KR102552632B1 - Marker for diagnosing cnsl, cnsl diagnostic kit comprising the same and method for diagnosing cnsl - Google Patents

Marker for diagnosing cnsl, cnsl diagnostic kit comprising the same and method for diagnosing cnsl Download PDF

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KR102552632B1
KR102552632B1 KR1020200148060A KR20200148060A KR102552632B1 KR 102552632 B1 KR102552632 B1 KR 102552632B1 KR 1020200148060 A KR1020200148060 A KR 1020200148060A KR 20200148060 A KR20200148060 A KR 20200148060A KR 102552632 B1 KR102552632 B1 KR 102552632B1
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nervous system
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system lymphoma
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김원석
김석진
윤상은
박동현
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사회복지법인 삼성생명공익재단
지니너스 주식회사
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Abstract

본 발명은 중추신경계 림프종을 진단하기 위한 마커, 이를 포함하는 중추신경계 림프종 진단 키트 및 중추신경계 림프종을 진단하는 방법에 관한 것으로, 중추신경계 림프종의 발병 여부를 진단할 수 있는 마커들을 제공함으로써, 중추신경계 림프종의 치료에 유용한 자료를 제공할 수 있다.The present invention relates to a marker for diagnosing central nervous system lymphoma, a central nervous system lymphoma diagnostic kit including the same, and a method for diagnosing central nervous system lymphoma, by providing markers capable of diagnosing the onset of central nervous system lymphoma, It can provide useful data for the treatment of lymphoma.

Description

중추신경계 림프종을 진단하기 위한 마커, 이를 포함하는 중추신경계 림프종 진단 키트 및 중추신경계 림프종을 진단하는 방법 {MARKER FOR DIAGNOSING CNSL, CNSL DIAGNOSTIC KIT COMPRISING THE SAME AND METHOD FOR DIAGNOSING CNSL}Marker for diagnosing central nervous system lymphoma, central nervous system lymphoma diagnostic kit including the same, and method for diagnosing central nervous system lymphoma

본 발명은 중추신경계 림프종을 진단하기 위한 마커, 이를 포함하는 중추신경계 림프종 진단 키트 및 중추신경계 림프종을 진단하는 방법에 관한 것이다.The present invention relates to a marker for diagnosing central nervous system lymphoma, a central nervous system lymphoma diagnosis kit including the same, and a method for diagnosing central nervous system lymphoma.

림프종은 림프조직에 생기는 악성종양으로 림프 조직이 아닌 부위에도 발생할 수 있다. 림프조직이 아닌 부위에서 발생하는 경우를 림프절 외 림프종이라고 하는데, 주로 코 속과 목구멍이 연결되는 곳이나 위장관·뇌 등에 잘 나타나는것으로 알려져 있다. 미국은 전체 암 발생의 2.1%, 영국은 2.8%를 차지하며, 우리 나라는 4% 를 차지해 동양에서는 빈도가 높은 편의 암이다. Lymphoma is a malignant tumor that develops in lymphoid tissue and can also occur in non-lymphoid tissue. Extranodal lymphoma occurs when it occurs in areas other than lymphoid tissue. It accounts for 2.1% of all cancers in the United States, 2.8% in the United Kingdom, and 4% in Korea, making it a high-frequency convenience cancer in the East.

림프종 중에서 원발성 중추신경계 림프종(primary central nervous system lymphoma, PCNSL)은 전신성 질병이 아니라 뇌 및 뇌간에 한정되는 림프종으로 정의된다. 이는 중추신경계에서 생기는 이에 한정되는 비-호지킨 림프종(NHL)에 적용되는 용어로서 PCNSL의 최적 치료법은 아직 밝혀지지 않았다. 따라서, 중추신경계 림프종의 조기 발견 및 진단을 위한 방법이 절실히 요구되고 있다.Among lymphomas, primary central nervous system lymphoma (PCNSL) is defined as a lymphoma confined to the brain and brainstem and not a systemic disease. This is a term applied to non-Hodgkin's lymphoma (NHL), which is limited to those arising in the central nervous system, and the optimal treatment for PCNSL has not yet been identified. Therefore, there is an urgent need for a method for early detection and diagnosis of central nervous system lymphoma.

한편, 세포의 괴사(necrosis), 세포자살(apoptosis), 분비(secretion)에 의해 혈액, 림프액, 소변 등에서 세포의 존재 여부와 관계없이 검출되는 무세포 DNA(cell-free DNA, cfDNA)가 존재한다. 그 중 종양세포로부터 유래되어 혈액을 떠다니는 작은 크기의 genomic DNA를 순환 종양 DNA (circulating tumor DNA, ctDNA)라고 일컫는다(Wan JCM et al., Nat Rev Cancer. Vol. 4 pp. 223-238, 2017).On the other hand, there is cell-free DNA (cfDNA) that is detected regardless of the presence of cells in blood, lymph, urine, etc. due to cell necrosis, apoptosis, and secretion. . Among them, small-sized genomic DNA derived from tumor cells and floating in the blood is called circulating tumor DNA (ctDNA) (Wan JCM et al., Nat Rev Cancer. Vol. 4 pp. 223-238, 2017 ).

일반적으로 건강한 사람의 혈액 속 cfDNA는 1-10ng/ml 정도의 매우 낮은 농도로 존재하지만 암 환자에게선 5-10 배 이상 높게 나타나며 만성 염증을 비롯한 다른 요인에 의해서도 증가할 수 있다고 알려져 있다(Wan JCM et al., Nat Rev Cancer. Vol. 4 pp. 223-238, 2017). 때문에 cfDNA 안에서 암 세포의 유전정보를 가지고 있는 ctDNA를 검출해 내는 것이 중요하다. ctDNA의 농도는 종양의 크기 또는 병기와 상관관계를 가지는 것으로 알려 져 있는데, 640명의 환자를 대상으로 한 조사에 따르면 1병기의 환자에 비해 4병기의 환자에게서 ctDNA 농도가 평균 100배 높게 나타났다 (Bettegowda C et al., Sci. Transl Med. Vol. 6, pp. 224-24, 2014). 차세 대염기서열분석법(NGS)과 디지털 PCR(dPCR) 기술의 발전으로 미량의 DNA분석이 가능해지면서 ctDNA의 분석연구 가 가속화되고 있다.In general, cfDNA in the blood of healthy people is present at a very low concentration of 1-10 ng/ml, but it is 5-10 times higher in cancer patients, and it is known that it can be increased by other factors including chronic inflammation (Wan JCM et al. al., Nat Rev Cancer. Vol. 4 pp. 223-238, 2017). Therefore, it is important to detect ctDNA containing the genetic information of cancer cells in cfDNA. The concentration of ctDNA is known to have a correlation with the size or stage of the tumor. According to a survey of 640 patients, the concentration of ctDNA was found to be 100 times higher on average in patients with stage 4 than in patients with stage 1 (Bettegowda C et al., Sci. Transl Med. Vol. 6, pp. 224-24, 2014). With the development of next-generation sequencing (NGS) and digital PCR (dPCR) technologies, it is possible to analyze trace amounts of DNA, and ctDNA analysis research is accelerating.

또한, ctDNA는 종양 특유의 돌연변이 및 유전적 변화를 포함하고 있으며, 반감기가 2시간 정도로 짧기 때문에 종양의 현재상태를 반영하고, 비침습적이고 반복적 채취가 가능하다는 특징을 가지고 있다(Diehl F et al., Nat Med Vol. 14, pp. 985-990, 2008). 이러한 특징으로 ctDNA는 종양 특이적 생체표지자로써 암 진단, 모니터링 및 예후 관측의 지표로써 각광받고 있으며 다양한 분야에 적용하기 위한 연구가 진행되고 있다.In addition, ctDNA contains mutations and genetic changes specific to tumors, and its half-life is as short as 2 hours, so it reflects the current state of the tumor and is characterized by non-invasive and repeated collection (Diehl F et al. , Nat Med Vol. 14, pp. 985-990, 2008). Due to these characteristics, ctDNA is a tumor-specific biomarker that is in the limelight as an index for cancer diagnosis, monitoring, and prognosis, and research is being conducted to apply it to various fields.

혈액 속에 존재하는 cfDNA의 존재는 1948년에 알려졌지만 혈액에 미량 존재하기 때문에 초기 시퀀싱 (sequencing) 기술로는 분석이 어려웠고, cfDNA를 종양의 생체지표로 이용하기에 분석의 일관성이나 신뢰성이 부족하였다. 하지만 최근 분자진단기술이 발전함에 따라 BEAMing 기법이나 PAP, Digital PCR, TAM-Seq 등의 고 감도 분석 기법들이 개발되어 미량의 ctDNA를 검출, 정량화가 가능하게 되면서 임상적으로 적용하기 위한 연구가 진행되고 있다.Although the existence of cfDNA in blood was known in 1948, it was difficult to analyze with early sequencing technology because it is present in trace amounts in blood, and the consistency and reliability of analysis were insufficient because cfDNA was used as a biomarker for tumors. However, with the recent development of molecular diagnostic technology, high-sensitivity analysis techniques such as BEAMing technique, PAP, Digital PCR, and TAM-Seq have been developed to enable detection and quantification of small amounts of ctDNA, and research for clinical application is in progress. there is.

ctDNA 분석의 임상적 적용 분야는 조기검진, 진단, 동반진단 및 예후추적 등으로 나누어지는데, 현재 동반진단 과 치료의 예후 분석 분야가 가장 진전되어 있다. 초기 단계의 치료가 중요한 암의 특성상 조기 진단을 위한 연구도 활발히 이루어지고 있으나 초기에 생성되는 ctDNA의 정도가 개인마다 다르며 아직 연구된 암의 종류가 다양하지 않다는 문제점이 있다.Clinical applications of ctDNA analysis are divided into early screening, diagnosis, companion diagnosis, and prognosis follow-up. Currently, the prognosis analysis of companion diagnosis and treatment is the most advanced. Due to the characteristics of cancer, in which treatment in the early stage is important, studies for early diagnosis are also being actively conducted, but there is a problem that the degree of ctDNA generated in the early stage varies from person to person and the types of cancer studied are not yet diverse.

현재 ctDNA를 검출하기 위한 노력이 다방면에서 진행되고 있지만, 아직 기술적인 한계로 인해 ctDNA의 임상적 적용에는 제약이 있으며 꾸준한 기술 개발과 연구가 진행 중인 실정이다. 최근 FDA에서 ctDNA를 통한 유전자검 사로 비소세포폐암(NSCLC)을 진단하는 방법이 승인됨에 따라 ctDNA 분석의 임상적 상용화가 시작되었다 (http://www.investor.jnj.com/releaseDetail.cfm?releaseid=296494).Efforts to detect ctDNA are currently being made in various fields, but there are still limitations in the clinical application of ctDNA due to technical limitations, and steady technology development and research are in progress. As a method for diagnosing non-small cell lung cancer (NSCLC) by genetic testing using ctDNA was recently approved by the FDA, clinical commercialization of ctDNA analysis began (http://www.investor.jnj.com/releaseDetail.cfm?releaseid =296494).

암은 세포의 유전자에 돌연변이가 누적되면서 세포분열이 정상적으로 조절되지 않아 발생한다. 때문에 암세포의 염색체는 결실이나 중복, 전좌와 같은 염색체 이상(chromosomal abnormality)이 빈번하게 나타나는 특징이 있다. 염색체 이상으로 인해 나타나는 암의 발생 기작에 관한 연구들이 이루어지면서 융합 유전자(Fusion gen e)와 같은 염색체이상을 암의 진단 및 예후관측의 지표로 활용하려는 노력이 계속되고 있다(Parker BC and Zhang W, Chin J Cancer. Vol. 11, pp. 594-603, 2013).Cancer occurs when mutations accumulate in the genes of cells and cell division is not normally regulated. For this reason, chromosomes of cancer cells are characterized by frequent chromosomal abnormalities such as deletions, duplications, and translocations. Efforts are being made to utilize chromosomal abnormalities such as fusion genes as indicators for diagnosis and prognosis of cancer as studies on the mechanism of cancer caused by chromosomal abnormalities have been conducted (Parker BC and Zhang W, Chin J Cancer. Vol. 11, pp. 594-603, 2013).

더 나아가 종양세포로부터 유래된 ctDNA는 정상세포에서는 나타나지 않는 염색체이상을 반영한다는 접근에서, cfDNA를 통한 염색체 이상 검출을 임상적으로 활용하려는 연구가 이루어지고 있다. 최근 분자진단기술의 발전으로 cfDNA에서 염색체 이상 검출이 가능해짐에 따라, Digital Karyotyping, PARE 분석을 통해서 암 환자의 cfDNA에서 종양 특이적인 염색체이상을 검출이 가능하다는 연구와 함께 이를 임상적으로 확인한 연구결과들이 보고되고 있다(Leary RJ et al., Sci Transl Med. Vol. 4, Issue 162. 2012).Furthermore, in the approach that ctDNA derived from tumor cells reflects chromosomal abnormalities that do not appear in normal cells, studies are being conducted to clinically utilize chromosomal abnormality detection through cfDNA. As chromosomal aberrations can be detected in cfDNA with the recent development of molecular diagnostic technology, studies have shown that tumor-specific chromosomal aberrations can be detected in cfDNA of cancer patients through Digital Karyotyping and PARE analysis, as well as clinically confirmed research results. have been reported (Leary RJ et al., Sci Transl Med. Vol. 4, Issue 162. 2012).

이에 본 발명자들은 중추신경계 림프종을 조기진단하기 위한 마커 동정을 위하여 예의 노력한 결과, 정상 림프 조직에 비하여 중추신경계 림프종에서 돌연변이가 있는 유전자를 동정하였고, 상기 유전자의 돌연변이를 확인함으로써 중추신경계 림프종을 진단할 수 있음을 확인하여 본 발명을 완성하였다. Accordingly, the present inventors made diligent efforts to identify markers for early diagnosis of central nervous system lymphoma, and as a result, identified genes with mutations in central nervous system lymphomas compared to normal lymphomas, and by confirming mutations in the genes, it was possible to diagnose central nervous system lymphomas. The present invention was completed by confirming that it was possible.

Wan JCM et al., Nat Rev Cancer. Vol. 4 pp. 223-238, 2017 Wan JCM et al., Nat Rev Cancer. Vol. 4 pp. 223-238, 2017 Bettegowda C et al., Sci. Transl Med. Vol. 6, pp. 224-24, 2014 Bettegowda C et al., Sci. Transl Med. Vol. 6, p. 224-24, 2014 Diehl F et al., Nat Med Vol. 14, pp. 985-990, 2008 Diehl F et al., Nat Med Vol. 14, p. 985-990, 2008 Parker BC and Zhang W, Chin J Cancer. Vol. 11, pp. 594-603, 2013 Parker BC and Zhang W, Chin J Cancer. Vol. 11, p. 594-603, 2013 Leary RJ et al., Sci Transl Med. Vol. 4, Issue 162. 2012 Leary RJ et al., Sci Transl Med. Vol. 4, Issue 162. 2012

본 발명의 일 목적은 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88) 중 어느 하나 이상의 유전자의 돌연변이를 확인하는 제제를 포함하는 중추신경계 림프종을 진단하기 위한 마커 검출용 조성물을 제공하는 것이다.One object of the present invention is to provide an agent for confirming mutations in any one or more genes of PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D) and MYD88 (Myeloid differentiation primary response 88) To provide a composition for detecting a marker for diagnosing central nervous system lymphoma, including

본 발명의 다른 일 목적은 상기한 조성물을 포함하는 중추신경계 림프종 진단용 키트를 제공하는 것이다. Another object of the present invention is to provide a kit for diagnosing central nervous system lymphoma comprising the above composition.

본 발명의 다른 일 목적은 진단 대상의 생물학적 시료로부터 제1항 내지 제3항 중 어느 한 항에 따른 마커 검출용 조성물을 통해 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88) 중 어느 하나 이상의 유전자의 돌연변이 여부를 확인하는 단계를 포함하는 중추신경계 림프종을 진단하는 방법을 제공하는 것이다. Another object of the present invention is to detect PIM1 (Proto-oncogene serine / threonine-protein kinase), KMT2D (Histone-lysine) through the marker detection composition according to any one of claims 1 to 3 from a biological sample of a diagnosis subject. N-methyltransferase 2D) and myeloid differentiation primary response 88 (MYD88) to provide a method for diagnosing central nervous system lymphoma, including the step of determining whether one or more genes are mutated.

본 발명의 일 양상은 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88) 중 어느 하나 이상의 유전자의 돌연변이를 확인하는 제제를 포함하는 중추신경계 림프종을 진단하기 위한 마커 검출용 조성물을 제공한다.One aspect of the present invention is an agent for confirming a mutation in any one or more genes of PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D) and MYD88 (Myeloid differentiation primary response 88) It provides a composition for detecting a marker for diagnosing central nervous system lymphoma, including.

본 발명의 상기 'PIM1'은 세린 또는 트레오닌 키나제를 인코딩하는 원종양유전자이다. PIM1은 세포 주기 진행, 세포자멸사, 전사 활성화, 및 신호 전달 경로에 관여된다. 예시적인 인간 PIM1 유전자 서열은 서열번호 1과 같다 (NCBI Reference Sequence: NG_029601.1).The 'PIM1' of the present invention is a proto-oncogene encoding serine or threonine kinase. PIM1 is involved in cell cycle progression, apoptosis, transcriptional activation, and signal transduction pathways. An exemplary human PIM1 gene sequence is SEQ ID NO: 1 (NCBI Reference Sequence: NG_029601.1).

본 발명의 상기 'KMT2D'는 히스톤-리신 N-메틸트랜스퍼레이즈 (KMT2D)는 MLL4, 또는 인간에서 MLL2로 알려져 있다. KMT2A (또는 MLL1), KMT2B (또는 MLL2), KMT2C (또는 MLL3), KMT2F (또는 SET1A), KMT2G (또는 KMT2G)도 포함하는 6개의 Set1-like H3K4 메틸트랜스퍼라아제 계열의 일부이다. 예시적인 인간 KMT2D 유전자 서열은 서열번호 2와 같다(NCBI Reference Sequence: NG_027827.1).The 'KMT2D' of the present invention is histone-lysine N-methyltransferase (KMT2D) is known as MLL4, or MLL2 in humans. It is part of a family of six Set1-like H3K4 methyltransferases that also include KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or KMT2G). An exemplary human KMT2D gene sequence is SEQ ID NO: 2 (NCBI Reference Sequence: NG_027827.1).

본 발명의 상기 'MYD88(Myeloid differentiation primary response 88) 유전자'는 면역세포 내에서 신호에 관여하는 단백질을 만든다. MYD88 단백질은 세포 밖에서 신호를 받는 단백질과 세포 내에서 신호를 전달하는 단백질을 연결하는 어댑터 역할을 한다. 예시적인 인간 MyD88 유전자 서열은 서열번호 3와 같다(NCBI Reference Sequence: NG_016964.1).The 'MYD88 (Myeloid differentiation primary response 88) gene' of the present invention makes proteins involved in signals in immune cells. The MYD88 protein serves as an adapter connecting proteins that receive signals outside the cell and proteins that transmit signals within the cell. An exemplary human MyD88 gene sequence is SEQ ID NO: 3 (NCBI Reference Sequence: NG_016964.1).

본 발명에서, "중추신경계 림프종"은 전신성 질병이 아니라 뇌 및 뇌간에 한정되는 림프종으로 정의된다. 이는 중추신경계에서 생기는 이에 한정되는 비-호지킨 림프종(NHL)에 적용되는 용어로서 바람직하게는 원발성 중추신 경계 림프종(primary central nervous system lymphoma, PCNSL)일 수 있다.In the present invention, "central nervous system lymphoma" is defined as a lymphoma confined to the brain and brainstem and not a systemic disease. This is a term applied to non-Hodgkin's lymphoma (NHL), which is limited to those occurring in the central nervous system, and may preferably be primary central nervous system lymphoma (PCNSL).

본 발명에서, "진단"은 병리 상태를 확인하는 것을 의미한다. 본 발명의 목적상, 진단은 중추신경계 림프종의 진단 마커의 돌연변이 여부를 확인하여 중추신경계 림프종의 발병 여부를 확인하는 것이다.In the present invention, “diagnosis” means identifying a pathological state. For the purpose of the present invention, diagnosis is to determine whether a central nervous system lymphoma has been diagnosed by checking whether a diagnostic marker for central nervous system lymphoma has been mutated.

본 발명에서 용어, "진단 마커(diagnosis marker), 진단용 마커"란 중추신경계 림프종 세포를 정상세포와 구분 하여 진단할 수 있는 물질로, 정상 세포에 비하여 중추신경계 림프종을 가진 세포에서 감소를 보이는 폴리펩타이드 또는 핵산(예: mRNA 등), 지질, 당지질, 당단백질 또는 당(단당류, 이당류, 올리고당류 등) 등과 같은 유기 생체 분자 등을 포함한다. 본 발명의 목적상, 본 발명의 중추신경계 림프종 마커는 진단 대상의 혈액 내 cfDNA 또는 ctDNA 확인 결과 돌인변이가 있는 유전자 및 이에 의하여 코딩되는 단백질일 수 있다.In the present invention, the term "diagnosis marker, diagnostic marker" is a substance that can diagnose central nervous system lymphoma cells by distinguishing them from normal cells, and is a polypeptide showing a decrease in cells with central nervous system lymphoma compared to normal cells or organic biomolecules such as nucleic acids (eg, mRNA, etc.), lipids, glycolipids, glycoproteins, or sugars (monosaccharides, disaccharides, oligosaccharides, etc.), and the like. For the purpose of the present invention, the central nervous system lymphoma marker of the present invention may be a gene having a mutation as a result of confirming cfDNA or ctDNA in the blood of a diagnosis subject and a protein encoded by the gene.

본 발명에서, "PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88) 중 어느 하나 이상의 유전자의 돌연변이를 확인하는 제제"란 중추신경계 림프종 세포에서 본 발명의 중추신경계 림프종 마커의 돌연변이 여부를 확인함으로써 마커의 검출에 사용될 수 있는 분자를 의미한다.In the present invention, "agent for confirming a mutation in any one or more genes of PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D), and MYD88 (Myeloid differentiation primary response 88)" It refers to a molecule that can be used to detect the central nervous system lymphoma marker by confirming whether or not the central nervous system lymphoma marker of the present invention is mutated in central nervous system lymphoma cells.

본 발명에서, "돌연변이 확인"이란 중추신경계 림프종을 진단하기 위하여 생물학적 시료에서 중추신경계 림프종 마커 유전자의 돌연변이 여부를 확인하는 과정으로, 이를 위한 방법으로는 중합효소연쇄반응, 역전사 중합효소연쇄반응, 경쟁적 중합효소연쇄 반응, Nuclease 보호 분석 (RNase, S1 nuclease assay), in situ 교잡법, 핵산 마이크로어레이, 노던블랏 또는 타겟 시퀀싱(target sequencing) 중 어느 하나일 수 있으나 이로 제한되는 것은 아니다.In the present invention, "mutation confirmation" is a process of confirming whether or not a mutation is present in a central nervous system lymphoma marker gene in a biological sample in order to diagnose central nervous system lymphoma. Methods for this include polymerase chain reaction, reverse transcription polymerase chain reaction, competitive It may be any one of polymerase chain reaction, nuclease protection assay (RNase, S1 nuclease assay), in situ hybridization, nucleic acid microarray, northern blot, or target sequencing, but is not limited thereto.

본 발명의 일 구체예로서 상기 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88)는 생물학적 시료에서 분리된 cfDNA 및 ctDNA 중 어느 하나 이상일 수 있다. As one embodiment of the present invention, the PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D) and MYD88 (Myeloid differentiation primary response 88) are isolated from biological samples. can be more than one.

본 발명에서 상기 "생물학적 시료"는 중추신경계 림프종 발병에 의해 전술한 마커의 돌연변이가 확인되는 조직, 세포, 전혈, 혈청, 혈장, 타액, 객담, 뇌척수액 또는 뇨와 같은 시료 등을 포함하나, 이에 제한되지 않으며, 구체적으로는 혈청, 혈장일 수 있다. In the present invention, the "biological sample" includes, but is not limited to, tissues, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid or urine samples in which mutations in the above-mentioned markers are confirmed by the onset of central nervous system lymphoma. It is not, and specifically, it may be serum or plasma.

본 발명의 상기 "cfDNA"는 세포유리 DNA (cell free DNA)를 의미하는 것으로 혈장에 존재하는 세포에서 유래한 DNA를 의미한다. 상기 cfDNA는 통상 이중나선구조를 가질 뿐 아니라, 코일드코일 구조를 가지는 경우가 많다. 상기 cfDNA는 80 bp 내지 10 kbp, 100 bp 내지 1 kbp, 120 bp 내지 500 bp의 크기를 가질 수 있다. 또한, cfDNA는 150 bp 내지 200 bp의 크기를 가질 수 있으며, 통상, 165 bp 내지 170 bp의 크기를 가질 수 있다.The "cfDNA" of the present invention refers to cell free DNA, and refers to DNA derived from cells present in plasma. The cfDNA usually has a double helix structure as well as a coiled coil structure in many cases. The cfDNA may have a size of 80 bp to 10 kbp, 100 bp to 1 kbp, or 120 bp to 500 bp. In addition, cfDNA may have a size of 150 bp to 200 bp, and usually may have a size of 165 bp to 170 bp.

본 발명의 상기 "ctDNA"는 순환종양 DNA (circulating tumor DNA, ctDNA)를 의미하는 것으로, 전술한 cfDNA 중 중추신경계 림프종에서 기인하여 환자로부터 유래된 소변, 뇌척수액, 혈장, 혈액, 또는 체액 등의 생물학적 시료에서 발견되는 것일 수 있다. The "ctDNA" of the present invention means circulating tumor DNA (ctDNA), and among the above-mentioned cfDNA, biological substances such as urine, cerebrospinal fluid, plasma, blood, or body fluid derived from a patient due to central nervous system lymphoma It may be found in the sample.

본 발명의 다른 일 양상은 전술한 조성물을 포함하는 중추신경계 림프종 진단용 키트를 제공한다. Another aspect of the present invention provides a kit for diagnosing central nervous system lymphoma comprising the above composition.

