaa aatccatttg 420 tttgaccagt ctacaaaaca aggtagaagg ataatactat agtcaataaa acaacacttc 480 actcctagag gtcagcaaat cacggtgggc ctgtctagta tctctcacat gactgacgaa 540 gaagggccca caatacagaa agtgactgcc atgccacagt ctctgctggt gcctaaagca 600 g 601 <210> 28 <211> 401 <212> DNA <213> Homo sapiens <400> 28 tatttggctc tgaaattgga actgggctta tttctaacgg ggccgaggaa ggagaaaaga 60 gcaggagtcg tcactcgtgt ccagatacgg aggcggtgta ccagcaccgc aggtagcaaa 120 gcacctagaa acacgttttg ttctgctttg gaaattagat ttttgcctat ataacagcag 180 ccagaggaat gtaattcata yttgatttta tgtcctgaaa aaaaagtctt ttgcctttca 240 aataaaagca gaaagtttac aatagaagtt tacgcttgtg aaagagtagc tgtcatttca 300 atgggaattg tttatatatt taaattttac acaaatttat tcatctttag tattatcatt 360 ggcttgttca caaaagagca ggcaaatgtt cttaacttgg g 401 <210> 29 <211> 610 <212> DNA <213> Homo sapiens <400> 29 ggcggcggag gatggaggaa ggaggcggcg gcgtacggag tctggtcccg ggcgggccgg 60 tgttactggt cctctgcggc ctcctggagg cgtccggcgg cggccgagcc cttcctcaac 120 tcagcgatga catccctttc cgagtcaact ggcccggcac cgagttctct ctggtcagtg 180 ccctcactaa ccccgcagcc acccctcctc ctgacactaa gkgttcggcc tcttccctcg 240 gttttctttg ctttttctcc ccaagacctt ctctgcagac tcttaccttc cccaagccaa 300 agctgctttt atgcagcgtt cattcattcg ttcgttctca cgttatgtgg atgcgtcccc 360 cttgctgagc attagggatc cagcaatcac ctgctctcca ccttttcaat tctgtcgcac 420 tagaccttgc ttcccaacat tcccaccctg cagaagcagc tttcgtagaa taacgtcagg 480 tgcacttact catcttcctt tcggaaaatt aactgtggct cttacttcac cagcagactt 540 ctttccttca gtattacatg tcaccctgcc cacaccacag tacttcagac tcgagttccc 600 tctctcgtat 610 <210> 30 <211> 501 <212> DNA <213> Homo sapiens <400> 30 ctgcggctta aagggcttgg taatgacaag tatttcaaat atttgaaaac agctttatca 60 tatatttgca cctaaacttt catttacatt aataggtgag taaattttcc tcctacattt 120 tgaaggacaa tctgcagtct ttgctttcta aaggatccat tcagaaacta aagatttatt 180 tgaccttata aaaagataaa taggcttttt cttctcctca cttctcatcc accctcagag 240 agtggcccat rctgtcttcc atgcccagtc aacagtgact tccaaacaca ggtcagcctc 300 tcccctcctc ctctagtaaa tcttgttacc acccttaaca cagttcctgc tgtcctcatg 360 ctttttaaca caccatatac atgttaagaa ctatcttaga ccatacaagc catgcaactc 420 ttttctccac cccctttctc cttttccctc ctggtagaaa atttcatttt tcctattggt 480 aaacaattaa ttcataggac a 501 <210> 31 <211> 1225 <212> DNA <213> Homo sapiens <400> 31 tgctttttaa cacaccatat acatgttaag aactatctta gaccatacaa gccatgcaac 60 tcttttctcc accccctttc tccttttccc tcctggtaga aaatttcatt tttcctattg 120 gtaaacaatt aattcatagg acaatgtcac tagggaaata tcaaagtaat aagcgacttc 180 caaacccaga atcagaatca cctgggagca tgttaggcac tcagattaag gtaccctctt 240 tttaggtctg tggtgggatt cgtgtggttc tcaaacctgg ctgaacaact gaatcatcat 300 agagcttcta atactgtaat gcctaagcac ccctgccaga gaagttttca ctgaggaaca 360 gagagggcac ccagtatctt acatctttgt ttaaagttcc catttaggaa ccattgctaa 420 ggcagtttca tacagcttaa ytaaaaaaag ctgaagtggt caacatacaa cataaagcct 480 cacttctcaa cgtgtggcct caggaccagg aattgatatc atgaagtggg aacaatgaat 540 tccctgtaca tttaaacaaa atcccctcat gattcttagg cacatcaatt taagaaccaa 600 tcagttagga tcaggcacgg tggctcacac ctgtaatcct agcactttgg gagtccgatg 660 caggtggact gcctgagctc aggagtttga ccccagcctg ggcaacatgg tgaaactgtc 720 tctactaaaa tacaaaaatc agccgggcgt ggtggtgcat gcctatagtc ccagctattc 780 tggaggctaa ggcatgagca ttcctcatgg gaacatggga ggcagaggtt gcagtaagcc 840 aagattgtgc cattgcactc cagcctggat gacagagcaa aactctgtct cccacacctc 900 cacacaaaaa caatcaatca cctaggtcag tgctaggtga actttctgtg atgatggaaa 960 agttcatcga tattattcag tgtggtaacc actagccaca tgtggctcaa gagtatttaa 1020 aatatgccgg tgagactgag ggaatacatt ttttatttaa ttaaatataa atagtcagat 1080 atggctagta gctactgtat tgtacagggc agatccagat aatttatact ggtcagagga 1140 catacattta cagatacaaa tctatggctg caaaaggaaa tccacaggag tcactgccta 1200 cagaactgtc ttctcctctt aatga 1225 <210> 32 <211> 501 <212> DNA <213> Homo sapiens <400> 32 caattaggta acaagacatc caactctaaa agcctaataa atgaaatttt tattcttcct 60 attccagtag aaaggcttct gggtactccc tctttaacag aatgggtgta agaatccaga 120 tcaagttctc acaactttta gaacccagag tcctcagggc cacacaaaat gtcccagccc 180 cacccaggag gcaaccaaga ataagatgta ttttccttta tctaactatt cccaggctga 240 caccactcat ytacaaaggt ccaaaagcag tcacacattt tctctgcttt aaacctaaag 300 caaggaggca cagcaaaatt ctcatttcca atggccgtag caaaagccat gtttaaaaac 360 aaacaatccc cgccatccaa ctttatctaa acactgacat ctaagaatgt cagcaaaaag 420 aaaaaaaaca ataaatatct agttctcagt caccaaacca atgtaaattc agaactttgc 480 tgacttacct ttctatgcat a 501 <210> 33 <211> 1355 <212> DNA <213> Homo sapiens <400> 33 caggaatctg tgtagtaatt acttctcaac ttttttgtat ttttttcaga agtcaatgtg 60 taaacatcat taagcagtta tgttatacat ctatatttta gagatgttaa aaacttacta 120 tcggccaggc gcagtggctc atgcctgtaa tcccagcact ttgggagccc gaggtgggca 180 gatcacttga ggccaggagt tcgagacccg cctggccaat gtggtaaaac cctgtctcta 240 ctaaaaatac aaaaattagc tgggtgtggt ggtgcatgcc tgtaatctca gctactcggg 300 aggctgacgc atgagaagag cttaaaccca ggaggtgaag gttgcagtga gccatgatcg 360 tctcactgta ctccagcctg ggcaacagag caagactctg tctcaaaaaa aagccaaaac 420 ttactatcta taatgtcatc tattgaagta caccattcat caattacctt agggcatcgg 480 cattcttttc ytgttggcgt ttaattcctt ccttaatttt ttctgggcta agcaatatct 540 ggttgataga ggggtttttt gactgttgaa gtaattccgc tatttcaaca catgactttg 600 gaatcttgtt aaaaagaaaa aagcaggaaa aaaaatgaag ttctgatgca tactacctga 660 acgaaccttg aaaatgtcat gctaagtgaa agaggccaga cacaaaagtc cacatatttt 720 acgattccat ttatatgaaa tatctaataa tgggcaaatt tattgacaga gaaagtggtt 780 tccaggggtt tggggtatgg aagaatggga agcgactgct attaggtact tgttttcttt 840 tggggtgatg aaaacattgt ggaggccaga catggtggct catctctgta atcctagcac 900 tttgggaggt caaggtgagg ggactgcttg aggccatgag tttgagacca gcccggggaa 960 cacagcaaga cccctgtctc tctctcaaaa aaaaaaaaac aacttaaatt agctgggtgt 1020 agtggtgcac acctatagtc ctagttacta ggaaggctga ggcaggggat gattatgcca 1080 ctgcactcta gccttggggg acagaatgag acagaatgag aatgagaaac aaagaaaaag 1140 gaaaatgttc tggaatttga gtagttacac agccctgtga atattctact gtgcatataa 1200 catgtccata ttaaaagggt gatatttatg atatgtgaat tacatctcaa ttaaaatttt 1260 tcttctaaaa aataaagtat aatctaatga cagtcgcaaa tagcaaccct atgtttgatt 1320 taaaaggaat acatttagaa cagtggtttt taaac 1355 <210> 34 <211> 601 <212> DNA <213> Homo sapiens <400> 34 gacaaatgta cctttataat aagaaacaat gacttagtat catcttctga attatcaagt 60 atgtggtcta taatggaaga aagaaaagga ttttggttaa aatattttga actactataa 120 gaatcttgag gcattagtca agaatctatt aagaaaaaaa atcactgccc aatattctca 180 ccatttagaa taaaaaacat taagtaaaca catgcatgtt atagattaaa attccaaaat 240 acttattcca aagtacaaat aagttaaatg tacagataca cttactaaga agtttcctta 300 yaactgtagc aattacttct cggtggttct ctcgagacag atctattttg aaaaaataaa 360 agaaggtatt ttagacactg aatgctcctc agacttttaa agtttatatc aacaggttag 420 gtcaaggagg gataaagtat tggagaaaaa aataggtctg cctttaccat agttgaatta 480 atggctaggc atgctacagc aacttctaaa acctctacac ttaaatgacc tgcttatgag 540 atgtctatca tgcttcaaga taaagaaaaa taataataat aaaaaataga taaaatgacc 600 t 601 <210> 35 <211> 601 <212> DNA <213> Homo sapiens <400> 35 atatctcaca aaataactga tatttttgaa ggtaacctct gaatggtggt tgtataagaa 60 tattaataaa gtaacatttt taagctactg ccaacctgga tgatatcttt tttggagaca 120 aattttcccc aaattgccaa tcaaaatatt gtgaagctaa aggaatctgt tgtcattaac 180 agagttttag aaaccaagaa aaaaacttat ccaaaattgt aaagagagaa taatgacctt 240 atgacttact cattgtaagc tgagttataa cactgcagca gtggggaaca aagagcttca 300 ragattcttc tgggcagcac tgaaaatgta tttgtataag taaggctttt ttgaaaggca 360 aatatataca agattatatt ttcagtggca gtaaaaggct gtaaataagc agctactgaa 420 agaactatgc attttaagca tagaagcacc tctaataatt aaccatataa actagttgat 480 tgttgagtca ttaatacatc agttcaaaaa aataaactca cctttacagc agcgcggcac 540 atgtctgcca ccatgcgacc tgctactctt gtttcaaata tatgtgaagt agaaaaatta 600 a 601 <210> 36 <211> 601 <212> DNA <213> Homo sapiens <400> 36 tggtgccagc tgccaacagg tacagaatgt gggctcagca actgttagct taaacaaagc 60 attgtttact caacagaggg gaaggaggag gacatgaaaa ggcaggtcta tttctaaaca 120 tcatttaaat ttcttttagg ggtggtaagc aacttgacct tgaaaactga ttcaaagaga 180 gaattctttg aattctttta acatcctgag aatatagaaa caagttgtaa ttttctgtct 240 gcagaagcgc tacatgttta ttttagaaca tttaaaaagg aaaaactaaa aattctttag 300 kttctaccac ctgaagagga ctgctatcga tactctgagg tagccacatc atttcaggct 360 catcaagagg ggtgtttctt aacaatatgg gtgtgttggc tgcctcctgc tttagacagt 420 aatcagacac cttggacctt ggttatttgc tctttggaac aagcatcgaa ttgaatccct 480 ttgagagttc tgtaaagttc agctctgagg tggaagctga gcctcttagc tgaaaacatg 540 gctgtaccta aggctggaca tctgctctcc ttctcttgcc caaatacggt ttctgaatag 600 a 601 <210> 37 <211> 701 <212> DNA <213> Homo sapiens <400> 37 cccttttggg gagaacaggg ttccacgttg gtgtagtttg tcttcccccc actccttgcc 60 caccaacttg agccacactg gcctctgtcc tgctttccct acaaactagt tccggcctca 120 ggacctttgc aggagctgtt tcctctgcct gtaacccttg cctccatctt tgcatgagca 180 gctgcttcat ttcattcagc tcttaacctc aatgtcactc ctcagaatgg gtcctgcagg 240 acctctctat ctgcttcaca gcaatgctca cccctaggca ctttatggaa ttgtgaattg 300 ttggcttgtt tactgtctgc ctcccatgag ctagagcatc agtcccgggg agcaagagct 360 taatttttca tggtcactac tgtaccccta gcacctagaa taccatctag gctatggtca 420 gtgctcaaca aatgtttgcc gaatgagatg cctccgtgtt ggtgagaggc tgcctctcag 480 taacatcact ctcttgtgtg ytcaggcaac caaaggaggt actgtcaaag ctgcttcagg 540 attcaatgcc atggaagatg cccagaccct gaggaaggcc atgaaagggc tcggtatgtg 600 tcctgctgga agtgaatcct cctgcgtgca ttgcacatca cagggtcaca caggagggtg 660 ccatgtctgc tggccatcac gtgggtcttc ctttaataaa a 701 <210> 38 <211> 1001 <212> DNA <213> Homo sapiens <400> 38 ttaatggaag acagatggct tctcatatct atttctactt caatttgtta tgatatgtgg 60 ttttggttgg ggtatatgaa gaaaatctgg cttgtacaga tatgtacttg aaaatggggg 120 gagtatttga acagacagtt gttgatgcac agacaatgtc aaatagcctt aggaaaaccc 180 cactgtatgc ttgtggaaga atgacagtga aaaggcaaat aacatctgag tgttattctg 240 aggatagttt tgacttgcag gccccttgaa agggtcttgg agaccccaga catccctgga 300 ccacacctgg agagtagctg gtctaatttg ctatagcagt taagcggagc tactttcttg 360 cattgcagga cttgatagac gacctgaagt