bộ y tế trờng đại học y hà nội chơng trình 33 Báo cáo Tổng kết đề tài nhánh Nghiên cứu phát thay đổi gen nạn nhân bị phơi nhiễm dioxin hệ (F1, F2) nạn nhân bị phơi nhiễm Chủ nhiệm đề tài nhánh: TS Nông Văn Hải Cơ quan chủ trì: Viện Công nghệ Sinh học Thuộc đề tài cấp nhà nớc (CT 33): Nghiên cứu biến đổi mặt di truyền, miễn dịch, sinh hoá, huyết học tồn lu dioxin đối tợng phơi nhiễm có nguy cao Chủ nhiệm đề tài: PGS TS Nguyễn Văn Tờng Cơ quan chủ quản: Bộ Y tế Cơ quan chủ trì: Trờng Đại học Y Hà Nội Hà nội 2003 5462-5 13/10/2005 y tế trờng đại học y hà nội chơng trình 33 Báo cáo Tổng kết đề tài nhánh đề tài cấp nhà nớc Đề tài nhánh: Nghiên cứu phát thay đổi gen nạn nhân bị phơi nhiễm dioxin hệ (F1, F2) nạn nhân bị phơi nhiễm Chủ nhiệm đề tài nhánh: TS Nông Văn Hải Cơ quan chủ trì: Viện Công nghệ Sinh học Thời gian thực hiện: 2001 2003 Kinh phí đợc cấp: 275.500.000 Hà nội 2003 Danh sách ngời thực đề tài Nhánh Chủ nhiệm đề tài nhánh: TS Nông Văn Hải Th ký đề tài nhánh: TS Lê Thị Thu Hiền Những ngời thực chính: TS Phan Văn Chi TS Quyền Đình Thi PGS TS Nguyễn Thị Ngọc Dao TS Nguyễn Thị Bích Nhi TS Lê Thị Thu Hiền ThS Nguyễn Huy Hoàng CN Nguyễn Đăng Tôn CN Nguyễn Hải Hà CN Cao Xuân Hiếu 10 CN Nguyễn Thuỳ Dơng 11 CN Phạm Thu Thuỷ 12 CN Nguyễn Đình Cờng 13 CN Đỗ Quỳnh Hoa 14 CN Nguyễn Nam Long 15 CN Lê Thị Thu Giang 16 CN Nguyễn Thị Thảo Lời cảm ơn: Đề tài nhánh chân thành cảm ơn giúp đỡ tạo điều kiện Lãnh đạo Chơng trình 33, Trung tâm Khoa học Tự nhiên Công nghệ Quốc gia, Viện Công nghệ Sinh học, Trờng Đại học Y Hà Nội, Học viện Quân y đặc biệt PGS TS Nguyễn Văn Tờng, GS TSKH Phan Thị Phi Phi, GS TS Trịnh Văn Bảo, GS TS Lê Bách Quang, GS TS Nguyễn Văn Nguyên cán Trờng Đại học Y Hà Nội, Học viện Quân y suốt trình thực nghiên cứu Mục lục Trang I Đặt Vắn đề II Tổng quan tài liệu III Đối tợng phơng pháp nghiên cứu IV Kết thảo luận V Bàn luận VI Kết luận VII Những hiệu nghiên cứu VIII Tàiliệu tham khảo IX Phụ lục Các phần báo cáo gồm: I Đặt vấn đề Trong thời kỳ chiến tranh Việt Nam, từ năm 1961 đến năm 1972, Mỹ sử dụng chất độc da cam (CĐDC) làm thuốc trụi (defoliant), có chứa dioxin với nồng độ trung bình 2mg/kg (Kramarova et al., 1998) Tính tổng số chất CĐDC, Mỹ sử dụng nớc ta lợng lớn dioxin (ớc tính: 170-500 kg) Theo công bố nhà khoa học trờng đại học Columbia (Mỹ), số lợng chất độc hoá học Mỹ sử dụng chiến tranh Việt Nam cao nhiều, lợng dioxin cao từ đến lần so với công bố trớc (Stellman et al., 2003) Nếu lấy số g dioxin sử dụng trực tiếp tiêu diệt toàn nhân loại trái đất số khủng khiếp Ô nhiễm dioxin chiến tranh hoá học Mỹ để lại gây hậu nghiêm trọng môi trờng sống, hệ sinh thái ngời Đặc biệt nghiêm trọng hàng triệu ngời dân nớc ta chịu hậu nặng nề dioxin Các hệ ngời Việt Nam phải chịu hậu khôn lờng huỷ hoại sức khoẻ, bệnh di truyền, ung th nhiều bệnh hiểm nghèo khác ảnh hởng trực tiếp hay gián tiếp dioxin Rất nhiều năm sau chiến tranh, nghiên cứu nhà khoa học Việt Nam Mỹ cho thấy nồng độ dioxin thể ngời Việt Nam sống vùng sinh thái bị nhiễm chất độc hoá học nặng nh sân bay Biên Hoà, cao (Schecter et al., 2000; Schecter et al., 2001) Các nghiên cứu nh nhiều nghiên cứu khác (Wiesmuller & Schlatterer, 1999) củng cố thêm giả thuyết cho dioxin vào thể ngời theo chuỗi thức ăn, chủ yếu cá Các nghiên cứu dịch tễ học bệnh học lâm sàng nạn nhân CĐDC đợc sở quan Bộ Y tế (Trờng Đại học Y Hà Nội, Bệnh viện), Uỷ ban 10/80 trớc Bộ Quốc phòng (Học viện Quân y) tiến hành từ 20 năm trở lại thu đợc kết quan trọng (Hoàng Đình Cầu, 2000; Phan Thị Phi Phi CS, 2000) Đồng thời, gần ảnh hởng dioxin ngời mức độ phân tử DNA bớc đầu đợc quan tâm nghiên cứu nớc ta DNA số đối tợng bị nhiễm độc đợc tách chiết phân tích sơ kỹ thuật PCR (Lê Đình Lơng CS; Phan Thị Phi Phi CS; Nguyễn Văn Nguyên, Lê Bách Quang CS; Nguyễn Thị Ngọc Dao CS; Phan Văn Chi CS; Nông Văn Hải CS; tài liệu báo cáo đề tài cha công bố) Mặc dù vậy, cha có nghiên cứu sâu thay đổi cấu trúc chức gen ngời, đặc biệt việc phân tích trình tự gen phả hệ nạn nhân bị nhiễm dioxin, sở có kết luận xác đáng ảnh hởng dioxin ngời mức độ gen Từ tháng năm 2001, đề tài nhánh (đề mục) Nghiên cứu phát thay đổi gen nạn nhân bị nhiễm dioxin hệ (F1, F2) nạn nhân bị phơi nhiễm Viện Công nghệ Sinh học chủ trì, thuộc đề tài PGS TS Nguyễn Văn Tờng (Trờng ĐH Y Hà Nội) làm Chủ nhiệm Nghiên cứu biến đổi mặt di truyền, miễn dịch, sinh hoá, huyết học tồn lu dioxin đối tợng bị phơi nhiễm thuộc Chơng trình 33, cấp Nhà nớc, đợc phê duyệt thức đợc tiến hành Mục tiêu nghiên cứu Đề tài nhánh đặt mục tiêu: ứng dụng kỹ thuật phân tử để phát thay đổi gen nói chung, nh thay đổi cấu trúc chức số gen chọn lọc nạn nhân bị nhiễm dioxin hệ cháu họ Đa kết luận xác đáng hiểm hoạ dioxin ngời nh có kiến nghị cần thiết biện pháp khắc phục hậu lâu dài Nội dung nghiên cứu (đã đăng ký) Thu thập mẫu (máu toàn phần) phả hệ (3-10 phả hệ, phả hệ 510 cá thể) cựu chiến binh ngời dân bị ảnh hởng trực tiếp dioxin (CĐDC) có biểu bệnh lý lâm sàng đặc trng thành viên gia đình họ (bố, mẹ, anh, chị, em ruột, con, cháu, ) có ngời bị ung th máu, dị tật bẩm sinh, bị bệnh đặc trng có liên quan đến dioxin ngời khoẻ mạnh bình thờng (đối chứng) Tiến hành tách chiết, tinh chế xử lý bảo quản lâu dài DNA sản phẩm gen từ mẫu máu Phân lập, xác định so sánh trình tự nucleotit đoạn gen Cyp1A1 P53 (exon 2-4, exon 5-7, exon 8-9) từ mẫu So sánh khác trình tự gen mẫu, qua hệ Nghiên cứu tìm yếu tố gây cảm ứng gen Cyp1A1 Xử lý số liệu phơng pháp phần mềm vi tính cho phân tích gen Tổng kết, báo cáo khoa học, công bố kết ảnh hởng dioxin lên hệ gen số gen chọn lọc II Tổng quan tài liệu II Cơ chế tác động dioxin mức độ phân tử Dioxin tên gọi tắt 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), chất siêu độc, thờng lẫn tạp thành phần thuốc bảo vệ thực vật, nh sinh chất thải công nghiệp, trình xử lý (đốt) rác thải, khói thuốc Xét độc tính, dioxin đứng sau chất thải phóng xạ Thời gian bán huỷ dioxin thể ngời năm rỡi, chí lâu Tác động dioxin gây hậu nghiêm trọng môi trờng sinh thái đặc biệt sức khoẻ ngời Những hậu ngời động vật dioxin gây bao gồm: bệnh ung th, suy giảm miễn dịch, rối loạn chức thần kinh, quái thai, dị tật bẩm sinh nhiều bệnh tật khác Những năm gần đây, với phát triển mạnh mẽ Sinh học phân tử Công nghệ gen, ngời ta làm sáng tỏ đợc nhiều vấn đề chế phân tử tác động tức thời (trực tiếp) nh hậu lâu dài (gián tiếp) dioxin cấu trúc chức gen sản phẩm chúng (protein/enzym) Có thể phân biệt tác động theo nhóm: A Sự rối loạn chức gen Theo số liệu nghiên cứu từ nhiều năm nhà khoa học giới, dioxin tác động trực tiếp lên tế bào chủ yếu thông qua chất (protein) thụ cảm (thụ thể) có tên aryl hydrocarbon receptor (AhR) Ngoài ra, tồn chế tác động khác (không qua AhR) Tuy nhiên, chế tác động thông qua AhR đợc nghiên cứu kỹ đợc khoa học thừa nhận Các nghiên cứu cho thấy tiếp xúc với dioxin, tế bào xảy biểu tăng cờng gen mã hoá AhR kèm theo rối loạn biểu (thay đổi trình phiên mã - transcription) hàng loạt gen tham gia vào trình điều khiển sinh trởng tế bào (cell growth control), nh gen tham gia vào chu trình phân bào (cell cycle), nh: TGF, cyclin A, c-myc Thông qua AhR, dioxin hoạt hoá biểu gen, nh: cytochrome P4501A1 (Cyp1A1), plasminogen activator inhibitor-2 (PAI-2) Trong đó, lại làm suy giảm (ức chế) biểu gen mã hoá yếu tố sinh trởng chuyển hoá TGF-beta2 (transforming growth factor -beta2) Kết trình phân bào bị rối loạn gây nên hậu đa dạng Dioxin làm thay đổi (ức chế, giảm biểu hiện) gen mã hoá glucose transporter- (GLUT-4, protein vận chuyển đờng glucose) Đặc biệt nguy hiểm, dioxin tác động lên gen tế bào sinh sản Nó bám vào chất thụ cảm hormone (hormone receptor) tế bào, làm thay đổi chức chế di truyền tế bào, gây hàng loạt hậu quả, nh: dioxin làm thay đổi biểu gen mã hoá 17-20 lyase Kết lợng hormone tế bào trứng nh progesterone (P) estradiol (E2) bị giảm dẫn đến hậu nghiêm trọng Dioxin tác động lên phát triển tinh hoàn (gây teo) Có chứng cho thấy, gen mã hoá Src kinase đóng vài trò định trình Liên quan đến tác động dioxin, gen đợc phát mã hoá cho protein có tên 25-Dx (thuộc siêu họ protein: cytokine/yếu tố sinh trởng/chất thụ cảm prolactin) gắn với progesterone (P), chất thụ cảm hormone Tác động dioxin lên gen định phụ thuộc vào giới tính: chẳng hạn dioxin làm tăng hoạt tính tyrosine kinase (TK) đực, lại làm giảm hoạt tính Dioxin liên quan đến phát sinh phát triển nhiều bệnh ung th, thông qua thay đổi gen quan trọng nh p53, p27Kip1, p21/waf1, cdc2 p34 kinase cdk4 Hiện nay, ngời ta thừa nhận: dioxin chất gây ung th! B Tác động đột biến (độc gen - genotoxicity) Mặc dù ngời ta cho cha có chứng đột biến gen ngời, nghiên cứu chuột thực nghiệm xử lý dioxin cho thấy, xâm nhập vào tế bào, dioxin chuyển hoá, tơng tác với protein-enzym gen khác, gây nên thay đổi DNA, dẫn đến đột biến chí tử vong sau 34 ngày đặc biệt, thí nghiệm chuột cho thấy dioxin gây ôxy hoá bazơ nitơ thành phần nucleic acid, chuyển đổi Guanosine thành 8Hydroxydeoxyguanosine trình sửa chữa phân tử sau không thành công dẫn đến sai lệch vị trí bazơ gen (Shertzer et al., 1998) Tình trạng bị ôxy thái (oxidative stress) (Shertzer et al., 1998; Hong et al , 1998; Slezak et al., 2000; Hassoun et al., 2001) chế quan trọng gây thay đổi gen (biến dị di truyền lại cho hệ cái) cần phải đợc tập trung nghiên cứu nạn nhân bị nhiễm CĐDC Giả thuyết chế phá huỷ DNA dioxin thông qua việc tạo gốc tự do, ảnh hởng trình sửa chữa DNA bị hỏng lên chu trình phân bào, phát sinh ung th đột biến gen đợc trình bày Hình DIOXIN SOD - O2 H2O2 Fe2+ Phá huỷ màng tế bào, protein, DNA OH- Hình 1: Tác động dioxin lên DNA thông qua việc tạo gốc tự DNA bị hỏng Ngừng chu trình G2 phân bào M G S Hoàn chỉnh Sửa chữa DNA Đột biến Không hoàn chỉnh Sai hình NST Chết tế bào Ung th bệnh di truyền Hình 2: Các ảnh hởng thay đổi DNA tế bào gtcaccaggg tagaaagtgc tagctaataa aaaggcccaa aggccagggc ccaaaggtag tggtgcactg cagttcacaa ggcaggaggt atgcctttgc ggcagaagtg ccttagccca caaaggggac gagtcatacc gctggggcag cctggagtct caacagatag ttgtctccca ctgagcatct ggatacaggg atgacagtat cctctttcac gatggtgggc ccacatcaat agctgaccca ccttctgttg tgggttcaag accacaccca caagttggcc cctgggatta ttggaaaaga aagctgccag agcagatctg atccagttat tatcaccatc gcctcattct aggtgggttt ctggcagagc aggttgaaca gtacctaaat cgtgatggtg tgttgatcag tgggagcaga caagggaaag gagctgtggc tacatgttcc aacctaactg ctaggacagt agtgctctac agcttgcttg aatatatggg gacttttaag cctcctttac actttctcag ggtttgcagt tcctgcctca ttttgtattt gacctcaggt ccacgcccag taatccccaa tcataaatgg gagatccgat gcacccgctt gctgcatcca caattaccca ctgactcata atactgtata ctggaagacc gttgctttgc aaccaattcg gtacgcatgg ccgtctcacc acagactcag gggttacaag taacaggaag tagaggacct gtgagaagct ctggggaggg gcaaaatcat tggaagacaa ctagacaagt gaggggtgtt aaggagcata tagtgggagg atgtgtcctc tcccttcctc ctcagatggg tttcccagga tctcaaaaga atgggtgggt tgtcctttcg ccccaggcca ctcgccagag caattcttct gctaattttt aggctggtct taggcgtgag gaggttctcc tagtcatttt ggagatgagg tcctgaagtc acctccccct cttcctcctc gggggactta tctctgagtg gagtcctaag ggccaccatc tcaagttgtt ttgagtctgc gctcaccacc gaggagaaaa cttcagtaga aacctcgctc gaagccagga gggcagagaa cccagggcct catttatctt gtacaagtgc gtacccaaaa cagaaaactc tatgccttct ggcatgatct gcctcccgag ttagtagaga gatccaccct actctcatat tgttggaggt tttagcacca tatttaaaag tgccttctgg tgctggtact gtctcaggta gtttctatcc ttttgcgtat aactagtgct ttgcattatc tctctcactt caaatcaaag ataacttatc cccctgggcc agatgttgca ggggcccaca tggcctggag ctttggctag gaaagggctc cagcctaggg gcaagatcca cctgtgatga aaagggatgc ggaagggcat tcggggtgag tccccaccca tcctgcctgt gcagctcttg cagtctaagc tcctggctta tttgggggcc ggatcacctc agccaatgag tgcagtggtg gactcagcct tttttttttt tgaactcctg ccaccacacc ttctgtcaga ttaaggaagc ggaggaagcg aatgaagttc tctcttcctg ttccctctcc caactgcaag actaaagcct aggttacttc cgaaccactg ggctggacag gccgtgtcac atggaggctg cggaacccag gggtcacagc cattcgtgct tgcaaagagt gggtggaaag ttgcacttgc ttcccccttc aattttgtta gcattgtaca ttctttccca cctatagttt cagctcactg tagctgggat cgggatttca cctcggcctc agtttggatg gggggctggt tccccttggt tatgtggcac gatgattgta gcctccagaa ttccttacct ttctctctac ttatgttgca agggctccca taagaggctc cttaggtgga cagagcctag atcccagact agggcccctc cttctcatca ctgagcactg ctgaacactc gattccctag tgggctggag ctttcagtga cagcaaaccc gtctggagat tccccggaga tcctagcatg gcagtttggg gtcatcccct gcccagagag gctccctggc ctgttgtcat gatgataata cagcatctgt acccctactc aaccctatgg cgatcttggc cccaggtagc tttgtatttt acctcaggtg tggcccccta ggtggctaca cggccttaga ggggggaaat acccatagaa tctccctctt tcctcctcct aacacaaacc ggtacttgca tatctagcag tgggaggcaa ttcctgtgag tgtgcagttc gaggctcctt agagggttgc tagtgctcaa ctctgtcctg ccatgaatgc tgagtctgga tcctcccttc cccaattttt catgcataga attacccatt aaatcctcat tgtttttgtt caacctctgc tacaggtgcc ccatgttggc ccaaagtgct tttgtctcct gggaggtgat gctaagtgag ctccccctac aggttcctga ccatgagcca tccttggcca ttaattttat gataggctat 104 accagggacc ttgactcctc gagatgggtg aactccagct atgagtgaag acctctccac ccaagccgta ggcagagaag attcctgggt tgatcaatac agatcgagac gccctgctga ctgccccatg gctgcaggag gtggagaact gggaagagac tggatgtgga tctcctactg ccagatagat tcttggctgc ggaagaattg agttatatag tctcccttct tcagcccata gagtttccca tcactgcaaa tgggattaca tagtagagac atcccccctg tgggagtttt ctggctagaa atgataccta tgaagacatt ggtccctgtt tttccttctt cttctttctt tgccagccag ggccccaaga cttcccactg attgtatctc agaagccatg ctcctgcact ggctccaagc tatggaaagg agacccgcag ctggtgactt agcctgcata gagacaagtg accagcaaac atttgtttat ttgcaaagtg aagtaatttc gtcttacttc tttttgagac ctcctgggtt caccaccatg cagccttgtc gggattacag ccaaatctca tgggtcatgg ttctcaccct ccttgttcct ggcccgcacc attacacctc tcccacctaa agcacttaga atccctcaac cttctcttga aaaaactcat ccagaaaaga tcttgcttct ccccaggggg acccctggac tcttggctaa gagggagtca caaagtttgc caggagcagg agctgagagg aggctgtggg gtagagatgg ctgtgaggag agagaaggcc acaatgtgaa gaactgggac agatctgagc tgagtttgca tatagttagg ttaaaagtgc tcaccccagt tttggcaata gggttactgt acaccccctg