상기 진단용 키트는 중추신경계 림프종을 진단하기 위한 마커인 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88) 중 어느 하나 이상의 유전자의 돌연변이 여부를 확인할 수 있다. The diagnostic kit contains any one or more genes of PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D) and MYD88 (Myeloid differentiation primary response 88), which are markers for diagnosing central nervous system lymphoma. mutations can be identified.

본 발명의 진단용 키트에는 중추신경계 림프종 진단 마커의 돌연변이 여부를 확인하기 위한 중합효소연쇄반응, 역전사 중합효소연쇄반응, 경쟁적 중합효소연쇄 반응, Nuclease 보호 분석 (RNase, S1 nuclease assay), in situ 교잡법, 핵산 마이크로어레이, 노던블랏 또는 타겟 시퀀싱 (target sequencing) 중 어느 하나에서 사용되는 제제를 포함될 수 있다.The diagnostic kit of the present invention includes polymerase chain reaction, reverse transcription polymerase chain reaction, competitive polymerase chain reaction, nuclease protection assay (RNase, S1 nuclease assay), in situ hybridization to determine whether a central nervous system lymphoma diagnostic marker has been mutated. , preparations used in any one of nucleic acid microarrays, northern blots, or target sequencing.

본 발명의 일 구체예에서 상기 키트가 역전사 중합효소연쇄반응 키트일 경우 상기 키트는 역전사 중합효소연쇄반응을 수행하기 위해 필요한 필수 요소를 포함하는 키트일 수 있다. 역전사 중합효소연쇄반응 키트는 마커 유전자에 대한 특이적인 각각의 프라이머 쌍 외에도 테스트 튜브 또는 다른 적절한 컨테이너, 반응 완충액(pH 및 마그네슘 농도는 다양), 데옥시뉴클레오타이드 (dNTPs), Taq-폴리머라아제 및 역전사효소와 같은 효소, DNase, RNAse 억제제, DEPC-수(DEPC-water), 멸균수 등을 포함할 수 있다. 또한, 정량 대조구로 사용되는 유전자에 특이적인 프라이머 쌍을 포함할 수 있다.In one embodiment of the present invention, when the kit is a reverse transcription polymerase chain reaction kit, the kit may be a kit including essential elements required to perform a reverse transcription polymerase chain reaction. The Reverse Transcription Polymerase Chain Reaction Kit contains, in addition to each pair of primers specific for a marker gene, a test tube or other suitable container, reaction buffer (with varying pH and magnesium concentration), deoxynucleotides (dNTPs), Taq-polymerase and reverse transcriptase. enzymes such as enzymes, DNase, RNAse inhibitors, DEPC-water, sterile water, and the like. In addition, a primer pair specific to a gene used as a quantitative control may be included.

본 발명의 다른 일 양상은 전술한 중추신경계 림프종 진단용 조성물 또는 진단 키트를 이용한 중추신경계 림프종을 진단하는 방법을 제공한다.Another aspect of the present invention provides a method for diagnosing central nervous system lymphoma using the above-described composition or diagnostic kit for diagnosing central nervous system lymphoma.

구체적으로 상기 방법은 진단 대상의 생물학적 시료로부터 제1항 내지 제3항 중 어느 한 항에 따른 마커 검출용 조성물을 통해 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88) 중 어느 하나 이상의 유전자의 돌연변이 여부를 확인하는 단계를 포함할 수 있다. Specifically, the method is to detect PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D (Histone-lysine N- methyltransferase 2D) and myeloid differentiation primary response 88 (MYD88).

상기 돌연변이 여부를 확인하는 단계는 진단 대상의 생물학적 시료로부터 상기한 마커 검출용 조성물을 통해 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및/또는 MYD88(Myeloid differentiation primary response 88) 유전자의 돌연변이 여부를 확인하는 단계이다.The step of determining whether or not the mutation is present is to detect PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D) and/or MYD88 ( Myeloid differentiation primary response 88) This step is to check whether the gene has been mutated.

상기 단계에서 상기 생물학적 시료는 진단 대상에서 분리된 cfDNA 및 ctDNA 중 어느 하나 이상일 수 있다. In the above step, the biological sample may be any one or more of cfDNA and ctDNA isolated from the diagnosis subject.

상기 단계에서 돌연변이를 확인하는 중합효소연쇄반응, 역전사 중합효소연쇄반응, 경쟁적 중합효소연쇄 반응, Nuclease 보호 분석 (RNase, S1 nuclease assay), in situ 교잡법, 핵산 마이크로어레이 또는 노던블랏 중 어느 하나일 수 있다. Any one of polymerase chain reaction, reverse transcription polymerase chain reaction, competitive polymerase chain reaction, nuclease protection assay (RNase, S1 nuclease assay), in situ hybridization, nucleic acid microarray or northern blot to identify mutations in the above step can

상기 방법은 진단 대상의 생물학적 시료로부터 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및/또는 MYD88(Myeloid differentiation primary response 88) 유전자의 돌연변이 여부를 확인함으로써, 데이터 베이스 또는 대조구 시료의 유전자와 비교하여 진단 대상의 시료의 유전자가 돌연변이가 있는 경우 중추신경계 림프종으로 진단할 수 있다. The method confirms mutations in PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D) and/or MYD88 (Myeloid differentiation primary response 88) genes from a biological sample to be diagnosed. , Central nervous system lymphoma can be diagnosed if there is a mutation in the gene of the sample to be diagnosed compared to the gene of the database or control sample.

본 발명은 중추신경계 림프종의 발병 여부를 진단할 수 있는 마커들을 제공함으로써, 중추신경계 림프종의 치료에 유용한 자료를 제공할 수 있다. 특히, 종래 중추신경계 림프종의 발병 여부를 진단하기 위해 조직의 채취가 필수적인 것과 비교하여, 혈장에서 확인 가능한 마커들의 돌연변이 여부만을 확인함으로써 중추신경계 림프종의 진단이 가능한 바, 상대적으로 비 침습적인 효과가 있다. The present invention can provide useful data for the treatment of central nervous system lymphoma by providing markers capable of diagnosing the onset of central nervous system lymphoma. In particular, compared to the conventional method of collecting tissue to diagnose the onset of central nervous system lymphoma, it is possible to diagnose central nervous system lymphoma only by checking whether there are mutations in identifiable markers in plasma, which has a relatively non-invasive effect. .

도 1은 실험예 1-1의 PCNSL 환자를 선별하는 과정을 나타내는 개념도이다.
도 2는 실험예 1-2에 따른 PCNSL 환자의 혈장으로부터 얻은 DNA 마커를 선별하는 과정을 나타내는 개념도이다.
도 3은 실험예 2에 따른 결과를 나타내는 도면으로, 순환종양 DNA 마커 별 대립유전자 빈도를 확인한 것이다. 1 is a conceptual diagram showing a process of selecting PCNSL patients of Experimental Example 1-1.
2 is a conceptual diagram showing a process of selecting DNA markers obtained from plasma of PCNSL patients according to Experimental Example 1-2.
3 is a view showing the results according to Experimental Example 2, confirming the allele frequencies for each circulating tumor DNA marker.

이하 하나 이상의 구체예를 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, one or more specific examples will be described in more detail through examples. However, these examples are intended to illustrate one or more specific examples, and the scope of the present invention is not limited to these examples.

실험예 1: PCNSL 환자 데이터 입수 및 마커의 선별Experimental Example 1: Acquisition of PCNSL patient data and selection of markers

1-1. PCNSL 환자의 선별1-1. Screening of PCNSL patients

삼성의료센터 제도 검토위원회가 승인한 프로토콜을 사용하여 (IRB number 2016-11-040) 진행하였다. 구체적으로, 중추신경계 림프종을 가진 성인환자들을 대상으로 실험을 진행하였고 (the Prospective Cohort Study for Lymphoma: Samsung Lymphoma Cohort Study III: ClinicalTrials.gov Identifier: NCT03117036), 환자들의 동의를 받은 뒤 생물학적 시료 (혈청 세포-유리 DNA, plasma cell-free DNA)를 채취하였다. 환자들은 신규한 원발성 중추신경계 림프종 환자 (newly PCNSL, n=39) 및 재발한 원발성 중추신경계 림프종 환자 (relapsed PCNSL, n=3)으로 총 42명을 분석하였고 그 중 DNA 분석이 분명치 않은 1명을 제외한 총 41명의 환자의 시료를 대상으로 실험하였다 (도 1 참조). It was conducted using the protocol approved by the Samsung Medical Center system review committee (IRB number 2016-11-040). Specifically, an experiment was conducted on adult patients with central nervous system lymphoma (the Prospective Cohort Study for Lymphoma: Samsung Lymphoma Cohort Study III: ClinicalTrials.gov Identifier: NCT03117036), and after obtaining consent from the patients, biological samples (serum and cell cells) were collected. -Free DNA, plasma cell-free DNA) were collected. A total of 42 patients were analyzed, including new primary central nervous system lymphoma patients (newly PCNSL, n=39) and relapsed primary central nervous system lymphoma patients (relapsed PCNSL, n=3). A total of 41 patients' samples were tested (see Fig. 1).

1-2. ctDNA 마커의 선별1-2. Screening of ctDNA markers

모든 혈액 샘플들은 Cell-Free DNA?? BCT tubes (Streck Inc., Omaha, NE, USA)을 이용하여 얻었다. 혈장은 실온에서 3번의 원심분리를 통해 얻어졌다 (840×g for 10 min, 1040×g for 10 min, and then 5000×g for 10 min). 혈장 DNA는 QIAamp Circulating Nucleic Acid Kit (Qiagen)를 이용하여 2 내지 5mL의 혈장으로부터 수득하였다. All blood samples are Cell-Free DNA?? It was obtained using BCT tubes (Streck Inc., Omaha, NE, USA). Plasma was obtained by centrifugation at room temperature three times (840×g for 10 min, 1040×g for 10 min, and then 5000×g for 10 min). Plasma DNA was obtained from 2 to 5 mL of plasma using the QIAamp Circulating Nucleic Acid Kit (Qiagen).

혈장 내 세포-유리 DNA 라이브러리는 KAPA Hyper Prep Kit (Kapa Biosystems, Woburn, MA, USA)를 이용하여 제작하였다. 구체적으로 시료 검사로부터 라이브러리 제작을 위해, 426개의 림프종 관련 유전자를 타겟하는 프로브를 사용하여 교차 선정 (hybrid selection)을 수행하였다. 특히 426개의 유전자 패널로부터 선별된 54개의 유전자를 대응되는 정상 시료에서의 세포-유리 DNA의 시퀀싱을 위해 사용하였다 (도 2 참조). A cell-free DNA library in plasma was prepared using the KAPA Hyper Prep Kit (Kapa Biosystems, Woburn, MA, USA). Specifically, hybrid selection was performed using probes targeting 426 lymphoma-related genes to construct a library from sample inspection. In particular, 54 genes selected from the 426 gene panel were used for sequencing of cell-free DNA in corresponding normal samples (see Fig. 2).

또한, 순환종양DNA (ctDNA)의 정량적 수준은 cell-free DNA 농도의 산물로 결정된 유전자 동증체 (genome equivalents, GE)와 체세포 돌연변이의 maximal variant allele fraction (VAF)로 측정되었다. In addition, the quantitative level of circulating tumor DNA (ctDNA) was measured by genome equivalents (GE) determined as the product of cell-free DNA concentration and maximal variant allele fraction (VAF) of somatic mutations.

실험예 2: PIM1, KMT2D 및 MYD88 유전자의 선별Experimental Example 2: Selection of PIM1, KMT2D and MYD88 genes

41명의 환자로부터 얻은 세포-유리 DNA에 대하여 타겟 시퀀싱을 수행하였고, 그 결과 총 11명의 환자 시료 (P152, P205, P223, P297, P309, P543, P582, P586, P596, P732, P764) 에서 체세포 변이를 확인하였다. Targeted sequencing was performed on cell-free DNA from 41 patients, resulting in somatic mutations in a total of 11 patient samples (P152, P205, P223, P297, P309, P543, P582, P586, P596, P732, P764). confirmed.

11명 환자의 시료들에서 유전자 돌연변이를 확인한 결과 도 3에서 확인되는 바와 같이 PIM 1, KMT2D 및 MYD88이 가장 빈번한 돌연변이로 확인되었고 (3/11, 27%), 이를 중추신경계 림프종을 진단하기 위한 마커로 선별하였다.As a result of confirming gene mutations in the samples of 11 patients, PIM 1, KMT2D, and MYD88 were identified as the most frequent mutations (3/11, 27%), as shown in FIG. 3, and these were identified as markers for diagnosing central nervous system lymphoma. was selected.

이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, the present invention has been looked at with respect to its preferred embodiments. Those skilled in the art to which the present invention pertains will be able to understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a limiting point of view. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the equivalent scope will be construed as being included in the present invention.