cagaactgag tggcaacttc gagcaggtga 420 ttgtggggat gatgacgccc acggtgctgt atgacgtgca agagctgcga agggccatga 480 aggtctgtgc tcttcctctc rtgctcttgg tgctgttggt gcaaacgctg atgtgctttc 540 ttaagaaact gtcacccaat aagaaagaca tggaagcaac ctaaacgccc atcaatggta 600 gactggataa agaaaatgtg gtacatgtac accatggaat agctgtaaaa aggaacaaga 660 tcatgtcctc tggaggaaca tggatggagc tggaggtcat tgtccttagc aaactaaggc 720 aggaacagaa aatcaaatac catatgtttt cacttacaag tgggagctaa atgatgaaaa 780 cacatggaca catagagggg aacaacacac actggggcct gttggaggat ggagggtggg 840 aggagggaga ggatcaggaa aaataactaa tgggtactag gcttaatacc tgggtaatga 900 aataatctgt acaacaaacc cccatgacac aagtttatct atataacaaa cctgcacatg 960 tacccctgca cttaaagtaa aagttaaatt tttttaaaaa a 1001 <210> 39 <211> 576 <212> DNA <213> Homo sapiens <400> 39 tattgttata ctgtctcgat gttccatggt ctaggcatgg ctcatcagag tggtaaatat 60 gggaggaaaa gagaaagtgg gaaagaaata tgagacacag gcaggcgtta ctaagtaaat 120 attggagaca agagcaaagt ggaaattgga gatgatttcc agggttctgc ttctttaggt 180 gtaggaggaa caacagcaat attaacagaa acaggcaagt ccggaagaag agctggtttg 240 aagggaaaat gagttctggt tcagttcatt aagggkatag tagaatatct gtaatgaaac 300 atctaaaaag caatgtgaaa tgagagtctc aagctcagga aggaggccgg ggataaagat 360 gcaattggga agtgatgtga aatgtctgaa gtctccagct tcccttttca ggcaaccctg 420 ccccacctag ctcagtcctg ctttattttc cagctggaat tttccaggta gcttcctacc 480 tggtcgtcca gcctccagtt cctctccact gttcatccta cacgtcacta ttacattact 540 cttctgaaag tgcagctcca gtcacatcac tcccat 576 <210> 40 <211> 671 <212> DNA <213> Homo sapiens <400> 40 tactgttctt taccaggcac cagacttcta ggagtcctaa gagggcatgg tagtggtgag 60 aaatggttca cctccctcaa agccaggcat tcctgggatt ttgtttcttg aggatgctgg 120 aagagtctca tggacatgaa agtgagacag atttccctag gagctaaggt tgcctgcact 180 gcaagcttca aatcagcgtt ygatctgtga actaaatatt ctgaatccta ctcaaagctt 240 ggagaggtgt gacaattagg tgattttaac tgcagatttt tttttttaga tggagtctca 300 ctctgtcgcc caggctggag tgtagtggcg caatctccac tcactgcaac ctccacctcc 360 taggttcaag tgatcctcct gcctcagcct cctgagtagc tgggactaca ggcatgagct 420 ttgtattttt tgtagaaatg gcgtttcacc atgttggcca ggctagtctt gaactcctga 480 cctcaagtga tccacccgtc tcggcctccc aaagtgctgg gattacaggt gtgagccacc 540 atgccccacc aagctgtgga ttttgttact acgtctacaa ggcatgcagg aacttgtttc 600 tatttctgac taggctatga ggtaacttga ttttgcagag ctgaactata taactagttt 660 aagattcaag g 671 <210> 41 <211> 701 <212> DNA <213> Homo sapiens <400> 41 attgctgctc tgtaaggccg ttaaagtaga aataacctct ctcactaagg aatgtaaaaa 60 caaatatggg tcagtcatac aatgagcagt gaaaattatc tagcgattga ccaaatggat 120 aaatcttgag agtataattt tgagagagga gaaaggtgca caatgagagg tacaactatg 180 attccattcc atgatatgtc taaacatgca aaagaaaata ttatttatgg gtatgcatat 240 aaggacatgc atggacatga tatacaacat tctcagcaca gtgattgcca ctggggaggg 300 agacagaatg agatggagga ggtacgcagg ggcttctgcc tatatgtatt gttctattta 360 aaaaagaatg aatcattgat tacacctcaa taaagctggg aggaaaaaag aatgaaagca 420 agtctgataa aatttcaagc tagtggtcgg tccacaggaa tctgtattac tctatttgaa 480 atattttcat tattttactt raaaagtaac agaagggagt cagggaatga acgctggctg 540 tccggagtcc atcacaagag ctgctactac tccaagcaga cactagtaaa ttttgctagg 600 gcctcctgaa ggcacttttg agtccagaca gtcatggtgc cagaccctat tcggacatcc 660 cactggcact tgagaggaaa ggaaaggagt gccgggaacg t 701 <210> 42 <211> 601 <212> DNA <213> Homo sapiens <400> 42 gtccacagga atctgtatta ctctatttga aatattttca ttattttact taaaaagtaa 60 cagaagggag tcagggaatg aacgctggct gtccggagtc catcacaaga gctgctacta 120 ctccaagcag acactagtaa attttgctag ggcctcctga aggcactttt gagtccagac 180 agtcatggtg ccagacccta ttcggacatc ccactggcac ttgagaggaa aggaaaggag 240 tgccgggaac gttcccataa cttaacgggt tccattcacg tctacagcag gggagggctc 300 mtgttaagga agcccaggaa tccagcatat cgcctcatcc tagggccccc tctcacagga 360 ggccacgccc aagcaagcag agcgtggccc cagcaagcgc cgagctcccg caaggagacc 420 aaatagcttc ggggttttgc cactagctta gcacaggccc ataagcaccg gggactcaag 480 gcacctttgt agaaacaatg agtgactgga gtcccaggtc ttgccactac agaggcgcgt 540 atgaaccacg gtttaacact acgtctacgc cgaagttcgg gttagtcaga ggccacgccc 600 a 601 <210> 43 <211> 1631 <212> DNA <213> Homo sapiens <400> 43 aagaattttc aaaagaggat tcaaaagaca aatattatga tgacatacca gaagataatc 60 gaacatacct gatccttttc aagtgtaagt atttgatagc cagttgttct actacatatt 120 agttttccac tactatcaaa agaagccaaa cgtaatctag gattaaaaaa aaaataaaaa 180 ataaacacaa gatttttaaa ccacagatta aacaagctct tcctyacttt catatttact 240 ttttcctctg ttttttattt gataaaagac ttttaggaag tcttttcaaa ctgtaatctg 300 actgcattca gtgacaagcc tgtgctatta tacatatctg gccaagagaa atcatttata 360 aatgttttta ttgtggtaaa atatacgtaa catttatcat tttaaccatt ttaaagtata 420 tagttctgtg gcattaaata tatttccaca ttgttctgca cccatctcta gaacatttta 480 attttccctc gctgaagctc cttacccatt aaacactaac tccccacttt cccttccctc 540 aggccctggc aaccaccagt gtatcctctg tacctatgaa tttgtctact ctaggtactt 600 cgtatgagtg gaatcttaca atatttgtgc tttgtgagtg gcttatttca cttggcatgt 660 cttccaggtt catccatgtt tagcatgtat gagaatttgc ttccttttca aggctaaata 720 atgttctatt ttatgtatat accacatttt gtttctctag catctgtcag tgaacatgtg 780 ggttgcttcc accttttggc tattgtgaat aatgctgtta tgaacataag tatacaaaaa 840 tatctgttta agtccctatt ttcaattctt ctggtctata gaagagaaac tgctggatca 900 tatggtaatt ctgtttaatt tttttgagga agtgtcatac catgctccat agtggctgtg 960 ccattttaca tggccacgag cagtacacaa gggttctaaa tactccacat ccttgccaac 1020 acctgttact tttgttgttt tttttctatt ctgtttttac taatagctat cctaataggt 1080 gtgaagtgat agctcattgt gattttggtt tgtatgtccc taattagtaa tgttgaacat 1140 cttttcatgt gtttattagc catttatata tcttctttgg agaaatgttt atggaagtct 1200 ttggcccatt tttgagctga gttgagtttt ctttttaaat tatagagttg taggagtttt 1260 ctatatattc tgggtattaa tgtcttatca aatgtagcgt tacaaatatc tgctctcatt 1320 ccatgggttg ccttttcact gtcttgacac tgtcctctga tacacaagtt tgtgattttg 1380 atgaagtcca attttatcta ctgcttcttt tgttgcctgt gcttgggtgt cttatggaag 1440 aaatcactgc caaatcaatt gttatgaagc ttttccccta tgttttcttc caagagtttc 1500 atagttgcag ttcttatgct tagatctttg atccatttta agttaatttt tgtatttggt 1560 gtaaggtaag tataaatata tgacttttaa atcatgttca ttaagctact gtccaatttg 1620 tcagcttctg g 1631 <210> 44 <211> 601 <212> DNA <213> Homo sapiens <400> 44 catctgtaaa tttcttttta tttggctaaa ataatctaaa agaataattt ggttggccaa 60 ttagaaatgc ctttttcagt tggtgtattg aaagctttcc tttaacattt tcacctgctc 120 attgtgattc ctccttttag tctaatatct ttccaggtca tacttgtttt taatcattaa 180 atattttctt cctggttttg gagactaagc tgataaactt tttttaaaac ttaagcattg 240 tcattgctat tttttttaat ttgactttcc taggagttta agaacagtga aagttagctt 300 ygcaccttca aatgatcttg aatgagggaa aaatcagttt gattccaagg atatttcttg 360 ccttacatgg tcttttcttt gacagtctgt acacctttat tattaggttt tgaattattt 420 atgtaccaga tattatagtt ttaaacattt taatattctc tgatctttag aattatttat 480 gttcaaattt tagttgggaa ctttgtttcc tacttaagct caggactttt taccctctga 540 attgagtgcc tttgagtgac acatgctaat agaaatttca tagtaaatgt aaataaggtc 600 a 601 <210> 45 <211> 401 <212> DNA <213> Homo sapiens <400> 45 attcagttaa aaaaccccca gacaaatgct tgttagtaat ctgatgggaa aacttacttt 60 atttatactt tctccaaaca gagcttggta gtaagaagtg tatttgtctt aatataattt 120 ttgcttactt ttttggaggc ctttgcttga gatacttttt tggaaaaagg aagatgttct 180 tagtttccat caaagacagt rttgcctgtg ttgtcatcct tactgtggag acgataagcc 240 atcaataagg ctgcatggtg ggcaacagct ttccaaaact gagtggtgaa tcacctcttt 300 tcaattatat atctaaactt ggtaatatca gcttgtaaga gaaggtcatg cagtatcttc 360 catccaatta acatgtatag aacacctcct ccacaactca t 401 <210> 46 <211> 601 <212> DNA <213> Homo sapiens <400> 46 gactaaactg acttcaaagc acaaagcaag cacttggtga cagtagagcc cttagttacc 60 tgctgtttct ctgtcagctg aggtcagctc tccgttgatc ccattctctt tggtatttga 120 ataggtgccc tgtgacccat gctctccaaa ggcaccctct tcatcctccc tgtatgggaa 180 tccattggcg cttcggacaa gtccttcccc tgctccgcct tgatccttaa tctcaggtgg 240 atgtgagtgt gcagatgcct ctgttagcgg tgctgaggtc cagtgaggtg cctttgcttc 300 rtctttccgt tcatctgcca ttcttcaatg ccttgttatt tctcctgcaa ctgaaagaga 360 aaaaatagta gctattactt tggggaaatc ttctgatctg atattggttg taccaagata 420 ggaaaaattt atagcaaacc gtgtggcttt ctatggtcaa agaaaacatg tacaataacc 480 tatgtttaat atcaagaatg ggtcaattag ttcatcttga gttttacaga ccatttctgg 540 aatattagtt cttttaaaat aagatcaatg tcattctaca catattcctt tttgtaaaca 600 a 601 <210> 47 <211> 601 <212> DNA <213> Homo sapiens <400> 47 ttgtggttga gaataaaata aaaatattat ttgcacattt catggttaca atgaggatta 60 attaagatag taaagtgtac aaagtgaatg gctcaagaaa taataactgt taattaattt 120 tattattatt ggtggtagtg gtggtatcaa tatggatgac atagcactct tgatcaagta 180 atatttttct atagctgagt atacacaact ttaacagggt ggaacttggg tgtcaggagc 240 actaagagga ttttcaaggg attgcagcat gaggagatga gagcatgtta tagcatattg 300 rttgtgagga agaaaagagt tagtatgata tgtcaaggtt tttttcatca tcgtatcttg 360 cagcattaga ccttcaatat tccataaatg tgtgttgagt gagcgagtga atgaaggaat 420 aaatgaataa attcaaaaag aagaaagtcc tcttcacatt aatgatgaaa acaattgaaa 480 agtcttactt tgtcccttgg gctctcgcca gttgactctc agtgcctgtt atgaaagctt 540 gtaatacaca aaaaaaaatc actgcagtgt gcttggtcat gcagtaaaaa ccaacaccat 600 t 601 <210> 48 <211> 601 <212> DNA <213> Homo sapiens <400> 48 atatccatat aagctagccc taaattaggt tcaaatccta ttcatcaaca agccaagcca 60 aatattatga ttgaagctaa tccccacaac cagcttcacc tagtagagag accacatagg 120 acaaagcaaa cgtgacaata caaacctcgt ggaactgcct tttctatcaa tccttgtctt 180 tctcactctt tctagccccg gatgcctaac ctttagaagg aaaacactga aaagatcccc 240 attttctgtc ctcatccatc ggtgccacca ggcccagatg cttcgcagtg aggctgtgtg 300 rttttctgca gatccaccct tgaatgctaa ataactctgc tctgcacact cctctctctg 360 cggagctcag ggaaatggca gccagagcaa tgagtggttg gcatggcaac taggaaagga 420 aaatctgcaa cctctcgcat tgttaggcga gcttgtttat ttgcttgggg ggttggtgtg 480 gatggcttta gtcattttgc aggagaaatg gctcagtgct attttgctcc gcataaatta 540 atatattaca tagaataggc catattttaa atgggatgct gactcctatt agtaaatcgc 600 a 601 <210> 49 <211> 401 <212> DNA <213> Homo sapiens <400> 49 aagtgaagtt cagtacttca tataagatac aaagtcactc acgattataa caaagctctg 60 gctataggtt ttgtgtagtc atttcaggaa