ctccacctcc ggcgcctgct ggggtttcac ccttggcctc gatgaaatca agtaagtctg ctcaaggaaa aagcctctag aaaaaaccaa cttcacccct ttctagtatg gaaggcttac agacctaccc gtctgcttct cagaagaccc tgcgtgacat cccagcagtc aaatagccaa ctatagacag agaaacagcc ccatgaatgg agttagccct gaaagcatct ttttttttaa ttttcataca gtcaggccag tcatcatcca ctcaaatatc agtctcaccg caagcaattc ctcagctaat tcgaactcct gtgtgagtca cgttgaaatg ggtcggatcc aagttcatgt gctttctctt ggaagcagat ttttctttat aactgttacc gactccaaac taaaatgtaa 15840 15900 15960 16020 16080 16140 16200 16260 16320 16380 16440 16500 16560 16620 16680 16740 16800 16860 16920 16980 17040 17100 17160 17220 17280 17340 17400 17460 17520 17580 17640 17700 17760 17820 17880 17940 18000 18060 18120 18180 18240 18300 18360 18420 18480 18540 18600 18660 18720 18780 18840 18900 18960 19020 19080 19140 19200 19260 19320 19380 19440 19500 19560 19620 19680 19740 19800 gctccaacag acatagcaga aagtgggaaa gtaggcaggg ttttaatgcc cactcctgcc gcttcactct atcctcagac ggcttctctc tgctctcagc aagatccagc tggactgacc tctgccttta ctaattcttc tgaaataagc ggaacactct taatgaacat agtgctccta aacataatcc gattagataa ggaagagaga tgttttggtg ctctgtcact caggttcaag accacacccg aggctggtct ggattacagg agaacagact ccactggggt aactgctcca ttagcactca gctttagggg cagtcattgt attctggcca actcttcaaa tcaaaaccaa ggaagcattg tttttttttt gtctcaaact ataggcatga acaggctgaa aaaggaaaca ctacccatct gaaaaagtct ctcaaaagaa cagagaaatg tccaaaagac actgttgaaa aactaaaaat aaggaaatca aaaagttaag atagtgcata gcagtggctc tcaggagata aatattagcc gaagaatggc tccagcctgg tcctgtcatt aggcacgggg ttgaactcat gggagggagt agtatttgat taaagacata ccgcgtgggt ggcagacaag atgagactta acctcccact agcaggcact tgctaaatag atacacgaga caccaagtcc tgctagatgg ttaagaagtt atccaagacc tttcccaacc tacacacccc aggattggga ctccgggatg ctagatggag ataacatcaa tcaggttagc cttgcagggg gtttccaagt tcatgtcctc gaagtgttcc caaaattcat ggtcatcaag cctgagctga ttttggcttg caggctggag tgattctctt gctaattttt ggaactcctg tgtgagccac gagacataca gtccagccag tcacttgtag ccgctcttgt aagctgaccc tgccctggct atgatatggg gagacacatg aatggattaa ggaaaactct tttttttttt tctgggctca gccaccttgc gcaaaaatgg atcaacaaag gacatgggat aataatctgg gaaatacaaa caaatcaaaa aggcaatgac atgtaaatca agagctacca gtatgtcaaa atttggaagc tacacaatgg acgccagtaa gagaccatcc gggcatggtg gtgaacccgg gcgacagagc tgcagcaaca agacaaactt ggagatagga agggatgatt ggcacaacaa gccgagactg ggggaggcct agaagacagc ttcactatca gggtccctcc ttgatctctt atagttgtta tttgaagtgg aagacagtca gcgttaatca catcttggtc aacatctggg tcctccaatt agatacacca caaaaatcct ctgcccagag ggcagtggag atatgattaa agtttattat aatgtttgag tagtaatgtc aatcaaagca gccctggtta atgttgatta gtggtactcc caccacactc ttttgtttgt tgcaatggtg gcctcagcct gcatttattc atctcaagta cacgcctgac tgctcccatg tgagggccac acacccaata tttgtctagg cagccccagc gtcttgctgg aaaaaatctg agaatgaaac aggcttcaat ccaggactgg tttttgtaga agctatcctc ctggcccgga acaaatgaga tgaagagaca taataactgg cttttaaatt tggcaagcaa ctacaatgag aaatgctgga gtgtaaacac tacgatccag gagatatttg aacctaagtg agtgctattc tcccagcact tggctaacac gcgggcacct gaggcggagc gagactccgt cggatggaac cacatgttct gaatgatggt aatgggtaca gatggctaca ggcaatttac cacaatcatg ttgtgcaggg cgagaacagc cacagcatgt gtgatcaatg aataattgaa cagaggcctt gctgaatgga ttttgctccc tggcctagct ctgggtctca ttaaagtctc cagtaatcag ccatgttttg aaagctgggg atgaaaggag tttaggtcca tgcacaaatg ctactgaagg tctttacata gagcctctgg gaatgtgcgc aaggtagtga catgatgaga ttgccctctt ttgtttgttt tgatctcggc cccaaatagc agtagagacg atccacctac ctagtcagtg gtctttgcca tcagccaact gcccttcctc aaccctccat ctcacagagt tgatttaatt ctgggacaac tagacccctg ctaagaccac acaaaaattc ggcacagtct ctgcctaggt caaagatgtc tctcatcaag atccacagaa aatatataag taatctggca gtatatgaaa atatcctctc gaggatgtgg tacaaagaac caatcccact cactcccatg tccaccaaca agctgtaaaa ttggaaggcg ggtgaaaccc gtagtcccag ttgcagtgag ctcaaaaaaa tggaggtcat cacttatttg tactagaggc aaatatagtt gtcaatgtat aaaagaaaga gcagaagatg aaattcccct acaggaaaca gggaattcaa 105 cttcacgaat tttaagcgtg gtgtgagagt tcccctcagc aggagatagg tagcatcctg ctgccaacca caggttcctc gggagatcag gtgggtgggg agcaggtggc atcttctttt tattatagat tttcccaagc gcatgttcgg taaacactga ggacacttct cccaattttc gggctttggg ctggaggctt accatgtaat gtttttgaga tcactacaac tgggattaca gggatttcac ctcaacctcc gtatcctgtt aggaggtagc tacgaatcct ccaatcttga cttcctttct gggtcttggc aaacatagat ttttaggaga tctctcacca aaactatgaa ctcttttctt caactatgct ctcacaaagt ttgagtgata ttaaaaggct tgggagaaaa gagctcaaac aaagatctga aggtgcttaa accagttaag aggaaagggg agtttggagg gttacgtata ttgactgcgg gatgaatagg agaatgagat taggagggcg cgtctctact ctactcagga ccgagaccac aaaaaaaaaa tatgttgagt agagctgaaa tgggaagggt agaaagaatg tagtccgttt ggtttaatgg aaaggcacat ttttaaaacc cctgccccca gatgagattt agcatctagc gcaggccccc ctggttcctg tcagatgctt tgatcaggta ccttgtgcca catggccatg ccaacaggat gctctgcagc aagggctatg ccagagcttc tcctttctct gagaatttga caatgaatta catgatcaga tgtttgttga ctatcagcca atgtgttgga aagtaattaa tataagaaga gccccctctg ttgagcctca caccacctcc ggcatgcacc catattggcc caaagtgctg atagcaaccg ctattcagat tttccaactc tttttcctcc agaactatgt tgatctgaac ctgtgacatg agctttcttc tatacataaa attactaaaa tttttctttc acccaggctg gctggaaatc tcttacaagt tctgcacagc tatttgcaaa aactcaacag atagacattt catcattgat atggcttttg accttcgtac ttcctcaata cacccaaaga cattgttcac taaagaaaat ccggccgggc gatcatgagg aaaaatacag ggctgaggca accactgcac accaatgaga caaataagcc attaaaacag agtgggagca aataagatct tcactgttga acttacagtt ctcacatggt accagatctc tgattcaatt aagtggggac 19860 19920 19980 20040 20100 20160 20220 20280 20340 20400 20460 20520 20580 20640 20700 20760 20820 20880 20940 21000 21060 21120 21180 21240 21300 21360 21420 21480 21540 21600 21660 21720 21780 21840 21900 21960 22020 22080 22140 22200 22260 22320 22380 22440 22500 22560 22620 22680 22740 22800 22860 22920 22980 23040 23100 23160 23220 23280 23340 23400 23460 23520 23580 23640 23700 23760 23820 acagccaaac agatgtctgt gatgtggtta tacacctact cgcctgtaat caagaccagc aggagtggtg ttgaacccag gtgacagtga acgcctgtaa aagaccatcc cgggcatggt catgaaccca ggcgacagag attaaataat actctagtct catcttgtga aaaaatgcag aactggatta gagaaactaa accttgggcc ctgcctagca ctcctacccg gggcggggag agtgatctag tgtttgcctg tttcctccta cactatgcag atgatcccag ctagcctggg atggtggtgt cccgggaggt agagcaagac tcacaagctg agagagacat ggtaccaagt atcataatat gtgtttgttg acatcatgtg gaaaattgtg acatgttgag tttgattaga cgtggagtgt cttaaattta gaccaagatg aaactccatc ttcccagcta cagtgagcca aaaaacaaaa atggttcgtg aatgcattat ttcctaaagt gtttttctga agccatggat gcatataatc ttgtagtatc catgcctgta tttaagacca cgggcatggt cttgaacccg ggaaacaaga atattattta ccatccatct gatacgaggg agaaaggcag acggatgctg gactcagaca catattagtc aacacaaagg ttacacattg atgtacccac cccagcactt ctggccaaca gcatgcacct gaggcagagg gacttcatct tcccagcact tggctaacac ggcaggcatc ggaggcagag tgagactcca tgcaaggtgt ctctggcctt ccacaaggga aaagatcctg ttagaagaat cccaggatag tgaaggagca ggtgtcttca cccatcttat cccatggaca aggacaaagg catattggcg gaacagcgga caggcactgt caatttggga caacatgatg gtgcctgtgg cgaggctgca tctccaaaaa gagagggaga gcccaaggaa gttgaaggac