<110> SAMSUNG LIFE PUBLIC WELFARE FOUNDATION <120> MARKER FOR DIAGNOSING CNSL, CNSL DIAGNOSTIC KIT COMPRISING THE SAME AND METHOD FOR DIAGNOSING CNSL <130> PN200123 <160> 3 <170> KoPatentIn 3.0 <210> 1 <211> 5277 <212> DNA <213> Homo sapiens <400> 1 actcctggct gcggggcgag ccgggcgtct gctgcagcgg ccgcggtggc tgaggaggcc 60 cgagaggagt cggtggcagc ggcggcggcg ggaccggcag cagcagcagc agcagcagca 120 gcagcaacca ctagcctcct gccccgcggc gctgccgcac gagccccacg agccgctcac 180 cccgccgttc tcagcgctgc ccgaccccgc tggcgcgccc tcccgccgcc agtcccggca 240 gcgccctcag ttgtcctccg actcgccctc ggccttccgc gccagccgca gccacagccg 300 caacgccacc cgcagccaca gccacagcca cagccccagg catagccttc ggcacagccc 360 cggctccggc tcctgcggca gctcctctgg gcaccgtccc tgcgccgaca tcctggaggt 420 tgggatgctc ttgtccaaaa tcaactcgct tgcccacctg cgcgccgcgc cctgcaacga 480 cctgcacgcc accaagctgg cgcccggtga gagcaccccc cgcctccggc ccggggatgc 540 ggggcggcgg cgggatctcc tgggtgggga gctggcggct cgcgggccgg cactgagtcc 600 ccgtgcttcc ccctttccta ggcaaggaga aggagcccct ggagtcgcag taccaggtgg 660 gcccgctact gggcagcggc ggcttcggct cggtctactc aggcatccgc gtctccgaca 720 acttgccggt gagtgggcgc cccgcggtgg ggagggcgcg ccgggcgggg ggcgcacggg 780 cgtgctttag cccggacgag ggaacctgac ggagaccctg ggcttccagg tggccatcaa 840 acacgtggag aaggaccgga tttccgactg gggagagctg gtgagtgccc tgcaggagcg 900 acccccagga tgagtgggtg gggtgagggg cgcccccgac tcccgcccta acgcggcccc 960 ctcgcccctg cagcctaatg gcactcgagt gcccatggaa gtggtcctgc tgaagaaggt 1020 gagctcgggt ttctccggcg tcattaggct cctggactgg ttcgagaggc ccgacagttt 1080 cgtcctgatc ctggagaggc ccgagccggt gcaagatctc ttcgacttca tcacggaaag 1140 gggagccctg caagaggagc tggcccgcag cttcttctgg caggtgctgg aggccgtgcg 1200 gcactgccac aactgcgggg tgctccaccg cgacatcaag gacgaaaaca tccttatcga 1260 cctcaatcgc ggcgagctca agctcatcga cttcgggtcg ggggcgctgc tcaaggacac 1320 cgtctacacg gacttcgatg gtgagccagg cccgggaggg agctgcccag gtgactcggc 1380 ccggcccggc ccagtccgga ggcctcggcc agtctcccgc gccagccttt tgtaaaggtc 1440 attgggccgc ctggctcgat gctagccggg gtgggacgca ggagagcctc ccagcgtagt 1500 aaagccgggg attttcagcc agctgaacct gtaatgtttc tggcatgatt ttattcttca 1560 agtggaattc agttagttcc aggctttccc gatgaataag aggttgtggg caaccggcgg 1620 tagcccagat ttttctaaag tctgacccag tttccccgcc agtaaaagga tgggggcggg 1680 ggaagaggtg gaaattgatg ccggttttgt aatttttgtt ttattttata agggagttag 1740 ttttctgtat ggtagtttta gagctgcagt tcttaactcc tttctgatct agggaaggtt 1800 aaggaatagg aactatatta ttactggtgg cttttttttt tctttagtgt taaggggaga 1860 gagagtcagg aatgaatgtt gtgaaataag atctgtcgct ggtttgaaaa ttagttgggt 1920 gtctccgcag agaggatgaa aacctatcct agggaggggc ttggagcggg ttctttcaga 1980 aaagaaggaa tggagagcct gagatcaaag ctgcggaggg tgggtcatca tctgagcggc 2040 ttaacctaac aaacgacagc ctttcaaaac ttgtgactcg ggcttgtggt ttatgtttat 2100 ttgcccttgg aggacgctgg gttgggctgc attttttgta tttaacagtt aatggctggc 2160 cgggtcctcc catgtttttt ctttcaagtc tttgctgccc cctggtgagc accagcggca 2220 tggcccctcc tttttctttt actacccaaa gtttgtaaac aggaatcacg tggtctgaaa 2280 ccaaccctgc agctctgtct acctttccag tctagggagg aaagggtgtg ggtgtctgct 2340 cctgcttgca tcgggtgggg aggaaggcct cccaaagggc accctgactt aggatgttgt 2400 gcaagcatcc ttgcttggat cctgtcggcc atgagaatct cacccgggct cctgggcagt 2460 ggtgaatgca atttaaggat agtctatgag atacctttct tggttgtgca gacatgcatc 2520 ccttcatcct tcgcaggcgg tcctgcctca cagggcctca agttttgggt ctgcggccag 2580 ctgtgtttgt ttcttggagc agttcataaa gaatttcagt ttatggtttg ggctagcaga 2640 gaggtgggta atgctttggg ttggagagat gccgtaaggt gcgcctccac tctccttagc 2700 ccagagggaa aaatggagtt cacctagctc ctgagagaag ggattttttt tttttttaaa 2760 agaaagagtt atatatacca cccagcttct ttgtgcttgt ttttgctaaa agtgtgtttt 2820 ctcttctatt cccttggctc acagggaccc gagtgtatag ccctccagag tggatccgct 2880 accatcgcta ccatggcagg tcggcggcag tctggtccct ggggatcctg ctgtatgata 2940 tggtgtgtgg agatattcct ttcgagcatg acgaagagat catcaggggc caggttttct 3000 tcaggcagag ggtctcttca ggtaactgat ggaaacccct ggccatgggg ttattggtct 3060 taatggggct attagtcttc atgggacagt ctttgaaatt ctggagagct tcactctcca 3120 gtagattctg tcacccttgg cttagaattg taggtgagtg atttacactt gagctggcct 3180 cataaatcac atggtttgca cttgagcttt ccttgggagg tcagaggaag gcatgtgtga 3240 gcatattaag aagaaaagac aatctggctt ctccaaaaac ttttttaaag gtaccaacag 3300 aaacctgata attcctggct gttttgccag ggagtaaaaa gttaaaagct cttttagcat 3360 cttctttaag gcagcagctc caaatatttt ggtaccagtg acctcactgt gggtggtgtt 3420 cgtgtttgta agttggtagg tgaattgaat catttcatca tgctcagtgg tgtctcatca 3480 aaatctcttg tcatcatcct tcctatttct ggtgagtggg tgttgtggga aaggccccca 3540 ctattgaagt ttgaaaacca caggtttaag aggggagtca gtttttagct gaaagcagac 3600 tggaggaccc agatattagt caataccttc ctattgaagg gtacccagca cagtgttcta 3660 gaaaatgctt ggcctccctg ggaccccaga cttgtgggcc tctgagaagc aaatggggaa 3720 gacctttgca gtgtaaaaac aagttgagtc attcataacc tcgtctatcc tcctttctgc 3780 agaatgtcag catctcatta gatggtgctt ggccctgaga ccatcagata ggccaacctt 3840 cgaagaaatc cagaaccatc catggatgca agatgttctc ctgccccagg aaactgctga 3900 gatccacctc cacagcctgt cgccggggcc cagcaaatag cagcctttct ggcaggtcct 3960 cccctctctt gtcagatgcc cgagggaggg gaagcttctg tctccagctt cccgagtacc 4020 agtgacacgt ctcgccaagc aggacagtgc ttgatacagg aacaacattt acaactcatt 4080 ccagatccca ggcccctgga ggctgcctcc caacagtggg gaagagtgac tctccagggg 4140 tcctaggcct caactcctcc catagatact ctcttcttct cataggtgtc cagcattgct 4200 ggactctgaa atatcccggg ggtggggggt gggggtgggt cagaaccctg ccatggaact 4260 gtttccttca tcatgagttc tgctgaatgc cgcgatgggt caggtagggg ggaaacaggt 4320 tgggatggga taggactagc accattttaa gtccctgtca cctcttccga ctctttctga 4380 gtgccttctg tggggactcc ggctgtgctg ggagaaatac ttgaacttgc ctcttttacc 4440 tgctgcttct ccaaaaatct gcctgggttt tgttccctat ttttctctcc tgtcctccct 4500 caccccctcc ttcatatgaa aggtgccatg gaagaggcta cagggccaaa cgctgagcca 4560 cctgcccttt tttctgcctc ctttagtaaa actccgagtg aactggtctt cctttttggt 4620 ttttacttaa ctgtttcaaa gccaagacct cacacacaca aaaaatgcac aaacaatgca 4680 atcaacagaa aagctgtaaa tgtgtgtaca gttggcatgg tagtatacaa aaagattgta 4740 gtggatctaa tttttaagaa attttgcctt taagttattt tacctgtttt tgtttcttgt 4800 tttgaaagat gcgcattcta acctggaggt caatgttatg tatttattta tttatttatt 4860 tggttccctt cctattccaa gcttccatag ctgctgccct agttttcttt cctcctttcc 4920 tcctctgact tggggacctt ttgggggagg gctgcgacgc ttgctctgtt tgtggggtga 4980 cgggactcag gcgggacagt gctgcagctc cctggcttct gtggggcccc tcacctactt 5040 acccaggtgg gtcccggctc tgtgggtgat ggggaggggc attgctgact gtgtatatag 5100 gataattatg aaaagcagtt ctggatggtg tgccttccag atcctctctg gggctgtgtt 5160 ttgagcagca ggtagcctgc tggttttatc tgagtgaaat actgtacagg ggaataaaag 5220 agatcttatt ttttttttta tacttggcgt tttttgaata aaaacctttt gtcttaa 5277 <210> 2 <211> 36350 <212> DNA <213> Homo sapiens <400> 2 atggacagcc agaagctggc tggtgaggat aaagattcag aaccggcagg tgagtaggac 60 aaattgtttg tttgctttta gatttcattg gcaaccttac atttctggtc ctggcacaag 120 gacatgagct aagtctatgt agcagataag taatggaaca actttgttct ttgggacaac 180 agttgaaata tcatcactct gatccactca ggttttggat aatctcatgc gtctggtgag 240 tggactttgt gttaaatagg gatgatggct gacacatgct gtttgtctgt ttattcagct 300 gatggacctg cagcttctga ggacccaagt gccactgagt cagacctgcc caacccacat 360 gtgggagagg tctctgtcct tagttctggg agtcccaggc ttcaggagac tcctcaggac 420 tgcaggtagc ttgtttgagg gcacatgagg atttgagagt ctagggcttt caaggaagag 480 aatttaggaa aatgagtgtt ggggaagcat gggcatgcca gatcatgggg ttgctggggg 540 cctggcgtgg tactgatgct tgtgtgtcca cagtgggggt ccggtgcggc gttgtgctct 600 ctgtaactgc ggggagccca gtctacacgg gcagcgggag ctacggcgct ttgagttgcc 660 atttgattgg ccccggtgtc cagtggtgtc ccctgggggg agcccagggc ccaatgaggc 720 agtgctgccc agtgaggacc tatcacagat tggtttccct gagggcctta cacctgccca 780 cctaggagaa cctggaggtg agtgaggaga atggggcagg aaatgggata agggctgggt 840 agtcctgagc cagcaatcct ctttttgtta attctttcct ttctctttac ctcttcccac 900 ctgtaaaggg tcctgctggg ctcaccattg gtgtgctgca tggtcggcag gcgtatgggg 960 gcaggagggc ccagaactat gtggtgtgga caaggccatc ttctcaggga tctcacaggt 1020 ggggctgggc caggggattg cataggtgaa gggcagggct ggtgggcttc tgagagtcag 1080 gttggaatga gaaggaccat gggtatactg gggcagagct agtgcctgaa ctgtttgtct 1140 ggggagagct ggctgacact gaggctcttt tttcaccctg gcagcgctgc tcccactgca 1200 ccaggctcgg tgcctccatc ccttgccgct cacctggatg tccacggctt taccacttcc 1260 cctgcgcgac tgccagcggt tccttcctat ccatgaaaac actgcagctg ctatgcccag 1320 agcacagtga gggggctgca tatctgggtg agaagtcctg atctttggtc atagggcaaa 1380 tgagagacca aatgtgcctt ggatttttgt actctacaga gcactgatca aagtatagca 1440 ttatttactg ttggtctgcc ccactaaaat aggtgtgaac tttgtgagca ccagggtttt 1500 gcctgtctca tttatcattt tgtctccagt gcctagaaca gtagctggca gacgttgggc 1560 aggcactcag taactttgtt gtttgttcat tctgtgccca tggagtgcct gttttgtgta 1620 cagcaatgtg ctgaggctta caaggaatcc atagctgacc tgtggtgtct ctaccccctg 1680 cagaggaggc tcgctgtgca gtgtgtgagg ggccagggga gttgtgtgac ctgttcttct 1740 gtaccagctg tgggcatcac tatcacgggg cctgcctgga cactgctctg actgcccgca 1800 aacgtgctgg ctggcagtgc cctgaatgca aagtgtgcca agcctgcagg taggaatgga 1860 agggcaggag gaaagtctta ggcacaacac aggttagggt tgaaaatgag ggcagtcgga 1920 gaaggcctgt taacatgaaa acaacaaaaa agaaaggaaa tgagggcaga gaggacactg 1980 taatgttcca tgtgcacctg caggaaacct gggaatgact ctaagatgtt ggtttgtgag 2040 acgtgtgaca aaggatacca tactttctgc ctaaaaccac ccatggagga actgcctgct 2100 cactcttgga agtgcaaggt gagtgtaccc tgattctgcc ctattgtccc taactgtgtc 2160 tgctacagca ttctctgtct tgacaagttg tgtactttcg tttagtcttt gctgtctgac 2220 caatgcctgt tttgcccact cccttccctt aggcgtgccg ggtgtgccgg gcctgtgggg 2280 cgggctcagc agaactgaat cccaactcgg agtggtttga gaactactct ctctgtcacc 2340 gctgtcacaa agcccaggga ggtcagacta tccgctccgt tgctgagcag cataccccgg 2400 tgtgtagcag gtaagtggtg gggactgact gagattgggc tggcaggttg gaagaactga 2460 cattggcagg ggccttgtta aattgagtgg actttgagag gagagcccta aggtgggcag 2520 tgccatccac agcattcgtg cctcccccca gtgtgctctc taggatttgt tagctggtga 2580 gagccacagt gcctgctccc ctgtaccctc tgcagatttt cacccccaga gcctggcgat 2640 acccccactg acgagcccga tgctctgtac gttgcatgcc aagggcagcc aaagggtggg 2700 cacgtgacct ctatgcaacc caaggaacca gggcccctgc aatgtgaagc caaaccacta 2760 ggtgagtagg gtttgagggt ccctgaaatt catccccttt tattctatgg caagagacag 2820 tttgtgcatt gccccagacc ccacactttc tgtggagtag atctgagcta gataggagca 2880 tcgtgttgtt gtgtctgcag ggaaagcagg ggtccaactt gagccccagt tggaggcccc 2940 cctaaacgag gagatgccac tgctgccccc acctgaggag tcacccctgt ccccaccacc 3000 tgaggaatca cccacgtccc caccacctga ggcatcacgc ctgtcaccac cacctgagga 3060 attgcccgca tccccacttc ctgaggcatt gcacctgtcc cggccgctgg aggaatcgcc 3120 cctctctccg ccgcctgagg agtctcctct gtctccccca cctgaatcat cacctttttc 3180 tccactggag gagtcgccct tgtctccacc ggaagagtca cccccatctc ctgcacttga 3240 gacgcctcta tccccaccac ctgaagcatc gcccctgtcc ccaccatttg aagaatctcc 3300 tttgtccccg ccacctgagg aattgcccac ttccccgcca cctgaagcat ctcgcctgtc 3360 tccaccacct gaggagtcac ccatgtcccc tccacctgaa gagtcaccca tgtctccacc 3420 accggaggca tctcgtctgt tcccaccatt tgaagagtct cctctgtccc ctccacctga 3480 ggagtctccc ctttccccac cacctgaggc atcacgcctg tccccaccac ctgaggactc 3540 gcctatgtcc ccaccacctg aagaatcacc tatgtccccc ccacctgagg tatcgcgcct 3600 atcccccctg cctgtggtgt cacgcctgtc tccaccgcct gaggaatctc ccttgtcccc 3660 accgcctgag gagtctccca cgtcccctcc acctgaggct tcacgcctct ccccaccacc 3720 tgaggactcc cccacatccc caccacctga ggactcacct gcttccccac caccggagga 3780 ctcgctcatg tccctgccgc tggaggagtc acccctgttg ccactacctg aggagccgca 3840 actctgcccc cggtccgagg ggccgcacct gtcaccccgg cctgaggagc cgcacctgtc 3900 cccccggcct gaggagccac acctatctcc gcaggctgag gagccacacc tgtcccccca 3960 gcctgaggag ccatgcctat gcgctgtgcc tgaggagcca cacttgtccc cccaggctga 4020 gggaccacat ctgtcccctc agcctgagga attgcacctg tccccccaga ctgaggagcc 4080 gcacctgtct cctgtgcctg aggagccatg cttgtccccc caacctgagg aatcacacct 4140 gtccccccag tctgaggagc catgcctgtc cccccggcct gaggaatcgc atctgtcccc 4200 tgagcttgag aagccacccc tgtcccctcg gcctgaaaag ccccctgagg agccaggcca 4260 atgccctgca cctgaggagc tgcccttgtt ccctccccct ggggaaccat ccttatctcc 4320 cttgcttgga gagccagccc tgtctgagcc tggggaacca cctctgtccc ctctgcccga 4380 ggagctgccg ttgtccccat ctggggagcc atccttgtcg cctcagctga tgccaccagg 4440 taaggggatg ttagtactct gttattctgg aacagctgta actcttcatg gcacatctaa 4500 tctaagagcc cttctttttt ctctttcctt ccagatcccc ttcctcctcc actctcaccc 4560 atcatcacag ctgcggcccc accggccctg tctcctttgg gggagttaga gtaccccttt 4620 ggtgccaaag gggacagtga ccctgagtca ccgttggctg cccccatcct ggagacaccc 4680 atcagccctc caccagaagc taactgcact gaccctgagc ctgtcccccc tatgatcctt 4740 cccccatctc caggctcccc agtggggccg gcttctccca tcctgatgga gccccttcct 4800 cctcagtgtt cgccactcct tcagcattcc ctggttcccc aaaactcccc tccttcccag 4860 tgctctcctc ctgccctacc actgtccgtt ccctccccgt tgagtcccat agggaaggta 4920 gtgggggtct cagatgaggc tgagctgcac gagatggaga ctgagaaagt ttcagaacct 4980 gaatgcccag ccttggaacc cagtgccacc agtcctctcc cttccccaat gggggacctt 5040 tcctgccccg cccccagccc tgccccagcc ctggatgact tctctggcct aggggaagac 5100 acagcccctc tggatgggat tgatgctccg ggttcacagc cagagcctgg acagacccct 5160 ggcagtttgg ctagtgaact taaaggctcc cctgtgctcc tggaccccga ggagctggcc 5220 cctgtgaccc ctatggaggt ctaccccgaa tgcaagcaga cagcagggca gggctcacca 5280 tgtgaagaac aggaagagcc acgtgcaccg gtggccccca caccacccac tctcatcaaa 5340 tccgacatcg ttaacgagat ctctaatctg agccagggtg atgccagtgc cagttttcct 5400 ggctcagagc ccctcctggg ctctccagac ccggaggggg gtggctccct gtccatggag 5460 ttgggggtct ctacggatgt tagtccagcc cgagatgagg gctccctacg gctctgtact 5520 gactcactgc cagagactga tgactcacta ttgtgcgatg ctgggacagc tatcagcgga 5580 ggcaaagctg agggggagaa ggggcggcgg cgcagctccc cagcccgttc ccgcatcaaa 5640 caggtgaggg gctatctagc tgcgggatgt gattagagtt agcccactgt cagaggtaca 5700 gtcctgtgtc actgatactt tcccaccttg ctttgtgaat cctagacttg gagatccttt 5760 attccagtta ttaaggagaa aatactaata cgtagaaggg acaagtaact tgcccagatt 5820 catggttact cagtaataga attgggacca gaaacttggt tctttcaagc cattgttttt 5880 tctccttgcc catctcaacc actcttggga ggggaagaat gggtttgggc tagagctatg 5940 cgcttgttga tatctgggag tttggccttt tcccttgccc tgagtgggac tcctgggctt 6000 attacctgtc ttactctgtc cgtttgtcac ttcttctgtt caagtgtgta aacccaacac 6060 actagccctt gacatgctcc tgtcattgtc cccttctttc actcagggtc gcagcagcag 6120 tttcccagga agacgccggc ctcgtggagg agcccatgga ggacgtggta gaggacgggc 6180 ccggctaaag tcaactgctt cttccattga gactctggta gtaaggagat gcctcctatt 6240 cctcccatcc cccaaccatg ctttagcacc ctctgagtcc tgccagtccc ttgcatgctt 6300 gcctacctgc ctgctcgtct agggcctgtc tggctatgtc tgaattcctg tccacttggc 6360 ccgcaggttt ttctgaaatc tctgctatca gactgaggct caatttggga gctggggtgt 6420 tctgtctgtt attcctggct tttggccttc atcttaacca agggttcaca ctttcttccc 6480 ccaacaccaa agaggaaagt agcttggtgg gggcagattt atctgcctca ctttccataa 6540 ctctctgccc atcaggttgc tgacattgat agctctccca gtaaggagga ggaggaagaa 6600 gatgatgaca ccatgcagaa taccgtggtt ctcttctcca acacagacaa atttgtccta 6660 atgcaggtac catacagtga gacctggcac actgaacatt gtgtatgtgt gtgtttggtg 6720 agaggataga tgggaaaact ggacctactt tggggatacc cagctaatga gaaaacagac 6780 catgaattct aatcatgtta ttcattggtt tgtccatcca tcacatttct cttgagtatc 6840 tcttctgagc ttggcactaa gctaggagct agagaaatag cagtgaaaaa gtctttgcct 6900 tattgaactt tatagcttag ggaacttaca tgtgtcctca cttgaataat cttgaagctg 6960 atagaatttt gtcacatatg tgattctcac ctgaccagtc tttactccat cttatcttcc 7020 tttaatttct tcttaacttc acccatgtca ggctttataa attcaagtga cctgattagg 7080 tgagtaaggc atcctaggaa ggagcagggt cccttggtag cttacagcat cctaacgctg 7140 tgggatgggg ttcctgactc tggtcgcaaa tcagtgttgt agcgtcatag tagactggat 7200 ctgagtggga tggggagatc tagttggaca tttgggtttc tctgtgtttc cccaggacat 7260 gtgtgtggta tgtggcagct ttggccgggg ggcagagggc cacctccttg cctgttcgca 7320 gtgctctcag tgctatcacc cttactgtgt caacagcaag gtgagttcag ggcccaagag 7380 gtgtaggctg gggaataggg tcagttattt cttaccctag ttccttgtcc tggccatacc 7440 acctcttaaa gcggccatcg gtcatggttg ttcattagtc accagtggtt atcaaacttt 7500 tcttggggaa aagtactttg gaactcaacg gtggacttga tagtttcttt gtggtaggcc 7560 ctgacttgct ggtataattc agtccatcgt aaaaaataac aacatggctg ggcatggtgg 7620 ctcccacctg taatcccagc actttgggag gcctaggtgg gtggatcacc tgagattagg 7680 agttcaggac catcgtggtc aacatggtga aaccccgtct cttctaaaaa ataacaaaaa 7740 ttagctgagt gtggtagcgc gtgcctgtaa tctcagcaac tcgggaggct gaggcaggag 7800 aattgcttga acccaggagg cggaggttgc agtgagccga gatcacgcca ctgtactcca 7860 ctccagcctg ggcaacagag tgagatccgt ctcaaaaaaa aaaaaaaaaa aaaaaaaagg 7920 aaaaactggg ggacctaatt cggtccacag tctcttttta ggggcttggc tagtggaaag 7980 attgctattc tattcacaat gaggcagtgg ctagtgcagc tcttctctga tcagcagaga 8040 tcattgggag cctaagttta gagtcactgt tttggggaca agggtgctct gcctaagtct 8100 ctgtgtgctc aaatggaggc ctagtctctg cattgggctg cctccagcct cacccttaga 8160 agttccacct cctaggctgg gcacggtggc gcacacctgt aatcccagca ctttacttcg 8220 ggagggtgag gcgggtggat cacctaaggt caggagttgg tgaccagcct gactaacatg 8280 gtgaaactct gactctacta aatacaaaaa aattagccag gtgtggtggc aggtgcctgt 8340 aatctcagct acttgggagg ctgagacaag agaatcactt gtacctgaga ggcagaggtt 8400 gcagtgagcc gagatcgcgc cattgcactc cagcctgggg aacaagagca aaactccatc 8460 tccaaaaaaa aataaaaaga agttctacct cttttccacc tcacaccctg agaagttccc 8520 atcttctgcc ccagatcacc aaggtgatgc tgctcaaggg ctggcgttgt gtggagtgta 8580 ttgtgtgtga ggtgtgtggc caggcctccg acccctcacg cctgctgctc tgtgatgact 8640 gtgatattag ctaccacaca tactgcctgg accccccact gctcaccgtc cccaagggcg 8700 gctggaagtg caagtggtaa ggagactggg atcttcagtg gagccctggg gccttgagat 8760 gttaaagtgg atatgatgtt gagtatgtga cagaggctgg gtttaggagg ccaggctggt 8820 ggcttgggtt tccggtgagg ggacttctgg gtacttcggg taggttgggt gctaaagctc 8880 tgttttcctg ctcctatcag gtgtgtgtcc tgtatgcagt gtggggctgc ttcccctggc 8940 ttccactgtg aatggcagaa tagttacaca cactgtgggc cctgtgccag cctggtgacc 9000 tgccctatct gtcatgctcc ttacgtagaa gaggacctac taatccagtg ccgccactgt 9060 gaacggtgag aacatccctt tctcctcact ttggccctgt tgccagcctc gcattgcctg 9120 agcttatttc ctccagtctc tgttctccag gtggatgcat gcaggctgtg agagcctctt 9180 cacagaggac gatgtggagc aggcagccga tgaaggcttt gactgtgtct cctgccagcc 9240 ctacgtggta aagcctgtgg gtgagtacca gctgctgggt agggggagga gtcagagcag 9300 gggtaccttg ctttgggaca ggacctcagc cacctccgtt tgtccttctc tccatagcgc 9360 ctgttgcacc tccagagctg gtgcccatga aggtgaaaga gccaggtgag tcacagaaat 9420 tttgaatgcc aaagccagac cagacgtcgg acatcatcta gtctagctcc aaccccctag 9480 cttcatctcc ttattttaag aggaggaaac tcagacccag agaagttaag tggcctgccc 9540 aaggtcacct agtaagttag tggcaaagtt atgcctagaa ccaaggtctc cagcttcccg 9600 ggcaatgttc ctttcatcag gcaccatggt ctcttcactg ctaggatttc gtcttcagat 9660 ctcttttttt tttttttttt tgagatggag tcttgctctg ttgcccaggc tggagtgcag 9720 tggcacaagc ttggcacatt gcaagctttg cctcccgggt tcacgccatt ctcctgcctc 9780 agcctcctga gtagctggga ctacaggtgc ccgccaccac gcccggctaa ttttttgtat 9840 tttttagtag agatggggtt tcaccgtgtt agccaggatg gtctcgatct ccggacctcg 9900 tgatctgcca gcctcggcct cccaaagggc tgggattaca agcatgagca ccgcgcccgg 9960 ctgagaacat aactcttttt cctaagtgaa aggggccagg gacatctcca tcgtgatatg 10020 gcactgctgc tggcatctag gacactgtgt gctggcattc agcaagtagg ggccctcata 10080 gccccagaca gcaagagaat ctatttagtg aacctagggt taatcatgag caaaggcagg 10140 cttctgagtt acagttcctc tctgaatctc cctgggtcac tgacagagaa ctcgggcctc 10200 agccagtgcc ccttggtggc ctgttctcct cagcatttag accctaagct ggacttttgt 10260 cactgccttt gtctcagcta aggacatagg ttgaaacttg cagttctggt ttccctgggg 10320 cttccatcca gggatcacat actctttcct cttatgcaga gccccagtac tttcgcttcg 10380 aaggtgtgtg gctgacagaa actggcatgg ccttgctgcg taacctgacc atgtcaccac 10440 tgcacaagcg gcgccaacgg cgaggacggc ttggcctccc aggcgaggca ggattggagg 10500 gttctgagcc ctcagatgcc cttggccctg atgacaagaa ggatggggac ctggacaccg 10560 atgagctgct caagggtgaa ggttagcttg gggaatctta gggagcggca gagtaggggg 10620 agcgtgactc tgggagtggg atgttgggtg ggggctacat tgccactcag ttacccttaa 10680 gcactgctgt ctcgtctaag tggctctgag gcaaggtatt cagctctctc agtggcagga 10740 tgacaaggtt aaaagggcct atagttctga tttgcctcca tctcttctgt caccatacgc 10800 aggtggtgtg gagcacatgg agtgcgaaat taaactggag ggccccgtca gccctgatgt 10860 ggagcctggc aaagaggaga ccgaggaaag caaaaaacgc aagcgtaaac catatcggcc 10920 tggtgaggtc ctgggatggg gttgtggggt ggtggggtgg tgcggggcag ctcaataggt 10980 cccccagcgg cttctcatcc acaactctgc ctcctcatag gcattggtgg tttcatggtg 11040 cgacagcgga aatcccacac acgcacgaaa aaggggcctg ctgcacaggc ggaggtgttg 11100 agtggggatg ggcagcccga cgagggtgag acgggtgagg gcaccagtgg ggcctgggag 11160 aaggtggggc aatgctagag agacccaggg ggtggactca ttgaaagggc caagagggtg 11220 gtagacccag ctggtgttgt gggagagagt aggcacaaag tgtcaccctg caagttggga 11280 gcagcatgct ctcaacccga gtctgacact tccgttctgt ccacagtgat acctgctgac 11340 ctgcctgcag agggcgccgt ggagcagagc ttagctgaag gggatgagaa gaagaagcaa 11400 cagcggcgag ggcgcaagaa gagcaaactg gaggacatgt tccctgctta cttgcaggtg 11460 ggtctcaggc tccaagcagt gagggaggtg tctgtgccct gcagggcatg aagaaaactg 11520 tttctccttg actgccccac aggaagcctt ctttgggaag gagctgctgg acctgagccg 11580 taaggccctt tttgcagttg gggtgggccg gccaagcttt ggactaggga ccccaaaagc 11640 caagggagat ggaggctcag aaaggaagga actccccaca tcgcagaaag gttagttatg 11700 tgggagtgag tggtgtgaga gaatccaact ttcttctggc ttaggagctg gcaagttatt 11760 tgatgggaaa tggactggcc tccaggagtc aagggtgggg tcaagggtcc tggcctgtag 11820 ggctgtggga ctggagacct gttctgggca tcagatgtag gacatctctg attggagggg 11880 ggactcttgc tcataggaga tgatggtcca gatattgcag atgaagaatc ccgtggcctc 11940 gagggcaaag ccgatacacc aggtgagggc tgccggggtt actgtgtcct gtcttggcct 12000 tgcttgcctc tgtccctctg ctgtgcccct gagcattgtc agtgttggag gctggaaact 12060 gtcccatggc cctctgtggt tcagagtggc catgacccat cctggccttg acccatgggt 12120 ttctcctggc atttacagga cctgaggatg ggggcgtgaa ggcatcccca gtgcccagtg 12180 accctgagaa gccaggcacc ccaggtgaag ggatgcttag ctctgactta gacaggattt 12240 ccacagaagg tgaggctgtg acccgtacct ctttgtgtat aagggttttc tatgggagaa 12300 ggaggaggtc ctatctttgg gactgtgatc tgtacagctt ctctggtggg gagtcctgga 12360 ctgttcctgg ccatgatcat ttgtagacct gtggtgtcac ctgaacttcc cagtcttcct 12420 caacagtgtc cttcattccc ccacagaact gcccaagatg gaatccaagg acctgcagca 12480 gctcttcaag gatgttctgg gctctgaacg agaacagcat ctgggttgtg gaacccctgg 12540 cctagaaggc agccgtacgc cactgcagag gccctttctt caaggtaata caggtgggag 12600 tggtctgaag actgacataa ccaagcttgc ctccaggatg ggccagttgc tcttttctct 12660 gatcctgtcc gtcttgtagg tggactccct ttgggcaatc tgccctccag cagcccaatg 12720 gactcctacc caggcctctg ccagtccccg ttcctggatt ctaggttggt gtctctgcgt 12780 aacctttgtg ggcagtcctc gttgtccttt ccctccatct gagttcatgc tttgcctccc 12840 tcggactcct gcagcacttc ccctgctcct ccccattccc ttgttagtga ccctcctctt 12900 ttggggcagg gcagtggcct ggggctctag gcagtttgtc tggggtggga cttggcatcc 12960 ctgcgccctg tgactctctg cccctgcgcc ccagggagcg cgggggcttc tttagcccgg 13020 aacccggtga