gacccaaaca aggctacagt ataatcattc 120 accaaaacct gtaaagggaa ataatcatct cttatgaaag ttttagtata ttatccttat 180 gggtggaggt catgaaataa kgcattggct ttattttaat aataactatt tctagtggtc 240 tggaaaatga aaaaattaag ggccacttag ggaaaagtct aactgtaagc tcaccaccct 300 aacgaaagac tatgcaaaca ctacaacaaa ccagtggaaa aagatgaaaa taggtcctag 360 tgcataccca gtcaaggtgt ctgatgaatg ttacatgtaa g 401 <210> 50 <211> 601 <212> DNA <213> Homo sapiens <400> 50 acctctctat aaaattcaga aaaagattca atagtaagcc gcatttggtt tatttatagg 60 cccattacct gattcatgca tttttgaaaa cctaaaaaat aagacaagca tttgatattt 120 tcaaaaaaaa atgattttat catctctaga aaaacagatt agagatgcct gctaaaattc 180 catcattaat ctcattaatg tgtctacctg ttcaattaat aaaatatttc attttggccc 240 taatttacca tatgaaaaca cacacaggca ggcaggtgtt tttagtctgg attcagctac 300 ygactgaaaa aactattaga actctctatt gttcaactgc tcaatctgga aacatgtgtt 360 atcttgatca ctaatagtta ttttagggaa tatatttttt aaacaacctt ttgttcactg 420 agtctaattt caaaacccat cttctgtatg tattctcaga aatggaaaaa taagctttca 480 tagcctgagt gaactttcag acaaaaacca tatgctgagt aaacttctgg tcttagcaat 540 caatacacat gaaaaggaac cagagaaaaa ggttctaaaa gatgtaattc atttacagtt 600 a 601 <210> 51 <211> 401 <212> DNA <213> Homo sapiens <400> 51 gggcctccgc actagactcc atttggccct tactgaggcc cttgggttgg tctgaggact 60 tagcagcccc acactctttc tcaggaagag cagcaggttt ctcttcctca gccatccgac 120 tctctagcgt ttcttcttct tagggatgaa aaagatgttg acatcatgac cacagaacaa 180 tacatgaaac gacagaaata ytgctaaagg aacactttca gctccattag aatgacctca 240 tgaagacctc agctgttttt ttattttacc attgggatga acaaattaat attctaatgc 300 aacatacatt aggtactggt tggaaaacta tgatgtataa tctgctaata gtgatgactt 360 ttaaagtctc attaaaaggc aatttatttt aaagtttgag a 401 <210> 52 <211> 801 <212> DNA <213> Homo sapiens <400> 52 attagcttat aacttttatg tatagaaggc acatgaattt gtttcttctg taatacacat 60 cacataatgt ttaggagaga ccaaaaaaaa aaaaaacaaa gaaaaaaaga gaaaagaata 120 tccagaaata tactgttctt acaattcctt tgcacattaa tttacaacca gagttcattt 180 tagtaatagt acacatatat ctcagtcctg accttttcat attgactttt acatgggtag 240 catgcttgca tgttccataa tttttgtttt tattctacca ttcatttatc acttcaaaat 300 ataattttaa gcttatttcc tgaacgcact tgcctattat ttgtttaaaa atcaacccga 360 ttacttcaga tttacttaca gcctcgaaga tggagttcca ygatcaacag gaattgactc 420 cctctacagc tgagccttca gaccagaagg aaaaggagtc agagaagcaa agtaagcctg 480 gtgaagacct taaacatgct gccttagttt ctcagccaga gacaactaaa acttaccctg 540 ataaaaagga catgcaaggc acggaagaag aaaaagcacc cctagctttg tttgggcaca 600 ctcttgttgc cagcctggaa gacatgaaac agaagacaga accaagcctt gtagtacctg 660 gcattgacct ccctaaagag cctccaactc caaaagaaca aaaggactgg ttcatcgaaa 720 tgccaacgga agcaaaaaag gatgagtggg gtttagttgc ccccatatct cctggccctc 780 tgactcccat gagggaaaaa g 801 <210> 53 <211> 121 <212> DNA <213> Homo sapiens <400> 53 agatttgtca ataccaacag atgcatcctc tgagaaagca gagaagggtc ttagttcagt 60 kccagagata gctgaggtag aaccatccaa aaaggtggaa caaggtctgg attttgctgt 120 c 121 <210> 54 <211> 401 <212> DNA <213> Homo sapiens <400> 54 aagatatatg catcttagga actcaacagc tttccaaatt atttgcctgc agtttgaaca 60 ttaattgctc ttctgtatgt acaggttttg tgcttaacag cagctatctc ttctgttaag 120 gtccaatttc tgttggcaga ggggctcagc tcagtgagtc acatcaatgc ctaatggaat 180 agataagcta gctgaagata maaggagctt tacagaaggc aataaagcta atcttttcag 240 ctaaaacaaa ttcattctat tggaaagaat atgggcaatc atagattcag tgtagataat 300 tagcttgatt gatttaactc aaggcatagg gaagactatc ttattaagtg tattaatttg 360 aaactgctct atgtagctag cctctcaatc tacattaaat c 401 <210> 55 <211> 501 <212> DNA <213> Homo sapiens <400> 55 gaaaagcccc tctgatttct taggttagac atgggtaaag gagaaaggta ttaatacgtg 60 aagcaatcca tataatagta taagaagggt gttatggtct tgcatcatat gaggaaatga 120 tatgggctag aaattctaaa agactctttt tacatatatg gttggaggga tggtaaagtt 180 aataaatttg tggtttgccg tagtctatct actgcagtca tttttgggaa atagttacca 240 cgaatgcaag rtatagttaa atcaaggtat ttcttccctc ataggtggcg gacgtgtgaa 300 aattgagagt gtaaaactag atttcaaaga aaaggcccaa gctaaagttg gttctcttga 360 taatgctcat catgtacctg gaggtggtaa tgtcaaggta agaaacaagg ttatgagcca 420 atcttgtctt tttaaaaaaa attcttctga aatactcttc atcaaaatag gtcccagatt 480 gtagacctgg acaaataaga a 501 <210> 56 <211> 501 <212> DNA <213> Homo sapiens <400> 56 aaatagttac cacgaatgca agatatagtt aaatcaaggt atttcttccc tcataggtgg 60 cggacgtgtg aaaattgaga gtgtaaaact agatttcaaa gaaaaggccc aagctaaagt 120 tggttctctt gataatgctc atcatgtacc tggaggtggt aatgtcaagg taagaaacaa 180 ggttatgagc caatcttgtc tttttaaaaa aaattcttct gaaatactct tcatcaaaat 240 aggtcccaga ytgtagacct ggacaaataa gaagtgggga taacagaggt gaatagaagt 300 cattaatgtc agccctggga gatggagaaa gaggtagggg ccagttaaga tgcatgagtt 360 aacgaggact gatgcttgtc ttaaacagat tgacagccaa aagttgaact tcagagagca 420 tgctaaagcc cgtgtggacc atggggctga gatcattaca cagtccccag gcagatccag 480 cgtggcatca ccccgacgac t 501 <210> 57 <211> 801 <212> DNA <213> Homo sapiens <400> 57 aacttcagag agcatgctaa agcccgtgtg gaccatgggg ctgagatcat tacacagtcc 60 ccaggcagat ccagcgtggc atcaccccga cgactcagca atgtctcctc gtctggaagc 120 atcaacctgc tcgaatctcc tcagcttgcc actttggctg aggatgtcac tgctgcactc 180 gctaagcagg gcttgtgaat atttctcatt tagcattgaa ataataatat ttaggcatga 240 gctcttggca ggagtgggct ctgagcagtt gttatattca ttctttataa accataaaat 300 aaataatctc atccccaaac tgtagtaatt gttacaattt tctatttaaa aaatgaatag 360 tacatgcaga aattgacctg atttccattt gcaacaggaa racactggct ttacatgggt 420 tcaattggac aattattttt gctctgctct gttttgcatg gagtattatt attttaaaaa 480 ttgcattttt acctttcatg tgcctgaagg ctatccacta cattctgaag gccttgttaa 540 aatccaagct gctcatttca ctattctgtt tctgagtgag aagataaaaa ctgcccattg 600 taacttattt caggttaaat taaaccaagg agtctgattg caggaaggga agagcatgta 660 agaaataagt ttttttaaag tgttattttg tataaatggg aagaaagatt caattaagtt 720 attaacattt gggacctgga taattatatc agagtatgtc agtccaataa attatttaac 780 taattaaaaa atagttgcaa a 801 <210> 58 <211> 201 <212> DNA <213> Homo sapiens <400> 58 ttttcaatca aatttgcaaa tgtatttgtt gctgtatagt gattgttttg caaaataaaa 60 ttgcttgtca cctaactgct agttttggtt tcagactgtt yaattgcttc tcctctggaa 120 aaaaaatttt atatatatat atagtgatat agtgcgtgtg tgtgtgcatg tgtgtaatac 180 aaccaaagaa aaattgtgaa a 201 <210> 59 <211> 917 <212> DNA <213> Homo sapiens <400> 59 atatatagtg atatagtgcg tgtgtgtgtg catgtgtgta atacaaccaa agaaaaattg 60 tgaaaacaag gctattatta tggctgagtt tctattatgt gtcaggctct atactaaatg 120 attttatatt agctcaatta ataaggaaat ttatttttat cactactgta ttagcaggat 180 gctatctttt gcaagtgaca raaattctaa ttaaacgggc ttaaacgtaa aggtgaattt 240 gtaggctcaa gtaactgact actcaggtgt atctgcctca ggcatggctg ggtccaggcc 300 ctcaaacgac gtcatcagga atcttccctt ttccaacttt tagttttgca tcctctgtgt 360 tggcttcctt ctcaggcagg caccccttcc gtgatgggca ccagaagctc cagatttcac 420 aacctatcaa agaaagcccc tttacagtag ctcaaatcca gggtctgaaa atcactgaac 480 gattaatact tggatctcct gcctacttat gctaattgac caggattggc tcacgtaccc 540 aactctgtca caggtggttg gagtagaagg agaataaggg gagaagtggc tttattctcc 600 tccatactac ctgagctaat cgtggagagg aaacgtttcc cccaaagtta attcaggcta 660 ctcctgccag aagagaggaa ttgatactgt acaggccaca aaaacaaata cgtggtatag 720 ctgcacccct gttcatcttt tagctcctta cagctcagat tatgctcagg cttcaccagg 780 gagcttgata gaaatacaaa tttctggact ccaccccaga ctaactaact aacattcctc 840 caggtgattc atctgcactc aaaaatttga gaaacactaa gctcattcag tccctgctaa 900 tgtgtttaag gagaaag 917 <110> College of Medicine Pochon CHA University Industry-Academic Cooperation Foundation <120> Polynucleotides derived from ALDH4A1, PINK1, DDOST, KIF17, LMX1A, SRGAP2, ASB3, PSME4, ANXA4, GMCL1, and MAP2 genes comprising single nucleotide polymorphisms, microarrays and diagnostic kits configuring the same, and analytic methods using the same <130> PN0304 <160> 59 <170> KopatentIn 1.71 <210> 1 <211> 801 <212> DNA <213> Homo sapiens <400> 1 ggaaccatga acccttctgg agggaatggt atctctgggc aactctcatg ccagctgctg 60 ctggaagcct ctgggacctg gacccttagt tctccgggtg tgggtttggc agggagagcc 120 agaaaatgtt tgcatctttt gccggcttgt ggtgggatgg acaggacagg gagctgggca 180 cgttgctgtc ctggagggaa cccaggagga ggcgacacct gacccttctt gcagacactg 240 aagtgtaaac tgaggcccag ggactgggga gagggtgagc cagagcaggg gcactgggag 300 ggctcagggc cctggtccct ggtcccgtgg agggtctgac gccggggcct ctctcctagg 360 agatcttcgg gcctgtactg tctgtgtacg tctacccgga ygacaagtac aaggagacgc 420 tgcagctggt tgacagcacc accagctatg gcctcacggg ggcagtgttc tcccaggata 480 agtgagtggc caggccgcag ccctggtgct gtgctccggg tgtcctgtcc gtgtccccat 540 ccccacctcc tggacgtggt tcccagtaat aatgctgccc ctaccttctc tctgtcccct 600 cccctcagcc cagacaggca gccagggctc gccacatggg cccacagcag caggctcttt 660 gttgccggta ctggtggtgc cggtgccagg gtgccactgg ggaccagtgg atctgaacct 720 ctaggggcag ggctaggaat tggtgtcttc gactggctct gcgggatctg gtgttgcccc 780 actgagtgag gtgattgtcc c 801 <210> 2 <211> 626 <212> DNA <213> Homo sapiens <400> 2 aacattttct ggctctccct gccaaaccca cacccggaga actaagggtc caggtcccag 60 aggcttccag cagcagctgg catgagagtt gcccagagat accattccct ccagaagggt 120 tcatggttcc ctctgccacc aaggggctgg ggggaagatc ttctcaggca cactccagcc 180 ctgcactacc aacttgggca agtgccttga cctcagtttc tcatctgtaa aatgggaaca 240 gtaacaccca cgtcatctca gccaagtgct cagccacagc yggccccaca gtaaaagtct 300 atcagtgtca gccattatga tggctgcagt ggacgtggtt gctgagggca ctggaaatgc 360 tcagacccca gccagggtca aggacacagc cccggatttg gagttaggca gcctgagctc 420 aaaacctggc tctactctct cccggtcgga ggcattccct tttagggtct ccctttaggg 480 cctcatctgt gaaatgggag aatgtctcca ggagaactgt gtgtgtgctg tgctccggtg 540 ggattgtcct cctctggacc ccaggctgcc caccccagtc acctccttca tgatgggctc 600 ctgagggtcc ttgctctcca cgatgc 626 <210> 3 <211> 641 <212> DNA <213> Homo sapiens <400> 3 acacacrtac acttgtgtgt gnnnnnnnnn nnnnnnnnnn ntnnnnnnnn nnnnnnnnnn 60 nnacacacac acacacacac agtgttcatg tctgtccttg tctctkctgt ggctcagcca 120 gaccctggct tttgcccttg gcgtccccta cccctgcccc tgtttcagga gttgggccct 180 tcagntgcag gtgtttcggg gtgagtgtgt tgtgggggct gccgcaggga tgccttccca 240 gcctcttaga cctccctcct ccctgcccac cccagtcctt tgcccgtatc