tgcagtatga aatggggaag tgcatgcaga tgaggaggaa ctgaggagtt gatctgacat gtggattgga aaattaggcc ggcttgttgc tctacaaaaa tttgggaggc aggctgtgcc cgaaaaaact ttaaccatgt tccttgcaat tcttggcagg ataggtgttc accaaaatct tttgcatagt taatacaaca atcccagcac gcctgagcaa ggcgcatgcc ggaggcggag gcaagactcc gggaataatg tttttccgaa ccaactgtgt aagctgcctt ctaaggaggg gtgtggtgac aatgaaaatt aaggataaat tatgcctgta aaaaattaaa tgggaggccc tagtgaaacc gtaatcccag ttacagtgag tcaaaaaata ttgggaggct agtgaaaccc tgtagtccca cttgcagtga tctcaaaaat ggggagtttt tgtcaggtgt gccagcgtgg catttttcag tcaataaggg tgtagtacca aggggcagga cagacagggt gccagtgcct atatgcagag attttcagca gtctcctccc tggctgcaca actagaaatc ggcttaggca agaccctgga tcccagctat gtgagccatg aaaaaaatca gtaaaaccaa ggaggctctg ttgttttaat gtaagtatct aagtggttgg aagacagaaa gggatgggaa caagctttgt gctcagattt aggatgaggg aggcgcagtg ttgagcccaa aatacaaaaa tgagatggga actgtactcc agtattcacc agcacagagc ttccataaaa tgagcattct ctcagtaact atggatgcca atttgcatat taagtgctat tttgggacac catggagaaa tgtaatccca gttgcagtga atctcaaaaa gcaagaaaag tattttccat ggctgcatgc gaccttcaag cagtatggag agctgagcag tattgtacat gtttgagatg tcaaaatatt aattaaaatt aggtggggtt ttgtctctac ctacttggga ccaagatcgt ataataataa gaggcgggca tgtctctact gctacttggg gccgagatcg aataataata tctgaaaggg ggatgatgtg ggggaagctg gatcctggta ggctatttac atggactagt acccagagag ctggagggga tccattggct gtcatcctcc ctacccgggc tgaaggcagg acttacgctc aaatgaagcc ggaggattgc tctacaagaa gcaagagact atggtgccac aatgaataaa agcaatatgg accagagtag ggagaggtga ctaacccaaa aaggaaggtt actagagaaa atgaggtgag tctgaatgcc gcaacttcag agcaggaagc gctcacacct gagttcgaga attagctgga gaatcacctg agcctgagca tcacagggtg ttggggcata ccaatgcagg tacttgtgaa gtggggaatt aagtccctga aatctatact atacagagtt caaggcagga ccccatcttt gctactaggg gccaagactg aaaaaaaaaa taagtttgta ctgtggttgg cagcccctgc gagctcaaag gctgtgggaa ggtataaaat 106 tattaaataa atggatacct taatgtgccc aggctggaca atcacttgag taaaaagaca agctgagaca actactgcac taggctgggt gatcacgagg aaaaatacaa aggctgaggc cgccactgca ataataataa ggataagtgg atggccagag cattcaaaga ataaacagag aaaagtgcag aacggagggg acactataag acaaccccaa gaacccaaca cagaacacag ctgcaattat aactgcctta aaagaatatg gggtgtggtg ttgagcccag ttttttaaaa gaaggggagg tatacgccag acatagcgtg catcttggtg ggcctggagg ggatgctttg agcaatgcat gggtgttcca ttgtccccac agaagagtag tgaagaaatt agacttcact cttagagctt gtaatcccaa ccagcctggg tgtggtggca agcccatgag acagagtgag gctataaagc gtaggtgctc aaatgccccc cactaattga ggttccagga tatacaatgg ttaaatcatc gttggccggg agatcacctg actaaaaata agactgaggt tgccattgca aaagatttgt catgttcagt ttgaatccat gttggagact tccagagggg cttaactgcg gatgagccaa ctgaaagaat catttaaccc cataaacata cggtggctca gtcaggaggt aaagttaacc tgagagtcac tccagcctgg gctattgctc tcaggagatc aaaaattagc aggagaatgg ctccagcctg aataaattaa caagagatac ctaccgcagc ttagcagtgc gatccactca gcagagcata agccctcacc gagaggagag actcattctt agaagccagt agactcgcag ctttttcatc ctgctgtaag gttgagcacc gctcacgact gagtttaaga ttagccaggc attgcttgag cctgggcaac cctcagttgt tcataccagg aggtgggcct tcattaatgc ttccttgagg aacagaggga tggctggtgg gaactggctc gataagggat tgagtggcag tgtgtggcta cactttggaa caacatggtg tgcatctgta gtcaaggttg accctttttt taaaacaggg aataaatctt aagcagagtc ttcaataaat cctccccact cataaaattt tccagattac cgcagtggct aggtcgggag caaaattagc aggagaattg ctccagcctt tagttatact accgatgcaa ggaacctaca agagatagga caacggtgtt ggggagctga agtggccggg 23880 23940 24000 24060 24120 24180 24240 24300 24360 24420 24480 24540 24600 24660 24720 24780 24840 24900 24960 25020 25080 25140 25200 25260 25320 25380 25440 25500 25560 25620 25680 25740 25800 25860 25920 25980 26040 26100 26160 26220 26280 26340 26400 26460 26520 26580 26640 26700 26760 26820 26880 26940 27000 27060 27120 27180 27240 27300 27360 27420 27480 27540 27600 27660 27720 27780 27840 gaatgcaggg ggtgggggca gaagcctttg agcactttta aaaatatcca gctgaagtag aactctgtcc ccagctactc tgagcagaga gaaagagaga gaaagaaaga gagggaagga gaaggaagga ctcatacaca gtttgtttgt ggagtgcagt ttcttgtgtg aatttttgta cctgagctca ccattgcacc tcctatgaac atgctcctgg aggacagatc ctctactaaa gcttaggcaa tcgcactcca tcctgacagc ttgaatgaat gaatgaacta aacagaaacc tggttaaaat caggctggtc gggttacagg ttatttcacc gcatcttaat tggctcacac aggagtttga attagccgag gaatcgcttg agcctgggca acgagtcttg ctccacctct aggcatgcgc catgttggcc caaagtgctg aacaacaaca accactgcaa ttacctccct aatctattag ctcatttatg gtacccttga agctggttat ctatacatga tgtcacccag attcaagcaa acgcccagct gctggtcttg tagaattaca ctgtaattta tcatacagga aatcccccac ggaaaggtgg ggtgatcaag atgtgacgag gcgttccatg tccaaccagt gtcacagcca tggggagaag agggtgacat ggtgtaagca aaagggaagt gtggtggcca gtggatcatc ctcctaaaga ggaaggctga ttgtgccact gagagagaga aagaaagaaa gggaaggaag agaaagaaag ccgggtgggg ttgtttgttt ggcactatct tcaacctctc tttttagtag agcgatctgc cagccaggaa tagcaattcc atgggcacgg acctgagttg aatacaaaat gagaatcgct gcctgggcaa agggctcatc gaataaggtg taactatgcc agaaaccaga ggtaaattaa ttgaactcct tgtgagccac acaaccaaaa ttaaactatg ctgtaatctc gaccaacctg catggtggtg aatctgggag acagaacaaa ctctatggcg ggggttcaaa caccatggtc aggctggtcc agattacaga acaaccagaa gatgttaata catcatactt ctttttraaa taaaatacaa gaaaggaaca atgtgtgttt catatgcact gctggagtgc ttgtcatgcc aatttttttt aactcctggc ggtgtgagtc atttttttaa gaatttcaaa tccttcggtg gaaaggagta gtcaacatcc aatggcaccn agaagaaaaa actcctgaaa agaggaatcc gtttcaagca ggggggcaac aaagagttgg agtcaacata ggcgtggtgg tgaggtcagg tacaaaaatt ggcaggagaa gcactccagc gaaagaaaga gaaggaaaga gaaggaagga aaaatatcca gtataaactg gtttgtttgt cggctcactg gagtagctgg agacaacgtt ctgccttggc agttgtttgg agcctgagca tggctcacgc ggagtttgag tagctgggca tgaaccggga caagagctaa ttagcccaac ttgggtattc caacatcatg cacaagatta aatttttttt gggcttaagc catgcctggc aagtgtaggt gtcgtcggtt aacactttgg gccaacacag tgtgcctgta gaagaggttg actttgtctc caggctggag ggattctcct ggctaatttt agaactcctg tgtgagcctc tgtatcaata ataggggaaa tccactcaat ttccttggct caagcaaaac caacgggact gttaagtttg tttccattta agtggtgcga ccagcttccc tgtattttta ctcactcaag accggtccca gttttaagaa tagtttatgg tgggctgtgc actttacagt acatctgtaa taacctccaa catcaggcac attgtcaagg aaagagacgt aagggatcag agagccagag ttttatcctg cctccagagt ctcatgccta agttcaagac agctgggcat tcatttgaac ctgggtgaca aagaaagaaa aagaaagaaa aggaaggaag gtggtggtga gttcaactgc gagacagggt caacctcctc gactacaggt ttgccatgtt ctcccaaagt tagaatatat gcaaacatgc cggtaatccc accagcctga tggtagcctg aggcagatgt actctgtctc agaggaagca atattataat aatgagtctc tataccgccc aaaatagaga gatcctccca cctatagtgt gggggaccat aataataatg gaggccgagg tgaaaccccg atcctagcta cagtgagctg tctttatttt tgcagtggcg gcctcagcct tttgtatttt acctcaagtg cacaccaggc ttcatccacg ctgcagagtg ttttctgtga cccctccaaa aaatccatgc tcttggatgc caaaaattca tttatttatt tcttggctca gagtagctgg gtagagatga tgatcctccc gctgacatat aacattaaaa agataatccc atagtgactt gaagagacct gtcacattga ggtcttccca attccaakrg tcatcaaaaa gatgactaaa 107 ctttggagaa agtgaacaga aaatctctgg ggctcaaatg taatcccagc cagcctggcc ggtggtgggt ttgggaggcg gagcgagact gaaagaaaga gagggaggga gaaggaagga ggatgagaag ttaggaaagt ctcactctgt