gcccgacagc ccctggacgg gctcaggtgg caccacgccc tccaccccca 13080 caacccccac cacggagggt gagggcgacg gactctccta taaccagcgg agtcttcagc 13140 gctgggagaa ggatgaggag ttgggccagc tgtccaccat ctcacctgtg ctctatgcca 13200 acattaattt tcctaatctc aagcaagact acccaggtac ctgtgggatg agggcaaggg 13260 agacagcctg gcaacatggc aggtggagga gtcgcctgcc aagtcttctc tgactcactc 13320 tctctgccct ccagactggt caagccgttg caaacaaatc atgaagctct ggagaaaggt 13380 tccagcagct gacaaagccc cctacctggt gaggcagaaa ggagcatgga ttagcgtggg 13440 aactgagagg gagggaggga tctttgggta atttacctca gttctttccg ctccccactc 13500 ctaaagcagc tgggccagaa gggatctgct tctgggtagg gagtgtgaaa acactacagt 13560 atgggggcgg ggcatgagac caagcactag gccctaaggc tgtgtcccat atccctcagc 13620 aaaaggccaa agataaccgg gcagctcacc gcatcaacaa ggtgcagaag gtgagtgggg 13680 ctgggctggg gtgtagcagt cctctagtgg gtggcctctc ttgagggtgg agggccatgg 13740 ggcctgcctg cagcagcctg actgccctat gcctggtctc cccctgtagc aggctgagag 13800 ccagatcaac aagcagacca aggtgggcga catagcccgt aagactgacc gaccggccct 13860 acatctccgc attcccccgc agccaggggc actgggcagc ccgccccccg ctgctgcccc 13920 caccattttc attggcagcc ccactacccc cgccggcttg tctacctctg cggacgggtt 13980 cctgaagccg ccggcgggct cggtgcctgg ccctgactcg cctggtgagc tcttcctcaa 14040 gctcccaccc caggtgcccg cccaagtgcc ttcgcaggac ccctttggac tggcccctgc 14100 ctatcccctg gagccccgct tccccacggc accgcccacc tatcccccct atcctagtcc 14160 tacgggggcc cctgcgcagc ccccgatgct gggcgcctca tctcgtcctg gggctggcca 14220 gccaggggaa ttccacacta ccccacctgg cacccccaga caccagccct ccacacctga 14280 cccattcctc aaaccccgct gcccctcgct ggataacttg gctgtgcctg agagccctgg 14340 ggtaggggga ggcaaagctt ccgagcccct gctctcgccc ccaccttttg gggagtcccg 14400 gaaggcccta gaggtgaaga aggaagagct tggggcatcc tctcctagct atgggccccc 14460 aaacctgggc tttgttgact caccctcctc aggcacccac ctgggtggcc tggagttaaa 14520 gacacctgat gtcttcaaag cccccctgac ccctcgggca tctcaggtag agccccagag 14580 cccgggcttg ggcctaaggc cccaggagcc accccctgcc caggctttgg caccttctcc 14640 tccaagtcac ccagacatct ttcgccctgg ctcctacact gacccatatg ctcagccccc 14700 attgactcct cggccccaac ctccgccccc tgagagctgc tgtgctctgc cccctcgctc 14760 actgccctcc gaccctttct cccgagtgcc tgccagtcct cagtcccagt ccagctccca 14820 gtctccactg acaccccggc ctctgtctgc tgaagctttt tgcccatcac ccgttacccc 14880 tcgcttccag tcccctgacc cttattctcg cccaccctca cgccctcagt cccgtgaccc 14940 atttgcccca ttgcataagc caccccgacc ccagccccct gaagttgcct ttaaggctgg 15000 gtctctagcc cacacttcgc tgggggctgg ggggttccca gcagccctgc ccgcggggcc 15060 agcaggtgag ctccatgcca aggtcccaag tgggcagccc cccaattttg tccggtcccc 15120 tgggacgggt gcatttgtgg gcaccccctc tcccatgcgt ttcactttcc ctcaggcagt 15180 aggggagcct tccctaaagc cccctgtccc tcagcctggt ctcccgccac cccatgggat 15240 caacagccat tttgggcccg gccccacctt gggcaagcct caaagcacaa actacacagt 15300 agccacaggg aacttccacc catcgggcag ccccctgggg cccagcagcg ggtccacagg 15360 ggagagctat gggctgtccc cactacgccc tccgtcggtt ctgccaccac ctgcacccga 15420 cggatccctc ccctacctgt cccatggagc ctcacagcga tcaggcatca cctctcctgt 15480 cgaaaagcga gaagacccag ggactggaat gggtagctct ttggcgacag ctgaactccc 15540 aggtacccag gacccaggca tgtccggcct tagccaaaca gagctggaga agcaacggca 15600 ggtaagttga caccctggag ctaagccccc tatatcgctc ctgtctctgg ggcagcccta 15660 tgattggagt agaatgggct tattcctctt ctcttttttt tgcatagcgc cagcgactac 15720 gagagctgct gattcggcag cagatccagc gcaacaccct gcggcaggag aaggaaacag 15780 ctgcagcagc tgcaggagca gtggggcctc caggcagctg gggtgctgag cccagcagcc 15840 ctgcctttga gcagctgagt cgaggccaga ccccctttgc tgggacacag gtaggtagag 15900 tggcaaggga tagtggggcc aggatattga aggttgctcc accttcatct accttgtctc 15960 ttctaggaca agagcagcct tgtggggttg cccccaagca agctgagtgg ccccatcctg 16020 gggccagggt ccttccctag cgatgaccga ctctcccggc cacctccacc agccacgcct 16080 tcctctatgg atgtgaacag ccggtgaggc tccaggaggt tccctggggg taaaccaagg 16140 gggatggatt ttatcactgt tggaagctct tgtgattttc ctgtatcact aatccttttc 16200 cagtatcact ttctcttctt cctcattcct tttctccctc actgcattaa ttctatcctt 16260 cctcactgcc ctaagcccat gttcttgctc cttttcatct gatttcatcc tactgactac 16320 tgtatattct tccaggcaac tggtaggagg ctcccaagct ttctatcagc gagcacccta 16380 tcctgggtcc ctgcccttac agcagcaaca gcaacaactg tggcagcaac aacaggcaac 16440 agcagcaacc tccatgcgat ttgccatgtc agctcgcttt ccatcaactc ctggacctga 16500 acttggccgc caagccctag gttccccgtt ggcgggaatt tccacccgtc tgccaggccc 16560 tggtgagcca gtgcctggtc cagctggtcc tgcccagttc attgagctgc ggcacaatgt 16620 acagaaagga ctgggacctg ggggcactcc gtttcctggt cagggcccac ctcagagacc 16680 ccgtttttac cctgtaagtg aggaccccca ccgactggct cctgaagggc ttcggggcct 16740 ggcggtatca ggtcttcccc cacagaaacc ctcagcccca ccggcccctg aattgaacaa 16800 cagtcttcat ccaacacccc acaccaaggg tcctaccctg ccaactggtt tggagctggt 16860 caaccggccc ccgtcgagca ctgagcttgg ccgccccaat cctctggccc tggaagctgg 16920 gaagttgccc tgtgaggatc ccgagctgga tgacgatttt gatgcccaca aggccctaga 16980 ggatgatgaa gagcttgctc acctgggtct gggtgtggat gtggccaagg gtgatgatga 17040 acttggcacc ttagaaaacc tggagaccaa tgacccccac ttggatgacc tgctcaatgg 17100 agacgagttt gacctgctgg catatactga tcctgagctg gacactgggg acaagaagga 17160 tatcttcaat gagcacctga ggctggtaga atcggctaat gagaaggctg aacgggaggc 17220 cctgctgcgg ggggtggagc caggaccctt gggccctgag gagcgccctc cccctgctgc 17280 tgatgcctct gaaccccgcc tggcatctgt gctccctgag gtgaagccca aggtggagga 17340 gggtggacgc cacccttctc cttgccaatt caccattgct acccccaagg tagagcccgc 17400 acctgctgcc aattcccttg gcctggggct aaagccagga cagagcatga tgggcagccg 17460 ggatacccgg atgggcacag ggccattttc tagcagtggg cacacagctg agaaggcctc 17520 ctttggggcc acgggaggac caccagctca cctgctgacc cccagcccac tgagtggccc 17580 aggaggatcc tccctgctgg aaaagtttga gctcgagagt ggggctttga ccttgcctgg 17640 tggacctgca gcatctgggg atgagctaga caagatggag agctcactgg tagccagcga 17700 gttacccctg ctcattgagg acctgttgga gcatgagaag aaggagctgc agaagaagca 17760 gcagctttca gcacagttgc agcctgccca gcagcagcag caacagcagc agcagcattc 17820 cctactgtct gcaccaggcc ctgcccaggc catgtctttg ccacatgagg gctcttctcc 17880 cagtttggct gggtcccaac agcagctttc cctgggtctt gcaggtgccc gacagccagg 17940 tttgccccag ccactgatgc ccacccagcc accagctcat gccctccagc aacgcctggc 18000 tccatccatg gctatggtgt ccaatcaagg gcatatgcta agtgggcagc atggagggca 18060 ggcaggcttg gtaccccagc agagctcaca gccagtgcta tcacagaagc ccatgggcac 18120 catgccacct tccatgtgca tgaagccgca gcaattggca atgcagcagc agctggcaaa 18180 cagcttcttc ccagatacag gtaacctcag ctggtaacat agccaagtta ctcagggtga 18240 ttattgttat ccctaaatgg gcactgaggc tagagacctc agataatccc tacttaagat 18300 gggacacaaa gaactttggc taaatatcat actagtggta gaggcagaaa cactgtagct 18360 tttaagaaga gagagaacag ttcctggcat atagtaggca tgtagcagat gtttgaataa 18420 atggaatgaa tgtatgaatg aagcctaatt agcagagcct ttgtagctgt agtgaagttg 18480 aaagcttaag acttgaagag aagtggtgca aaaaaaagca gttgaggcca ggcacaatgg 18540 ctcatgcctg taatcccagc actttgggag accaaggcag gtggatcact taagatcagg 18600 agttcaagac cagcctggcc aagatgatga aaccccatct ctactaaaca tacaaaaatt 18660 agctgggtgt gagccgggcg cggtggtgca tccctgtaat cccagctact cgggaggctg 18720 aggcaggaga gttgattgaa cccatgaggc agaggttgtg gtgagccgag atcgcctcat 18780 tgcactccag cctgggcaac aagagcgaaa ctccatctca aaaaaaaaaa aaaaaaaaaa 18840 aaaaaattag ctgggtgtgg tggtgcacgc ctgtagttcc agctactcga gaggctgagg 18900 caggagaatt gcttgaaccc aggaggtgga ggttgcagtt agctgagatc acgccattgc 18960 acttcaggct gggcaacaga gcgagactct gtcttaaaaa aaaaaaaaaa agcgattggg 19020 ataggtgaaa aagttcattg aggctgcaat ggtgggaaaa cctatgggat gtttcaagaa 19080 cagtgagtga attggttagg ctggagtaaa ctgtttcgag tgaagtaagt gacataattt 19140 tggtgagata agatgggggc cagattgaaa aagacctcaa attataatag catttattga 19200 gtaattacta tttgccaagg agtttactga gcactttata ctttttgtcc aatttaatca 19260 ttatagcaga ctcattaaat aggtattgtt attatctttg attacagaag aggaaacaga 19320 agtggaggtt aagtaacttg tccaagatta cacagcagct agcagagcta gatctgaagt 19380 ctggtcggta ctcctcttaa ctgtttactg cctcaggatt ccaggagagg gagtttgggt 19440 tagtccttaa gaaagtggga gctctggcca ggtgctgtgg ctcacgcctt taatcccagc 19500 actttgggag gctgaggcgg gtggatcacc tgaggtcagg agttccagac cagcctggcc 19560 aacatggtga aacctcgttt ctactaaaaa tacaaaaatt agctgggctt ggtggtgggc 19620 acctgtaatc acagctactc ggcaggctga ggcaggagaa tcgcttgaac ccaggaagca 19680 gaggttgcag tgagcctaaa ttgcaccatt gcactccagc ctgggtgaca agagcaagac 19740 tctgtcttta aaaaagaaaa gaaaagaaaa aaagaaagtg gatgctcagt taagttttct 19800 gagcagtgga gaaatataca aagtgtggga ttttaggatg atgtaagttt ttggtggttg 19860 gttgtttctt cttttttgcc cagcattcta gacagacagg agagtggact acaggtgatg 19920 cccaaaacag ctctggaatc tagggctttg caacagtgcc agcatcttgg gtgcttgggc 19980 tgtgctagtt ggactaagaa cattaccttt gaagaatgct ttccgagtca taaagtgtac 20040 ttatattctt gtcacatttg atcctcttaa cacctctgtg aggtagacgg agtagggatc 20100 atcatctgta tcaaataaaa gggtaaactg aggtgaaata acacaggttg actcaacaaa 20160 tatttacgga gccccttttt gtagcacggt gcaagtaaaa acaggcccac atgtcctgtg 20220 aatagagctg attcacccag gccgactggc tcctaattca gtggtctttc tgccttgccg 20280 tgccattgtt ctgcctggcg tggttgaagt caggatgttg aagggaatcg cagatattca 20340 ctggagcatt ggccccatag cccagctcac ttggttctcc cctctccaga cctggacaaa 20400 tttgctgcag aagatatcat tgatcccatt gcaaaggcca agatggtggc tttgaaaggc 20460 atcaagaaag tgatggctca gggcagcatt ggggtggcac ctggtatgaa caggtaagac 20520 tcagggctgg aatggggttg gcccttttct ttcccagtca caccccttct tggctcccct 20580 ccctacttgt cccacgtctc tttgctttcc aactttctta ttgccaacac ttatcttctg 20640 tgctttggtg gactccagac agcaagtgtc tctgctagcc cagaggctct cggggggacc 20700 tagcagtgat ctgcagaacc atgtggcagc tgggagtggc caggtaagtg gtcaggtggg 20760 agtaggaact tgtgtcttat gccactgggc cacccttctt agggcctagc agggaacaat 20820 gaccctttag cagcctctct cattgcagga gcggagtgct ggtgatccct cccagcctcg 20880 tcccaacccg cccacttttg ctcagggagt gatcagtgag tatggggcgt gggaggaagg 20940 tgcaggggag tggtttgggt catatggagg aagagggatt gggattaccc ttttgcaggt 21000 cctgacaccc agcttctttt cccagatgaa gctgaccagc ggcagtatga ggagtggctg 21060 ttccataccc agcagctcct acagatgcag ctgaaggtgc tagaggagca gattggtgta 21120 caccgcaagt cccggaaggc tctgtgtgcc aagcagcgca ctgccaaaaa agctggccgt 21180 gagttcccag aagctgatgc tgagaagctc aagctggtta cagagcagca gagcaagatc 21240 cagaaacaac tggatcaggt gggggaaagc aaacttcagc ctagcaccca gaaggcaggg 21300 aagagggttg gcatgggggg agcatgcccc agcctgacct ctccgaccct cccatgttag 21360 gtccggaaac agcagaagga gcacactaat ctcatggcag aatatcggaa caagcagcag 21420 caacaacagc agcagcagca gcaacaacag caacagcact cagctgtgct ggctctcagc 21480 ccttcccaga gtccccggct gctcaccaag ctccctggtc agctgctccc tggccatggg 21540 ctgcagccac cacaggggcc tccgggtggg caagccggag gtcttcgcct gacccctggg 21600 ggtatggcac tacctggaca gcctggtggc cccttcctta atacagctct ggcccaacag 21660 cagcaacagc aacattctgg tggggctgga tccctggctg gcccttcagg gggcttcttc 21720 cctggcaacc ttgctcttcg aagcctcgga cctgattcaa ggcttttaca ggaaaggcag 21780 ctgcagctgc agcagcaacg tatgcagctg gcccagaaac tgcagcagca gcagcagcag 21840 caacagcagc agcagcacct tctaggacag gtggcaatcc agcagcaaca gcagcagggt 21900 cctggagtac agacaaacca agctctgggt cccaagcccc agggccttat gcctcccagc 21960 agccaccaag gcctcctggt ccagcagctg tcccctcaac caccccaggg gccccagggc 22020 atgctgggcc ctgcccaggt ggctgtgttg cagcagcagc accctggagc tttgggcccc 22080 cagggccctc acagacaggt gcttatgacc cagtcccggg tgctcagttc cccccagctg 22140 gcacagcagg gtcagggcct tatgggacac aggctggtca cagcccagca gcagcagcag 22200 caacaacagc accaacagca agggtccatg gcagggctgt cccatcttca gcagagtctg 22260 atgtcacaca gtgggcagcc caaactgagc gctcagccca tgggctcttt acagcagctt 22320 cagcagcagc agcagctgca acagcaacag caacttcagc agcagcagca gcagcagcta 22380 caacagcaac agcaacttca gcagcaacag cttcaacagc agcaacagca gcagcagctt 22440 caacaacagc agcagcaaca gcttcaacag cagcaacagc agctacaaca gcaacagcaa 22500 caacaacagc agcagtttca acagcagcag caacagcagc agatgggcct tttaaaccag 22560 agtcgaactt tactgtctcc tcagcaacaa cagcagcagc aagtggcact tggccctggc 22620 atgccagcaa agcctcttca acacttttct agccctggag ccctgggtcc aaccctcctc 22680 ctgacgggca aggaacaaaa caccgtagac ccagccgttt cttcagaggc cactgagggg 22740 ccctctacac atcagggagg gccgttagca ataggaacta cccctgagtc aatggccact 22800 gaaccaggag aggtaaagcc ctcactctct ggggactcac aactcctgct tgtccaaccc 22860 cagccccagc ctcagcccag ctctctgcag ctgcagccac ctctgaggct tccaggacaa 22920 cagcagcagc aagttagcct gctccacaca gcaggtggag gaagccatgg gcagctaggc 22980 agtggatcat cttctgaggc ctcatctgtg ccccacctgc tggctcagcc ctctgtttcc 23040 ttaggggatc agcctgggtc catgacccag aaccttctgg gcccccaaca gcccatgcta 23100 gagcggccca tgcaaaataa tacagggcca caacctccca aaccaggacc tgtcctccag 23160 tctgggcagg gtctgcctgg ggttggaatc atgcctacgg tgggtcagct tcgagcacag 23220 ctccaaggag tcctggccaa aaacccacag ctgcggcact taagtcctca gcagcagcag 23280 cagctacagg cactcctcat gcagcggcag ctgcagcaga gtcaggcagt acgccagacc 23340 ccaccctacc aggagcctgg gacccagacc tctcccctcc agggcctcct gggctgccaa 23400 cctcaacttg ggggcttccc tggaccacag acaggccccc tccaggagct aggggcaggg 23460 cctcgacctc agggcccacc ccggctccct gccccaccag gagccttatc tacaggacca 23520 gtccttggcc ctgtccatcc cacacctcca ccatccagcc ctcaagagcc aaagagacct 23580 tcacaattac cttcccccag ctcccagctt cccactgagg cccagctccc tcccacccat 23640 ccagggaccc ccaaacctca ggggccaacc ttggagccgc ctcctgggag ggtctcacct 23700 gctgctgccc agcttgcaga taccttgttt agcaagggtc tgggaccttg ggatccccca 23760 gacaacctag cagaaaccca gaagccagag cagagcagcc tggtacctgg gcatctggac 23820 caggtgaatg gacaggtggt gcctgaggca tcccaactca gcatcaagca ggaacctcgg 23880 gaagagccat gtgccctggg agcccagtca gtgaagaggg aggccaatgg ggagccaata 23940 ggggcaccag gaaccagcaa ccacctcctg ctggcaggcc ctcgctcaga agctgggcat 24000 ctgctcttgc agaagctact ccgggcaaag aatgtgcaac tcagcactgg gcgggggtcc 24060 gaggggctgc gagctgagat caacgggcac attgacagca agctggctgg gctggagcag 24120 aaactacagg gtacccccag caacaaggag gtgagtactc tgagtagagt ggagcaggta 24180 gagtgggtcc tagagccagc ggggggcaga atgagtgagc ctgggtcaga cagaagagat 24240 gagggctctg aggaggaggg tagcagcctt caatgggctt atttggctta ggatgcagca 24300 gcaaggaagc ctttgacacc gaagcccaag cgggtacaga aggcaagcga caggttggtg 24360 agctcccgaa agaagctgcg gaaggaggac ggggtcaggg ccagcgaggc cttgctgaaa 24420 cagctgaaac aggtgacccc ccaggagaca gtccccctgg tcccatccca ggataggggg 24480 caccctgtcc cccagctgtg caagacagcg atgcaaacgc tgcaggtttt gaactttgtc 24540 atcttgcccc ttgtaggagc tgtccctgct gcccctaacg gagcctgcta tcaccgccaa 24600 ttttagcctc tttgccccct ttggcagtgg ctgcccagtc aatgggcaga gccagctgag 24660 gggggccttt ggaagtgggg cgctgcccac tggccctgac tactattccc agctgcttac 24720 caaggtcaga aaaatggcaa tattttttgg gaatagtgaa gttcttggga aggtgagggt 24780 gggaatagaa aacttgaggg aattgctgac gtagagtggg gccaggagat tatatcagtc 24840 tccctatgcc atcttgcaca caacacccca ccccccaccc ctcagaataa cctgagtaac 24900 ccgccgacac caccctcgtc gctgcccccc accccacccc catcggtgca gcagaagatg 24960 gtgaatggcg tcaccccatc tgaagagctg ggggagcacc ccaaggatgc tgcctctgcc 25020 cgggatagtg aaagggcact gaggggtaag tcaagagcag atgccacccc tggtggagtt 25080 tggtagctgg agtccaaacc agttagtatg ctgtacagtt tagaaattag tgggttgcct 25140 gctgtcctgt gtgtttacat aacagggcac ctgaggtagg aagggccctt tcaggactga 25200 tttcttgggg gccagaatgg acatttggag tctagagcaa atgcaatagg agaggtgggt 25260 ggcagggagc atctttatga agctttgtat agaaggaaca gtccagcttt agtgagtgtg 25320 gagctagact ctgatctgga tttgaattct ggttcctgca ttcattcaac tgtgttactg 25380 tatccaagta acttgattga cttgtgtgag cctcagtttc ctcactgtaa aatggctatt 25440 gtagtactca cttaatggag ttattaaatg actaaacaaa ctccaaagag tatatctaaa 25500 gccagctgcc accaggcctg gtagcttatg cctgtaatcc caacattttg ggaggccaag 25560 atggaaggat tgcttgaggc caggagttcg agaccagctt gggcaatata acaagacccc 25620 atctctacgg gaaaaaaaaa aaaaaaacaa aaaaaacaaa aaacaacagt gcctggcatg 25680 caggacagac tcaataaata taccttgttt gccccaaact ggtaggtggg aggacagcta 25740 atcatgatag ctgagatctc atgctaatta ggcctaaaat attgggagaa ggtaccatca 25800 gccctggcca ccctcacctg acttttcttc tccctaccca cccctcagat acttcagagg 25860 tgaagagtct agacctgctg gctgccttgc ctacaccccc tcacaatcag actgaggatg 25920 tcaggtaggg gcggggccag aaatggggat gaggaacaag ggtggggtac aggttgcctc 25980 atatttcctt tggccaatgg agatttcaag taagacatct attcatctct agatttggga 26040 ggggagtctg cagggctgta gcaacaaatg tctacttttg gtccccagga tggagagtga 26100 tgaggatagc gattctcctg acagcattgt gccagcttca tcccctgaga gcatcttggg 26160 ggaggaggcc cctcgtttcc ctcatctggg ctcaggccgg tgggagcaag aggaccgggc 26220 cctctcccct gtcatccccc tcattcctcg ggccagcatc ccaggtatgt gctactctgg 26280 atgtgggcca ggcccagttc acctgggttg tccgaagctg ggggagaggc ggccaagtgt 26340 tacacaaatt cctctttctc attcagtctt cccagatacc aaaccttatg gggcccttgg 26400 cctggaggtc cctggaaagc tgcctgtcac aacttgggaa aagggcaaag gaagtgaggt 26460 gtcagtcatg ctcacagtct ctgctgctgc agccaaggtg tgtcctaggg gtacctcgag 26520 gctgagggga acctgatcag agggcagtcc ctggaatttg tctggataag gaaaaatgta 26580 gtcgttcaag cacatgtact gagtacctat tgtatgtgaa agcctgggct agaggctgtg 26640 agattcgggt aaatgaatca tggttcctgc cctcacgggg ctcgtagtcc catggtaaag 26700 acagacaagt caacaactaa ggagcacctg tgtgtgtaat gacacaggta ctacatgaca 26760 gcattgcccc agtcatgttt ggtgggactc tgtcagctgt tttgaaaata ttaacgggct 26820 tttgtggtca aagaaagttg gaaaacacag ttaaaatgac aatatgggtt tctttactac 26880 aagagtcctc aggtcctttt aatttgctaa cgtgtatcat gagcctccaa gtcatggata 26940 gagcatgcat catttcctaa acgtagttga tgtagttccc ttttcgtgga gctcccgtca 27000 gtgcccacag cagtttggga aaggctgctg tgagggaagt gtatgaaaag agctgggtga 27060 cataggatag aactaccctg gggagtgggt tctaggtgtc cttgtcccca cccagctggt 27120 agtagagctc acctcagaca cttggctgat atgtttcttc catcccttcc ctggccctgg 27180 cagaacctga atggcgtgat ggtggcagtg gcggagctgc tgagcatgaa gatccccaac 27240 tcctatgagg tgctgttccc agagagcccc gcccgggcag gcactgagcc aaagaagggg 27300 gaagctgagg gtcctggtga gtgtggcagg gaagcccttt gggacttgag gggagtgatt 27360 ctggtgggag gctctgatcc actcctttct gcaggtggga aggaaaaggg tctggaaggc 27420 aagagcccag acactggccc tgattggctg aagcagtttg atgcagtgtt gcctggctat 27480 accctgaaga gccaactaga catcttgagc ctcctgaaac aggtaggtct gggggagaaa 27540 aaggggtggg tgttagaaaa aaggggctgc cggccaggcg cggtggctca catctgtaat 27600 cccagtgctt tgggaggcaa ggcgagtgaa tcactttagg ccaggagttt gagaccagcc 27660 tggccaacat ggcgaaaccc cgtctctact aaaaacaaaa acaaaacagt agccaggcgt 27720 gatggtgcgt gcctgtaatc ccagctactc gaaaggctga ggcatgagaa tcccttgaac 27780 ccaggaggca gaggttgcag tgagccaaga ttgtgccact ggatccagcc tgggcaacag 27840 agcaagactg tgtctcaaaa aaaaaagaaa agaaaagaaa aaagaggctg tctagggcaa 27900 agaatgtgga ggccttttgg gagggtggca tatgggtgag gggaaggagg gagctagtta 27960 gatgaggagc tggcactaat gatacagggc accctcctac aggagagccc cgccccagag 28020 ccacccactc agcacagcta tacctacaat gtctccaatc tggatgtgcg acagctctcg 28080 gccccacctc ctgaagaacc ctccccgccc ccttccccct tggcaccttc tcctgccagt 28140 ccccctactg agcccttggt tgaacttccc accgaaccct tggctgagcc acccgtcccc 28200 tcacctctgc cactggcctc atcccctgaa tcagcccgac ccaagccccg tgcccggccc 28260 cctgaagaag gtgaagattc ccgtcctcct cgcctcaaga aatggaaagg agtgcgctgg 28320 aagcggcttc ggctgctgct gaccatccag aagggcagtg ggcggcagga ggatgagcgg 28380 gaagtggcag agtttatgga gcagcttggc acagccttgc gacctgacaa ggtaccgcga 28440 gacatgcgtc gctgctgttt ctgtcatgag gagggtgacg gggccactga tgggcctgcc 28500 cgtctgctga acctggacct ggacctgtgg gtgcacctca actgtgccct ttggtccacg 28560 gaggtgtatg agacccaggg cggggcactg atgaatgtgg aggttgccct gcaccgagga 28620 ctgctaacca agtgctccct gtgccagcga actggtgcca ccagcagctg caatcgcatg 28680 cgttgcccca atgtctacca ttttgcttgt gccatccgtg ccaagtgcat gttcttcaag 28740 gacaagacca tgctgtgtcc aatgcataag atcaaggggc cctgtgagca agagctgagc 28800 tcttttgctg tcttccggcg ggtctacatt gagcgggacg aggtgaagca aatcgctagc 28860 atcattcagc ggggagaacg gctgcacatg ttccgtgtgg ggggccttgt gttccacgcc 28920 atcggacagc tgctgcctca ccagatggct gactttcata gtgccactgc cctctatccc 28980 gtgggctacg aggccacgcg catctattgg agcctccgca ccaacaatcg tcgctgctgc 29040 tatcgctgtt ctattggtga gaacaacggg cggccggagt ttgtaatcaa agtcatcgag 29100 cagggcctgg aggacctggt cttcactgac gcctctcccc agggtgagca gtgggccctt 29160 gaaatggata atatggaatg ggaaaagttt ctcccagggt cactgttaca atgtctataa 29220 gaggacctgt agcttctatg tgaatgatcc tccttccccc acctcaggca ggcagggggt 29280 ctcttgaaaa ctcccagtga aagtgtttga gcctctcttg tcaccctaaa ttcccttgta 29340 gttgaaaata ttttgctggt ctaatctcac atattctagt tctgttgcta tccccagtgg 29400 aacaaaagga aacagttctg agactatcat ctgcctcacc caacctaatc ctaaccaagt 29460 tccttggggt tgtttttccc tggacgaaat cagaattatt ttgattttag ttttagtgtt 29520 aatgataaaa taacagtaag agcaggtacc tttttttgag tgtgtactgt gagccacaaa 29580 ctaagctaag tgatttgtgt agtttatttt gttcatacaa ccctatgagg taagtattat 29640 actacgatta tgcccagttt gttcataaag aaactgagtc tcagatttca gtacagtcgt 29700 gcattgctaa atgacaggga tacattctga gaaatgcatt gttaggtgat tttgtcattg 29760 tgtgaacttc atagagtgta ctacacaaac ctagatggca tagcatacta cacacctagg 29820 ctctgcggta taccccattg ctcctaggct acaaatctgt acagcatgta actgtactga 29880 atactgtagg cagttgtaac atacggtaag tatgtgcatc tagacataga aaagatacag 29940 taaaaataca gtacagtatt ataatcttac cagaccactg ttgtatatat gattcctcat 30000 tgaatgaaat gttgttaagc tgcacgtgac tgtatttggc tcaaggtctc atgaccagta 30060 ctagaacctg aacccaagtc tttccaactc caaagcatgc ctgctctttc actagggacc 30120 ttccatggcc tatgctgggt ctcctgggcc ctgggtttgt atctcaaggc tctgtgatga 30180 ccccttgggg ttggaaacct cctgcttctt aagagagagt gagactagga ggccaagaga 30240 ggatctggaa gaccaacaca acttcatgat agggaggctt gaaggcctca gaaaactgca 30300 gttctggatt ggggttaggg actggaggtc agtgagcaga agttgcctct gaggactgct 30360 ctcttccctg cttcttagcc gtgtggaatc gcatcattga gcctgtggct gccatgagaa 30420 aagaggctga catgctgcga ctcttccctg agtatctgaa gggcgaggag ctctttgggc 30480 tgacggtgca tgccgtgctt cgcatagctg aatcagtaag gaaggggctg ggagctgggg 30540 ggcttggcgg gcactgagaa ctttggccta accccaaaaa aactcaggct aaggtgagta 30600 tgaactgtgc ccacagctgc ccggggtgga gagctgtcaa aactatttat tccgctatgg 30660 gcgccacccc cttatggagc tgccactcat gatcaacccc actggctgtg cccgatcaga 30720 gcctaaaatc ctcacacact acaaacggtg agcttgtgat gctggagcca agggatgtgg 30780 gtgtgggtgt tgacagggat cctctggtcc cattatgagg atttaggata cagatcagag 30840 ttcccgtgga gaaaatgggg aatcactctt agacttccta attagagggc atgcaggtat 30900 tagtagggta tccttttcct cctctcccaa cctgctcaga tgcacttggg atataggaca 30960 gaattatctt gggcaccctg gggaggtaat gggtaaactg gtgaaatttt atgaaatata 31020 taagggactt ggtcacctct ttcttctcct gttttacttc tgggggaggg cctgtgattc 31080 tcccaaacct cagatacccc atgggtgcta gggtcacctt cccttcccca tgagtgttgg 31140 tgtcaaaaat aaatagttag agatataata gaaaaataat aaaaccttac atttgtatag 31200 cactttatac tttttttttc aaagcgtttt cacatccatt atctcatttg atcctcacaa 31260 caaccttatg aggtaggtag ggcaggtggt atgaccccca ttttacagct gagaaaactg 31320 agacccagaa agattaaatg actaggcaaa ggtcacacag