aagaagtggc 300 tggagcacgc rcgctcctcr cccagcctca ccatcctggc ygggggcaag tgtgatgact 360 ccgtgggcta ctttgtggag ccctgcatcg tggagagcaa ggaccctcag gagcccatca 420 tgaaggaggt gactggggtg ggcagcctgg ggtccagagg aggacartcc caccggagca 480 cagcacacac acagttctcc tggagacatt ctcccatttc acagatgagg ccctaaaggg 540 agaccctaaa agggaatgcc tccgaccggg agagagtaga gccaggtttt gagctcaggc 600 tgcctaactc caaatccggg gctgtgtcct tgaccctggc t 641 <210> 4 <211> 924 <212> DNA <213> Homo sapiens <400> 4 cggccaacca agttgacttc tgattaacca gcttttaggg aaggcctcta agatttccag 60 tttatctatt gttccttgtg taaaagtatg tacttaccat aaatcctgcc cttaggcaga 120 ttcacacagc attcttgcct ttccctgggg gactgacttc aaatgtccgt cacattcctt 180 tcctatagca tataggccct gggtcttggg ggtaatggca tggggatcca ccatcttgtc 240 tccctgccgc tgaagccaga gactatggct tctgttcata aatccctttc tccttaaata 300 tgaagtcaaa ggtcatgtag ataggagctg ctgctgaaga agggattttt tgtctgaaga 360 gttctgtccc ctgggcttac ttggctatgg ggtggacccc tggccaggag acagcaaact 420 gtttcagtaa tgtgcgtgtc gtgcgtgtgt gtgttctgtg gtgagcaggc ctatgccatt 480 aaacaaacgg tgtggctttg rgcaagctgc tatcttggga cctcagcaca ctcattcata 540 aattgtgtct tttgggtgag atttgtcttg gggtcttcaa aacccctgag actgtggaca 600 catacagcag cctaacggca ttgaggaggg caagcattca acagttagga caatgtgaac 660 tgtagctcag ctctgctagg taccttcaca agacctcgaa tgctgcccct tactatgcct 720 cggttttctt atctataaaa acggcatttt tatcttgttg gtggagctgt taaataaatt 780 aaaagacgta aagggtctgg caccatggtt ggcaaaaaat atcagtttcc cttctcgact 840 tctcgatttt gcccaggacc agtgatgttc acattcagga cctgcctgaa ccggcaagcc 900 ctccacgtgg gtccaaagtg caaa 924 <210> 5 <211> 677 <212> DNA <213> Homo sapiens <400> 5 tgggcttact tggctatggg gtggacccct ggccaggaga cagcaaactg tttcagtaat 60 gtgcgtgtcg tgcgtgtgtg tgttctgtgg tgagcaggcc tatgccatta aacaaacggt 120 gtggctttgg gcaagctgct atcttgggac ctcagcacac tcattcataa attgtgtctt 180 ttgggtgaga tttgtcttgg ggtcttcaaa acccctgaga ctgtggacac atacagcagc 240 ctaacggcat tgaggagggc aagcattcaa cagttaggac aatgtgaact gtagctcagc 300 tctgctaggt accttcacaa gacctcgaat gctgcccctt actatgcctc ggttttctta 360 tctataaaaa cggcattttt atcttgttgg tggagctgtt aaataaatta aaagacgtaa 420 agggtctggc accatggttg gcaaaaaata tcagyttccc ttctcgactt ctcgattttg 480 cccaggacca gtgatgttca cattcaggac ctgcctgaac cggcaagccc tccacgtggg 540 tccaaagtgc aaagggaaag tcactgctag aggcgccagt accagcatag cgcccccacg 600 cgccgagtcg gggaactgcc gcgggggccg gccccgccca ccagcgcctg cgcctgcgca 660 gaggcaccgc cccaagt 677 <210> 6 <211> 601 <212> DNA <213> Homo sapiens <400> 6 agagaagcct ggcacattcg gggaaggagc tatgaagcca gcgtggtgga gtgtagggtg 60 ctgatgagaa gggtgagaga taaggcggga gacgtggtga gatgagcagg ttaagcgcct 120 tcaatctctg ggccccagga gagcagaggc taggaggaaa tgaacccagg gtgttcttgg 180 gaaagcttct cccaaggtgt accagaagtt gaggtaatgt acctgctgcc acatctatcc 240 ggtcattcaa caggtattta ctgagggtat gcagtaaaca aagagtgttt acagtacagc 300 yggagcaaaa aggaaccaac agaaaaagac gtgttatttg aggccagaca gtgagaactg 360 ctaaaggaac aaagtccctg aagagggaca gggactatgt cagatgggag gtctcagcag 420 cagacatcat ggtgctccgg cagcaggaca gcaccacgtc ggccggctgc cactcatgcc 480 acaaaaggag gcatcaagga tcatgttagc cccaaagcag ctgacattca ggtgtccact 540 ttctccaaaa aggcctcagg agaagcagca gccacttgag cagctacctc caccggcctg 600 c 601 <210> 7 <211> 699 <212> DNA <213> Homo sapiens <400> 7 tgaatatagg gagccccaac tcttacttcc taatttgagg atggtgagtg ggagggaaca 60 gaaaggatgc tggggaaaag tgggaatcaa agtgctcctg gaaggggaag aggaacggcc 120 taaccctaac agtgattaag gttattagga ggccgggaat ggtggctgac gcctgtaatc 180 ccagcacttt ggaaggcgga ggtgggtaga tcacttgagg tcaggagttt gagaccagcc 240 tggccaacat gatgaaaccc tgtatctact aaacatacaa aaattagcct ggtgtggtgg 300 cgggcaccta taatcccagc tactcgggag gctgaggtag gagaattgct tgaacctgga 360 aggtggaggt tgcagtgagc caagatcgtg ctactgcact ccagcttggc gacagagtga 420 gactccatct caaaaaaaaa aaaaaaaacg tattgggagt cgtcgatgtg tggtagccag 480 aggccctctc ccctctccrc cagctatccc tgtaccctgc gccagtacct ttgtgtgaac 540 acacccagcc cccgcctcgc cgccatgatg ctgctgcagc tgctggaagg cgtggaccat 600 ctggttcaac agggcatcgc gcacagagac ctgaaatccg acaacatcct tgtggagctg 660 gacccaggta ggaacctgct gcaccatcag agctctcca 699 <210> 8 <211> 601 <212> DNA <213> Homo sapiens <400> 8 gagagagaaa aggaggcatt tttgagaaat gtttaatgga gatgtagctc atggaagcag 60 ctgagaactg atcagagaga gatggaaaac atctcctgag agcagatctg gacattgtga 120 aattaatata aaggaatgca aaggcagacc tatccgaagc cataattgga gtggcagctg 180 gctcaggggc aggcttagtg caaagagctg agccatacct gcatcccagc actgttctgc 240 cactccgtta actgctctct gtacgtggcc tgctatcttg gtgcgcagtg aaggttagaa 300 yaacagctgc aaccagttat gaaatgatag aggagactac ttacctggtt caagggacca 360 gatagctgtg cacaagaggc actaggcttt ccacccaggg ggaaaggcta tttcaacaat 420 gcatgctgcc ccatgcagag gtgtacacat ggaaaagctt ggagcacggg taggggacag 480 gcagtatttg tcacctgagt gaagggcatc agtaggagat agggtagagg aagaattggg 540 ttgggaccag agaagggaag accctcacta acaaagcagg ctttgggttg agactgtgtt 600 a 601 <210> 9 <211> 801 <212> DNA <213> Homo sapiens <400> 9 atcagagaga gatggaaaac atctcctgag agcagatctg gacattgtga aattaatata 60 aaggaatgca aaggcagacc tatccgaagc cataattgga gtggcagctg gctcaggggc 120 aggcttagtg caaagagctg agccatacct gcaccccagc actgttctgc cactccgtta 180 actgctctct gtacgtggcc tgctatcttg gtgcgcagtg aaggttagaa caacagctgc 240 aaccagttat gaaatgatag aggagactac ttacctggtt caagggacca gatagctgtg 300 cacaagaggc actaggcttt ccacccaggg ggaaaggcta tttcaacaat gcatgctgcc 360 ccatgcagag gtgtacacat ggaaaagctt ggagcacggg yaggggacag gcagtatttg 420 tcacctgagt gaagggcatc agtaggagat agggtagagg aagaattggg ttgggaccag 480 agaagggaag accctcacta acaaagcagg ctttgggttg agactgtgtt aacagatgtt 540 ctagctacag cttcccttcc tgttgcagag accatctgcc cgagtagccg caaatgtgct 600 tcatctaagc ctctggggtg aacatattct agccctgaag aatctgaagt tagacaagat 660 ggttggctgg ctcctccaac aatcggccgc cactttgttg gccaacaggc tcacagagaa 720 gtgttgtgtg gaaacaaaaa tgaagatgct ctttctggct aacctggagt gtgaaacgct 780 ctgccaggca gccctcctcc t 801 <210> 10 <211> 801 <212> DNA <213> Homo sapiens <400> 10 accagttatg aaatgataga ggagactact tacctggttc aagggaccag atagctgtgc 60 acaagaggca ctaggctttc cacccagggg gaaaggctat ttcaacaatg catgctgccc 120 catgcagagg tgtacacatg gaaaagcttg gagcacgggc aggggacagg cagtatttgt 180 cacctgagtg aagggcatca gtaggagata gggtagagga agaattgggt tgggaccaga 240 gaagggaaga ccctcactaa caaagcaggc tttgggttga gactgtgtta acagatgttc 300 tagctacagc ttcccttcct gttgcagaga ccatctgccc gagtagccgc aaatgtgctt 360 catctaagcc tctggggtga acatattcta gccctgaaga mtctgaagtt agacaagatg 420 gttggctggc tcctccaaca atcggccgcc actttgttgg ccaacaggct cacagagaag 480 tgttgtgtgg aaacaaaaat gaagatgctc tttctggcta acctggagtg tgaaacgctc 540 tgccaggcag ccctcctcct ctgctcatgg agggcagccc tgtgatgtcc ctgcatggag 600 ctggtgaatt actaaaagaa catggcatcc tctgtgtcgt gatggtctgt gaatggtgag 660 ggtgggagtc aggagacaag acagcgcaga gagggctggt tagccggaaa aggcctcggg 720 cttggcaaat ggaagaactt gagtgagagt tcagtctgca gtcctctgct cacagacatc 780 tgaaaagtga atggccaagc t 801 <210> 11 <211> 801 <212> DNA <213> Homo sapiens <400> 11 tctggaccag ctactgaatt attaatctca cttagcgaaa gtgacggatg agcagtaagt 60 aagtaagtgt ggggatttaa acttgagggt ttccctcctg actagcctct cttacaggaa 120 ttgtgaaata ttaaatgcaa atttacaact gcagatgacg tatgtgcctt gaactgaata 180 tttggcttta agaatgattc ttatactctg aaggtgagaa tattttgtgg gcaggtatca 240 acattgggga agagatttca tgtctaacta actaacttta tacatgattt ttaggaagct 300 attgcctaaa tcagcgtcaa catgcagtaa aggttgtctt caactgagct gttctagttt 360 tctcttcccc agcactgtca tctagatttt ccatttcagt rattcccacc cctcggtcta 420 ctagcaacaa caactttctt gtatcctttg aggagacgtt agggagaacc atcatttcac 480 agttaaaaga aagacagtcc agtcctaggc aaaatttcat gaagccactt aggattttgt 540 atccagtcag tcatcaccca cagcaacccc cacccacagc cattagcaaa ccaggaccgg 600 ggccaggtga agtttgaggg caacatctcg ctttattttt atttatttat ttatttattt 660 atttatttat ttatatttga gacagagtct taacactgtt gcccaggctg gagtgcaatg 720 gcgtgatctc agctcactgc aagctctgcc tcttggattc atgcctttct cctgcctcag 780 cctcccgagt agctgggact a 801 <210> 12 <211> 801 <212> DNA <213> Homo sapiens <400> 12 ttctaaaagg aacggtggag gttagggatc tctagataag tcactactac cttaaaaaat 60 tggaagtgcc aataccagca atatagcaat aaagccctga aataatctga cagcacctga 120 aacactcagc ctctgacact tttagctaaa agcctccttc ttccccttct gagtcctccc 180 catatacaca cactgcacca cccggatccc cggcccctaa gcctcctggc agctacctct 240 gggagccggg cgccgccttc tgcactgctg agttgaagaa ggagtcgctg aagaagtcga 300 gggagccgct gaagatgacg cgggcattgt tcctggcctg gagcccagca atgaggaggg 360 tgttcttccc caccgcatgt ggatactggg aacaaaacga rgctgtgacc caagcagttc 420 caagtaaggg aaaagctgcc acgcctcccg aacaagagga cagcaggcca gaccaaaacg 480 accctggccc tacctgaagg gggagcctga gaccacaccg cttctgccca tgccccaccc 540 caccaactag tcatttcctt cgcctcagcc aaatgtgctg ttctgcttca tttttatttc 600 gaagcctcaa ggttgtgaag cccttacctg ggtgataggc ttgtccggga agaaggagta 660 agaggtggaa gagcccgtca ggatgtccag caccaaaggg ttatcaggat cggccaccat 720 cctgcagcag gacgagagca gcccagcact ggccccagga actgagccca aggacatggg 780 atccccgaga gccagttctt c 801 <210> 13 <211> 635 <212> DNA <213> Homo sapiens <400> 13 atcataccta gccttttctt tttttttttt ttaagcaggt caatttgaag aaaaatatta 60 ggtagttatt agcacaggag atacgtaaca tggtaaaaac catgaaggac gtgtgcaaat 120 gactaaagtt tgggaaacac tgttttacac tctctgtcgt ttctcccacc aacagtatcc 180 tctctcagcc ctctcccgag cagtctcatt cactgctttt ttccttctga cctatacaag 240 ctgacagtgc ctccgcttca tcttacatcc tgacacaggg tttggtaact catttcaggt 300 ctttatttcc tcaaaaacag actgaaaaaa ctcctccagg gcagactccc tatccttaag 360 atctcaccca gtccactgta aggtacctat ttcaaagttt caaacacagc aaaaacttgg 420 caaacaccag ttactgcacc raagcccagt catcagaaga tttcaacttc taccaatttg 480 gggtgacatc cgcctaacta atcttgcctc caaaaagcca attccaaaag cacatgttgc 540 aagggagttg ggagtgacac agtaagtaac agaagcctag ggaaagtact tgagggattc 600 ggtggaactg aatctcgcat gaactacaga gaata 635 <210> 14 <211> 601 <212> DNA <213> Homo sapiens <400> 14 cagacttgtc