cgcctcccga gcacaccacc tgcctggctg gctgggatta tactgctgga attcaaaagc agcactttgg ccaacatgga taatctcagc ggtgagccga aaaagaaaaa accgaagtat ggaataccgt ataaaaaaag actgaaatgt tggggtctca cctcagcctc taaatgttat agaactgtac tatcacgagg tgggcagatc tctatactaa ctcaggaggc agattgtacc attttattat cgatcttggc ccctgagtag tagtagagat atccgcccac ctgagactct aattgtaaca ggggtggtaa accaaagact aagtgtacat aatagatgtt ttatgatgtc tcaagctaca tttgagacag ccgcaacctc aattacaggt ggtttcacta acctcggcct gcacttttct atawaaagat ccctcaagga ccttccaaaa gacacgcact taggatgtaa ccaacaaacc tscgagcatc caaggatatc tgtcatgtga agacagtaaa aactgctgct ggaatattga aaaaagatca actttgggag aacatggtga gcctgtaatc gaggctgcag ccatcagaaa aagaaagaaa gggaggaagg aggaaggaag cagctggagc tggagttttt cacccaggtt attcaaacga acacccagct gtctcaaact caggtgtgaa cattcaccta aggttcgaga gaggccaagg gaaaccccat tactcaggag gatcacgcca aaaaagatgc caatcaacag gcagcaatga aatgttaagt atacttaaaa ctatgttgcc ccaagtgcta gttatgtata aacacaaagt ctgggcgtgg acctgaggtc aaatacaaaa tgaggcacca accgcacttc tttttttgag tcactgcaac ctgggactac ggggttttat atcagcctcc gtctcaaaac aatatattac atggccactt gctctaaaaa atgacatgat ggggtcatgg tcttgattag catgatcgag aatcttgctc cgcctctcgg gtgcaccatc tgttggccag cccaaagtgc atattgtatc aaatagtctg gaaggagcgt ggtacagtat accttagcca ccctgatatg ataaccccag ctacaaaatg ctgagaaact tatccaatgg 27900 27960 28020 28080 28140 28200 28260 28320 28380 28440 28500 28560 28620 28680 28740 28800 28860 28920 28980 29040 29100 29160 29220 29280 29340 29400 29460 29520 29580 29640 29700 29760 29820 29880 29940 30000 30060 30120 30180 30240 30300 30360 30420 30480 30540 30600 30660 30720 30780 30840 30900 30960 31020 31080 31140 31200 31260 31320 31380 31440 31500 31560 31620 31680 31740 31800 31860 gtcctggaac tttagttaat cgagcctaac gacaggaaac ttggattccc ttcaggaata cacagtggct ggcccagaag gtttaaaaat actcaggagg atgattgtgg aaaaaaaaag cttagatctg atatcctcac ttgatagata ggggtacatg gagtatccat tttaaaggtg agtggagtgg ctgcctcagc ttgtattttt tctcaggtga gcgcctggcc catgacactt atgacactct agtccgtgct tttgtttaaa gttatgtctc catctcttct atttactgtt ggggccgtga cagtgggaaa actcttcaga agggacccag gtggagctga tccagctttc taaaaaggcc tcaagcacct aactatagaa ggtcctgagt gcagtttgga gggcagccct actcatccct atcacaggct gaactcctgg tctttggtac gcttccccat tgatgtgtgg tcagattctg cttagtcttt atgactgagg ttttccctgc cttctcctgg cgggtcccca gtgctgaccc gacgtcctgc atccggcagg tccaccctca gctgcccgcc gcttcctcat agcaggttgc gtgtcagtgg gatgagatgc aaccccctgg aaggccttca gactttgaca cagcccctcc aggaaaagga tagagagaca ctcaaacctt aactttcctc catccatctg aaagcccact cacacctgta ttcaagacca aaaaaaatta ctgaggcaag cacatgaacc atagcaaact actgagatct gtaagtccat ggtatacatt aaatgttttg cccctcaagc tacatttttt cacgatcttg ctcccgagta agtagagacg tccgcccatc tagaggtgta ccatgctaca gttcacacct tacatgtccc tgccatatcc ttagtctttt tttccacttg tggttttgca gcctggttgg gaagcccaga gaaataggct caccccttct gggataatgg atatcaggtg actcacctag gcctctacag cctggaagct tccgggcttt ctaagccatt ggccctggct ggaggaggtg atttgaacca tcccttgggt aatacccagc tttggagtgg aggagagagc tgatgctcaa ctggtatcca aaatgaatga agttggtaca cctctgccat aaggcctgaa tggggaagaa agatccgcat ccctggtgcg tcactgatgg ggcgcctggc cctcctgcta aggagctgat ccaacgtcat tcagcctcgt acttcttccc accagaggtt aggtgagccc ctcccagctc cattaggtaa gacagacaga gacctttttc ttctcccatt ccttggcatc ccagtctaaa atcccagcag acctgggcaa gccaggcatg aggattgttt ccaacctggg tccttttcac gggtccatat gaatatctga gttttaattt atacaggcat aaggataaac ttttttttga gctcactgca gctgggatca gagtttcacc tcggcctctc cattttttaa gcattaatct aaaaaaattt caattgtccc aatcgatatg tgcataaggg gggacttggg ggttgttgga cctagactga tcagtccaaa ccctaccctg ggcctatccc cccaaggcca atcaggacaa agccagaagc gtacctttct agtggggaca gctacccagc tttaaggaga gaagcccaac cccctcctgg gccctgggac atatggaagg atgcatgctg tcacttgcct cagcgttcat agggtgagct gctgggagcc atgaatgtct gatggcattg cttctgcctg aagtccacca cccgcacctg tggctccacg gcagggcgac ccagagcttg ccagaatgcc cctggaggag ggcagggcct tggtgccatg gaagaacact catccttcgc cctgtggttc ggggtgcagg cagcatgccc aacgcaagga gagaaagaaa attgagtcat catggccttc ttcacaggtt tcaaaacttc tttgggaggc catggcaaga gtgcacacac gagctcagga tgacagagca atccaattta taaagactcc catttctcat tatgggtaca gcaatatgaa ctttgagtta gacggagtct gcctccacct caggcacatg aggttggcca aaagtgctgg cagaaccatt cctaagaata acatttattc caaaacatct gcaatcaaat gggcctctct ctgaaaatca gggtactaca gtgccctggc ggcctaaccc aaccctaaag caaagagtca agagttgatc ccaggccaat tccacaccag tgggaccaat gaaagacggg tcttgacttc gcgatgggga cccaacctcc tattgataaa cttggccacc tatcagcaga tgccaggggc ctactccagc gttgggaatc ctgtgggcac aagcacagaa ccatctcaac tcccagtctg gtattctggg gagccatggg gcactgtcaa cccgtgctgg gatttcaagg accttcagca ctcaacacct catgtgagca gggcacttcg tgcttcggac catgagttcg tacctgccta ctgcagaaaa tggcaagggg acacagctgc 108 aatctaagta gagtccattt ctgaacccaa aaacatgctc gatcccacag cctctcacat caaggcagaa cctcctctct ctgtgattgt ggtcgaggct agactctgta aggcttgtcc tttagtacaa atctactttc tagtaggtgt ataagcattc caaacaatcc cactctgtcg cccaagttca ccaccatgcc ggctggtctt gattacaggt caaaaggagg aggatacact cagaatatca tttatagatt gcaaatccat ttaggatgca ggagtggctg gaagaacatc agagctcttc ccactcccag acagctgtac ccctgggtct cttccaactt ctgatagggg ccattacaac ttacaatctc gagcctgggc tgtttcccga gggcttcccc aagactgtga gaatgccctg tcagtgtcac aagccagcac tgacaagggt cccagaagtg ttgaggctcc aggacgcatg cacgcatcag cctcagcctg ttcccttctc tgctcaaggg gctggccctt ggatgagcca tgctgagccg gccggcctga cagactctgg tctccatcgc aggaggctaa acccttacaa agcacttccc tggagactgc accctgccct cagtccagga caccttgcag tgtgttgcca aaccatgaac tctataaaac tggagatata tgtttctcta ttttctcatt ccatgccggg ggattgcttg acaaaaaaat ggtcccagct gcagtgagcc tctaaaaaaa tcctcctcct caaacaccat tctcgattta atatatgtat atggagaatg aattacactc cccaggctgg agccattctc tggctaattt gaacacctga gcgagccatc ttgtggggat cccacatacc tctaatctcc tttttaaaat attgcatttg aaatctttat gaacacgccc cctctggaga ctcatgtgtg accctaccct cttcatcccc taggtagtag tgttcagtga gcggtgttta cctgccaatc tgggatcccc taggtgtagg ttttaaatga cttagcacaa gaggatgggg gggagggggc tgggtagggg tggcagggac gctgtccttg gaaactgaga tttccagctc gtagatggag tgtttatcaa gtccctcctt ggccacagag tttgaggcct gctcgggcat gcgctacggg cctggacacc cctctacacc accggtgtgg ctctgaccca ggccctgatc tcaggtggtg tgagagtagc ctcctccggg gcagaggttc gcactatcag ggcctgggtg aggcctagga 31920 31980 32040 32100 32160 32220 32280 32340 32400 32460 32520 32580 32640 32700 32760 32820 32880 32940 33000 33060 33120 33180 33240 33300 33360 33420 33480 33540 33600 33660 33720 33780 33840 33900 33960 34020 34080 34140 34200 34260 34320 34380 34440 34500 34560 34620 34680 34740 34800 34860 34920 34980 35040 35100 35160 35220 35280 35340 35400 35460 35520 35580 35640 35700 35760 35820 35880 aggctctgga cctcagtttc agccctggaa ctttcattct tgcttccctg ggaggaaggg ctcctgctgc cagccaccag cagaggtgcc gttcaagcac tgtcaacctt caacaatgcc ccaaccctac tgggctatgc cagtttcccc ccagcagcta ttcaggaaac acttgggaaa ggttcaggat aagcctgaga tagccaggag cctgctgtgt ggttagtggg agaggggata ctacagacac cctacttgga