ctgggaccag acccttactt 31380 cttcactgca ggtccttgtt ctttctgtgt accagggacc ttagtccctg ggtagaggga 31440 ggcagaatct gtggtagcag ggctttctcg aaggtctttg gtggctccta ggctgttgta 31500 gaatgtcaga gactctccat ccctagccag ccttgtcctt gatgccctgc aatggtggtt 31560 ttcaaactgt gagtgcctgt gttccaaaaa gtcctggatc acttaaactg atgggttgaa 31620 cttttccttc ccatgcatat ctcttccttc cccaaattgg attaaaccag aagagctcca 31680 ttgtcatcta gtttatgtat tggagttcca gtcaacattt tgttaaagaa aaaagcaaag 31740 atttctgcta aataaaaaaa gaaccagaaa cgtttgaaaa ccactgctct gggatggcaa 31800 gaatttggct ggtgccctaa ggtggtaaaa ggcatcctgc caggcagccg tcattcccct 31860 gcactgagcc atctgcacag agcccaatgt tatgtcagag aaggggacag tccgaagaaa 31920 ggataccacc tttaggctgt gagttcacag ccagttttaa ttcaaatcta gcccagcgtg 31980 gtaggcacag tccccatttt cagggcttcc agtatgtgca ggaggtagga ttcagacatt 32040 caagcaaacc atcagcttaa attctaggcc tgggctgctt gcggaaaact tcccagagga 32100 gcatggcctt gagaatggtt tggcaggaga gtggtaggaa gtgggagatg ggagaacagg 32160 ctcagtgtag gggaattggt gccccccatc tccctccaca ccccacccct caccctgggc 32220 tctctgtgcc acccagggtg tcagaagggt ccctgtagct agttgcttcc tcaccagagc 32280 tgagacccag ttgcctctac tcctttccca aggctgcact tccagtgctt gccagcagca 32340 cacgccccta actggtgtgt tgcacatccc aggaggtggc agaggaggtg ggtggtatgt 32400 acttggtctg agggagagct gtcttgtcat ggattatatc acctcccagg ccccataccc 32460 tgaacagcac cagcatgtct aaggcatatc agagcacctt cacaggcgag accaacaccc 32520 cctacagcaa gcagtttgtg cactccaagt catctcagta ccggcggctg cgcaccgaat 32580 ggaagaacaa cgtgtacctg gctcgctccc gtatccaggg cctggggctc tatgcagcca 32640 aggacctaga aaagcacaca atggttatcg agtacattgg caccatcatt cggaacgagg 32700 tggccaaccg gcgggagaaa atctacgaag agcaggtatg agctggcaga ggggccattg 32760 tggtgcatag tctgcactca accaaggagc aagggcagga ttggtcacag gagagcagga 32820 ggaaagctgt ggtggggaga agggaaaggc aggagaaatg aagtacatgc aacaaaagcc 32880 cccactgcct gagtctccta cctgatccca cagccaccac tgccactctc tgatactctt 32940 gtcccttctt ctgcaacctc tgcctttcta gaatcgaggc atctacatgt tccgaataaa 33000 caatgaacat gtgattgatg ctacgttgac cggcggccct gccaggtgag agatgacgag 33060 gaaggaggga tttagtggtc cctgagagtg gcactctggg ggatagacga acaaggaatc 33120 aaaattgtcc caagttagtt gcctgacatc cctgactctg tcccactgcc caggtacatt 33180 aaccattcct gtgcccctaa ctgtgtggcc gaagtcgtga catttgacaa agaggacaaa 33240 atcatcatca tctccagccg gcgaatcccc aaaggagagg aggtgagagg aagtatcctg 33300 actgagtgac aaagcagctc ctcctccttt caccccttct ctgccattcc ctaaatgtgg 33360 attcctaggc tgggcacctc agatcatatc ttctctggcc tcccctcttc ctgtggggga 33420 ctagcattga ttctgccctc ttctcttttc agctaaccta tgactatcag tttgattttg 33480 aggacgatca gcacaagatc ccctgccact gtggagcctg gaattgtcgg aaatggatga 33540 actaagaagc tttgaggcta ccaggcaggg gagtccccct acccacaacc tcttccctga 33600 aagggatgag ggggaagaga ggtagcagcc agagccagga cccagggttg gggctgccgg 33660 ctgacccgga gcccctggag caggaggctg gggcagaggg ccctaggcca agcccaccct 33720 gggcaccagg gacaatcctc ttccccacca ccggccctca ggctggcatc tctgccccca 33780 gctccaggag gggccagaca gaagcagcca ttgggcatct caggtttgag ggggatatgg 33840 gccgggaact acccagaagc atctgggagg cagcagggtg ggggaagagg atgtgtggcc 33900 gggcctcaca gccctgctgc tcccactgac ctctccggcc caactcacgg ctgcaaagag 33960 acttgactaa gcttgacaat cccaaaggcc gggtcccaca cctggccctg cctgccgggt 34020 cctgccccca ccctcacccc catccccctc cctcttgatc tgtctctgtt tccctctttt 34080 cctctgtgtt tctgtctctc tatgggttgt gtttccttgt tttccactct gacaaatgca 34140 acatgaacgg gaaagaggcg cccagctgcc taggagggca agctgggcaa gccgggcaag 34200 gagaccccgc acccacacct acctcattta agtgttggat tttttgctgt tttgaaatgt 34260 gagaccctct ccaagccccc tactgcccca accctctccc ccacctcact gccctcttct 34320 gagtgggtgg aaggggggta ggaggaggaa gaaaaacaac aacaaaaaat ccatctttgt 34380 ttttaattat gggcatggga tggtggttga ggcaaatgat gatgaagatt ggggatgact 34440 ggcccctagt tgctctagga cttccttctc catctggaca tgggggcagg agggagctaa 34500 acctaggacc aggatatctc cctcctgttt tcccaacctc atcatgagcc tgtttgccct 34560 ccagcccctg gacgggttgg gtggggggta gggtgagggc tatccctgag tggcatgccc 34620 atacctagtg aggcagggtg tggcccggag ctcccacttt ccctcagtca ccaaactgct 34680 gctggtctgg tgggaagggg tggtgatgtg ggggtggggg agcttagtgt cagcgcgggg 34740 agggtggggg gtatttatct atttatacat gggattgtac atagtcttgt ggggcatggg 34800 ggagccggct ggaggtgaga accctcccct ctccccccac cccccgggga gagcaaatgt 34860 aaaactacta atttttgtgc tttatatatt ctatataaat atatctattt tctttttaca 34920 aaaccagttt ataaatggta ggggggtgtg gggcggacac atggagctcc ccttgtgggg 34980 gggccccctc cattacccga cctaccgccc ttttcctcac cccccacccc actccccacc 35040 ccctggctgt gactgctgta agatgggggt atagaggctg ggcaattccc accccctgtt 35100 gtatagttgg actatgttat aacgcacaaa agagagctga ccccaggggg agccagaggg 35160 tgatgggttc cttgcctccc tttccttccc ctttctgccc aagcttgtgc tgcagttgaa 35220 cctcttcctg ggggtgggag taggtaaggg gtgggtgagg ccccaaaccc ctctctggta 35280 gggaaccgtg gggatgaaga tgaagcttat atgcagttct cttctagggg ctgtgggcaa 35340 agggcatttt gtaattaata ttttcaagaa tcagatgtct ggagtgtagg ggtgggcttg 35400 gtggtggtgg acgggcgggc ctgctggagg gggagcttgg tcgctgttgt gattttaggt 35460 ttgtttttgt tttgttttga atttgggggg ttgtggattg ttgggggtag ggagattttt 35520 tttttttaaa gctgcttcct caactgtttc aagctgcaaa tgtttaagag aataacagcc 35580 cccactccca caggaaccgc tgtaattaaa tcagacagta ggaagactgg gctgctgccc 35640 tcaaagccac agcccttgga tgttcctttt ccgagagcag aaggtctagg ctacagggag 35700 ggggagattg gctcccgtga gtcaggctgt gtttggggct tgggccctgg gattgggaaa 35760 aggggatggg gcagactttg taagcatatg ctaggtatcc gatagtcctg tagaatttag 35820 tgaagaaacc ttatacagtt tttaattttt atataaacta taactcagac ccaagctaca 35880 aggttggaat tttggttggt ttttttttta agtaccctgc ctgtataatt gcatcagaat 35940 cccccacccc accccccgcc cccgtgtttg tattttgggt tggtttacac tcgcacatac 36000 tcagttttca gttttcccct ttacagtctt ctcccctcac ctccaggacc ctcccccttt 36060 ttaaaaaata aatcgctgac aagtgtgaat cccgtgaaga ctttattttg tgttgtgtgt 36120 atcctgtaca gcaaggttgg tccttcgtaa caacggatga aatggttccc ttttttaaag 36180 cgccctctct ccctccaccc tcagcgcccc tgtccttggc atgttttgta tcagcgatca 36240 ttctgaactg tacatattta tgttgcgaga ggcaaagggc aagttttgga ttttgcttct 36300 tccaagtttg tttttaaacg acaaataaaa aaagaacatt ttaaatacaa 36350 <210> 3 <211> 4545 <212> DNA <213> Homo sapiens <400> 3 agattcctac ttcttacgcc ccccacatca cccgcctcga gacctcaagg gtagaggtgg 60 gcacccccgc ctccgcactt ttgctcgggg ctccagattg tagggcaggg cggcgcttct 120 cggaaagcga aagccggcgg ggcggggcgg gtgccgcagg agaaagagga agcgctggca 180 gacaatgcga cccgaccgcg ctgaggctcc aggaccgccc gccatggctg caggaggtcc 240 cggcgcgggg tctgcggccc cggtctcctc cacatcctcc cttcccctgg ctgctctcaa 300 catgcgagtg cggcgccgcc tgtctctgtt cttgaacgtg cggacacagg tggcggccga 360 ctggaccgcg ctggcggagg agatggactt tgagtacttg gagatccggc aactggagac 420 acaagcggac cccactggca ggctgctgga cgcctggcag ggacgccctg gcgcctctgt 480 aggccgactg ctcgagctgc ttaccaagct gggccgcgac gacgtgctgc tggagctggg 540 acccagcatt ggtgaggacg tccccttcct ggcctcgtac ctggggggtg aggaggctga 600 ctttccgcgg cctcagcatc ctgtctccca tggagagacc ccatttcctg cctcgggggc 660 ccgaagaagc ctgcagaggg agaaccatgc gggtcccgtt ccttcttaat aaccggtcgc 720 ggttattaag aaggactgga gaaaggtccg gataggcgga gatgggaagg aagcagctta 780 ggcagaggct ttcaggtagg gccaggagtc agaatcaggc ttctgtgggg gcatctgggc 840 tgtttcaagt agagcaacag gacaggtggg gcgattgaca gtggactgtc ttagaaacct 900 caagtcctgg ggaaatgcag cccttctttc tactcactgg cacttacata atatacatgc 960 ataggcgttg gatacagccg cccacagaca ggcacacctt gctgagttgg aatcactgca 1020 ccataaccag tgggtctcct gagcctttct ggcatgccca gccccttgct cacatctgcc 1080 ctggatccca gaagaagcag acctaccttg gtaccattct taggatccct aggaagggac 1140 agagatacaa acctgacttt gatggccttc cagaaagcca gaacaccact gacatccctt 1200 tgggtcagtt agagccagtg ggagctcaac ttctcagagc cgttgagctt cgcgtggcac 1260 cagtgaactg gggaagccct ctagaacaac ccagccagag gaggtgggac agcggctgga 1320 tcctgactgt gggtaaagag gtaggcactc ccagggaggc tgctttactc tgtctcttcc 1380 ccacagagga ggattgccaa aagtatatct tgaagcagca gcaggaggag gctgagaagc 1440 ctttacaggt ggccgctgta gacagcagtg tcccacggac agcagagctg gcgggcatca 1500 ccacacttga tgaccccctg ggtaagggtc caatactgtt cccatgggac aggtggaata 1560 ggacattgtg gtgttaagag catgggtgtt tgaagcagat gggctgtgag accttgggca 1620 agtcacttaa tctttctgag cctcagtttc ctcacctaag aaatggagat aatagtccta 1680 cctctggatt gctgtgagat gctcatgaaa taatgtctgt ctcgtggtta atccagagct 1740 tagcccctga ggtactcatc tttcctctcc tggaaagggc actttctctg aggagtatca 1800 tcttgggaag ggtgcagggc ccagggttgc ctaggcaggg gactcttggc tggatccctc 1860 ccaagccttc ccatggagct ctgaccacca cccttgtgct ctgcacccag ggcatatgcc 1920 tgagcgtttc gatgccttca tctgctattg ccccagcgac atccagtttg tgcaggagat 1980 gatccggcaa ctggaacaga caaactatcg actgaagttg tgtgtgtctg accgcgatgt 2040 cctgcctggc acctgtgtct ggtctattgc tagtgagctc atcgaaaaga ggttggctag 2100 aaggccacgg ggtgggtgcg tggatgcatg aagccctgcc ctggggtcca gatactgggc 2160 atctcctcct agctgtgcac tgtccagcct gggcacagtg ggcccttcct gaagctattc 2220 ccaggggata tgctgaacta agttgccaca ggacctgcag cctgcccact ctcccctagg 2280 tgccgccgga tggtggtggt tgtctctgat gattacctgc agagcaagga atgtgacttc 2340 cagaccaaat ttgcactcag cctctctcca ggtaagctca accctgctct ggcaagagaa 2400 tgagggaatg tgtaggtggg gcctctggat tgtcagcctt ccctccccaa ggactgtgga 2460 tgcagtacca aagaactgct gaagatctct gcacacctga gcatgtgtgc atgtgtgtgc 2520 ctttttgtgt gagtgaatgt gtgccagggg tacttagatg ggggatggct gttgttaacc 2580 ctggggttga agactgggct tgtcccacca tggggcaagg gcctgatgcc agcatggcac 2640 cccttggctt gcaggtgccc atcagaagcg actgatcccc atcaagtaca aggcaatgaa 2700 gaaagagttc cccagcatcc tgaggttcat cactgtctgc gactacacca acccctgcac 2760 caaatcttgg ttctggactc gccttgccaa ggccttgtcc ctgccctgaa gactgttctg 2820 aggccctggg tgtgtgtgta tctgtctgcc tgtccatgta cttctgccct gcctcctcct 2880 ttcgttgtag gaggaatctg tgctctactt acctctcaat tcctggagat gccaacttca 2940 cagacacgtc tgcagcagct ggacatcaca tttcatgtcc tgcatggaac cagtggctgt 3000 gagtggcatg tccacttgct ggattatcag ccaggacact atagaacagg accagctgag 3060 actaagaagg accagcagag ccagctcagc tctgagccat tcacacatct tcaccctcag 3120 tttcctcact tgaggagtgg gatggggaga acagagagta gctgtgtttg aatccctgta 3180 ggaaatggtg aagcatagct ctgggtctcc tgggggagac caggcttggc tgcgggagag 3240 ctggctgttg ctggactaca tgctggccac tgctgtgacc acgacactgc tggggcagct 3300 tcttccacag tgatgcctac tgatgcttca gtgcctctgc acaccgccca ttccacttcc 3360 tccttcccca cagggcaggt ggggaagcag tttggcccag cccaaggaga ccccaccttg 3420 agccttattt cctaatgggt ccacctctca tctgcatctt tcacacctcc cagcttctgc 3480 ccaaccttca gcagtgacaa gtccccaaga gactcgcctg agcagcttgg gctgcttttc 3540 atttccacct gtcaggatgc ctgtggtcat gctctcagct ccacctggca tgagaaggga 3600 tcctggcctc tggcatattc atcaagtatg agttctgggg atgagtcact gtaatgatgt 3660 gagcagggag ccttcctccc tgggccacct gcagagagct ttcccaccaa ctttgtacct 3720 tgattgcctt acaaagttat ttgtttacaa acagcgacca tataaaagcc tcctgcccca 3780 aagcttgtgg gcacatgggc acatacagac tcacatacag acacacacat atatgtacag 3840 acatgtactc tcacacacac aggcaccagc atacacacgt ttttctaggt acagctccca 3900 ggaacagcta ggtgggaaag tcccatcact gagggagcct aaccatgtcc ctgaacaaaa 3960 attgggcact catctattcc ttttctcttg tgtccctact cattgaaacc aaactctgga 4020 aaggacccaa tgtaccagta tttatacctc taatgaagca cagagagagg aagagagctg 4080 cttaaactca cacaacaatg aactgcagac acagctgttc tctccctctc tccttcccag 4140 agcaatttat actttaccct caggctgtcc tctggggaga aggtgccatg gtcttaggtg 4200 tctgtgcccc aggacagacc ctaggaccct aaatccaata gaaaatgcat atctttgctc 4260 cactttcagc caggctggag caaggtacct tttcttagga tcttgggagg gaatggatgc 4320 ccctctctgc atgatcttgt tgaggcattt agctgccatg cacctgtccc cctttaatac 4380 tgggcatttt aaagccatct caagaggcat cttctacatg ttttgtacgc attaaaataa 4440 tttcaaagat atctgagaaa agccgatatt tgccattctt cctatatcct ggaatatatc 4500 ttgcatcctg agtttataat aataaataat attctacctt ggaaa 4545 <110> SAMSUNG LIFE PUBLIC WELFARE FOUNDATION <120> MARKER FOR DIAGNOSING CNSL, CNSL DIAGNOSTIC KIT COMPRISING THE SAME AND METHOD FOR DIAGNOSING CNSL <130> PN200123 <160> 3 <170> KoPatentIn 3.0 <210> 1 <211> 5277 <21 2 > DNA <213> Homo sapiens <400> 1 actcctggct gcggggcgag ccgggcgtct gctgcagcgg ccgcggtggc tgaggaggcc 60 cgagaggagt cggtggcagc ggcggcggcg ggaccggcag cagcagcagc agcagcagca 120 gcagcaacca ctagcctcct gcc ccgcggc gctgccgcac gagccccacg agccgctcac 180 cccgccgttc tcagcgctgc ccgaccccgc tggcgcgccc tcccgccgcc agtcccggca 240 gcgccctcag ttgtcctccg actcgccctc ggccttccgc gccagccgca gccacagccg 30 0 caacgccacc cgcagccaca gccacagcca cagccccagg catagccttc ggcacagccc 360 cggctccggc tcctgcggca gctcctctgg gcaccgtccc tgcgccgaca tcctggaggt 420 tgggatgctc ttgtccaaaa tcaactcgct tgcccacctg cgcgccgcgc cctgcaacga 480 cctgcacgcc acca agctgg cgcccggtga gagcaccccc cgcctccggc ccggggatgc 540 ggggcggcgg cgggatctcc tgggtgggga gctggcggct cgcgggccgg cactgagtcc 600 ccgtgcttcc ccctttccta ggcaaggaga aggagcccct ggaggtcgcag taccaggtgg 660 gcccgct act gggcagcggc ggcttcggct cggtctactc aggcatccgc gtctccgaca 720 acttgccggt gagtgggcgc cccgcggtgg ggagggcgcg ccgggcgggg ggcgcacggg 780 cgtgctttag cccggacgag ggaacctgac ggagaccctg ggcttccagg tggccatcaa 840 acacgtggag aaggaccgga tttccgactg gggagagctg gtgagtgccc tgcaggagcg 900 acccccagga tgagtgggtg gggtgagggg cgcccccg ac tcccgcccta acgcggcccc 960 ctcgcccctg cagcctaatg gcactcgagt gcccatggaa gtggtcctgc tgaagaaggt 1020 gagctcgggt ttctccggcg tcattaggct cctggactgg ttcgagaggc ccgacagttt 1080 cgtcctgatc ctggagaggc ccgagccggt gcaagatctc ttcgacttca tcacggaaag 1140 gggagccctg caagaggagc tggcccgcag cttcttctgg caggtgctgg aggccgtgcg 1200 gcactgccac aactgcgggg tgctccaccg cgacatcaag gacgaaaaca tccttatcga 1260 cctcaatcgc ggcgagctca agctcatcga cttcgggtcg ggggcgctgc tcaaggacac 1320 cgtctacacg gacttcgatg gtgagccagg cccgggaggg agctgcccag gtgactcggc 1380 ccggcccggc ccagtccgga ggcctcggcc agtctcccgc gccagccttt tgtaaaggtc 1440 attgggccgc ctggctcgat gctagccggg gtgggacgca ggagagcctc ccagcgtagt 1500 aaagccgggg attttca gcc agctgaacct gtaatgtttc tggcatgatt ttattcttca 1560 agtggaattc agttagttcc aggctttccc gatgaataag aggttgtggg caaccggcgg 1620 tagcccagat ttttctaaag tctgacccag tttccccgcc agtaaaagga tggggggcggg 1680 ggaagaggtg gaaattgatg ccggttttgt aatttttgtt ttattttata agggagttag 1740 ttttctgtat ggtagtttta gagctgcagt tcttaactcc tt tctgatct agggaaggtt 1800 aaggaatagg aactatatta ttactggtgg cttttttttt tctttagtgt taaggggaga 1860 gagagtcagg aatgaatgtt gtgaaataag atctgtcgct ggtttgaaaa ttagttgggt 1920 gtctccgcag agaggatgaa aacctatcct agggagg ggc ttggagcggg ttctttcaga 1980 aaagaaggaa tggagagcct gagatcaaag ctgcggaggg tgggtcatca tctgagcggc 2040 ttaacctaac aaacgacagc ctttcaaaac ttgtgactcg ggcttgtggt ttatgtttat 2100 ttgcccttgg aggacgctgg gttgggctgc attttttgta tttaacagtt aatggctggc 2160 cgggtcctcc catgtttttt ctttcaagtc tttgctgccc cctggt gagc accagcggca 2220 tggcccctcc tttttctttt actacccaaa gtttgtaaac aggaatcacg tggtctgaaa 2280 ccaaccctgc agctctgtct acctttccag tctaggggagg aaagggtgtg ggtgtctgct 2340 cctgcttgca tcgggtgggg agggaaggcct cccaaagggc accctgactt aggatgttgt 2400 gcaagcatcc ttgcttggat cctgtcggcc atgagaatct cacccgggct cctgggcagt 2460 ggtgaatgca atttaaggat agtctatgag atacctttct tggttgtgca gacatgcatc 2520 ccttcatcct tcgcaggcgg tcctgcctca cagggcctca agttttgggt ctgcggccag 2580 ctgtgtttgt ttcttggagc agttcataaa gaatttcagt ttatggtttg ggctagcaga 26 40 gaggtgggta atgctttggg ttggagagat gccgtaaggt gcgcctccac tctccttagc 2700 ccagagggaa aaatggagtt cacctagctc ctgagagaag ggattttttt tttttttaaaa 2760 agaaagagtt atatatacca cccagcttct ttgtgcttgt tt ttgctaaa agtgtgtttt 2820 ctcttctatt cccttggctc acaggaccc gagtgtatag ccctccagag tggatccgct 2880 accatcgcta ccatggcagg tcggcggcag tctggtccct ggggatcctg ctgtatgata 2940 tggtgtgtgg agatattcct ttcgagcatg acgaagagat catcaggggc caggttttct 3000 tcaggcagag ggtctcttca ggtaactgat ggaaacccct ggccatgggg ttatattggtct 3060 taatggggct attagtct tc atgggacagt ctttgaaatt ctggagagct tcactctcca 3120 gtagattctg tcacccttgg cttagaattg taggtgagtg atttacactt gagctggcct 3180 cataaatcac atggtttgca cttgagcttt ccttgggagg tcagaggaag gcatgtgtga 3240 gcatattaag aagaaaaga c aatctggctt ctccaaaaac ttttttaaag gtaccaacag 3300 aaacctgata attcctggct gttttgccag ggagtaaaaa gttaaaagct cttttagcat 3360 cttctttaag gcagcagctc caaatatttt ggtaccagtg acctcactgt gggtggtgtt 3420 cgtgtttgta agttggtagg tgaattgaat catttcatca tgctcagtgg tgtctcatca 3480 aaatctcttg tcatcatcct tcctattt ct ggtgagtggg tgttgtggga aaggccccca 3540 ctattgaagt ttgaaaacca caggtttaag aggggagtca gtttttagct gaaagcagac 3600 tggaggaccc agatattagt caataccttc ctattgaagg gtacccagca cagtgttcta 3660 gaaaatgctt ggcctccctg ggaccccaga cttgtgggcc tctgagaagc aaatggggaa 3720 gacctttgca gtgtaaaaac aagttgagtc attcataacc tcgtctatcc tcctttctgc 3780 agaatgtcag catctcatta gatggtgctt ggccctgaga ccatcagata ggccaacctt 3840 cgaagaaatc cagaaccatc catggatgca agatgttctc ctgccccagg aaactgctga 3900 gatccacctc cacagcctgt cgccggggcc cagcaaatag cagcc tttct ggcaggtcct 3960 cccctctctt gtcagatgcc cgagggaggg gaagcttctg tctccagctt cccgagtacc 4020 agtgacacgt ctcgccaagc aggacagtgc ttgatacagg aacaacattt acaactcatt 4080 ccagatccca ggcccctgga ggctgcctcc caacagtggg gaagagtgac tctccagggg 4140 tcctaggcct caactcctcc catagatact ctcttcttct cataggtgtc cagcattgct 4200 ggactctgaa atatcccggg ggtggggggt gggggtgggt cagaaccctg ccatggaact 4260 gtttccttca tcatgagttc tgctgaatgc cgcgatgggt caggtagggg ggaaacaggt 4320 tgggatggga taggactagc accattttaa gtccctgtca cctcttccga ctctttctga 4380 gtgccttctg tggggactcc ggctgtgctg ggagaaatac ttgaacttgc ctcttttacc 4440 tgctgcttct ccaaaaatct gcctgggttt tgttccctat tttctctcc tgtcctccct 4500 caccccctcc ttcatatgaa aggtg ccatg gaagaggcta cagggccaaa cgctgagcca 4560 cctgcccttt tttctgcctc ctttagtaaa actccgagtg aactggtctt cctttttggt 4620 ttttacttaa ctgtttcaaa gccaagacct cacacaca aaaaatgcac aaacaatgca 4680 atcaacagaa aagctgtaaa tgtgt gtaca gttggcatgg tagtatacaa aaagattgta 4740 gtggatctaa tttttaagaa attttgcctt taagttattt tacctgtttt t gtttcttgt 4800 tttgaaagat gcgcattcta acctggaggt caatgttatg tatttattta tttatttatt 4860 tggttccctt cctattccaa gcttccatag ctgctgccct agttttcttt cctcctttcc 4920 tcctctgact tggggacctt ttgggggagg gctgcgacgc ttgctctgtt tgtggggtga 4980 cgggactcag gcgggacagt gctgcagctc cctggcttct gtggggcccc tcacctactt 5040 acccaggtgg gtcccggctc tgtgggtgat ggggaggggc attgctgact gtgtatatag 5100 gataattatg aaaagcagtt ctggatggtg tgccttccag atcctctctg gggctgtgtt 5160 ttgagcagca ggtagcctgc tggttttatc tgagtgaaatgtactacagg ggaataaaag 5 220 agatcttatt ttttttttta tacttggcgt tttttgaata aaaacctttt gtcttaa 5277 <210> 2 <211> 36350 <212> DNA <213> Homo sapiens <400> 2 atggacagcc agaagctggc tggtgaggat aaagattcag aaccggcagg tgagtaggac 60 aaattgtttg tttgctttta gatttcattg gcaaccttac atttctggtc ctggcacaag 120 gacatgagct aagtctatgt agcagataag taatggaaca actttgttct ttgggacaac 180 agttgaaata tcat cactct gatccactca ggttttggat aatctcatgc gtctggtgag 240 tggactttgt gttaaatagg gatgatggct gacacatgct gtttgtctgt ttattcagct 300 gatggacctg cagcttctga ggaccaagt gccactgagt cagacctgcc caacccacat 360 gtggggagagg tctct gtcct tagttctggg agtcccaggc ttcaggagac tcctcaggac 420 tgcaggtagc ttgtttgagg gcacatgagg atttgagagt ctagggcttt caaggaagag 480 aatttaggaa aatgagtgtt ggggaagcat gggcatgcca gatcatgggg ttgctggggg 540 cctggcgtgg tactgatgct tgtgtgtcca cagtgggggt ccggtgcggc gttgtgctct 600 ctgtaactgc ggggagccca gtct acacgg gcagcgggag ctacggcgct ttgagttgcc 660 atttgattgg ccccggtgtc cagtggtgtc ccctgggggg agcccagggc ccaatgaggc 720 agtgctgccc agtgaggacc tatcacagat tggtttccct gagggcctta cacctgccca 780 cctaggagaa cctgg aggtg agtgaggaga atggggcagg aaatgggata agggctgggt 840 agtcctgagc cagcaatcct ctttttgtta attctttcct ttctctttac ctcttcccac 900 ctgtaaaggg tcctgctggg ctcaccattg gtgtgctgca tggtcggcag gcgtatgggg 960 gcaggagggc ccagaactat gtggtgtgga caaggccatc ttctcaggga tctcacaggt 1020 ggggctgggc caggggattg cat aggtgaa gggcagggct ggtgggcttc tgagagtcag 1080 gttggaatga gaaggaccat gggtatactg gggcagagct agtgcctgaa ctgtttgtct 1140 ggggagagct ggctgacact gaggctcttt tttcaccctg gcagcgctgc tcccactgca 1200 cca ggctcgg tgcctccatc ccttgccgct cacctggatg tccacggctt taccacttcc 1260 cctgcgcgac tgccagcggt tccttcctat ccatgaaaac actgcagctg ctatgcccag 1320 agcacagtga gggggctgca tatctgggtg agaagtcctg atctttggtc atagggcaaa 1380 tgagagacca aatgtgcctt ggatttttgt actctacaga gcactgatca aagtatagca 1440 ttatttactg ttggtctgcc ccactaaaat aggtgtga ac tttgtgagca ccagggtttt 1500 gcctgtctca tttatcattt tgtctccagt gcctagaaca gtagctggca gacgttgggc 1560 aggcactcag taactttgtt gtttgttcat tctgtgccca tggagtgcct gttttgtgta 1620 cagcaatgg ctgaggctta caaggaatcc atagctgacc tgtggtgtct ctaccccctg 1680 cagaggaggc tcgctgtgca gtgtgtgagg ggccagggga gttgtgtgac ctgttcttct 1740 gtaccagctg tgggcatcac tatcacgggg cctgcctgga cactgctctg actgcccgca 1800 aacgtgctgg ctggcagtgc cctgaatgca aagtgtgcca agcctgcagg taggaatgga 1860 agggcaggag gaaagtctta ggcacaacac aggttagggt tgaaaatga c taaaaccac ccatggagga actgcctgct 2100 cactcttgga agtgcaaggt gagtgtaccc tgattctgcc ctattgtccc taactgtgtc 2160 tgctacagca ttctctgtct tgacaagttg tgtactttcg tttagtcttt gctgtctgac 2220 caatgcctgt tttgcccact cccttccctt aggcgtgccg ggtgtgccgg gcctgtgggg 2280 cgggctcagc agaactgaat cccaactcgg agtggtttga ga actactct ctctgtcacc 2340 gctgtcacaa agcccaggga ggtcagacta tccgctccgt tgctgagcag cataccccgg 2400 tgctgagcag gtaagtggtg gggactgact gagattgggc tggcaggttg gaagaactga 2460 cattggcagg ggccttgtta aattgagtgg actttgaga g gagagcccta aggtgggcag 2520 tgccatccac agcattcgtg cctcccccca gtgtgctctc taggatttgt tagctggtga 2580 gagccacagt gcctgctccc ctgtaccctc tgcagatttt cacccccaga gcctggcgat 2640 acccccactg acgagcccga tgctctgtac gttgcatgcc aagggcagcc aaagggtggg 2700 cacgtgacct ctatgcaacc caaggaacca gggcccctgc aatgtgaagc caaaccacta 2760 ggtgagtagg gtttgagggt ccctgaaatt catccccttt tattctatgg caagagacag 2820 tttgtgcatt gccccagacc ccacactttc tgtggagtag atctgagcta gataggagca 2880 tcgtgttgtt gtgtctgcag ggaaagcagg ggtccaactt gagccccagt tggaggcccc 2940 cctaaacgag gagatgccac tgctgccccc acctgaggag tcacccctgt ccccaccacc 3000 tgaggaatca cccacgtccc caccacctga ggcatcacgc ctgtcaccac cacctgagga 3060 attgcccgca tccccacttc ctgaggcatt gcacctgtcc cggccgctgg aggaatcgcc 3120 cctctctccg ccgcctgagg agtctcctct gtctccccca cctgaatcat cacctttttc 3180 tccactgg ag gagtcgccct tgtctccacc ggaagagtca cccccatctc ctgcacttga 3240 gacgcctcta tccccaccac ctgaagcatc gcccctgtcc ccaccatttg aagaatctcc 3300 tttgtccccg ccacctgagg aattgccacac ttccccgcca cctgaagcat ctcgcctgtc 3 360 tccaccacct gaggagtcac ccatgtcccc tccacctgaa gagtcaccca tgtctccacc 3420 accggaggca tctcgtctgt tcccaccatt tgaagagtct cctctgtccc ctccacctga 3480 ggaggtctccc ctttccccac cacctgaggc atcacgcctg tccccaccac ctgaggactc 3540 gcctatgtcc ccaccacctg aagaatcacc