gtcggctgct gggggacaga ctcctcccca ccctgactgc ctcgcctctg 60 cacaggccat ttccacagcc agggatgcct tttctgcttc catcaatgca cagccacccc 120 ttccttcaaa acggagggga gaccacgccc ctggagacac ctccacaccc ctctgttctc 180 accacgcagg ccctaaggcg gcattgaatg cagtctggag tcaagaactc aagttcaaat 240 cctggctcag actctttgct gtgtgacctt gggcaagtcc tggcatctct ttgagcttca 300 rctttctcag gaccaaaccc acggtgaagg tacggtgata tcgcgttgga ccccagcggc 360 agccctgccc ttcccgctgg gccccacctg cctgtccctt ctccatgttc ccacccgctt 420 gggtctcacc tcccggatca gctgcttctc ggcctccatg tcatgctgga tcacaggttg 480 gggcaacagc ttctcctcca cctgcacagg gtctgggggc acctgcctgg acagcagggc 540 tgggggagaa acagaaatta gcagccagga tgaggggcac attgtgtgca ggaactaagc 600 a 601 <210> 15 <211> 801 <212> DNA <213> Homo sapiens <400> 15 tgcacaggcc atttccacag ccagggatgc cttttctgct tccatcaatg cacagccacc 60 ccttccttca aaacggaggg gagaccacgc ccctggagac acctccacac ccctctgttc 120 tcaccacgca ggccctaagg cggcattgaa tgcagtctgg agtcaagaac tcaagttcaa 180 atcctggctc agactctttg ctgtgtgacc ttgggcaagt cctggcatct ctttgagctt 240 cagctttctc aggaccaaac ccacggtgaa ggtacggtga tatcgcgttg gaccccagcg 300 gcagccctgc ccttcccgct gggccccacc tgcctgtccc ttctccatgt tcccacccgc 360 ttgggtctca cctcccggat cagctgcttc tcggcctcca ygtcatgctg gatcacaggt 420 tggggcaaca gcttctcctc cacctgcaca gggtctgggg gcacctgcct ggacagcagg 480 gctgggggag aaacagaaat tagcagccag gatgaggggc acattgtgtg caggaactaa 540 gcagaaatct ataaaaagac gacctcatgg tcattcaaga agactttaaa gtattcagct 600 tatttcaaac acatctccat gtaaaaggct gttagtcatc caacaaatat ttatggagca 660 cctcgatgtt ccagactctg aggatgcggc attgaacaaa gacaaaaact ccacacccac 720 gctgagtttt ccactgggaa aaagaggaga aaagcagatg gacaaggtga aatgcctcgt 780 ggtggtgttc gaggccctct c 801 <210> 16 <211> 801 <212> DNA <213> Homo sapiens <400> 16 ggtggggggt gtggtggggg tgggggggat aatggatgag cagatgagag gcggggagtg 60 ggcaacagcc tgcgtcagat gggacaggcc agacggactg ccctcctccc aggacactga 120 caagcagata ccatctgggc cgtctccaac cagggccctg cgctcacatg gggctgaggg 180 gtgggaggat gctgctccca ctgtctttta ggtgggaagt tggaggcgag aagacagagg 240 gaaggaagct ttctcctggg gacctggccc tcccgccact accccaacgt ggtcccacct 300 gacaggctgc tggggctcat ctgctgtgtc aggatggcct tgagcttctt gatctcctcc 360 tggtactcgc gaagcagcgc atccttgggg tcctcattga ygcgcggctt gttcctgatg 420 ttcttggccc ggttggcgta gcgcagcgtg ctgagtgtct catcgtagtt gttgtccgca 480 ggcgacaggc aggccaccat gagcgtcttg gtgttgccgc ccagtgagtc ctgcagcagc 540 cgcgtcagct tcgagtcacg gtaggggacg tgcttacagc gcccgtccac cagcgccgag 600 atgacattgc ccagtgccga gagcgacagg ttgatcttgg tggcctcctt gagccgctcg 660 cccgtggccc cggtcttgga ctgccgctcg ctgcccgcca ggtccaccag gttcagcttg 720 cccgcccgga ggtggtcctt gccccgctca tctgcacaca gaccaggcaa agtggcgagg 780 gcctcgggtg agccctatgt a 801 <210> 17 <211> 401 <212> DNA <213> Homo sapiens <400> 17 tcagatgttt ggggctcaga gctcagtcta gataaaagct cattaatcca gcttccctat 60 ggttcactag gcttggagta ttatatgcat gacattgtat taggttcaaa tgaataaggt 120 ttgagtgtgt ttgtcctaat ttgggaagta acttaagtgg atcgaatacc atctctcttt 180 ggagtagtcc aattctgcta yattaattac tagtcttttg aaggataaat tatctgagaa 240 aattaaattg tttctaggca agggttggaa gacaaagggt taattatctc tccaaattga 300 aaaagaccaa gacaacaatc ctgtaggtgg ttaggaaggt gcggtaagtt gactaacact 360 caaaatgttc tcattgcaaa agtgagtcct cattggtcaa a 401 <210> 18 <211> 601 <212> DNA <213> Homo sapiens <400> 18 tcccctttga aaaccaggaa tgaattcaca tagagaatca gaccttgagg agttgagttg 60 ttctctattt tctaaagaat ttagtttata ccttcaaaag ggcttccctt tgtcttgaga 120 tattctaagt tccaagtagt ctcaagtggt ttttgtagca ggagctagac tggaaaaact 180 ctagagcttt gtatttcatt ataagcattt gtctattgtg tgcagttagg atatagagag 240 cataagatgg attcagtgcc ctcgcgccag ggaggctgta tgaaggggaa gacaagaatt 300 ktatgagcac atgttaatgt ccctgtcact cttgcttctg ttgcagtgat agccctcatg 360 gagagactac ctcggttgaa gactcaaccc aggatgtgac cgcagagcac cacacgagcg 420 atgacggtac gaggccctgc ttcctggtca gtggggacgc caggggtgag gcagaaggaa 480 gcgattatat atcctgtgca tctgatgaac ctgtctgccc agcggtcccc tgagggcagg 540 cagagagctc cctgtctcaa tttcattccc ttccttcctt ggagaggtag cccaccttct 600 c 601 <210> 19 <211> 801 <212> DNA <213> Homo sapiens <400> 19 gcgacagagt aagactccat cccaaaaaaa aaaaaaaaaa aaaaaaaaaa gggatgcttg 60 agttgtgttt tgatgtgctt catcaggcag ataagagaga agaagattcc tggtggaggg 120 aacagtgtga gcaaaggcag gtaaaaggtg ataccagtgc tttcaggata atggtatagt 180 ctgcgtgaga attacttgct ttatagatca tccatggctt cgttttccca ctaagtaatt 240 tcctaccact gtaagttcag ctaattcagc ttttccaccc agtttcctga gtctgcaggt 300 cccaagaaca tgtgtttact tcttttccac ccttctcaga atgtgagccc atcgaggcca 360 ttgccaagtt tgactacgtg ggccggacag cccgagagct rtcctttaag aagggagcat 420 ccctgctgct ttaccagcgg gcttccgacg actggtggga aggccggcac aatggcatcg 480 acggactcat cccccatcag tacatcgtgg tccaagacac gtacgttggg cccatggcat 540 ctttgggggt ggtccccagc tgctctatgg gaatgagact tcatttctgg agccatagga 600 ctatgaggga ggccaacccc tcgggggtcc agtgcagtcc tgaggctcac acagttcctt 660 gaagagcagc ccccccaccc cccgccccac tccctgcact cagtggagaa tttttttaaa 720 tctctccact atctgtgccc cctgcaaatc accccctaat ccagtcattt tagaaacctg 780 ccagccagcc agcactcatc c 801 <210> 20 <211> 801 <212> DNA <213> Homo sapiens <400> 20 aaccagtcat tttaatttgc aagtggaaga gtggctcaac aggttggggt gagcatagtt 60 gtttaaaaaa aaaagagagt aacaaaaatg ttttcccagc ctgatctttc gagaaaagaa 120 atataggtgg tcaaataaaa accccttgtt atcactcatc aggtataaat atggatgagt 180 gctggctggc tggcaggttt ctaaaatgac tggattaggg ggtgatttgc agggggcaca 240 gatagtggag agatttaaaa aaattctcca ctgagtgcag ggagtggggc ggggggtggg 300 ggggctgctc ttcaaggaac tgtgtgagcc tcaggactgc actggacccc cgaggggttg 360 gcctccctca tagtcctatg gctccagaaa tgaagtctca ytcccataga gcagctgggg 420 accaccccca aagatgccat gggcccaacg tacgtgtctt ggaccacgat gtactgatgg 480 gggatgagtc cgtcgatgcc attgtgccgg ccttcccacc agtcgtcgga agcccgctgg 540 taaagcagca gggatgctcc cttcttaaag gacagctctc gggctgtccg gcccacgtag 600 tcaaacttgg caatggcctc gatgggctca cattctgaga agggtggaaa agaagtaaac 660 acatgttctt gggacctgca gactcaggaa actgggtgga aaagctgaat tagctgaact 720 tacagtggta ggaaattact tagtgggaaa acgaagccat ggatgatcta taaagcaagt 780 aattctcacg cagactatac c 801 <210> 21 <211> 601 <212> DNA <213> Homo sapiens <400> 21 atatgttttt ctagtctctg gcatgggtag cctctcctgg tcatagacca gtctctttgt 60 aagttattgt ggcagttcac acagtagcca ccaggggtct ctgtttccat tacaaacttt 120 gttctgtctg ggccagagaa cctagccttt gaaatctctc catcatatga aacataacgg 180 gatgggacaa tcccgtaacc tgtttggggt tgggggcttt ctctctgtgt tctttccatt 240 gatgtgaatt ggtcattggt gtttgctctt gcctctcctc catcccctag aagtacaccc 300 ycgtcttatt aaggagcttt taaagttttt ctgaatgtat agacatttct cgggttccta 360 cctttgtctc tgatggacca ttttccattt aagacatttt cctgtataag acagttttat 420 agctggttcc ttttagggta aagagtctta agagagtttt attgtgtcta tggcaggttt 480 gggaaaggta agaaatgggt cctttttcct cctaatgttt ttggcactta aaacataaaa 540 ttcattatcc tattaaaaaa ttaaattcag ctttgctaat ccagaaattg ttcccaaatg 600 a 601 <210> 22 <211> 601 <212> DNA <213> Homo sapiens <400> 22 agagaacata actccacaga cattccaaag agaaaaatta agtttagcat ttttctgacc 60 acaaagtaca gaataagcag atttttagga cctacttttg tgtatataat ccttattaaa 120 aataaaagga tatcataaaa ttaaaatatc agtaaacatc tgcttttctt tatatgttcc 180 ttaggctaag attataaaat caaatatgat ttttactgaa gggaattact agccatcccc 240 taacaacccc atcttttcct cacataagaa aatgcaaatt atgtctaatt tgtgttcacc 300 ratgaatctt atcacttaaa attacaacac agctagagaa gcaagagaag gaaaagtagt 360 gaagtgtgtt taaaagttat tctttcttac caatatgttg ctgtagaatc caagcgtttg 420 aggcacgagc agagagcatc ctttcaacag ctggtgcaag tgtcttccaa ttagtaaact 480 ccaaagtgaa gataagggtg tcaatgctga ctgagtcaat cctatgttag caagatgtta 540 atataatatt agaaacaaaa catgccaagg gttcgtactt gaaacaaaca ccacatacct 600 a 601 <210> 23 <211> 611 <212> DNA <213> Homo sapiens <400> 23 gaattcttta tctgtcattt ctgagtttcc atttgggtca ggaaccattg tgggaacacg 60 actgtgatcc ttcagtggtg tcactatatt tagatttttc acaaatccaa aattcttggg 120 gtagttcctt ttcatctgga gatgttcaca cttctaattt ttgtaattat tttcatgcag 180 gtgggatttt tttctttttc tttctttcac tataatatta ttgtttttcc ctttcacatt 240 tatgatttta aatatcaact cagaaacctg ttgaaagaga ccctttttct ctgattgtag 300 gcattattta tcatgcagtg gttatgaaga aagagatgta atagagagta tagtcaatat 360 tagttttaag gcgtggctcc catatatgtc atatctactg ataatttttc ataaatctta 420 gcctgaatca attagtkgca taatttggat tttatctttt tcagcagtta tcagaaatat 480 tatccatgtt tgatagtttg tatttttctt tttaaatgtt tacttattgg gccccagaat 540 gcttgttgga ggagggattg gaatgaaatg tatccttcat tgaataggat nttttgtttt 600 agcttaaaaa t 611 <210> 24 <211> 601 <212> DNA <213> Homo sapiens <400> 24 aaactgctca agtccctaca ggaaaggaca gccccatcat tcaacttgcc aataaacctg 60 ctttagtgat agatcattat gttcctactc agataaatta gtagctgtgc actgcattgt 120 tagtaataga tacttaataa ccaggtttat aaatcaattt gtatttactc ttatttacca 180 cttacataaa accataaatt tcacaacctg atttatattt gagacaagaa ttattcctct 240 aggaaatata gtttaaagct catgatctta acagtacaaa ggctaatgga taatcttacc 300 ygatgaaata agtatgctca agctttctag cttgccatac tgagcagcca caaataaagg 360 tgtgattcca aagtcatcct ggcattcctt gtttgctcct tttctaagaa gcaattttat 420 gatctcagca ttttcctaaa gcacagattc acattttaaa taagaaaaaa acaaagaaaa 480 tagaaggtat ctttcttctt actgtgtttt ttttttcttt tttatcctct cactaaagga 540 taacttgaag gaaaaaacaa aacagtatac tgctgtatta gttggaaaga aattggccaa 600 a 601 <210> 25 <211> 701 <212> DNA <213> Homo sapiens <400> 25 ataagatttt tttttcattt caatcataca gttattctgt atctcccact atagtaggag 60 gcaggaagtg ggaatcaaca cttctcagtc acaaaattag aaaggcacat ttggataatg 120 agtcacatta gaaaacacta atacacatga aacaatggga atataaaaat ccttaaaagt 180 gtaaaacaag aaatgataag ygtgcttatt actgaagaca agtaacatgc cattgatatt 240 gtactagttt tatatattga atttatacca aagcttattt cccctataag acactcagaa 300 gttctttaat aaaaaattct ccaccgagtg tggtggctcc cgcctgtaat cccagcactt 360 tgggaggcta aggcgggtgg accacgagtt caggagatcg agaccatcct ggctaacatg 420 gtgaaacccc gtctctacta aaaatacaaa aaaattagct gggcatggtg gcacgcacct 480 