tcccccacag tctcttcctg cacagatccc caggagaaag cccagtgccc tccaatcttg ccagaatcct tttgactcat gcccttgatc acccaaacgt aattccccgg tagaaaatag gtgcgcagcc gcaaggaaga gggatggaga cccagctttc acaacgctga gtcaaccatg aggaaggctg gctatagtct atcaactagg gaggcaggca cctatctcta ccagctactc tgagccgaga aaaaaaaaaa tgtggtatct tttggaaagc actgggacat acaataaaca atgaagaaac cttcctatgt cctcccaaag taatttcttt aggctggtca ctcatgcctg agtctgagac tagccggata gagctgggga gtgataggag catcaaagtt cacctcagac ctcatccttg atggggccct gcagaaacct tgttcacact tcaatggggc aagctgcaac gtacaggcca cctaagcttg agcaagaagg gtcaatgaca tgctgttcac accagatggt caccaattcc atctgaacaa attctgaaac tcacaggcta tgatggtttc ttgacacagt tacagaggaa aagccttgaa gcaagccctg gtcgcagact attcatgggg tgtgattggc ggccttcatc gtgaggcctg gcttctcagc ggcctcagtc ttccacttgt tctgtgccag ctaacgctga acccttgctc ccagctggca atgccctgga tgttctagtt ggctgcccca aaaaacattt aggcgcaaag gggaggatgt tggcggtggg cagccctgag atggcttcta acccgtgagt tttgtccctg gctctaagtg atggccaggc gatcacttga ctaaaaatac cagaggctga tcgctccact aaaatcaacc aaggtggggt cccactttag ttgagtgtga taagccagga gtatgtcttt ggtccaggct tgctagggtt tagataaagc ttttagagag taaccccagc cagtgaaacc tggtgcctgt ggcagagaga ccggagggtg cagtttggtt cagctgtgtg aagccccctt agcagagtcc aaaccccaac aaccttttcc ataaaatgac cccctgccta ggggagtgga tgccccctca ggcctagagc tctttggagc ccacagcctt acaacatact cagtggagaa taaggtgttc ctgtatctca gggccagaga cttgtttctg caccacagcc gatccagaag acccaggttg ggcacacagt tgtgaataga cagttagggc agggagcggc ctggagacct ccggttctgc cctggccctg tgcccccatc gatctcagcg tcaggtcggc accttctgcc aaagtcaatg cagcttcatt attttaacaa attcctgcag ggctgcctgc atctgaaatt agaagtttag ttctacctct caggctgtct cctcacagtg catccccaag acatacccct ctaggaactg acgatattta gcagtggctc ggtcaggagt aaaacaaaaa ggcaggagaa gcactccagc aagacgtttg acctcaggcg tgtataggta aaatgctatc catactgttg ctttcttcct ggttttgaac acgggtgtaa attatttaaa agctttgtaa actttgggag ccgtctctgc agtcccagct gtgcagtgag tctcaaaaaa ccttcccacc acctggagcc ctcagggctc tgcaatgtgg agaggctaat ttctttgaaa actttaagcc gagaccaagt gcaacgttca gaacagtgtc cagcggcaac aggtaggaac gcccagcccc gagatctggc acagcaaagt tctggcctgt agtttatgtt aagctaatgc tcttccttct atctcctgga gagctgggta tttgttcagt agtgcctgcc cagtcttaca agcccctgag ggccccggct tccgacactc cctcccacct gctcagcatc cagtccaaac ctcattcccc ctcaccctca tggaatacct ccgacacgag cctgatgtct tgtcaagaga taagaggcct tgcttttttt gcctgcttct taaatacttg tccctgttcc ggatggggtg ccctcttccc aaatgctgtg cacgaaaaaa tttatataat caaaagtttc aagcctataa ttgagaccag ttagccggac ttgcttgaac ctgggtgacg ttacaggtga attctgatgt gggggaccat aatgtttatg aggcccctta ttcactttaa tcctgggttc gccaccaaac gtaaattaat aagaaataag tccgaggaag aaaaaaaaaa acacgggagg ctgagatcgc aaaaaaagaa tacccttcat 109 gactcttccc ctcaaagccc ggggcctatg ccccagctct ttggacccct atacccaggg tgggaggata gcctttgacc cgggacatca ctcatcccac cagaaccttg tcagtccatg ttgggatcag ccttctcctc aagtctaggc gaagagaccc tggatacata ttcctcacct gcctcatgta catgggggcc ctacaaacac cttgcctaga taagagtgac ctctgcttgt ctctgacaga ctccttcttg ctaaagtgct tccttcccga ataatctaac tctgttcata caagcatgac tctagcctct cttcctctcc tataggactt gttagtgagc gaatccccag tttttttttt tggctccaga ctgaagttaa tcccctcccc gaggtaggag tcctcagcac tcttcgtaaa tgtgtgcagg gaaaggaggg acaaacttta tcccagcagt cctgggcaac atggtggtgc tctggaggta gagtgagact tggttccccc gaatggctca atatataatt ctagtcatca ggaggcatat tttttaaata aagggatctt ccagcctgtt attaaaaggc catcaggcca gtggatcgct aaaaaaaaaa ctcaggtggg accactgtac agaaaagaaa tgctttcaaa cttctctggg ccaagaaaaa agtgagaaag ggtgtcacgt ggtgttattg ctgctaccag ggggggtacc ttggaagtgc cgggtgccct aggagaagat cccctccatc aaataaccca ggtttgagcc ccctaggctt ccctataatt agcctctgtc catagcagat tacactacac ccttgtgacc cccaacccta ctgttatgtg agatgtggga atggggtata cctctgtgtt ccccagctgc cccttcacca tgccatgttt cctcgttccc ccccagctct ttccctccct cctattggcc tctctgacca ccagaagcct acagccatca atttacttct ccaggctaga ttttttttca gaacagccaa agaacaggac tcccagtgta caacacatgc aacaagggac ccagtggcag ttcagcagtc gacctcaatt gtgcacagga ttgggaggcc atggtgaaac gcctataatc gaggctgcag ctgcctcaaa aggattctac gagacctctc taccatccac ttactccaaa tttgagtagg gagacaaggt cctgcctcag tttcttcttt actatcttta ggtgtggtga tgagctcatg atacaaaaat tggttggctt tccagcctgg aagaaataag gtgccctcac 35940 36000 36060 36120 36180 36240 36300 36360 36420 36480 36540 36600 36660 36720 36780 36840 36900 36960 37020 37080 37140 37200 37260 37320 37380 37440 37500 37560 37620 37680 37740 37800 37860 37920 37980 38040 38100 38160 38220 38280 38340 38400 38460 38520 38580 38640 38700 38760 38820 38880 38940 39000 39060 39120 39180 39240 39300 39360 39420 39480 39540 39600 39660 39720 39780 39840 39900 acttgtgttc cctgaggtcc ccggcctgag gatgatgctg gatcttcctc gaaagtcgac ccaggcgcgg gcgagtgggg aatagcagct gaggatcatt ctacaaaaaa aaaacaaaca atataattct ctcagtctgt ctcgcaggtt agtcactacg caggcttgtc gggattacag cttctagtgt gagacagagt aacctccgcc ataggcatgc tgtgttggcc aagtgctggg gagacagagt caacctctgc tacaggcaca catgttggct ctcaaagtgc cattttcatc tagcctgcct gatttgcctt ctggcttctt taagctcttg ataggcacct aattgaaggg ggggatccct tttcttcatt aaggcccagg ctcacgcctg agtttgagac agctgaatgt gctgtaatcc gggttgcagt tgtctcaaaa aaaacatata cgatgcctca gtcaggagtt aaaattagcc ggaaaatcgc tgcagtggca accttgggac tggggtttta tcaacagaag catctcctct cggttcctca tttggcatgg ttcctggcca ctgaccccca ctgcgcttct gccagccacg ttagccaagt tgagcccagg aaaatttgcc aacaaaaaaa tatgccatat cacccaggtt caagcaatcc cctggctgat tcgaactcct gtgtgagcca agaattgtgc cttactctgt tcccatgttc gccaccatgg aggatggtct attaacaggt cttcctctgt ctcccaggtt caccaccacg agactagtct tggcattaca acccctaaaa cccctgcctc ctctaaacat tcacttagca gtgcttgagt ccttcactcc aacaaggaga cctgtcccat cacagcccgg tctcatcaaa taatcccagc cagcctggac agtggctagc cagctactca gagctgagac aaaaaaaaaa gctgttgaag cccctgtaat tgagaccagc aggcatggtg ttgaacccag ccatcttggc aacatatgca ccatgttgcc tctccctccc gttcctcttg ccgccgatgg gcaagcgccg tcctgctaca tctacgggct ccatcaattg gggactcagc gcagggcctg aattggaaag aagagcctga aaaccatata aattcacctt ggagtgcagt tcccacttca ttttgtagtt gaccccaagt ccacatccag aaccatcacc tgccaggctg aagcgattct ccagctaatt ccatctcttg atgaaccacc ctcctaagct caagtgcttc cctggctaat caaactcctg ggtgtgagcc gaaaccctgc accagccctg ttcatataaa caatgttttc cctgagactg tctcctctcc aagggatcca tctcaaaagg gaggggataa ggacactatc actttggaac aacatagtga ctcagctgct ggaggctgag cctgctgttg aattgaaaag catttatata tccagcactt ctggccaaca gcgggcaact ggacagagtt ttactgcagc ggccaccatg caaactggtc ccaggcacct cagagagctg cactgccatt gtgtatcggg gcaactggag gaccatgaag aagaagacac ccttgtttct taatcccagc cagcctggcc gtgacagagc tatacatata cttttttttt ggcgtgatct gcctcccaag ttagtggaga tatccacctg cctaacttac agaattaatt gagtgcagtg cctgcctcag tttgtatttt acctcgtgat gcgcccagcc ggagtgcagt tccagcctca ttttgtattt acctcaagtg acggtgcccg acccattagc gcaactgcta tggaattaca aaggcttatg ggtctaggtc tttcatgttg gtctcagggg cagaacacgt gcttcccaga aagaaattga gccaaggcag aacctcatct caggagactg gcatgagaat cactccagcc acaacccaca tagaatatat cgggaggcca tggtgaaatc