tatgtccccc ccacctgagg tatcgcgcct 3600 atcccccctg cctgtggtgt c acgcctgtc tccaccgcct gaggaatctc ccttgtcccc 3660 accgcctgag gagtctccca cgtcccctcc acctgaggct tcacgcctct ccccaccacc 3720 tgaggactcc cccacatccc caccacctga ggactcacct gcttccccac caccggagga 3780 ctcgctcatg t ccctgccgc tggaggagtc acccctgttg ccactacctg aggagccgca 3840 actctgcccc cggtccgagg ggccgcacct gtcaccccgg cctgaggagc cgcacctgtc 3900 cccccggcct gaggagccac acctatctcc gcaggctgag gagccacacc tgtccccccca 3960 gcctgaggag ccatgcctat gcgctgtgcc tgaggagcca cacttgtccc cccaggctga 4020 gggaccacat ctgtcccctc agcctgagga att gcacctg tccccccaga ctgaggagcc 4080 gcacctgtct cctgtgcctg aggagccatg cttgtccccc caacctgagg aatcacacct 4140 gtccccccag tctgaggagc catgcctgtc cccccggcct gaggaatcgc atctgtcccc 4200 tgagcttgag aagccaccct gtcccctcg gcctgaaaag ccccctgagg agccaggcca 4260 atgccctgca cctgaggagc tgcccttgtt ccctccccct ggggaaccat ccttatctcc 4320 cttgcttgga gagccagccc tgtctgagcc tggggaacca cctctgtccc ctctgcccga 4380 ggagctgccg ttgtccccat ctggggagcc atccttgtcg cctcagctga tgccaccagg 4440 taaggggatg ttagtactct gttatctgg aacag ctgta actcttcatg gcacatctaa 4500 tctaagagcc cttctttttt ctctttcctt ccagatcccc ttcctcctcc actctcaccc 4560 atcatcacag ctgcggcccc accggccctg tctcctttgg gggagttaga gtaccccttt 4620 ggtgccaaag gggacagtga ccctgagtca ccgttggctg cccccatcct ggagacaccc 4680 atcagccctc caccagaagc taactgcact gaccctgagc ctgtcccccc tatgatcctt 4740 cccccatctc caggctcccc agtggggccg gcttctccca tcctgatgga gccccttcct 4800 cctcagtgtt cgccactcct tcagcattcc ctggttcccc aaaactcccc tccttcccag 4860 tgctctcctc ctgccctacc actgtccgtt ccctccccgt t gagtcccat agggaaggta 4920 gtgggggtct cagatgaggc tgagctgcac gagatggaga ctgagaaagt ttcagaacct 4980 gaatgcccag ccttggaacc cagtgccacc agtcctctcc cttccccaat gggggacctt 5040 tcctgccccg cccccagccc tgcccc agcc ctggatgact tctctggcct aggggaagac 5100 acagcccctc tggatgggat tgatgctccg ggttcacagc cagagcctgg acagacccct 5160 ggcagtttgg ctagtgaact taaaggctcc cctgtgctcc tggaccccga ggagctggcc 5220 cctgtgaccc ctatggaggt ctaccccgaa tgcaagcaga cagcagggca gggctcacca 5280 tgtgaagaac aggaagagcc acgtgcaccg gtggccccca caccacccac tctcatcaaa 5340 tccgacatcg ttaacgagat ctctaatctg agccagggtg atgccagtgc cagttttcct 5400 ggctcagagc ccctcctggg ctctccagac ccggaggggg gtggctccct gtccatggag 5460 ttgggggtct ctacggatgt tagtccagcc cgagatgagg gctccctac g gctctgtact 5520 gactcactgc cagagactga tgactcacta ttgtgcgatg ctgggacagc tatcagcgga 5580 ggcaaagctg agggggagaa ggggcggcgg cgcagctccc cagcccgttc ccgcatcaaa 5640 caggtgaggg gctatctagc tgcgggatgt gattagagtt agcccactgt cagaggtaca 5700 gtcctgtgtc actgatactt tcccaccttg ctttgtgaat cctagacttg gagatccttt 5760 attccagtta ttaaggagaa aatactaata cgtagaaggg acaagtaact tgcccagatt 5820 catggttact cagtaataga attgggacca gaaacttggt tctttcaagc cattgttttt 5880 tctccttgcc catctcaacc actcttggga ggggaagaat gggtttgggc tagagctatg 59 40 cgcttgttga tatctgggag tttggccttt tcccttgccc tgagtgggac tcctgggctt 6000 attacctgtc ttactctgtc cgtttgtcac ttcttctgtt caagtgtgta aacccaacac 6060 actagccctt gacatgctcc tgtcattgtc cccttctttc actcagggtc gcagcagcag 6120 tttcccagga agacgccggc ctcgtggagg agcccatgga ggacgtggta gaggacgggc 6180 ccggctaaag tcaactgctt cttccattga gactctggta gtaaggagat gcctcctatt 6240 cctcccatcc cccaaccatg ctttagcacc ctctgagtcc tgccagtccc ttgcatgctt 6300 gcctacctgc ctgctcgtct agggcctgtc tggctatgtc tgaattcctg t ccacttggc 6360 ccgcaggttt ttctgaaatc tctgctatca gactgaggct caatttggga gctggggtgt 6420 tctgtctgtt attcctggct tttggccttc atcttaacca agggttcaca ctttcttccc 6480 ccaacaccaa agaggaaagt agcttggtgg gggcagattt atctgcctca ctttccataa 6540 ctctctgccc atcaggttgc tgacattgat agctctccca gtaaggagga ggaggaagaa 6600 gatgatgaca ccatgca gaa taccgtggtt ctcttctcca acacagacaa atttgtccta 6660 atgcaggtac catacagtga gacctggcac actgaacatt gtgtatgtgt gtgtttggtg 6720 agaggataga tgggaaaact ggacctactt tggggatacc cagctaatga gaaaacagac 6780 catgaattct aatcatgtta t tcattggtt tgtccatcca tcacatttct cttgagtatc 6840 tcttctgagc ttggcactaa gctaggagct agagaaatag cagtgaaaaa gtctttgcct 6900 tattgaactt tatagcttag ggaacttaca tgtgtcctca cttgaataat cttgaagctg 6960 atagaatttt gtcacatatg tgattctcac ctgaccagtc tttactccat cttatcttcc 7020 tttaatttct tcttaacttc acccatgtca gg ctttataa attcaagtga cctgattagg 7080 tgagtaaggc atcctaggaa ggagcagggt cccttggtag cttacagcat cctaacgctg 7140 tgggatgggg ttcctgactc tggtcgcaaa tcagtgttgt agcgtcatag tagactggat 7200 ctgagtggga tggggagatc tagt tggaca tttgggtttc tctgtgtttc cccaggacat 7260 gtgtgtggta tgtggcagct ttggccgggg ggcagagggc cacctccttg cctgttcgca 7320 gtgctctcag tgctatcacc cttactgtgt caacagcaag gtgagttcag ggcccaagag 7380 gtgtaggctg gggaataggg tcagttattt cttaccctag ttccttgtcc tggccatacc 7440 acctcttaaa gcggccatcg gtcatggttg t tcattagtc accagtggtt atcaaacttt 7500 tcttggggaa aagtactttg gaactcaacg gtggacttga tagtttcttt gtggtaggcc 7560 ctgacttgct ggtataattc agtccatcgt aaaaaataac aacatggctg ggcatggtgg 7620 ctcccacctg taatcccagc actttgggg gcctaggtgg gtggatcacc tgagattagg 7680 agttcaggac catcgtggtc aacatggtga aaccccgtct cttctaaaaa ataacaaaaa 7740 ttagctgagt gtggtagcgc gtgcctgtaa tctcagcaac tcgggaggct gaggcaggag 7800 aattgcttga acccaggagg cggaggttgc agtgagccga gatcacgcca ctgtactcca 7860 ctccagcctg ggcaacagag tgagatccgt ctcaaaaaaa aaaaaaaaaa aaaaaaaagg 7920 aaaaactggg ggacctaatt cggtccacag tctcttttta ggggcttggc tagtggaaag 7980 attgctattc tattcacaat gaggcagtgg ctagtgcagc tcttctctga tcagcagaga 8040 tcattgggag cctaagt tta gagtcactgt tttggggaca agggtgctct gcctaagtct 8100 ctgtgtgctc aaatggaggc ctagtctctg cattgggctg cctccagcct cacccttaga 8160 agttccacct cctaggctgg gcacggtggc gcacacctgt aatcccagca ctttacttcg 8220 ggaggggtgag gcgggtggat cacctaaggt caggagttgg tgaccagcct gactaacatg 8280 gtgaaactct gactctacta aatacaaaaa aattagccag gtgtggtggc aggtgcctgt 8340 aatctcagct acttgggagg ctgagacaag agaatcactt gtacctgaga ggcagaggtt 8400 gcagtgagcc gagatcgcgc cattgcactc cagcctgggg aacaagagca aaactccatc 8460 tccaaaaaaa aataaaaaga agttctacct cttttccacc tcacaccctg agaagttccc 8520 atcttctgcc ccagatcacc aaggtgatgc tgctcaaggg ct ggcgttgt gtggagtgta 8580 ttgtgtgtga ggtgtgtggc caggcctccg acccctcacg cctgctgctc tgtgatgact 8640 gtgatattag ctaccacaca tactgcctgg accccccact gctcaccgtc cccaagggcg 8700 gctggaagtg caagtggtaa ggagactggg atcttcagtg gagccctggg gccttgagat 8760 gttaaagtgg atatgatgtt gagtatgtga cagaggctgg gtttaggagg ccaggctggt 8820 ggctt gggtt tccggtgagg ggacttctgg gtacttcggg taggttgggt gctaaagctc 8880 tgttttcctg ctcctatcag gtgtgtgtcc tgtatgcagt gtggggctgc ttcccctggc 8940 ttccactgtg aatggcagaa tagttacaca cactgtgggc cctggtgccag cctggtga cc 9000 tgccctatct gtcatgctcc ttacgtagaa gaggacctac taatccagtg ccgccactgt 9060 gaacggtgag aacatccctt tctcctcact ttggccctgt tgccagcctc gcattgcctg 9120 agcttatttc ctccagtctc tgttctccag gtggatgcat gcaggctgtg agagcctctt 9180 cacagaggac gatgtggagc aggcagccga tgaaggcttt gactgtgtct cctgccagcc 9240 ct acgtggta aagcctgtgg gtgagtacca gctgctgggt agggggagga gtcagagcag 9300 gggtaccttg ctttgggaca ggacctcagc cacctccgtt tgtccttctc tccatagcgc 9360 ctgttgcacc tccagagctg gtgcccatga aggtgaaaga gccaggtgag tc acagaaat 9420 tttgaatgcc aaagccagac cagacgtcgg acatcatcta gtctagctcc aaccccctag 9480 cttcatctcc ttatttaag aggaggaaac tcagacccag agaagttaag tggcctgccc 9540 aaggtcacct agtaagttag tggcaaagtt atgcctagaa ccaaggtctc cagcttcccg 9600 ggcaatgttc ctttcatcag gcaccatggt ctcttcactg ctaggatttc gtcttcagat 9660 ctctttttt t tttttttttt tgagatggag tcttgctctg ttgcccaggc tggagtgcag 9720 tggcacaagc ttggcacatt gcaagctttg cctcccgggt tcacgccatt ctcctgcctc 9780 agcctcctga gtagctggga ctacaggtgc ccgccacacac gc ccggctaa ttttttgtat 9840 tttttagtag agatggggtt tcaccgtgtt agccaggatg gtctcgatct ccggacctcg 9900 tgatctgcca gcctcggcct cccaaagggc tgggattaca agcatgagca ccgcgcccgg 9960 ctgagaacat aactcttttt cctaagtgaa aggggccagg gacatctcca tcgtgatatg 10020 gcactgctgc tggcatctag gacactgtgt gctggcattc agcaagtagg ggccctcata 10080 gccccagaca gcaagagaat ctatttagtg aacctagggt taatcatgag caaaggcagg 10140 cttctgagtt acagttcctc tctgaatctc cctgggtcac tgacagagaa ctcgggcctc 10200 agccagtgcc ccttggtggc ctgttctcct cagcatttag accctaagct ggacttttgt 10260 cactgccttt gtctcagcta aggacatagg ttgaaacttg cagttctggt ttccctgggg 10320 cttccatcca gggatcacat actctttcct cttatgcaga gccccagtac tttcgcttcg 10380 aaggtgtgg gctgacagaa actggcatgg ccttgctgcg taacctgacc atgtcaccac 10440 tgcacaagcg gcgccaacgg cgaggacggc ttggcctccc aggcgaggca ggattggagg 10500 gttctgagcc ctcagatgcc cttggcc ctg atgacaagaa ggatggggac ctggacaccg 10560 atgagctgct caagggtgaa ggttagcttg gggaatctta gggagcggca gagtaggggg 10620 agcgtgactc tgggagtggg atgttgggtg ggggctacat tgccactcag ttacccttaa 10680 gcactgctgt ctcgt ctaag tggctctgag gcaaggtatt cagctctctc agtggcagga 10740 tgacaaggtt aaaagggcct atagttctga tttgcctcca tctcttctgt caccatacgc 10800 aggtggtgtg gagcacatgg agtgcgaaat taaactggag ggccccgtca gccctgatgt 10860 ggagcctggc aaagaggaga ccgaggaaag caaaaaacgc aagcgtaaac catatcggcc 10920 tggtgaggtc ctgggatggg gttgtggggt ggtggggt gg tgcggggcag ctcaataggt 10980 cccccagcgg cttctcatcc acaactctgc ctcctcatag gcattggtgg tttcatggtg 11040 cgacagcgga aatcccacac acgcacgaaa aaggggcctg ctgcacaggc ggaggtgttg 11100 agtggggatg ggcagc ccga cgagggtgag acgggtgagg gcaccagtgg ggcctgggag 11160 aaggtggggc aatgctagag agacccaggg ggtggactca ttgaaagggc caagagggtg 11220 gtagacccag ctggtgttgt gggagagagt aggcacaaag tgtcaccctg caagttggga 11280 gcagcatgct ctcaacccga gtctgacact tccgttctgt ccacagtgat acctgctgac 11340 ctgcctgcag agggcgccgt ggagcagagc ttagctgaag gggatgagaa ga agaagcaa 11400 cagcggcgag ggcgcaagaa gagcaaactg gaggacatgt tccctgctta cttgcaggtg 11460 ggtctcaggc tccaagcagt gagggaggtg tctgtgccct gcagggcatg aagaaaactg 11520 tttctccttg actgccccac aggaagcctt ctttgggaag gagctgctgg acctgagccg 11580 taaggccctt tttgcagttg gggtgggccg gccaagcttt ggactaggga ccccaaaagc 11640 caagggagat ggaggctcag aaaggaagga actccccaca tcgcagaaag gttagttatg 11700 tgggagtgag tggtgtgaga gaatccaact ttcttctggc ttaggagctg gcaagttat 11760 tgatgggaaa tggactggcc tccaggagtc aagggtgggg tcaagggtcc tggcctg tag 11820 ggctgtggga ctggagacct gttctgggca tcagatgtag gacatctctg attggagggg 11880 ggactcttgc tcataggaga tgatggtcca gatattgcag atgaagaatc ccgtggcctc 11940 gagggcaaag ccgatacacc aggtgagggc tgccggggtt act gtgtcct gtcttggcct 12000 tgcttgcctc tgtccctctg ctgtgcccct gagcattgtc agtgttggag gctggaaact 12060 gtcccatggc cctctgtggt tcagagtggc catgacccat cctggccttg acccatgggt 12120 ttctcctggc atttacagga cctgaggatg ggggcgtgaa ggcatcccca gtgcccagtg 12180 accctgagaa gccaggcacc ccaggtgaag ggatgcttag ctctgactta gacaggattt 12240 ccacagaagg tga ggctgg acccgtacct ctttgtgtat aagggttttc tatggggagaa 12300 ggaggaggtc ctatctttgg gactgtgatc tgtacagctt ctctggtggg gagtcctgga 12360 ctgttcctgg ccatgatcat ttgtagacct gtggtgtcac ctgaacttcc cagtcttcct 12420 caacagtgtc cttcattccc ccacagaact gcccaagatg gaatccaagg acctgcagca 12480 gctcttcaag gatgttctgg gctctgaacg agaacagcat ctgggttgtg gaacccctgg 12540 cctagaaggc agccgtacgc cactgcagag gccctttctt caaggtaata caggtgggag 12600 tggtctgaag actgacataa ccaagcttgc ctccaggatg ggccagttgc tcttttctct 12660 gatcctgtcc gtcttgtagg tggactccct ttgggcaatc tgccctccag cagcccaatg 12720 gactcctacc caggcctctg ccagtccccg ttcctggatt ctaggttggt gtctctgcgt 12780 aacctttgtg ggcagtcctc gttgtccttt ccctccatct gagttcatgc ttt gcctccc 12840 tcggactcct gcagcacttc ccctgctcct ccccattccc ttgttagtga ccctcctctt 12900 ttggggcagg gcagtggcct ggggctctag gcagtttgtc tggggtggga cttggcatcc 12960 ctgcgccctg tgactctctg cccctgcgcc ccagggagcg cgggggcttc tttagcccgg 13020 aacccggtga gcccgacagc ccctggacgg gctcaggtgg caccacgccc tccaccccca 13080 caacccccac cacgg agggt gagggcgacg gactctccta taaccagcgg agtcttcagc 13140 gctggggagaa ggatgaggag ttgggccagc tgtccaccat ctcacctgg ctctatgcca 13200 acattaattt tcctaatctc aagcaagact acccaggtac ctgtgggatg agggcaaggg 13260 aga cagcctg gcaacatggc aggtggagga gtcgcctgcc aagtcttctc tgactcactc 13320 tctctgccct ccagactggt caagccgttg caaacaaatc atgaagctct ggagaaaggt 13380 tccagcagct gacaaagccc cctacctggt gaggcagaaa ggagcatgga ttagcgtggg 13440 aactgagagg gagggaggga tctttgggta atttacctca gttctttccg ctccccactc 13500 ctaaagcagc tgggccagaa gggatctgct tctgggtagg gagtgtgaaa acactacagt 13560 atgggggcgg ggcatgagac caagcactag gccctaaggc tgtgtcccat atccctcagc 13620 aaaaggccaa agataaccgg gcagctcacc gcatcaacaa ggtgcagaag gtgagtgggg 13680 ctgggctggg gtgtagcagt cctctagtgg gtggcctctc ttgagggtgg agggccatgg 13740 ggcctgcctg cagcagcctg actgccctat gcctggtctc cccctgtagc aggctgagag 13800 ccagatcaac aagcagacca aggtgggcga catagcccgt aagactgacc gaccggccct 13860 acatctccgc attcccccgc agccaggggc actgggcagc ccgccccccg ctgctgcccc 13920 caccattttc attggcagcc ccactacccc cgccggcttg tct acctctg cggacgggtt 13980 cctgaagccg ccggcgggct cggtgcctgg ccctgactcg cctggtgagc tcttcctcaa 14040 gctcccaccc caggtgcccg cccaagtgcc ttcgcaggac ccctttggac tggcccctgc 14100 ctatcccctg gag ccccgct tccccacggc accgcccacc tatcccccct atcctagtcc 14160 tacgggggcc cctgcgcagc ccccgatgct gggcgcctca tctcgtcctg gggctggcca 14220 gccaggggaa ttccacacta ccccacctgg cacccccaga caccagccct ccacacctga 14280 cccattcctc aaaccccgct gcccctcgct ggataacttg gctgtgcctg agagccctgg 14340 ggtaggggga ggcaaagctt ccgagcccct gctctcgccc ccaccttttg gggagtcccg 14400 gaaggcccta gaggtgaaga aggaagagct tggggcatcc tctcctagct atgggccccc 14460 aaacctgggc tttgttgact caccctcctc aggcacccac ctgggtggcc tggagttaaa 14520 gacacctgat gtcttcaaag cccccctgac ccctcgggca tctcaggtag agccccagag 14580 cccgggcttg ggcctaaggc cccaggagcc accccctgcc caggctttgg caccttctcc 14640 tccaagtcac ccagacatct ttcgccctgg ctcctacact gacccatatg ctcagcccccc 14700 attgactcct cggccccaac ctccgccccc tgagagctgc tgtgctctgc cccctcgctc 14760 actgccctcc gaccctttct cccgagtgcc tgccagtcct cagtcccagt ccagct ccca 14820 gtctccactg acaccccggc ctctgtctgc tgaagctttt tgcccatcac ccgttacccc 14880 tcgcttccag tcccctgacc cttattctcg cccaccctca cgccctcagt cccgtgaccc 14940 atttgcccca ttgcataagc caccccgacc ccag ccccct gaagttgcct ttaaggctgg 15000 gtctctagcc cacacttcgc tgggggctgg ggggttccca gcagccctgc ccgcggggcc 15060 agcaggtgag ctccatgcca aggtcccaag tgggcagccc cccaattttg tccggtcccc 15120 tgggacgggt gcatttgtgg gcaccccctc tcccatgcgt ttcactttcc ctcaggcagt 15180 aggggagcct tccctaaagc cccctgtccc tcagcctggt ctcccgccac cccatgggat 15240 caacagccat tttgggcccg gccccacctt gggcaagcct caaagcacaa actacacagt 15300 agccacaggg aacttccacc catcgggcag ccccctgggg cccagcagcg ggtccacagg 15360 ggagagctat gggctgtccc cactacgccc tccgtcggtt ctgcca ccac ctgcacccga 15420 cggatccctc ccctacctgt cccatggagc ctcacagcga tcaggcatca cctctcctgt 15480 cgaaaagcga gaagacccag ggactggaat gggtagctct ttggcgacag ctgaactccc 15540 aggtacccag gacccaggca tgtccggcct tagccaaaca gagctggaga agcaacggca 15600 ggtaagttga caccctggag ctaagccccc tatatcgctc ctgtctctgg ggcagcccta 15660 tgattggagt agaatg ggct tattcctctt ctcttttttt tgcatagcgc cagcgactac 15720 gagagctgct gattcggcag cagatccagc gcaacaccct gcggcaggag aaggaaacag 15780 ctgcagcagc tgcaggagca gtggggcctc caggcagctg gggtgctgag cccagcagcc 1 5840 ctgcctttga gcagctgagt cgaggccaga ccccctttgc tgggacacag gtaggtagag 15900 tggcaaggga tagtggggcc aggatattga aggttgctcc accttcatct accttgtctc 15960 ttctaggaca agagcagcct tgtggggttg cccccaagca agctgagtgg ccccatcctg 16020 gggccagggt ccttccctag cgatgaccga ctctcccggc cacctccacc agccacgcct 16080 tcctctatgg atgtgaacag ccgg tgaggc tccaggaggt tccctggggg taaaccaagg 16140 gggatggatt ttatcactgt tggaagctct tgtgattttc ctgtatcact aatccttttc 16200 cagtatcact ttctcttctt cctcattcct tttctccctc actgcattaa ttctatcctt 16260 cctcactgcc ctaagcccat gttcttgctc cttttcatct gatttcatcc tactgactac 16320 tgtatattct tccaggcaac tggtaggagg ctcccaagct ttctatcagc gagcaccta 16380 tcctgggtcc ctgcccttac agcagcaaca gcaacaactg tggcagcaac aacaggcaac 16440 agcagcaacc tccatgcgat ttgccatgtc agctcgcttt ccatcaactc ctggacctga 16500 acttggccgc caagccctag gttccccgtt ggcgggaatt tccacccgtc tgccaggccc 16560 tggtgagcca gtgcctggtc cagctggtcc tgcccagttc attgagctgc ggcacaatgt 16620 acagaaagga ctgggacctg ggggcactcc gtttcctggt cagggcccac ctcagagacc 16680 ccgt ttttac cctgtaagtg aggacccccca ccgactggct cctgaagggc ttcggggcct 16740 ggcggtatca ggtcttcccc cacagaaacc ctcagcccca ccggcccctg aattgaacaa 16800 cagtcttcat ccaacacccc acaccaaggg tcctaccctg ccaactggtt tggagctggt 16860 caaccggccc ccgtcgagca ctgagcttgg ccgccccaat cctctggccc tggaagctgg 16920 gaagttgccc tgtgaggatc ccgagctgga tgacg atttt gatgcccaca aggccctaga 16980 ggatgatgaa gagcttgctc acctgggtct gggtgtggat gtggccaagg gtgatgatga 17040 acttggcacc ttagaaaacc tggagaccaa tgacccccac ttggatgacc tgctcaatgg 17100 agacgagttt gacctgct gg catatactga tcctgagctg gacactgggg acaagaagga 17160 tatcttcaat gagcacctga ggctggtaga atcggctaat gagaaggctg aacgggaggc 17220 cctgctgcgg ggggtggagc caggaccctt gggccctgag gagcgccctc cccctgctgc 17280 tgatgcctct gaaccccgcc tggcatctgt gctccctgag gtgaagccca aggtggagga 17340 gggtggacgc cacccttctc cttgccaatt caccattgct accccca agg tagagcccgc 17400 acctgctgcc aattcccttg gcctggggct aaagccagga cagagcatga tgggcagccg 17460 ggatacccgg atgggcacag ggccattttc tagcagtggg cacacagctg agaaggcctc 17520 ctttggggcc acgggaggac caccagctca cctgctga cc cccagcccac tgagtggccc 17580 aggaggatcc tccctgctgg aaaagtttga gctcgagagt ggggctttga ccttgcctgg 17640 tggacctgca gcatctgggg atgagctaga caagatggag agctcactgg tagccagcga 17700 gttacccctg ctcattgagg acctgttgga gcatgagaag aaggagctgc agaagaagca 17760 gcagctttca gcacagttgc agcctgccca gcagcagcag caacagcagc agcagcattc 17820 cctactgtct gcaccaggcc ctgcccaggc catgtctttg ccacatgagg gctcttctcc 17880 cagtttggct gggtcccaac agcagctttc cctgggtctt gcaggtgccc gacagccagg 17940 tttgccccag ccactgatgc ccacccagcc accagctcat gccctccagc aacgcct ggc 18000 tccatccatg gctatggtgt ccaatcaagg gcatatgcta agtgggcagc atggagggca 18060 ggcaggcttg gtaccccagc agagctcaca gccagtgcta tcacagaagc ccatgggcac 18120 catgccacct tccatgtgca tgaagccgca gcaattggca atgcagcagc agctggcaaa 18180 cagcttcttc ccagatacag gtaacctcag ctggtaacat agccaagtta ctcagggtga 18240 tt attgttat ccctaaatgg gcactgaggc tagagacctc agataatccc tacttaagat 18300 gggacacaaa gaactttggc taaatatcat actagtggta gaggcagaaa cactgtagct 18360 tttaagaaga gagagaacag ttcctggcat atagtaggca tgtagcagat gtttgaataa 18420 at ggaatgaa tgtatgaatg aagcctaatt agcagagcct ttgtagctgt agtgaagttg 18480 aaagcttaag acttgaagag aagtggtgca aaaaaaagca gttgaggcca ggcacaatgg 18540 ctcatgcctg taatcccagc actttgggag accaaggcag gtggatcact taagatcagg 18600 agttcaagac cagcctggcc aagatgatga aaccccatct ctactaaaca tacaaaaatt 18660 agctgggtgt gagccgggc g cggtggtgca tccctgtaat cccagctact cgggaggctg 18720 aggcaggaga gttgattgaa cccatgaggc agaggttgg gtgagccgag atcgcctcat 18780 tgcactccag cctgggcaac aagagcgaaa ctccatctca aaaaaaaaaa aaaaaaaaaa 18840 aaaaaattag ctgggtgtgg tggtgcacgc ctgtagttcc agctactcga gaggctgagg 18900 caggagaatt gcttgaaccc aggaggtgga ggttgcagtt agctgagatc acgccattgc 18960 acttcaggct gggcaacaga gcgagactct gtcttaaaaa aaaaaaaaaa agcgattggg 19020 ataggtgaaa aagttcattg aggctgcaat ggtgggaaaa cctatgggat gtttcaagaa 19080 cagtgagtga attggtta gg ctggagtaaa ctgtttcgag tgaagtaagt gacataattt 19140 tggtgagata agatgggggc cagattgaaa aagacctcaa attataatag catttattaga 19200 gtaattacta tttgccaagg agtttactga gcactttata ctttttgtcc aatttaatca 19260 ttatagca ga ctcattaaat aggtattgtt attatctttg attacagaag aggaaacaga 19320 agtggaggtt aagtaacttg tccaagatta cacagcagct agcagagcta gatctgaagt 19380 ctggtcggta ctcctcttaa ctgtttaactg cctcaggatt ccaggagagg gagtttgggt 19440 tagtccttaa gaaagtggga gctctggcca ggtgctgtgg ctcacgcctt taatcccagc 19500 actttgggag gctgaggcgg gtggatcacc tgagg tcagg agttccagac cagcctggcc 19560 aacatggtga aacctcgttt ctactaaaaa tacaaaaatt agctgggctt ggtggtgggc 19620 acctgtaatc acagctactc ggcaggctga ggcaggagaa tcgcttgaac ccaggaagca 19680 gaggttgcag tga gcctaaa ttgcaccatt gcactccagc ctgggtgaca agagcaagac 19740 tctgtcttta aaaaagaaaa gaaaagaaaa aaagaaagtg gatgctcagt taagttttct 19800 gagcagtgga gaaatataca aagtgtggga ttttaggatg atgtaagttt ttggtggttg 19860 gttgtttctt cttttttgcc cagcattcta gacagacagg agagtggact acaggtgatg 19920 cccaaaacag ctctggaatc tagggctttg caaca gtgcc agcatcttgg gtgcttgggc 19980 tgtgctagtt ggactaagaa cattaccttt gaagaatgct ttccgagtca taaagtgtac 20040 ttatattctt gtcacatttg atcctcttaa cacctctgtg aggtagacgg agtagggatc 20100 atcatctgta tcaaataaaa gggtaaactg aggtgaaata acacaggttg actcaacaaa 20160 tatttacgga gccccttttt gtagcacggt gcaagtaaaa acaggcccac atgtcctgtg 20220 aatagagctg attcacccag gccgactggc tcctaattca gtggtctttc tgccttgccg 20280 tgccattgtt ctgcctggcg tggttgaagt caggatgttg aagggaatcg cagatattca 20340 ctggagcatt ggccccatag cccagctcac ttggttctcc c ctctccaga cctggacaaa 20400 tttgctgcag aagatatcat tgatcccatt gcaaaggcca agatggtggc tttgaaaggc 20460 atcaagaaag tgatggctca gggcagcatt ggggtggcac ctggtatgaa caggtaagac 20520 tcagggctgg aatggggtt g gcccttttct ttcccagtca caccccttct tggctcccct 20580 ccctacttgt cccacgtctc tttgctttcc aactttctta ttgccaacac ttatcttctg 20640 tgctttggtg gactccagac agcaagtgtc tctgctagcc cagaggctct cgggggggacc 20700 tagcagtgat ctgcagaacc atgtggcagc tgggagtggc caggtaagtg gtcaggtggg 20760 agtaggaact tgtgtcttat gccactgggc cacccttctt agggcctagc agggaacaat 2082 0 gaccctttag cagcctctct cattgcagga gcggagtgct ggtgatccct cccagcctcg 20880 tcccaacccg cccacttttg ctcagggagt gatcagtgag tatggggcgt gggaggaagg 20940 tgcaggggag tggtttgggt catatggagg aagagggatt gggattaccc tt ttgcaggt 21000 cctgacccc agcttctttt cccagatgaa gctgaccagc ggcagtatga ggagtggctg 21060 ttccataccc agcagctcct acagatgcag ctgaaggtgc tagaggagca gattggtgta 21120 caccgcaagt cccggaaggc tctgtgtgcc aagcagcgca ctgccaaaaa agctggccgt 21180 gagttcccag aagctgatgc tgagaagctc aagctggtta cagagcagca gagcaagatc 2124 0 cagaaacaac tggatcaggt gggggaaagc aaacttcagc ctagcaccca gaaggcaggg 21300 aagagggttg gcatgggggg agcatgcccc agcctgacct ctccgaccct cccatgttag 21360 gtccggaaac agcagaagga gcacactaat ctcatggcag aatatcggaa caagcag cag 21420 caacaacagc agcagcagca gcaacaacag caacagcact cagctgtgct ggctctcagc 21480 ccttcccaga gtccccggct gctcaccaag aac attctgg tggggctgga tccctggctg gcccttcagg gggcttcttc 21720 cctggcaacc ttgctcttcg aagcctcgga cctgattcaa ggcttttaca ggaaaggcag 21780 ctgcagctgc agcagcaacg tatgcagctg gcccagaaac tgcagcagca gcagcagcag 21840 caacagcagc agcagcacct tctaggacag gtggcaatcc agcagcaaca gcagcagggt 21900 cctggagtac agacaaacca agctctctgggt cccaagcccc aggg ttat gcctcccagc 21960 agccaccaag gcctcctggt ccagcagctg tcccctcaac caccccaggg gccccagggc 22020 atgctgggcc ctgcccaggt ggctgtgttg cagcagcagc accctggagc tttgggcccc 22080 cagggccctc