gtaatcctag ctacttgaga ggctgaggca ggagaatcgc ttaaacctgg gaggtggagg 540 ttgcactgca ctccacctgg gttgctgcac tgcactccag cctgggcgac agagcaagac 600 tccatctcaa aaaacaaaac aaaacaaaac aaaaaaccaa aactcttact ctgaagggtt 660 tcagaaatgt aaccaatggc tgtgacagta ccactgaggt a 701 <210> 26 <211> 696 <212> DNA <213> Homo sapiens <400> 26 cttagtcaat acaaatttac catttacaaa atggtaaatt cactgccaca gaaacaaaat 60 aaatcctact actaaaaata agtgatttaa agttatttac tggtttgaat tatctcccat 120 cccttgcttc attaacataa aaaagtacaa gttaactaca tgttgaaata taaaccccta 180 aaaactatgc atctctaatt ktctccaaat actaataaaa gtaggcacaa tactgaattt 240 cataaatggg actctaataa taataataat aatttgaaac tgtaaactat gtggccagaa 300 tagcatttct caaatagtcc catggaatat caatgtttct ggaggtattc ctaaatgttc 360 cataaagaaa aagaatacag ctgggcacag tggctcatgc ctgtaatccc agcacttaga 420 gaggctgagg caggcagatc gcctgaggtc aggagttcca gattagcctg gccaacatgg 480 tgaaacccca tctctactaa aaatataaaa attagccagg cgtggtggcg ggggcttgta 540 atcccagcta ctcgggaggc tgaggcagga gaaacacttg aacccgggag gcagaggttg 600 cagtgagccg agattgtgcc attgcactcc aggctggaca acgagactga aagaacagta 660 cagtcaaata cgtttcaaag ctctgcgata aacaaa 696 <210> 27 <211> 601 <212> DNA <213> Homo sapiens <400> 27 ccagacagag gcacttccgt ataagatgtc caactagagt atcatactaa ttgaatccaa 60 ggcaggcaat cttactatcc ttaataaata aattcaggca gttattttat gactatagaa 120 agggaaacaa atactactgt taataagtta tgtattatac ttttttatgt tttattaatc 180 cagcttgtag gcaaagcctc cataccttga atttacttta cctgcattaa ttaacatttg 240 caaacattct acagagttgt gataagctgc ttcatgaatt ggcatccatc ccctgttatc 300 wgcaacatcg acacttcggc cctttttgag cagtttcctt aagactttaa cattgccttc 360 cctggcagca agtccaactg tagagcacgt gtccgcgtaa gcctctgtaa aatccatttg 420 tttgaccagt ctacaaaaca aggtagaagg ataatactat agtcaataaa acaacacttc 480 actcctagag gtcagcaaat cacggtgggc ctgtctagta tctctcacat gactgacgaa 540 gaagggccca caatacagaa agtgactgcc atgccacagt ctctgctggt gcctaaagca 600 g 601 <210> 28 <211> 401 <212> DNA <213> Homo sapiens <400> 28 tatttggctc tgaaattgga actgggctta tttctaacgg ggccgaggaa ggagaaaaga 60 gcaggagtcg tcactcgtgt ccagatacgg aggcggtgta ccagcaccgc aggtagcaaa 120 gcacctagaa acacgttttg ttctgctttg gaaattagat ttttgcctat ataacagcag 180 ccagaggaat gtaattcata yttgatttta tgtcctgaaa aaaaagtctt ttgcctttca 240 aataaaagca gaaagtttac aatagaagtt tacgcttgtg aaagagtagc tgtcatttca 300 atgggaattg tttatatatt taaattttac acaaatttat tcatctttag tattatcatt 360 ggcttgttca caaaagagca ggcaaatgtt cttaacttgg g 401 <210> 29 <211> 610 <212> DNA <213> Homo sapiens <400> 29 ggcggcggag gatggaggaa ggaggcggcg gcgtacggag tctggtcccg ggcgggccgg 60 tgttactggt cctctgcggc ctcctggagg cgtccggcgg cggccgagcc cttcctcaac 120 tcagcgatga catccctttc cgagtcaact ggcccggcac cgagttctct ctggtcagtg 180 ccctcactaa ccccgcagcc acccctcctc ctgacactaa gkgttcggcc tcttccctcg 240 gttttctttg ctttttctcc ccaagacctt ctctgcagac tcttaccttc cccaagccaa 300 agctgctttt atgcagcgtt cattcattcg ttcgttctca cgttatgtgg atgcgtcccc 360 cttgctgagc attagggatc cagcaatcac ctgctctcca ccttttcaat tctgtcgcac 420 tagaccttgc ttcccaacat tcccaccctg cagaagcagc tttcgtagaa taacgtcagg 480 tgcacttact catcttcctt tcggaaaatt aactgtggct cttacttcac cagcagactt 540 ctttccttca gtattacatg tcaccctgcc cacaccacag tacttcagac tcgagttccc 600 tctctcgtat 610 <210> 30 <211> 501 <212> DNA <213> Homo sapiens <400> 30 ctgcggctta aagggcttgg taatgacaag tatttcaaat atttgaaaac agctttatca 60 tatatttgca cctaaacttt catttacatt aataggtgag taaattttcc tcctacattt 120 tgaaggacaa tctgcagtct ttgctttcta aaggatccat tcagaaacta aagatttatt 180 tgaccttata aaaagataaa taggcttttt cttctcctca cttctcatcc accctcagag 240 agtggcccat rctgtcttcc atgcccagtc aacagtgact tccaaacaca ggtcagcctc 300 tcccctcctc ctctagtaaa tcttgttacc acccttaaca cagttcctgc tgtcctcatg 360 ctttttaaca caccatatac atgttaagaa ctatcttaga ccatacaagc catgcaactc 420 ttttctccac cccctttctc cttttccctc ctggtagaaa atttcatttt tcctattggt 480 aaacaattaa ttcataggac a 501 <210> 31 <211> 1225 <212> DNA <213> Homo sapiens <400> 31 tgctttttaa cacaccatat acatgttaag aactatctta gaccatacaa gccatgcaac 60 tcttttctcc accccctttc tccttttccc tcctggtaga aaatttcatt tttcctattg 120 gtaaacaatt aattcatagg acaatgtcac tagggaaata tcaaagtaat aagcgacttc 180 caaacccaga atcagaatca cctgggagca tgttaggcac tcagattaag gtaccctctt 240 tttaggtctg tggtgggatt cgtgtggttc tcaaacctgg ctgaacaact gaatcatcat 300 agagcttcta atactgtaat gcctaagcac ccctgccaga gaagttttca ctgaggaaca 360 gagagggcac ccagtatctt acatctttgt ttaaagttcc catttaggaa ccattgctaa 420 ggcagtttca tacagcttaa ytaaaaaaag ctgaagtggt caacatacaa cataaagcct 480 cacttctcaa cgtgtggcct caggaccagg aattgatatc atgaagtggg aacaatgaat 540 tccctgtaca tttaaacaaa atcccctcat gattcttagg cacatcaatt taagaaccaa 600 tcagttagga tcaggcacgg tggctcacac ctgtaatcct agcactttgg gagtccgatg 660 caggtggact gcctgagctc aggagtttga ccccagcctg ggcaacatgg tgaaactgtc 720 tctactaaaa tacaaaaatc agccgggcgt ggtggtgcat gcctatagtc ccagctattc 780 tggaggctaa ggcatgagca ttcctcatgg gaacatggga ggcagaggtt gcagtaagcc 840 aagattgtgc cattgcactc cagcctggat gacagagcaa aactctgtct cccacacctc 900 cacacaaaaa caatcaatca cctaggtcag tgctaggtga actttctgtg atgatggaaa 960 agttcatcga tattattcag tgtggtaacc actagccaca tgtggctcaa gagtatttaa 1020 aatatgccgg tgagactgag ggaatacatt ttttatttaa ttaaatataa atagtcagat 1080 atggctagta gctactgtat tgtacagggc agatccagat aatttatact ggtcagagga 1140 catacattta cagatacaaa tctatggctg caaaaggaaa tccacaggag tcactgccta 1200 cagaactgtc ttctcctctt aatga 1225 <210> 32 <211> 501 <212> DNA <213> Homo sapiens <400> 32 caattaggta acaagacatc caactctaaa agcctaataa atgaaatttt tattcttcct 60 attccagtag aaaggcttct gggtactccc tctttaacag aatgggtgta agaatccaga 120 tcaagttctc acaactttta gaacccagag tcctcagggc cacacaaaat gtcccagccc 180 cacccaggag gcaaccaaga ataagatgta ttttccttta tctaactatt cccaggctga 240 caccactcat ytacaaaggt ccaaaagcag tcacacattt tctctgcttt aaacctaaag 300 caaggaggca cagcaaaatt ctcatttcca atggccgtag caaaagccat gtttaaaaac 360 aaacaatccc cgccatccaa ctttatctaa acactgacat ctaagaatgt cagcaaaaag 420 aaaaaaaaca ataaatatct agttctcagt caccaaacca atgtaaattc agaactttgc 480 tgacttacct ttctatgcat a 501 <210> 33 <211> 1355 <212> DNA <213> Homo sapiens <400> 33 caggaatctg tgtagtaatt acttctcaac ttttttgtat ttttttcaga agtcaatgtg 60 taaacatcat taagcagtta tgttatacat ctatatttta gagatgttaa aaacttacta 120 tcggccaggc gcagtggctc atgcctgtaa tcccagcact ttgggagccc gaggtgggca 180 gatcacttga ggccaggagt tcgagacccg cctggccaat gtggtaaaac cctgtctcta 240 ctaaaaatac aaaaattagc tgggtgtggt ggtgcatgcc tgtaatctca gctactcggg 300 aggctgacgc atgagaagag cttaaaccca ggaggtgaag gttgcagtga gccatgatcg 360 tctcactgta ctccagcctg ggcaacagag caagactctg tctcaaaaaa aagccaaaac 420 ttactatcta taatgtcatc tattgaagta caccattcat caattacctt agggcatcgg 480 cattcttttc ytgttggcgt ttaattcctt ccttaatttt ttctgggcta agcaatatct 540 ggttgataga ggggtttttt gactgttgaa gtaattccgc tatttcaaca catgactttg 600 gaatcttgtt aaaaagaaaa aagcaggaaa aaaaatgaag ttctgatgca tactacctga 660 acgaaccttg aaaatgtcat gctaagtgaa agaggccaga cacaaaagtc cacatatttt 720 acgattccat ttatatgaaa tatctaataa tgggcaaatt tattgacaga gaaagtggtt 780 tccaggggtt tggggtatgg aagaatggga agcgactgct attaggtact tgttttcttt 840 tggggtgatg aaaacattgt ggaggccaga catggtggct catctctgta atcctagcac 900 tttgggaggt caaggtgagg ggactgcttg aggccatgag tttgagacca gcccggggaa 960 cacagcaaga cccctgtctc tctctcaaaa aaaaaaaaac aacttaaatt agctgggtgt 1020 agtggtgcac acctatagtc ctagttacta ggaaggctga ggcaggggat gattatgcca 1080 ctgcactcta gccttggggg acagaatgag acagaatgag aatgagaaac aaagaaaaag 1140 gaaaatgttc tggaatttga gtagttacac agccctgtga atattctact gtgcatataa 1200 catgtccata ttaaaagggt gatatttatg atatgtgaat tacatctcaa ttaaaatttt 1260 tcttctaaaa aataaagtat aatctaatga cagtcgcaaa tagcaaccct atgtttgatt 1320 taaaaggaat acatttagaa cagtggtttt taaac 1355 <210> 34 <211> 601 <212> DNA <213> Homo sapiens <400> 34 gacaaatgta cctttataat aagaaacaat gacttagtat catcttctga attatcaagt 60 atgtggtcta taatggaaga aagaaaagga ttttggttaa aatattttga actactataa 120 gaatcttgag gcattagtca agaatctatt aagaaaaaaa atcactgccc aatattctca 180 ccatttagaa taaaaaacat taagtaaaca catgcatgtt atagattaaa attccaaaat 240 acttattcca aagtacaaat aagttaaatg tacagataca cttactaaga agtttcctta 300 yaactgtagc aattacttct cggtggttct ctcgagacag atctattttg aaaaaataaa 360 agaaggtatt ttagacactg aatgctcctc agacttttaa agtttatatc aacaggttag 420 gtcaaggagg gataaagtat tggagaaaaa aataggtctg cctttaccat agttgaatta 480 atggctaggc atgctacagc aacttctaaa acctctacac ttaaatgacc tgcttatgag 540 atgtctatca tgcttcaaga taaagaaaaa taataataat aaaaaataga taaaatgacc 600 t 601 <210> 35 <211> 601 <212> DNA <213> Homo sapiens <400> 35 atatctcaca aaataactga tatttttgaa ggtaacctct gaatggtggt tgtataagaa 60 tattaataaa gtaacatttt taagctactg ccaacctgga tgatatcttt tttggagaca 120 aattttcccc aaattgccaa tcaaaatatt gtgaagctaa aggaatctgt tgtcattaac 180 agagttttag aaaccaagaa aaaaacttat ccaaaattgt aaagagagaa taatgacctt 240 atgacttact cattgtaagc tgagttataa cactgcagca gtggggaaca aagagcttca 300 ragattcttc tgggcagcac tgaaaatgta tttgtataag taaggctttt ttgaaaggca 360 aatatataca agattatatt ttcagtggca gtaaaaggct gtaaataagc agctactgaa 420 agaactatgc attttaagca tagaagcacc tctaataatt aaccatataa actagttgat 480 tgttgagtca ttaatacatc agttcaaaaa aataaactca cctttacagc agcgcggcac 540 atgtctgcca ccatgcgacc tgctactctt gtttcaaata tatgtgaagt agaaaaatta 600 a 601 <210> 36 <211> 601 <212> DNA <213> Homo sapiens <400> 36 tggtgccagc tgccaacagg tacagaatgt gggctcagca actgttagct taaacaaagc 60 attgtttact caacagaggg gaaggaggag gacatgaaaa ggcaggtcta tttctaaaca 120 tcatttaaat ttcttttagg ggtggtaagc aacttgacct tgaaaactga ttcaaagaga 180 gaattctttg aattctttta acatcctgag aatatagaaa caagttgtaa ttttctgtct 240 gcagaagcgc tacatgttta ttttagaaca tttaaaaagg aaaaactaaa aattctttag 300 kttctaccac ctgaagagga ctgctatcga tactctgagg tagccacatc atttcaggct 360 catcaagagg ggtgtttctt