gtaatcccag tgcagtctca ctcaacctcc cctggctgat tcgaactcct cctcccaggg tgggaggacc aacaagccct gaagtcctgg ttcagcgtgc cacgcccgct caccattctg cttcctttct attttaggag aacatagtgg aagaccccat tatatagcag ttttttgtct cagctcactg cacctgggat tggggtttca ccttggcttc attcttaaag ttattattct gcgcgatctc cctcccgagt tagtagagac ccacccgcct tttttgtttt ggcatcatct gcctcccaag ttagtagaga atctgcccgc gcccacaatt agtccctcca atctactttc caatgagtgg tgtgttgtgg tgtgctctct tttgacccaa ccaaacccag gacttctcac agtgcttagg aaggaggcca gcggatcact ctactaaata taatctcagc cacttgaact tgggctacag gaatgagaga aaagaactcc aggcaggtgg ctgtctctac ctactcagga ctctgtcgcc caggctcaat ttttctaatt gatc cctctccagc cctctgagtt tgagtgagaa ccaagtggga cgccgggcgt gtgaacatgt aggccaggga ttttttaaaa gccaaggttg gaccctgtct ctcaaaaaaa ctttatggag gagacagaat caacctccac tacaagcatg ccatgttggc ccaaagtcct tgtcgaatga tattattttt agctcactac agctgggact gaggtttcac cagcctccca tttttttttt cagctcactg tagctgagac cgggtttcac ctcgacctct aattttagaa catttccccc tgtgtctatg tcttttgtga tgtgcgtcag taagtcgttg gttttttaac ttgggtggat aaggccttga ttatttgaaa agcacagagg tgaggtcagg tacaaaaact tgatcaggag caggaggcag agtgagactc aaatatttgc tggccgggca atcatctgag taaaaataca ggctgaggct caggctggag cgatcctccc tttgtagaga 39960 40020 40080 40140 40200 40260 40320 40380 40440 40500 40560 40620 40680 40740 40800 40860 40920 40980 41040 41100 41160 41220 41280 41340 41400 41460 41520 41580 41640 41700 41760 41820 41880 41940 42000 42060 42120 42180 42240 42300 42360 42420 42480 42540 42600 42660 42720 42780 42840 42900 42960 43020 43064 // Một số điểm đa hình đột biến gen CYP1A1 Key Kim loại Đa hình Đa hình Begin 457 279 461 End 457 279 461 Length 1 Đa hình 462 462 Description Sắt (HEME AXIAL LIGAND) R -> W /FTId=VAR_9280 T -> N (in allele CYP1A1*4; dbSNP:1799814) /FTId=VAR_8342) I -> V 110 Đa hình Đa hình Đa hình 26 235 381 26 235 381 1 (in allele CYP1A1*2B and allele CYP1A1*2C; dbSNP:1048943)/FTId=VAR_1243 I -> M D -> E F -> L 111 Trình tự gen (cDNA) mã hoá >AhR-mRNA LOCUS DEFINITION ACCESSION VERSION KEYWORDS SOURCE ORGANISM REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE Aryl hydrocarbon receptor (AHR) NM_1621 5496 bp mRNA linear PRI 03-APR-23 Homo sapiens aryl hydrocarbon receptor (AHR), mRNA NM_1621 NM_1621.2 GI:5016091 Homo sapiens (human) Homo sapiens Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Primates; Catarrhini; Hominidae; Homo (bases to 5496) Schultz,R., Suominen,J., Varre,T., Hakovirta,H., Parvinen,M., Toppari,J and Pelto-Huikko,M Expression of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator messenger ribonucleic acids and proteins in rat and human testis Endocrinology 144 (3), 767-776 (23) 22474035 12586752 GeneRIF: experiments revealed a complex distribution of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator mRNAs and proteins in rat and human testis (bases to 5496) Hayashibara,T., Yamada,Y., Mori,N., Harasawa,H., Sugahara,K., Miyanishi,T., Kamihira,S and Tomonaga,M Possible involvement of aryl hydrocarbon receptor (AhR) in adult T-cell leukemia (ATL) leukemogenesis: constitutive activation of AhR in ATL Biochem Biophys Res Commun (1), 128-134 (23) 22368090 12480531 GeneRIF: Possible involvement of aryl hydrocarbon receptor (AhR) in adult T-cell leukemia (ATL) leukemogenesis: constitutive activation of AhR in ATL (bases to 5496) Harper,P.A., Wong,J.Y., Lam,M.S and Okey,A.B Polymorphisms in the human AH receptor Chem Biol Interact 141 (1-2), 161-187 (22) 22201993 12213390 GeneRIF: Polymorphisms that regulate the phenotype of AHR-mediated responses, especially differences among ethnic groups (bases to 5496) Zhao,D., Pritts,E.A., Chao,V.A., Savouret,J.F and Taylor,R.N Dioxin stimulates RANTES expression in an in-vitro model of endometriosis Mol Hum Reprod (9), 849-854 (22) 22189036 122463 GeneRIF: functional AhR are present in endometrial and endometriotic stromal cells and that TCDD up-regulates the expression of RANTES, providing a possible mechanistic link between dioxin exposure and chemokine expression in endometriosis (bases to 5496) Berg,P and Pongratz,I Two parallel pathways mediate cytoplasmic localization of the dioxin (aryl hydrocarbon) receptor J Biol Chem 277 (35), 32310-32319 (22) 22191291 12065584 GeneRIF: Two parallel pathways mediate cytoplasmic localization (bases to 5496) Rushing,S.R and Denison,M.S The silencing mediator of retinoic acid and thyroid hormone receptors can interact with the aryl hydrocarbon (Ah) receptor but fails to repress Ah receptor-dependent gene expression 112 JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE Arch Biochem Biophys 403 (2), 189-201 (22) 22135251 12139968 GeneRIF: The silencing mediator of retinoic acid and thyroid hormone receptors can interact with the aryl hydrocarbon (Ah) receptor but fails to repress Ah receptor-dependent gene expression (bases to 5496) Beischlag,T.V., Wang,S., Rose,D.W., Torchia,J., Reisz-Porszasz,S., Muhammad,K., Nelson,W.E., Probst,M.R., Rosenfeld,M.G and Hankinson,O Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex Mol Cell Biol 22 (12), 4319-4333 (22) 22022026 12024042 GeneRIF: SRC-1, NCoA-2, and p/CIP are capable of independently enhancing TCDD-dependent induction of a luciferase reporter gene by the AHR/ARNT dimer (bases to 5496) Wang,S and Hankinson,O Functional involvement of the Brahma/SWI2-related gene protein in cytochrome P4501A1 transcription mediated by the aryl hydrocarbon receptor complex J Biol Chem 277 (14), 11821-11827 (22) 21922818 11805098 GeneRIF: Functional involvement of the Brahma/SWI2-related gene protein in cytochrome P4501A1 transcription mediated by the aryl hydrocarbon receptor complex (bases to 5496) Karchner,S.I., Franks,D.G., Powell,W.H and Hahn,M.E Regulatory interactions among three members of the vertebrate aryl hydrocarbon receptor family: AHR repressor, AHR1, and AHR2 J Biol Chem 277 (9), 6949-6959 (22) 21850650 117422 GeneRIF: Phylogenetic analysis shows that AHRR, AHR1, and AHR2 are distinct genes, members of an AHR gene family; these three vertebrate AHR-like genes descended from a single invertebrate AHR 10 (bases to 5496) Fujita,H., Kosaki,R., Yoshihashi,H., Ogata,T., Tomita,M., Hasegawa,T., Takahashi,T., Matsuo,N and Kosaki,K Characterization of the aryl hydrocarbon receptor repressor gene and association of its Pro185Ala polymorphism with micropenis Teratology 65 (1), 10-18 (22) 21824525 11835227 GeneRIF: Arg554Lys was investigated and no association with micropenis was found 11 (bases to 5496) Khorram,O., Garthwaite,M and Golos,T Uterine and ovarian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA expression in benign and malignant gynaecological conditions Mol Hum Reprod (1), 75-80 (22) 216358 11756572 GeneRIF: The female reproductive tract expresses AHR and ARNT mRNA, and changes in expression at target sites in conditions such as endometriosis and