acagacaggt gcttatgacc cagtcccggg tgctcagttc cccccagctg 22140 gcacagcagg gtcagggcct tatgggacac aggctggtca cagcccagca gcagcagcag 22200 caacaacagc accaacagca agggtccatg gcagggctgt cccatcttca gcagagtctg 22260 atgtcacaca gtgggcagcc caaactgagc gctcagccca tgggctcttt acagcagctt 22320 cagcagcagc agcagctgca acagcaacag caacttcagc agcagcagca gcagcagcta 2 2380 caacagcaac agcaacttca gcagcaacag cttcaacagc agcaacagca gcagcagctt 22440 caacaacagc agcagcaaca gcttcaacag cagcaacagc agctacaaca gcaacagcaa 22500 caacaacagc agcagtttca acagcagcag caacagcagc agatgggcct tttaaaccag 22560 agtcgaactt tactgtctcc tcagcaacaa cagcagcagc aagtggcact tggccctggc 22620 atgccagcaa agcctcttca acacttttct agccctggag ccctgggtcc aaccctcctc 22680 ctgacgggca aggaacaaaa caccgtagac ccagccgttt cttcagaggc cactgagggg 22740 ccctctacac atcagggagg gccgttagca ataggaacta cccctgagtc aatggccact 22800 gaaccaggag agg taaagcc ctcactctct ggggactcac aactcctgct tgtccaaccc 22860 cagccccagc ctcagcccag ctctctgcag ctgcagccac ctctgaggct tccaggacaa 22920 cagcagcagc aagttagcct gctccacaca gcaggtggag gaagccatgg gcagctaggc 2298 0 agtggatcat cttctgaggc ctcatctgg ccccacctgc tggctcagcc ctctgtttcc 23040 ttaggggatc agcctgggtc catgacccag aaccttctgg gcccccaaca gcccatgcta 23100 gagcggccca tgcaaaataa tacagggcca caacctccca aaccaggacc tgtcctccag 23160 tctgggcagg gtctgcctgg ggttggaatc atgcctacgg tgggtcagct tcgagcacag 23220 ctccaag gag tcctggccaa aaacccacag ctgcggcact taagtcctca gcagcagcag 23280 cagctacagg cactcctcat gcagcggcag ctgcagcaga gtcaggcagt acgccagacc 23340 ccaccctacc aggagcctgg gacccagacc tctcccctcc agggcctcct gggctgccaa 2 3400 cctcaacttg ggggcttccc tggaccacag acaggccccc tccaggagct aggggcaggg 23460 cctcgacctc agggcccacc ccggctccct gccccaccag gagccttatc tacaggacca 23520 gtccttggcc ctgtccatcc cacacctcca ccatccagcc ctcaagagcc aaagagacct 23580 tcacaattac cttcccccag ctcccagctt cccactgagg cccagctccc tcccacccat 23640 ccagggaccc ccaaacctca ggggccaacc ttggagccgc ctcctgggag ggtctcacct 23700 gctgctgccc agcttgcaga taccttgttt agcaagggtc tgggaccttg ggatccccca 23760 gacaacctag cagaaaccca gaagccagag cagagcagcc tggtacctgg gcatctggac 23820 caggtgaatg gacaggtggt gcctgaggca tcccaactca gcatcaagca ggaacctcgg 23880 gaagagccat gtgccctggg agcccagtca gtgaagaggg aggccaatgg ggagccaata 23940 ggggcaccag gaaccagcaa ccacctcctg ctggcaggcc ctcgctcaga agctgggcat 24000 ctgctcttgc agaagctact ccgggcaaag aatgtgcaac tcagcactgg gcgggggtcc 24060 gaggggctgc gagctgagat caacgggcac attgacagca agctggctgg gctggagcag 24120 aaactacagg gtacccccag caacaaggag gtgagtactc tgagtagagt ggagcaggta 24180 gagtgggtcc tagagccagc ggggggcaga atgagtgagc ctgggtcaga cagaagagat 24240 gagggctctg aggagggaggg tagcagcctt caatgggctt atttggctta ggatgcagca 24300 gcaaggaagc ctttgacacc gaagcccaag cgggtacaga aggcaagcga caggttggtg t gcaggtttt gaactttgtc 24540 atcttgcccc ttgtaggagc tgtccctgct gcccctaacg gagcctgcta tcaccgccaa 24600 ttttagcctc tttgccccct ttggcagtgg ctgcccagtc aatgggcaga gccagctgag 24660 gggggccttt ggaagtgggg cgctgcccac tggccctgac tactattccc agctgcttac 24720 caaggtcaga aaaatggcaa tattttttgg gaatagtgaa gttcttggga aggtgagggt 24780 gggaatagaa aacttgaggg aattgctgac gtagagtggg gccaggagat tatatcagtc 24840 tccctatgcc atcttgcaca caacacccca ccccccaccc ctcagaataa cctgagtaac 24900 ccgccgacac caccctcgtc gctgcccccc accccaccccc catcggtgca gcagaagatg 24960 gtgaatggcg tcaccccatc tgaagagctg ggggagcacc ccaaggatgc tgcctctgcc 25020 cgggatagtg aaagggcact gaggggtaag tcaagagcag atgccacccc tggtggagtt 25080 tggtagctgg agtccaaacc agttagtatg ctgtacagt t tagaaattag tgggttgcct 25140 gctgtcctgt gtgtttacat aacagggcac ctgaggtagg aagggccctt tcaggactga 25200 tttcttgggg gccagaatgg acatttggag tctagagcaa atgcaatagg agaggtgggt 25260 ggcagggagc atctttatga agctttgtat agaaggaaca gtccagcttt agtgagtgtg 25320 gagctagact ctgatctgga tttgaattct ggttcctgca ttcattcaac tgtgttactg 253 80 tatccaagta acttgattga cttgtgtgag cctcagtttc ctcactgtaa aatggctatt 25440 gtagtactca cttaatggag ttattaaatg actaaacaaa ctccaaagag tatatctaaa 25500 gccagctgcc accaggcctg gtagcttatg cctgtaatcc caacattttg ggagccca ag 25560 atggaaggat tgcttgaggc caggagttcg agaccagctt gggcaatata acaagacccc 25620 atctctacgg gaaaaaaaaa aaaaaaacaa aaaaaacaaa aaacaacagt gcctggcatg 25680 caggacagac tcaataaata taccttgttt gccccaaact ggtaggtggg aggacagcta 25740 atcatgatag ctgagatctc atgctaatta ggcctaaaat attgggagaa ggtaccatca 25800 gccctgg cca ccctcacctg acttttcttc tccctaccca cccctcagat acttcagagg 25860 tgaagagtct agacctgctg gctgccttgc ctacaccccc tcacaatcag actgaggatg 25920 tcaggtaggg gcggggccag aaatggggat gaggaacaag ggtggggtac aggttgcctc 25980 atatttcctt tggccaatgg agatttcaag taagacatct attcatctct agatttggga 26040 ggggagtctg cagggctgta gcaacaaatg tctacttttg gtccccagga tggagagtga 26100 tgaggatagc gattctcctg acagcattgt gccagcttca tcccctgaga gcatcttggg 26160 ggaggaggcc cctcgtttcc ctcatctggg ctcaggccgg tgggagcaag aggaccgggc 26220 cctctcccct gt catcccccc tcattcctcg ggccagcatc ccaggtatgt gctactctgg 26280 atgtggggcca ggcccagttc acctgggttg tccgaagctg ggggagaggc ggccaagtgt 26340 tacacaaatt cctctttctc attcagtctt cccagatacc aaaccttatg gggcccttgg 26400 c ctggaggtc cctggaaagc tgcctgtcac aacttgggaa aagggcaaag gaagtgaggt 26460 gtcagtcatg ctcacagtct ctgctgctgc agccaaggtg tgtcctaggg gtacctcgag 26520 gctgagggga acctgatcag agggcagtcc ctggaatttg tctggataag gaaaaatgta 26580 gtcgttcaag cacatgtact gagtacctat tgtatgtgaa agcctgggct agaggctgtg 26640 agattcgggt aaatgaatca t ggttcctgc cctcacgggg ctcgtagtcc catggtaaag 26700 acagacaagt caacaactaa ggagcacctg tgtgtgtaat gacacaggta ctacatgaca 26760 gcattgcccc agtcatgttt ggtgggactc tgtcagctgt tttgaaaata ttaacgggct 26820 tttgt ggtca aagaaagttg gaaaacacag ttaaaatgac aatatgggtt tctttactac 26880 aagagtcctc aggtcctttt aatttgctaa cgtgtatcat gagcctccaa gtcatggata 26940 gagcatgcat catttcctaa acgtagttga tgtagttccc ttttcgtgga gctcccgtca 27000 gtgcccacag cagtttggga aaggctgctg tgagggaagt gtatgaaaag agctgggtga 27060 cataggatag aactaccctg gggagtgggt t ctaggtgtc cttgtcccca cccagctggt 27120 agtagagctc acctcagaca cttggctgat atgtttcttc catcccttcc ctggccctgg 27180 cagaacctga atggcgtgat ggtggcagtg gcggagctgc tgagcatgaa gatccccaac 27240 tcctatgagg tgctgtt ccc agagagcccc gcccgggcag gcactgagcc aaagaagggg 27300 gaagctgagg gtcctggtga gtgtggcagg gaagcccttt gggacttgag gggagtgatt 27360 ctggtgggag gctctgatcc actcctttct gcaggtggga aggaaaaggg tctggaaggc 27420 aagagcccag acactggccc tgattggctg aagcagtttg atgcagtgtt gcctggctat 27480 accctgaaga gccaactaga catcttgagc ctcctgaaac aggtaggtct gggggagaaa 27540 aagggggtggg tgttagaaaa aaggggctgc cggccaggcg cggtggctca catctgtaat 27600 cccagtgctt tgggaggcaa ggcgagtgaa tcactttagg ccaggagttt gagaccagcc 27660 tggccaacat ggcgaaaccc cgtctctact aa aaacaaaa acaaaacagt agccaggcgt 27720 gatggtgcgt gcctgtaatc ccagctactc gaaaggctga ggcatgagaa tcccttgaac 27780 ccaggaggca gaggttgcag tgagccaaga ttgtgccact ggatccagcc tgggcaacag 27840 agcaagactg tgtctcaaaa aaaaaagaaa agaaaagaaa aaagaggctg tctagggcaa 27900 agaatgtgga ggccttttgg gagggtggca tatgggtgag c cttccccct tggcaccttc tcctgccagt 28140 ccccctactg agcccttggt tgaacttccc accgaaccct tggctgagcc acccgtcccc 28200 tcacctctgc cactggcctc atcccctgaa tcagcccgac ccaagccccg tgcccggccc 28260 cctgaagaag gtgaagattc ccgtcctcct cgcctcaaga aatggaaagg agtgcgctgg 28320 aagcggcttc ggctgctgct gaccatccag aagggcagtg ggcggcagga ggatgagc gg 28380 gaagtggcag agtttatgga gcagcttggc acagccttgc gacctgacaa ggtaccgcga 28440 gacatgcgtc gctgctgttt ctgtcatgag gagggtgacg gggccactga tgggcctgcc 28500 cgtctgctga acctggacct ggacctgtgg gtgcacctca actgtgccct ttggtccacg 28560 gaggtgtatg agacccaggg cggggcactg atgaatgtgg aggttgccct gcaccgagga 28620 ctgctaacca agtgctccct gtgccagcga actggtgcca ccagcagctg caatcgcatg 28680 cgttgcccca atgtctacca ttttgcttgt gccatccgtg ccaagtgcat gttcttcaag 28740 gacaagacca tgctgtgtcc aatgcataag atcaaggggc cctgtgagca agagctgagc 28800 tcttttgctg tcttccggcg ggtctacatt gagcgggacg aggtgaagca aatcgctagc 28860 atcattcagc ggggagaacg gctgcacatg ttccgtgtgg ggggccttgt gttccacgcc 28920 atcggacagc tgctgcctca ccagatggct gactttcata gtgccact gc cctctatccc 28980 gtgggctacg aggccacgcg catctattgg agcctccgca ccaacaatcg tcgctgctgc 29040 tatcgctgtt ctattggtga gaacaacggg cggccggagt ttgtaatcaa agtcatcgag 29100 cagggcctgg aggacctggt cttcactgac gcctctcccc agggtgagca gtgggccctt 29160 gaaatggata atatggaatg ggaaaagttt ctcccagggt cactgttaca atgtctataa 29220 gaggacctgt agctt ctatg tgaatgatcc tccttccccc acctcaggca ggcagggggt 29280 ctcttgaaaa ctcccagtga aagtgtttga gcctctcttg tcaccctaaa ttcccttgta 29340 gttgaaaata ttttgctggt ctaatctcac atattctagt tctgttgcta tcc ccagtgg 29400 aacaaaagga aacagttctg agactatcat ctgcctcacc caacctaatc ctaaccaagt 29460 tccttggggt tgtttttccc tggacgaaat cagaattatt ttgattttag ttttagtgtt 29520 aatgataaaa taacagtaag agcaggtacc tttttttgag tgtgtactgt gagccacaaa 29580 ctaagctaag tgatttgtgt agtttatttt gttcatacaa ccctatgagg taagtattat 29640 actacgatta tgcccagttt gttcataaag aaactgagtc tcagatttca gtacagtcgt 29700 gcattgctaa atgacaggga tacattctga gaaatgcatt gttaggtgat tttgtcattg 29760 tgtgaacttc atagagtgta ctacacaaac ctagatggca tagcatacta cacacctagg 29820 ctctgcggta taccccatt g ctcctaggct acaaatctgt acagcatgta actgtactga 29880 atactgtagg cagttgtaac atacggtaag tatgtgcatc tagacataga aaagatacag 29940 taaaaataca gtacagtatt ataatcttac cagaccactg ttgtatatat gattcctcat 30000 tgaatgaaat gttgttaagc tgcacgtgac tgtatttggc tcaaggtctc atgaccagta 30060 ctagaacctg aacccaagtc tttccaactc ca aagcatgc ctgctctttc actagggacc 30120 ttccatggcc tatgctgggt ctcctgggcc ctgggtttgt atctcaaggc tctgtgatga 30180 ccccttgggg ttggaaacct cctgcttctt aagagagagt gagactagga ggccaagaga 30240 ggatctggaa gacca acaca acttcatgat agggaggctt gaaggcctca gaaaactgca 30300 gttctggatt ggggttaggg actggaggtc agtgagcaga agttgcctct gaggactgct 30360 ctcttccctg cttcttagcc gtgtggaatc gcatcattga gcctgtggct gccatgagaa 30420 aagaggctga catgctgcga ctcttccctg agtatctgaa gggcgaggag ctctttgggc 30480 tgacggtgca tgccgtgctt cgcatagctg aatcagtaag gaaggggctg ggagctgggg 30540 ggcttggcgg gcactgagaa ctttggccta accccaaaaa aactcaggct aaggtgagta 30600 tgaactgtgc ccacagctgc ccggggtgga gagctgtcaa aactatttat tccgctatgg 30660 gcgccacccc cttatggagc tg ccactcat gatcaacccc actggctgtg cccgatcaga 30720 gcctaaaatc ctcacacact acaaacggtg agcttgtgat gctggagcca agggatgtgg 30780 gtgtgggtgt tgacagggat cctctggtcc cattatgagg atttaggata cagatcagag 30840 ttcccgtgga gaaaatgggg aatcactctt agacttccta attagagggc atgcaggtat 30900 tagtagggta tccttttcct cctctcccaa cctgctcaga tgcacttggg atataggaca 30960 gaattatctt gggcaccctg gggaggtaat gggtaaactg gtgaaatttt atgaaatata 31020 taagggactt ggtcacctct ttcttctcct gttttacttc tgggggaggg cctgtgattc 31080 tcccaaacct cagatacccc atgggtgcta gggtcacctt cccttcc cca tgagtgttgg 31140 tgtcaaaaat aaatagttag agatataata gaaaaataat aaaaccttac atttgtatag 31200 cactttatac tttttttttc aaagcgtttt cacatccatt atctcatttg atcctcacaa 31260 caaccttatg aggtaggtag ggcaggtggt atgaccccca ttttacagct gagaaaactg 31320 agacccagaa agattaaatg actaggcaaa ggtcacacag ctgggacag acccttactt 31380 cttcactgca ggtccttgtt ctttctgtgt accagggacc ttagtccctg ggtagaggga 31440 ggcagaatct gtggtagcag ggctttctcg aaggtctttg gtggctccta ggctgttgta 31500 gaatgtcaga gactctccat ccctagccag ccttgtcctt gatgcc ctgc aatggtggtt 31560 ttcaaactgt gagtgcctgt gttccaaaaa gtcctggatc acttaaactg atgggttgaa 31620 cttttccttc ccatgcatat ctcttccttc cccaaattgg attaaaccag aagagctcca 31680 ttgtcatcta gtttatgtat tggagttcca gtcaacattt tgttaaagaa aaaagcaaag 31740 atttctgcta aataaaaaaa gaaccagaaa cgtttgaaaa ccactgctct gggatggcaa 31800 gaatttggct ggtgccctaa ggtggtaaaa ggcatcctgc caggcagccg tcattcccct 31860 gcactgagcc atctgcacag agcccaatgt tatgtcagag aaggggacag tccgaagaaa 31920 ggataccacc tttaggctgt gagttcacag ccagttttaa ttcaaatcta gcccagcgtg 31980 gtaggcacag tccccatttt cagggcttcc agtatgtgca ggaggtagga ttcagacatt 32040 caagcaaacc atcagcttaa attctaggcc tgggctgctt gcggaaaact tccccagagga 32100 gcatggcctt gagaatggtt tggcaggaga gtggtaggaa gtgggagatg ggagaacagg 32160 ctcagtgtag gggaattggt gcccccccatc tccctccaca ccccacccct caccctgggc 32220 tctctgtgcc accca gggtg tcagaagggt ccctgtagct agttgcttcc tcaccagagc 32280 tgagacccag ttgcctctac tcctttccca aggctgcact tccagtgctt gccagcagca 32340 cacgccccta actggtgtgt tgcacatccc aggaggtggc agaggaggtg ggtggtatgt 32400 acttggtctg agggagagct gtcttgtcat ggattatatc acctcccagg ccccataccc 32460 tgaacagcac cagcatgtct aaggcatatc agagcacctt cacaggcgag accaacaccc 32520 cctacagcaa gcagtttgtg cactccaagt catctcagta ccggcggctg cgcaccgaat 32580 ggaagaacaa cgtgtacctg gctcgctccc gtatccaggg cctggggctc tatgcagcca 32640 aggacctaga aaagcacaca atggttatcg agt acattgg caccatcatt cggaacgagg 32700 tggccaaccg gcgggagaaa atctacgaag agcaggtatg agctggcaga ggggccattg 32760 tggtgcatag tctgcactca accaaggagc aagggcagga ttggtcacag gagagcagga 32820 ggaaagctgt ggtggggaga agggaaaggc aggagaaatg aagtacatgc aacaaaagcc 32880 cccactgcct gagtctccta cctgatccca cagccacac tgccactctc cctg agagtg gcactctggg ggatagacga acaaggaatc 33120 aaaattgtcc caagttagtt gcctgacatc cctgactctg tcccactgcc caggtacatt 33180 aaccattcct gtgcccctaa ctgtgtggcc gaagtcgtga catttgacaa agaggacaaa 33240 atcatcatca tctccagcc g gcgaatcccc aaaggagagg aggtgagagg aagtatcctg 33300 actgagtgac aaagcagctc ctcctccttt caccccttct ctgccattcc ctaaatgtgg 33360 attcctaggc tgggcacctc agatcatatc ttctctggcc tcccctcttc ctgtggggga 33420 ctagcattga ttctgccctc ttctcttttc agctaaccta tgactatcag tttgattttg 33480 aggacgatca gcacaagatc ccctgccact gtggagcctg gaattgtcgg aaatggatga 33540 actaagaagc tttgaggcta ccaggcaggg gagtccccct acccacaacc tcttccctga 33600 aagggatgag ggggaagaga ggtagcagcc agagccagga cccagggttg gggctgccgg 33660 ctgacccgga gcccctggag caggaggctg gggcagaggg ccctaggcca agcccaccct 33720 gggcaccagg gacaatcctc ttccccacca ccggccctca ggctggcatc tctgccccca 33780 gctccaggag gggccagaca gaagcagcca ttgggcatct caggtttgag ggggatatgg 33840 gccgggaact acccagaagc atctgggagg cagcagggtg ggggaagagg atgtgtggcc 33900 gggcctcaca gccctgctgc tcccactgac ctctccggcc caactcacgg ctgcaaagag 33960 acttgactaa gcttgacaat cccaaaggcc gggtcccaca cctggccctg cctgccgggt 34020 cctgccccca ccctcacccc catccccctc cctcttgatc tgtctctgtt tccctctttt 34080 cctctgtgtt tctgtctctc tatgggttgt gtttccttgt tt tccactct gacaaatgca 34140 acatgaacgg gaaagaggcg cccagctgcc taggagggca agctgggcaa gccgggcaag 34200 gagaccccgc acccacacct acctcattta agtgttggat tttttgctgt tttgaaatgt 34260 gagaccctct ccaagccccc tactgcccca accctctccc ccacctcact gccctcttct 34320 gagtgggtgg aaggggggta ggagggaggaa gaaaaacaac aacaaaaaat ccatctttgt 3438 0 ttttaattat gggcatggga tggtggttga ggcaaatgat gatgaagatt ggggatgact 34440 ggcccctagt tgctctagga cttccttctc catctggaca tgggggcagg agggagctaa 34500 acctaggacc aggatatctc cctcctgttt tcccaacctc atcatgagcc tgttt gccct 34560 ccagcccctg gacgggttgg gtggggggta gggtgagggc tatccctgag tggcatgccc 34620 atacctagtg aggcagggtg tggcccggag ctcccacttt ccctcagtca ccaaactgct 34680 gctggtctgg tgggaagggg tggtgatgtg ggggtggggg agcttagtgt cagcgcgggg 34740 agggtggggg gtattttct atttatacat gggattgtac atagtcttgt ggggcatggg 34800 ggagcc ggct ggaggtgaga accctcccct ctccccccac cccccgggga gagcaaatgt 34860 aaaactacta atttttgtgc tttatatatt ctatataaat atatctattt tctttttaca 34920 aaaccagttt ataaatggta ggggggtgtg gggcggacac atggagctcc ccttgtgggg 3498 0 gggccccctc cattacccga cctaccgccc ttttcctcac cccccacccc actccccacc 35040 ccctggctgt gactgctgta agatgggggt atagaggctg ggcaattccc accccctgtt 35100 gtatagttgg actatgttat aacgcacaaa agagagctga ccccaggggg agccagaggg 35160 tgatgggttc cttgcctccc tttccttccc ctttctgccc aagcttgtgc tgcagttgaa 35220 cctctt cctg ggggtgggag taggtaaggg gtgggtgagg ccccaaaccc ctctctggta 35280 gggaaccgtg gggatgaaga tgaagcttat atgcagttct cttctagggg ctgtgggcaa 35340 agggcatttt gtaattaata ttttcaagaa tcagatgtct ggagtgtagg ggtgggcttg 35400 gtggtggtgg acgggcgggc ctgctggagg gggagcttgg tcgctgttgt gattttaggt 35460 ttgtttttgt tttgttttga atttgggggg ttgtgg attg ttgggggtag ggagattttt 35520 tttttttaaa gctgcttcct caactgtttc aagctgcaaa tgtttaagag aataacagcc 35580 cccactccca caggaaccgc tgtaattaaa tcagacagta ggaagactgg gctgctgccc 35640 tcaaagccac ag cccttgga tgttcctttt ccgagagcag aaggtctagg ctacagggag 35700 ggggagattg gctcccgtga gtcaggctgt gtttggggct tgggccctgg gattgggaaa 35760 aggggatggg gcagactttg taagcatatg ctaggtatcc gatagtcctg tagaatttag 35820 tgaagaaacc ttatacagtt tttaattttt atataaacta taactcagac ccaagctaca 35880 aggttggaat tttggttggt ttttttttta agtaccctgc ctgtataatt gcatcagaat 3594 0 cccccacccc accccccgcc cccgtgtttg tattttgggt tggtttacac tcgcacatacac 36000 tcagttttca gttttcccct ttacagtctt ctcccctcac ctccaggacc ctcccccttt 36060 ttaaaaaata aatcgctgac aagtgtgaat cccgtgaaga cttt attttg tgttgtgtgt 36120 atcctgtaca gcaaggttgg tccttcgtaa caacggatga aatggttccc ttttttaaag 36180 cgccctctct ccctccaccc tcagcgcccc tgtccttggc atgttttgta tcagcgatca 36240 ttctgaactg tacatattta tgttgcgaga ggcaaagggc aagttttgga ttttgcttct 36300 tccaagtttg tttttaaacg acaaataaaa aaagaacatt ttaaatacaa 36350 <210> 3 <211> 4545 <212> DNA <213> Homo sapiens <400> 3 agattcctac ttcttacgcc ccccacatca cccgcctcga gacctcaagg gtagaggtgg 60 gcacccccgc ctccgcactt ttgctcgggg ctccagattg tagggcaggg cggcgcttct 120 cggaaagcga aagccggcgg ggcggggcgg gtgccgcagg agaaagagga agcgctggca 180 gacaatgcga cccgaccgcg ctgaggctcc aggaccgccc gccatggctg caggaggtcc 240 cggcgcgggg tctgcggccc cggtctcc tc cacatcctcc cttcccctgg ctgctctcaa 300 catgcgagtg cggcgccgcc tgtctctgtt cttgaacgg cggacacagg tggcggccga 360 ctggaccgcg ctggcggagg agatggactt tgagtacttg gagatccggc aactggagac 420 acaagcggac cccactggca ggctgctgga cgcctggcag ggacgccctg gcgcctctgt 480 aggccgactg ctcgagctgc ttaccaagct gggccgcgac gacgtgctgc tggagctggg 540 acccagcatt ggtgaggacg tccccttcct ggcctcgtac ctggggggtg aggaggctga 600 ctttccgcgg cctcagcatc ctgtctccca tggagagacc ccatttcctg cctcgggggc 660 ccgaagaagc ctgcagaggg agaaccatgc gggtcc cgtt ccttcttaat aaccggtcgc 720 ggttattaag aaggactgga gaaaggtccg gataggcgga gatgggaagg aagcagctta 780 ggcagaggct ttcaggtagg gccaggagtc agaatcaggc ttctgtgggg gcatctgggc 840 tgtttcaagt agagcaacag gacaggtggg gcgattgaca gtggactgtc ttagaaacct 900 caagtcctgg ggaaatgcag cccttctttc tactcactgg cacttacata atatacatgc 960 ataggcgttg gatacagccg cccacagaca ggcacacctt gctgagttgg aatcactgca 1020 ccataaccag tgggtctcct gagcctttct ggcatgccca gccccttgct cacatctgcc 1080 ctggatccca gaagaagcag acctaccttg gtaccattct taggatccct aggaaggg ac 1140 agagatacaa acctgacttt gatggccttc cagaaagcca gaacaccact gacatccctt 1200 tgggtcagtt agagccagtg ggagctcaac ttctcagagc cgttgagctt cgcgtggcac 1260 cagtgaactg gggaagccct ctagaacaac ccagccagag gaggtggg ac agcggctgga 1320 tcctgactgt gggtaaagag gtaggcactc ccagggaggc tgctttactc tgtctcttcc 1380 ccacagagga ggattgccaa aagtatatct tgaagcagca gcaggaggag gctgagaagc 1440 ctttacaggt ggccgctgta gacagcagtg tcccacggac agcagagctg gcgggcatca 1500 ccacacttga tgaccccctg ggtaagggtc caatactgtt cccatgggac aggt ggaata 1560 ggacattgtg gtgttaagag catgggtgtt tgaagcagat gggctgtgag accttgggca 1620 agtcacttaa tctttctgag cctcagtttc ctcacctaag aaatggagat aatagtccta 1680 cctctggatt gctgtgagat gctcatgaaa taatgtctgt ctcgtggtta atccaga gct 1740 tagcccctga ggtactcatc tttcctctcc tggaaagggc actttctctg aggagtatca 1800 tcttgggaag ggtgcagggc ccagggttgc ctaggcaggg gactcttggc tggatccctc 1860 ccaagccttc ccatggagct ctgaccacca cccttgtgct ctgcacccag ggcatatgcc 1920 tgagcgtttc gatgccttca tctgctattg ccccagcgac atccagtttg tg caggagat 1980 gatccggcaa ctggaacaga caaactatcg actgaagttg tgtgtgtctg accgcgatgt 2040 cctgcctggc acctgtgtct ggtctattgc tagtgagctc atcgaaaaga ggttggctag 2100 aaggccacgg ggtgggtgcg tggatgcatg aagccctgcc ctggggtcca gatactgggc 2160 atctcctcct agctgtgcac tgtccagcct gggcacagtg ggcccttcct gaagctattc 2220 ccaggggata tgctgaacta agttgccaca ggacctgcag cctgcccact ctcccctagg 2280 tgccgccgga tggtggtggt tgtctctgat gattacctgc agagcaagga atgtgacttc 2340 cagaccaaat ttgcactcag cctctctcca ggtaagctca accctgctct ggcaagagaa 2400 tgagg gaatg tgtaggtggg gcctctggat tgtcagcctt ccctccccaa ggactgtgga 2460 tgcagtacca aagaactgct gaagatctct gcacacctga gcatgtgtgc atgtgtgtgc 2520 ctttttgtgt gagtgaatgt gtgccagggg tacttagatg ggggatggct gttgttaacc 2580 ctggggttga agactgggct tgtccccacca tggggcaagg gcctgatgcc agcatggcac 2640 cccttggctt gcaggtgccc atcagaagcg actgatcccc atcaagtaca aggcaatgaa 2700 gaaagagttc cccagcatcc tgaggttcat cactgtctgc gactacacca acccctgcac 2760 caaatcttgg ttctggactc gccttgccaa ggccttgtcc ctgccctgaa gactgttctg 2820 aggccctggg tgtgtgtgta tctgtctgcc tgtccatgta cttctgccct gcctcctcct 2880 ttcgttgtag gaggaatctg tgctctactt acctctcaat tcctggagat gccaacttca 2940 cagacacgtc tgcagcagct ggacatcaca tttcatgtcc tgcatggaac cagtggctgt 3000 ga gtggcatg tccacttgct ggattatcag ccaggacact atagaacagg accagctgag 3060 actaagaagg accagcagag ccagctcagc tctgagccat tcacacatct tcaccctcag 3120 tttcctcact tgaggagtgg gatggggaga acagagagta gctgtgtttg aatccctgta 3180 ggaaatggtg aagcatagct ctgggtctcc tgggggagac caggcttggc tgcgggagag 3240 ctggctgttg ctggactaca tgct ggccac tgctgtgacc acgacactgc tggggcagct 3300 tcttccacag tgatgcctac tgatgcttca gtgcctctgc acaccgccca ttccacttcc 3360 tccttcccca cagggcaggt ggggaagcag tttggcccag cccaaggaga ccccaccttg 3420 agcctattt cctaatgggt ccacctctca tctgcatctt tcacacctcc cagcttctgc 3480 ccaaccttca gcagtgacaa gtccccaaga gactcgcctg agcagcttgg gctgcttttc 3540 atttccacct gtcaggatgc ctgtggtcat gctctcagct ccacctggca tgagaaggga 3600 tcctggcctc tggcatattc atcaagtatg agttctgggg atgagtcact gtaatgatgt 3660 gagcagggag ccttcctccc tgggccacct gcagaga gct ttcccaccaa ctttgtacct 3720 tgattgcctt acaaagttat ttgtttacaa acagcgacca tataaaagcc tcctgcccca 3780 aagcttgtgg gcacatgggc acatacagac tcacatacag acacacacat atatgtacag 3840 acatgtactc tcacacaacac aggcaccagc atacacacgt ttttctaggt acagctccca 3900 ggaacagcta ggtgggaaag tcccatcact gagggagcct aaccatgtcc ctgaacaaaa 3960 attgggcact catctattcc ttttctcttg tgtccctact cattgaaacc aaactctgga 4020 aaggacccaa tgtaccagta tttatacctc taatgaagca cagagagagg aagagagctg 4080 cttaaactca cacaacaatg aactgcagac acagctgttc tctccctctc tcctt cccag 4140 agcaatttat actttaccct caggctgtcc tctggggaga aggtgccatg gtcttaggtg 4200 tctggtgcccc aggacagacc ctaggaccct aaatccaata gaaaatgcat atctttgctc 4260 cactttcagc caggctggag caaggtacct tttcttagga tcttgggagg gaatggatgc 4320 ccctctctgc atgatcttgt tgaggcattt agctgccatg cacctgtccc cctttaatac 4380 TGGGCATTT AAAGCATTCT CAAGAGGCATG TTTTTACACGC ATTTTACGC ATTTAAATAA 4440 TTTCAAAGAAGAGAAA AGCCGAAA AGCCGATT TGCTCTTTATCT GGAATATC 4500TTTGCATCTG A gtttataat ATTCTACCTT GGAA 4545