aacaatatgg gtgtgttggc tgcctcctgc tttagacagt 420 aatcagacac cttggacctt ggttatttgc tctttggaac aagcatcgaa ttgaatccct 480 ttgagagttc tgtaaagttc agctctgagg tggaagctga gcctcttagc tgaaaacatg 540 gctgtaccta aggctggaca tctgctctcc ttctcttgcc caaatacggt ttctgaatag 600 a 601 <210> 37 <211> 701 <212> DNA <213> Homo sapiens <400> 37 cccttttggg gagaacaggg ttccacgttg gtgtagtttg tcttcccccc actccttgcc 60 caccaacttg agccacactg gcctctgtcc tgctttccct acaaactagt tccggcctca 120 ggacctttgc aggagctgtt tcctctgcct gtaacccttg cctccatctt tgcatgagca 180 gctgcttcat ttcattcagc tcttaacctc aatgtcactc ctcagaatgg gtcctgcagg 240 acctctctat ctgcttcaca gcaatgctca cccctaggca ctttatggaa ttgtgaattg 300 ttggcttgtt tactgtctgc ctcccatgag ctagagcatc agtcccgggg agcaagagct 360 taatttttca tggtcactac tgtaccccta gcacctagaa taccatctag gctatggtca 420 gtgctcaaca aatgtttgcc gaatgagatg cctccgtgtt ggtgagaggc tgcctctcag 480 taacatcact ctcttgtgtg ytcaggcaac caaaggaggt actgtcaaag ctgcttcagg 540 attcaatgcc atggaagatg cccagaccct gaggaaggcc atgaaagggc tcggtatgtg 600 tcctgctgga agtgaatcct cctgcgtgca ttgcacatca cagggtcaca caggagggtg 660 ccatgtctgc tggccatcac gtgggtcttc ctttaataaa a 701 <210> 38 <211> 1001 <212> DNA <213> Homo sapiens <400> 38 ttaatggaag acagatggct tctcatatct atttctactt caatttgtta tgatatgtgg 60 ttttggttgg ggtatatgaa gaaaatctgg cttgtacaga tatgtacttg aaaatggggg 120 gagtatttga acagacagtt gttgatgcac agacaatgtc aaatagcctt aggaaaaccc 180 cactgtatgc ttgtggaaga atgacagtga aaaggcaaat aacatctgag tgttattctg 240 aggatagttt tgacttgcag gccccttgaa agggtcttgg agaccccaga catccctgga 300 ccacacctgg agagtagctg gtctaatttg ctatagcagt taagcggagc tactttcttg 360 cattgcagga cttgatagac gacctgaagt cagaactgag tggcaacttc gagcaggtga 420 ttgtggggat gatgacgccc acggtgctgt atgacgtgca agagctgcga agggccatga 480 aggtctgtgc tcttcctctc rtgctcttgg tgctgttggt gcaaacgctg atgtgctttc 540 ttaagaaact gtcacccaat aagaaagaca tggaagcaac ctaaacgccc atcaatggta 600 gactggataa agaaaatgtg gtacatgtac accatggaat agctgtaaaa aggaacaaga 660 tcatgtcctc tggaggaaca tggatggagc tggaggtcat tgtccttagc aaactaaggc 720 aggaacagaa aatcaaatac catatgtttt cacttacaag tgggagctaa atgatgaaaa 780 cacatggaca catagagggg aacaacacac actggggcct gttggaggat ggagggtggg 840 aggagggaga ggatcaggaa aaataactaa tgggtactag gcttaatacc tgggtaatga 900 aataatctgt acaacaaacc cccatgacac aagtttatct atataacaaa cctgcacatg 960 Tacccctgca cttaaagtaa aagttaaatt tttttaaaaa a 1001 <210> 39 <211> 576 <212> DNA <213> Homo sapiens <400> 39 tattgttata ctgtctcgat gttccatggt ctaggcatgg ctcatcagag tggtaaatat 60 gggaggaaaa gagaaagtgg gaaagaaata tgagacacag gcaggcgtta ctaagtaaat 120 attggagaca agagcaaagt ggaaattgga gatgatttcc agggttctgc ttctttaggt 180 gtaggaggaa caacagcaat attaacagaa acaggcaagt ccggaagaag agctggtttg 240 aagggaaaat gagttctggt tcagttcatt aagggkatag tagaatatct gtaatgaaac 300 atctaaaaag caatgtgaaa tgagagtctc aagctcagga aggaggccgg ggataaagat 360 gcaattggga agtgatgtga aatgtctgaa gtctccagct tcccttttca ggcaaccctg 420 ccccacctag ctcagtcctg ctttattttc cagctggaat tttccaggta gcttcctacc 480 tggtcgtcca gcctccagtt cctctccact gttcatccta cacgtcacta ttacattact 540 cttctgaaag tgcagctcca gtcacatcac tcccat 576 <210> 40 <211> 671 <212> DNA <213> Homo sapiens <400> 40 tactgttctt taccaggcac cagacttcta ggagtcctaa gagggcatgg tagtggtgag 60 aaatggttca cctccctcaa agccaggcat tcctgggatt ttgtttcttg aggatgctgg 120 aagagtctca tggacatgaa agtgagacag atttccctag gagctaaggt tgcctgcact 180 gcaagcttca aatcagcgtt ygatctgtga actaaatatt ctgaatccta ctcaaagctt 240 ggagaggtgt gacaattagg tgattttaac tgcagatttt tttttttaga tggagtctca 300 ctctgtcgcc caggctggag tgtagtggcg caatctccac tcactgcaac ctccacctcc 360 taggttcaag tgatcctcct gcctcagcct cctgagtagc tgggactaca ggcatgagct 420 ttgtattttt tgtagaaatg gcgtttcacc atgttggcca ggctagtctt gaactcctga 480 cctcaagtga tccacccgtc tcggcctccc aaagtgctgg gattacaggt gtgagccacc 540 atgccccacc aagctgtgga ttttgttact acgtctacaa ggcatgcagg aacttgtttc 600 tatttctgac taggctatga ggtaacttga ttttgcagag ctgaactata taactagttt 660 aagattcaag g 671 <210> 41 <211> 701 <212> DNA <213> Homo sapiens <400> 41 attgctgctc tgtaaggccg ttaaagtaga aataacctct ctcactaagg aatgtaaaaa 60 caaatatggg tcagtcatac aatgagcagt gaaaattatc tagcgattga ccaaatggat 120 aaatcttgag agtataattt tgagagagga gaaaggtgca caatgagagg tacaactatg 180 attccattcc atgatatgtc taaacatgca aaagaaaata ttatttatgg gtatgcatat 240 aaggacatgc atggacatga tatacaacat tctcagcaca gtgattgcca ctggggaggg 300 agacagaatg agatggagga ggtacgcagg ggcttctgcc tatatgtatt gttctattta 360 aaaaagaatg aatcattgat tacacctcaa taaagctggg aggaaaaaag aatgaaagca 420 agtctgataa aatttcaagc tagtggtcgg tccacaggaa tctgtattac tctatttgaa 480 atattttcat tattttactt raaaagtaac agaagggagt cagggaatga acgctggctg 540 tccggagtcc atcacaagag ctgctactac tccaagcaga cactagtaaa ttttgctagg 600 gcctcctgaa ggcacttttg agtccagaca gtcatggtgc cagaccctat tcggacatcc 660 cactggcact tgagaggaaa ggaaaggagt gccgggaacg t 701 <210> 42 <211> 601 <212> DNA <213> Homo sapiens <400> 42 gtccacagga atctgtatta ctctatttga aatattttca ttattttact taaaaagtaa 60 cagaagggag tcagggaatg aacgctggct gtccggagtc catcacaaga gctgctacta 120 ctccaagcag acactagtaa attttgctag ggcctcctga aggcactttt gagtccagac 180 agtcatggtg ccagacccta ttcggacatc ccactggcac ttgagaggaa aggaaaggag 240 tgccgggaac gttcccataa cttaacgggt tccattcacg tctacagcag gggagggctc 300 mtgttaagga agcccaggaa tccagcatat cgcctcatcc tagggccccc tctcacagga 360 ggccacgccc aagcaagcag agcgtggccc cagcaagcgc cgagctcccg caaggagacc 420 aaatagcttc ggggttttgc cactagctta gcacaggccc ataagcaccg gggactcaag 480 gcacctttgt agaaacaatg agtgactgga gtcccaggtc ttgccactac agaggcgcgt 540 atgaaccacg gtttaacact acgtctacgc cgaagttcgg gttagtcaga ggccacgccc 600 a 601 <210> 43 <211> 1631 <212> DNA <213> Homo sapiens <400> 43 aagaattttc aaaagaggat tcaaaagaca aatattatga tgacatacca gaagataatc 60 gaacatacct gatccttttc aagtgtaagt atttgatagc cagttgttct actacatatt 120 agttttccac tactatcaaa agaagccaaa cgtaatctag gattaaaaaa aaaataaaaa 180 ataaacacaa gatttttaaa ccacagatta aacaagctct tcctyacttt catatttact 240 ttttcctctg ttttttattt gataaaagac ttttaggaag tcttttcaaa ctgtaatctg 300 actgcattca gtgacaagcc tgtgctatta tacatatctg gccaagagaa atcatttata 360 aatgttttta ttgtggtaaa atatacgtaa catttatcat tttaaccatt ttaaagtata 420 tagttctgtg gcattaaata tatttccaca ttgttctgca cccatctcta gaacatttta 480 attttccctc gctgaagctc cttacccatt aaacactaac tccccacttt cccttccctc 540 aggccctggc aaccaccagt gtatcctctg tacctatgaa tttgtctact ctaggtactt 600 cgtatgagtg gaatcttaca atatttgtgc tttgtgagtg gcttatttca cttggcatgt 660 cttccaggtt catccatgtt tagcatgtat gagaatttgc ttccttttca aggctaaata 720 atgttctatt ttatgtatat accacatttt gtttctctag catctgtcag tgaacatgtg 780 ggttgcttcc accttttggc tattgtgaat aatgctgtta tgaacataag tatacaaaaa 840 tatctgttta agtccctatt ttcaattctt ctggtctata gaagagaaac tgctggatca 900 tatggtaatt ctgtttaatt tttttgagga agtgtcatac catgctccat agtggctgtg 960 ccattttaca tggccacgag cagtacacaa gggttctaaa tactccacat ccttgccaac 1020 acctgttact tttgttgttt tttttctatt ctgtttttac taatagctat cctaataggt 1080 gtgaagtgat agctcattgt gattttggtt tgtatgtccc taattagtaa tgttgaacat 1140 cttttcatgt gtttattagc catttatata tcttctttgg agaaatgttt atggaagtct 1200 ttggcccatt tttgagctga gttgagtttt ctttttaaat tatagagttg taggagtttt 1260 ctatatattc tgggtattaa tgtcttatca aatgtagcgt tacaaatatc tgctctcatt 1320 ccatgggttg ccttttcact gtcttgacac tgtcctctga tacacaagtt tgtgattttg 1380 atgaagtcca attttatcta ctgcttcttt tgttgcctgt gcttgggtgt cttatggaag 1440 aaatcactgc caaatcaatt gttatgaagc ttttccccta tgttttcttc caagagtttc 1500 atagttgcag ttcttatgct tagatctttg atccatttta agttaatttt tgtatttggt 1560 gtaaggtaag tataaatata tgacttttaa atcatgttca ttaagctact gtccaatttg 1620 tcagcttctg g 1631 <210> 44 <211> 601 <212> DNA <213> Homo sapiens <400> 44 catctgtaaa tttcttttta tttggctaaa ataatctaaa agaataattt ggttggccaa 60 ttagaaatgc ctttttcagt tggtgtattg aaagctttcc tttaacattt tcacctgctc 120 attgtgattc ctccttttag tctaatatct ttccaggtca tacttgtttt taatcattaa 180 atattttctt cctggttttg gagactaagc tgataaactt tttttaaaac ttaagcattg 240 tcattgctat tttttttaat ttgactttcc taggagttta agaacagtga aagttagctt 300 ygcaccttca aatgatcttg aatgagggaa aaatcagttt gattccaagg atatttcttg 360 ccttacatgg tcttttcttt gacagtctgt acacctttat tattaggttt tgaattattt 420 atgtaccaga tattatagtt ttaaacattt taatattctc tgatctttag aattatttat 480 gttcaaattt tagttgggaa ctttgtttcc tacttaagct caggactttt taccctctga 540 attgagtgcc tttgagtgac acatgctaat agaaatttca tagtaaatgt aaataaggtc 600 a 601 <210> 45 <211> 401 <212> DNA <213> Homo sapiens <400> 45 attcagttaa aaaaccccca gacaaatgct tgttagtaat ctgatgggaa aacttacttt 60 atttatactt tctccaaaca gagcttggta gtaagaagtg tatttgtctt aatataattt 120 ttgcttactt ttttggaggc ctttgcttga gatacttttt tggaaaaagg aagatgttct 180 tagtttccat caaagacagt rttgcctgtg ttgtcatcct tactgtggag acgataagcc 240 atcaataagg ctgcatggtg ggcaacagct ttccaaaact gagtggtgaa tcacctcttt 300 tcaattatat atctaaactt ggtaatatca gcttgtaaga gaaggtcatg cagtatcttc 360 catccaatta acatgtatag aacacctcct ccacaactca t 401 <210> 46 <211> 601 <212> DNA <213> Homo sapiens <400> 46 gactaaactg acttcaaagc acaaagcaag cacttggtga cagtagagcc cttagttacc 60 tgctgtttct ctgtcagctg aggtcagctc tccgttgatc ccattctctt tggtatttga 120 ataggtgccc tgtgacccat gctctccaaa ggcaccctct tcatcctccc tgtatgggaa 180 tccattggcg cttcggacaa gtccttcccc tgctccgcct tgatccttaa tctcaggtgg 240 atgtgagtgt gcagatgcct ctgttagcgg tgctgaggtc cagtgaggtg cctttgcttc 300 rtctttccgt tcatctgcca ttcttcaatg ccttgttatt tctcctgcaa ctgaaagaga 360 aaaaatagta gctattactt tggggaaatc ttctgatctg atattggttg taccaagata 420 ggaaaaattt atagcaaacc gtgtggcttt ctatggtcaa agaaaacatg tacaataacc 480 tatgtttaat atcaagaatg ggtcaattag ttcatcttga gttttacaga ccatttctgg 540 aatattagtt cttttaaaat aagatcaatg tcattctaca catattcctt tttgtaaaca 600 a 601 <210> 47 <211> 601 <212> DNA <213> Homo sapiens <400> 47 ttgtggttga gaataaaata aaaatattat ttgcacattt catggttaca atgaggatta 60 attaagatag taaagtgtac aaagtgaatg gctcaagaaa taataactgt taattaattt 120 tattattatt ggtggtagtg gtggtatcaa tatggatgac atagcactct tgatcaagta 180 atatttttct atagctgagt atacacaact ttaacagggt ggaacttggg tgtcaggagc 240 actaagagga ttttcaaggg attgcagcat gaggagatga gagcatgtta tagcatattg 300 rttgtgagga agaaaagagt tagtatgata tgtcaaggtt tttttcatca tcgtatcttg 360 cagcattaga ccttcaatat tccataaatg tgtgttgagt gagcgagtga atgaaggaat 420 aaatgaataa attcaaaaag aagaaagtcc tcttcacatt aatgatgaaa acaattgaaa 480 agtcttactt tgtcccttgg gctctcgcca gttgactctc agtgcctgtt atgaaagctt 540 gtaatacaca aaaaaaaatc actgcagtgt gcttggtcat gcagtaaaaa ccaacaccat 600 t 601 <210> 48 <211> 601 <212> DNA <213> Homo sapiens <400> 48 atatccatat aagctagccc taaattaggt tcaaatccta ttcatcaaca agccaagcca 60 aatattatga ttgaagctaa tccccacaac cagcttcacc tagtagagag accacatagg 120 acaaagcaaa cgtgacaata caaacctcgt ggaactgcct tttctatcaa tccttgtctt 180 tctcactctt tctagccccg gatgcctaac ctttagaagg aaaacactga aaagatcccc 240 attttctgtc ctcatccatc ggtgccacca ggcccagatg cttcgcagtg aggctgtgtg 300 rttttctgca gatccaccct tgaatgctaa ataactctgc tctgcacact cctctctctg 360 cggagctcag ggaaatggca gccagagcaa tgagtggttg gcatggcaac taggaaagga 420 aaatctgcaa cctctcgcat tgttaggcga gcttgtttat ttgcttgggg ggttggtgtg 480 gatggcttta gtcattttgc aggagaaatg gctcagtgct attttgctcc gcataaatta 540 atatattaca tagaataggc catattttaa atgggatgct gactcctatt agtaaatcgc 600 a 601 <210> 49 <211> 401 <212> DNA <213> Homo sapiens <400> 49 aagtgaagtt cagtacttca tataagatac aaagtcactc acgattataa caaagctctg 60 gctataggtt ttgtgtagtc atttcaggaa gacccaaaca aggctacagt ataatcattc 120 accaaaacct gtaaagggaa ataatcatct cttatgaaag ttttagtata ttatccttat 180 gggtggaggt catgaaataa kgcattggct ttattttaat aataactatt tctagtggtc 240 tggaaaatga aaaaattaag ggccacttag ggaaaagtct aactgtaagc tcaccaccct 300 aacgaaagac tatgcaaaca ctacaacaaa ccagtggaaa aagatgaaaa taggtcctag 360 tgcataccca gtcaaggtgt ctgatgaatg ttacatgtaa g 401 <210> 50 <211> 601 <212> DNA <213> Homo sapiens <400> 50 acctctctat aaaattcaga aaaagattca atagtaagcc gcatttggtt tatttatagg 60 cccattacct gattcatgca tttttgaaaa cctaaaaaat aagacaagca tttgatattt 120 tcaaaaaaaa atgattttat catctctaga aaaacagatt agagatgcct gctaaaattc 180 catcattaat ctcattaatg tgtctacctg ttcaattaat aaaatatttc attttggccc 240 taatttacca tatgaaaaca cacacaggca ggcaggtgtt tttagtctgg attcagctac 300 ygactgaaaa aactattaga actctctatt gttcaactgc tcaatctgga aacatgtgtt 360 atcttgatca ctaatagtta ttttagggaa tatatttttt aaacaacctt ttgttcactg 420 agtctaattt caaaacccat cttctgtatg tattctcaga aatggaaaaa taagctttca 480 tagcctgagt gaactttcag acaaaaacca tatgctgagt aaacttctgg tcttagcaat 540 caatacacat gaaaaggaac cagagaaaaa ggttctaaaa gatgtaattc atttacagtt 600 a 601 <210> 51 <211> 401 <212> DNA <213> Homo sapiens <400> 51 gggcctccgc actagactcc atttggccct tactgaggcc cttgggttgg tctgaggact 60 tagcagcccc acactctttc tcaggaagag cagcaggttt ctcttcctca gccatccgac 120 tctctagcgt ttcttcttct tagggatgaa aaagatgttg acatcatgac cacagaacaa 180 tacatgaaac gacagaaata ytgctaaagg aacactttca gctccattag aatgacctca 240 tgaagacctc agctgttttt ttattttacc attgggatga acaaattaat attctaatgc 300 aacatacatt aggtactggt tggaaaacta tgatgtataa tctgctaata gtgatgactt 360 ttaaagtctc attaaaaggc aatttatttt aaagtttgag a 401 <210> 52 <211> 801 <212> DNA <213> Homo sapiens <400> 52 attagcttat aacttttatg tatagaaggc acatgaattt gtttcttctg taatacacat 60 cacataatgt ttaggagaga ccaaaaaaaa aaaaaacaaa gaaaaaaaga gaaaagaata 120 tccagaaata tactgttctt acaattcctt tgcacattaa tttacaacca gagttcattt 180 tagtaatagt acacatatat ctcagtcctg accttttcat attgactttt acatgggtag 240 catgcttgca tgttccataa tttttgtttt tattctacca ttcatttatc acttcaaaat 300 ataattttaa gcttatttcc tgaacgcact tgcctattat ttgtttaaaa atcaacccga 360 ttacttcaga tttacttaca gcctcgaaga tggagttcca ygatcaacag gaattgactc 420 cctctacagc tgagccttca gaccagaagg aaaaggagtc agagaagcaa agtaagcctg 480 gtgaagacct taaacatgct gccttagttt ctcagccaga gacaactaaa acttaccctg 540 ataaaaagga catgcaaggc acggaagaag aaaaagcacc cctagctttg tttgggcaca 600 ctcttgttgc cagcctggaa gacatgaaac agaagacaga accaagcctt gtagtacctg 660 gcattgacct ccctaaagag cctccaactc caaaagaaca aaaggactgg ttcatcgaaa 720 tgccaacgga agcaaaaaag gatgagtggg gtttagttgc ccccatatct cctggccctc 780 tgactcccat gagggaaaaa g 801 <210> 53 <211> 121 <212> DNA <213> Homo sapiens <400> 53 agatttgtca ataccaacag atgcatcctc tgagaaagca gagaagggtc ttagttcagt 60 kccagagata gctgaggtag aaccatccaa aaaggtggaa caaggtctgg attttgctgt 120 c 121 <210> 54 <211> 401 <212> DNA <213> Homo sapiens <400> 54 aagatatatg catcttagga actcaacagc tttccaaatt atttgcctgc agtttgaaca 60 ttaattgctc ttctgtatgt acaggttttg tgcttaacag cagctatctc ttctgttaag 120 gtccaatttc tgttggcaga ggggctcagc tcagtgagtc acatcaatgc ctaatggaat 180 agataagcta gctgaagata maaggagctt tacagaaggc aataaagcta atcttttcag 240 ctaaaacaaa ttcattctat tggaaagaat atgggcaatc atagattcag tgtagataat 300 tagcttgatt gatttaactc aaggcatagg gaagactatc ttattaagtg tattaatttg 360 aaactgctct atgtagctag cctctcaatc tacattaaat c 401 <210> 55 <211> 501 <212> DNA <213> Homo sapiens <400> 55 gaaaagcccc tctgatttct taggttagac atgggtaaag gagaaaggta ttaatacgtg 60 aagcaatcca tataatagta taagaagggt gttatggtct tgcatcatat gaggaaatga 120 tatgggctag aaattctaaa agactctttt tacatatatg gttggaggga tggtaaagtt 180 aataaatttg tggtttgccg tagtctatct actgcagtca tttttgggaa atagttacca 240 cgaatgcaag rtatagttaa atcaaggtat ttcttccctc ataggtggcg gacgtgtgaa 300 aattgagagt gtaaaactag atttcaaaga aaaggcccaa gctaaagttg gttctcttga 360 taatgctcat catgtacctg gaggtggtaa tgtcaaggta agaaacaagg ttatgagcca 420 atcttgtctt tttaaaaaaa attcttctga aatactcttc atcaaaatag gtcccagatt 480 gtagacctgg acaaataaga a 501 <210> 56 <211> 501 <212> DNA <213> Homo sapiens <400> 56 aaatagttac cacgaatgca agatatagtt aaatcaaggt atttcttccc tcataggtgg 60 cggacgtgtg aaaattgaga gtgtaaaact agatttcaaa gaaaaggccc aagctaaagt 120 tggttctctt gataatgctc atcatgtacc tggaggtggt aatgtcaagg taagaaacaa 180 ggttatgagc caatcttgtc tttttaaaaa aaattcttct gaaatactct tcatcaaaat 240 aggtcccaga ytgtagacct ggacaaataa gaagtgggga taacagaggt gaatagaagt 300 cattaatgtc agccctggga gatggagaaa gaggtagggg ccagttaaga tgcatgagtt 360 aacgaggact gatgcttgtc ttaaacagat tgacagccaa aagttgaact tcagagagca 420 tgctaaagcc cgtgtggacc atggggctga gatcattaca cagtccccag gcagatccag 480 cgtggcatca ccccgacgac t 501 <210> 57 <211> 801 <212> DNA <213> Homo sapiens <400> 57 aacttcagag agcatgctaa agcccgtgtg gaccatgggg ctgagatcat tacacagtcc 60 ccaggcagat ccagcgtggc atcaccccga cgactcagca atgtctcctc gtctggaagc 120 atcaacctgc tcgaatctcc tcagcttgcc actttggctg aggatgtcac tgctgcactc 180 gctaagcagg gcttgtgaat atttctcatt tagcattgaa ataataatat ttaggcatga 240 gctcttggca ggagtgggct ctgagcagtt gttatattca ttctttataa accataaaat 300 aaataatctc atccccaaac tgtagtaatt gttacaattt tctatttaaa aaatgaatag 360 tacatgcaga aattgacctg atttccattt gcaacaggaa racactggct ttacatgggt 420 tcaattggac aattattttt gctctgctct gttttgcatg gagtattatt attttaaaaa 480 ttgcattttt acctttcatg tgcctgaagg ctatccacta cattctgaag gccttgttaa 540 aatccaagct gctcatttca ctattctgtt tctgagtgag aagataaaaa ctgcccattg 600 taacttattt caggttaaat taaaccaagg agtctgattg caggaaggga agagcatgta 660 agaaataagt ttttttaaag tgttattttg tataaatggg aagaaagatt caattaagtt 720 attaacattt gggacctgga taattatatc agagtatgtc agtccaataa attatttaac 780 taattaaaaa atagttgcaa a 801 <210> 58 <211> 201 <212> DNA <213> Homo sapiens <400> 58 ttttcaatca aatttgcaaa tgtatttgtt gctgtatagt gattgttttg caaaataaaa 60 ttgcttgtca cctaactgct agttttggtt tcagactgtt yaattgcttc tcctctggaa 120 aaaaaatttt atatatatat atagtgatat agtgcgtgtg tgtgtgcatg tgtgtaatac 180 aaccaaagaa aaattgtgaa a 201 <210> 59 <211> 917 <212> DNA <213> Homo sapiens <400> 59 atatatagtg atatagtgcg tgtgtgtgtg catgtgtgta atacaaccaa agaaaaattg 60 tgaaaacaag gctattatta tggctgagtt tctattatgt gtcaggctct atactaaatg 120 attttatatt agctcaatta ataaggaaat ttatttttat cactactgta ttagcaggat 180 gctatctttt gcaagtgaca raaattctaa ttaaacgggc ttaaacgtaa aggtgaattt 240 gtaggctcaa gtaactgact actcaggtgt atctgcctca ggcatggctg ggtccaggcc 300 ctcaaacgac gtcatcagga atcttccctt ttccaacttt tagttttgca tcctctgtgt 360 tggcttcctt ctcaggcagg caccccttcc gtgatgggca ccagaagctc cagatttcac 420 aacctatcaa agaaagcccc tttacagtag ctcaaatcca gggtctgaaa atcactgaac 480 gattaatact tggatctcct gcctacttat gctaattgac caggattggc tcacgtaccc 540 aactctgtca caggtggttg gagtagaagg agaataaggg gagaagtggc tttattctcc 600 tccatactac ctgagctaat cgtggagagg aaacgtttcc cccaaagtta attcaggcta 660 ctcctgccag aagagaggaa ttgatactgt acaggccaca aaaacaaata cgtggtatag 720 ctgcacccct gttcatcttt tagctcctta cagctcagat tatgctcagg cttcaccagg 780 gagcttgata gaaatacaaa tttctggact ccaccccaga ctaactaact aacattcctc 840 caggtgattc atctgcactc aaaaatttga gaaacactaa gctcattcag tccctgctaa 900 tgtgtttaag gagaaag 917
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| KR101597808B1 (en) | 2015-10-13 | 2016-02-25 | 이화여자대학교 산학협력단 | Gene that is specific to anti-cancer drug resistance and whose expression is regulated by epigenetic changes |
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| KR101597806B1 (en) | 2015-10-13 | 2016-02-25 | 이화여자대학교 산학협력단 | Markers for predicting the response of a patient with ovarian cancer to anti-cancer drugs |
| KR101597812B1 (en) | 2015-10-13 | 2016-02-25 | 이화여자대학교 산학협력단 | Development of epigenetic diagnostic method using integrated epigenetic and transcriptomic analysis |
| KR101597813B1 (en) | 2015-10-13 | 2016-02-25 | 이화여자대학교 산학협력단 | Molecular diagnostic test for anticancer therapy |
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| Journal of Animal Science, Vol. 86, No. 11, pp. 2897-2902 (2008) * |
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