Claims (7)

PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88) 유전자의 돌연변이를 확인하는 제제를 포함하는 중추신경계 림프종을 진단하기 위한 마커 검출용 조성물로서
상기 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88)는 생물학적 시료에서 분리된 cfDNA 및 ctDNA 중 어느 하나 이상인 마커 검출용 조성물.
Markers for diagnosing central nervous system lymphoma, including agents for identifying mutations in PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D) and MYD88 (Myeloid differentiation primary response 88) genes As a composition for detection
The PIM1 (Proto-oncogene serine / threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D), and MYD88 (Myeloid differentiation primary response 88) are any one or more of cfDNA and ctDNA isolated from biological samples A composition for detecting markers .
 제1항에 있어서,
상기 돌연변이를 확인하는 제제는 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88) 유전자의 돌연변이 여부를 핵산 수준에서 검출하는 것으로,
상기 제제는 중합효소연쇄반응, 역전사 중합효소연쇄반응, 경쟁적 중합효소연쇄 반응, Nuclease 보호 분석 (RNase, S1 nuclease assay), in situ 교잡법, 핵산 마이크로어레이 또는 노던블랏 중 어느 하나에서 사용되는 것인 중추신경계 림프종을 진단하기 위한 마커 검출용 조성물.
According to claim 1,
The agent for confirming the mutation is to detect mutations in PIM1 (Proto-oncogene serine / threonine-protein kinase), KMT2D (Histone-lysine N-methyltransferase 2D) and MYD88 (Myeloid differentiation primary response 88) genes at the nucleic acid level ,
The agent is used in any one of polymerase chain reaction, reverse transcription polymerase chain reaction, competitive polymerase chain reaction, nuclease protection assay (RNase, S1 nuclease assay), in situ hybridization, nucleic acid microarray or northern blot A composition for detecting a marker for diagnosing central nervous system lymphoma.
 삭제delete 제1항 또는 제2항에 따른 조성물을 포함하는 중추신경계 림프종 진단용 키트.
A kit for diagnosing central nervous system lymphoma comprising the composition according to claim 1 or 2.
 진단 대상에서 분리된 cfDNA 및 ctDNA 중 어느 하나 이상인 생물학적 시료로부터 제1항 내지 제2항 중 어느 한 항에 따른 마커 검출용 조성물을 통해 PIM1 (Proto-oncogene serine/threonine-protein kinase), KMT2D(Histone-lysine N-methyltransferase 2D) 및 MYD88(Myeloid differentiation primary response 88) 유전자의 돌연변이 여부를 확인하는 단계를 포함하는 중추신경계 림프종 진단을 위한 정보를 제공하는 방법.
PIM1 (Proto-oncogene serine / threonine-protein kinase), KMT2D (Histone -lysine N-methyltransferase 2D) and myeloid differentiation primary response 88 (MYD88) gene mutations A method for providing information for diagnosis of central nervous system lymphoma, including the step of checking.
 삭제delete 제5항에 있어서,
상기 돌연변이를 확인하는 방법은 중합효소연쇄반응, 역전사 중합효소연쇄반응, 경쟁적 중합효소연쇄 반응, Nuclease 보호 분석 (RNase, S1 nuclease assay), in situ 교잡법, 핵산 마이크로어레이 또는 노던블랏 중 어느 하나인 방법.According to claim 5,
The method for confirming the mutation is any one of polymerase chain reaction, reverse transcription polymerase chain reaction, competitive polymerase chain reaction, Nuclease protection assay (RNase, S1 nuclease assay), in situ hybridization, nucleic acid microarray or Northern blot method.
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