uterine leiomyomas suggest a potential role for these factors in the pathogenesis of these conditions 12 (bases to 5496) Wong,J.M., Okey,A.B and Harper,P.A Human aryl hydrocarbon receptor polymorphisms that result in loss of CYP1A1 induction 113 JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REMARK REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REFERENCE AUTHORS TITLE JOURNAL MEDLINE PUBMED REFERENCE AUTHORS Biochem Biophys Res Commun 288 (4), 990-996 (21) 21547797 116897 GeneRIF: polymorphisms that result in loss of CYP1A1 induction 13 (bases to 5496) Komura,K., Hayashi,S., Makino,I., Poellinger,L and Tanaka,H Aryl hydrocarbon receptor/dioxin receptor in human monocytes and macrophages Mol Cell Biochem 226 (1-2), 107-118 (21) 21618346 11768231 GeneRIF: Aryl hydrocarbon receptor/dioxin receptor in human monocytes and macrophages 14 (bases to 5496) Hahn,M.E The aryl hydrocarbon receptor: a comparative perspective Comp Biochem Physiol C, Pharmacol Toxicol Endocrinol 121 (1-3), 23-53 (1998) 99138396 9972449 15 (bases to 5496) Micka,J., Milatovich,A., Menon,A., Grabowski,G.A., Puga,A and Nebert,D.W Human Ah receptor (AHR) gene: localization to 7p15 and suggestive correlation of polymorphism with CYP1A1 inducibility Pharmacogenetics (2), 95-101 (1997) 97313745 9170146 16 (bases to 5496) Le Beau,M.M., Carver,L.A., Espinosa,R III, Schmidt,J.V and Bradfield,C.A Chromosomal localization of the human AHR locus encoding the structural gene for the Ah receptor to 7p21 >p15 Cytogenet Cell Genet 66 (3), 172-176 (1994) 94170697 8125016 17 (bases to 5496) Ema,M., Matsushita,N., Sogawa,K., Ariyama,T., Inazawa,J., Nemoto,T., Ota,M., Oshimura,M and Fujii-Kuriyama,Y Human arylhydrocarbon receptor: functional expression and chromosomal assignment to 7p21 J Biochem 116 (4), 845-851 (1994) 95189785 7883760 18 (bases to 5496) Eguchi,H., Hayashi,S., Watanabe,J., Gotoh,O and Kawajiri,K Molecular cloning of the human AH receptor gene promoter Biochem Biophys Res Commun 203 (1), 615-622 (1994) 94354867 8074712 19 (bases to 5496) Hayashi,S., Watanabe,J., Nakachi,K., Eguchi,H., Gotoh,O and Kawajiri,K Interindividual difference in expression of human Ah receptor and related P450 genes Carcinogenesis 15 (5), 801-806 (1994) 94258765 7515333 20 (bases to 5496) Dolwick,K.M., Schmidt,J.V., Carver,L.A., Swanson,H.I and Bradfield,C.A Cloning and expression of a human Ah receptor cDNA Mol Pharmacol 44 (5), 911-917 (1993) 94067047 8246913 21 (bases to 5496) Itoh,S and Kamataki,T 114 TITLE JOURNAL MEDLINE PUBMED REFERENCE AUTHORS JOURNAL COMMENT Human Ah receptor cDNA: analysis for highly conserved sequences Nucleic Acids Res 21 (15), 3578 (1993) 93347997 8393992 22 (bases to 5496) Hayashi,S Unpublished REVIEWED REFSEQ: This record has been curated by NCBI staff The reference sequence was derived from L19872.1 and D31708.1 On Jun 8, 1999 this sequence version replaced gi:45022 Summary: Aryl hydrocarbon receptor is a ligand-activated transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons AHR has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450 AHR ligands included a variety of aromatic hydrocarbons COMPLETENESS: full length FEATURES Location/Qualifiers source 5496 /organism="Homo sapiens" /mol_type="mRNA" /db_xref="taxon:9606" /chromosome="7" /map="7p15" gene 5496 /gene="AHR" /db_xref="LocusID:196" /db_xref="MIM:6253" misc_feature 29 /gene="AHR" /standard_name="alternative 5' end" /evidence=experimental CDS 644 3190 /gene="AHR" /codon_start=1 /product="aryl hydrocarbon receptor" /protein_id="NP_1612.1" /db_xref="GI:45023" /db_xref="LocusID:196" /db_xref="MIM:6253" /translation="MNSSSANITYASRKRRKPVQKTVKPIPAEGIKSNPSKRHRDRLN TELDRLASLLPFPQDVINKLDKLSVLRLSVSYLRAKSFFDVALKSSPTERNGGQDNCR AANFREGLNLQEGEFLLQALNGFVLVVTTDALVFYASSTIQDYLGFQQSDVIHQSVYE LIHTEDRAEFQRQLHWALNPSQCTESGQGIEEATGLPQTVVCYNPDQIPPENSPLMER CFICRLRCLLDNSSGFLAMNFQGKLKYLHGQKKKGKDGSILPPQLALFAIATPLQPPS ILEIRTKNFIFRTKHKLDFTPIGCDAKGRIVLGYTEAELCTRGSGYQFIHAADMLYCA ESHIRMIKTGESGMIVFRLLTKNNRWTWVQSNARLLYKNGRPDYIIVTQRPLTDEEGT EHLRKRNTKLPFMFTTGEAVLYEATNPFPAIMDPLPLRTKNGTSGKDSATTSTLSKDS LNPSSLLAAMMQQDESIYLYPASSTSSTAPFENNFFNESMNECRNWQDNTAPMGNDTI LKHEQIDQPQDVNSFAGGHPGLFQDSKNSDLYSIMKNLGIDFEDIRHMQNEKFFRNDF SGEVDFRDIDLTDEILTYVQDSLSKSPFIPSDYQQQQSLALNSSCMVQEHLHLEQQQQ HHQKQVVVEPQQQLCQKMKHMQVNGMFENWNSNQFVPFNCPQQDPQQYNVFTDLHGIS QEFPYKSEMDSMPYTQNFISCNQPVLPQHSKCTELDYPMGSFEPSPYPTTSSLEDFVT CLQLPENQKHGLNPQSAIITPQTCYAGAVSMYQCQPEPQHTHVGQMQYNPVLPGQQAF LNKFQNGVLNETYPAELNNINNTQTTTHLQPLHHPSEARPFPDLTSSGFL" misc_feature 980 1174 /gene="AHR" /note="PAS; Region: PAS domain CAUTION This family does not currently match all known examples of PAS domains PAS motifs appear in archaea, eubacteria and eukarya Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels" /db_xref="CDD:pfam989" misc_feature 1685 1810 /gene="AHR" /note="PAC; Region: PAC motif PAC motif occurs C-terminal to a subset of all known PAS motifs It is proposed to 115 contribute to the PAS domain fold" /db_xref="CDD:pfam785" variation 2304 /gene="AHR" /allele="G" /allele="A" /db_xref="dbSNP:2066853" variation 2351 /gene="AHR" /allele="G" /allele="A" /db_xref="dbSNP:4986826" variation 3563 /gene="AHR" /allele="C" /allele="A" /db_xref="dbSNP:4987097" variation 3579 /gene="AHR" /note="WARNING: map location ambiguous" /allele="T" /allele="G" /allele="A" /db_xref="dbSNP:4986756" variation complement(3609) /allele="T" /allele="C" /db_xref="dbSNP:1557737" variation 5302 /gene="AHR" /allele="T" /allele="C" /db_xref="dbSNP:1803080" variation 5374 /gene="AHR" /allele="T" /allele="C" /db_xref="dbSNP:1803079" polyA_signal 5478 5483 /gene="AHR" BASE COUNT 1637 a 1190 c 1086 g 1583 t ORIGIN attcagccgg tgcgcgcggc ggcgggaggc agtggctggg gagtcccgtc 61 tccgagagcg tgccccggac cgccagctca gaacaggggc agccgtgtag 121 gctgggagca gccgggactg gtggcccgcg cccgagctcc gcaggcggga 181 atttgggaag tcccgggagc agcgcggcgg cacctccctc acccaagggg 241 ggtcacgggg cgcggcgcca ccgtgagcga cccaggccag gattctaaat 301 ggctcctcct ccgcccgggc cgcctcacct gcgggcattg ccgcgccgcc 361 tagacggcac ctgcgccgcc ttgctcgcgg gtctccgccc ctcgcccacc 421 caggcccagg cagctcacct gtactggcgc gggctgcgga agcctgcgtg 481 ttgaggcgcg gcgcccacgc cactgtcccg agaggacgca ggtggagcgg 541 gcggaacccg gcgccggccg ccgcagtggt cccagcctac accgggttcc 601 ccgccagtgc ccggggagta gccgccgccg tcggctgggc accatgaaca 661 caacatcacc tacgccagtc gcaagcggcg gaagccggtg cagaaaacag 721 cccagctgaa ggaatcaagt caaatccttc caagcggcat agagaccgac 781 gttggaccgt ttggctagcc tgctgccttt cccacaagat gttattaata 841 actttcagtt cttaggctca gcgtcagtta cctgagagcc aagagcttct 901 attaaaatcc tcccctactg aaagaaacgg aggccaggat aactgtagag 961 cagagaaggc ctgaacttac aagaaggaga attcttatta caggctctga 1021 attagttgtc actacagatg ctttggtctt ttatgcttct tctactatac 1081 agggtttcag cagtctgatg tcatacatca gagtgtatat gaacttatcc 1141 ccgagctgaa tttcagcgtc agctacactg ggcattaaat ccttctcagt 1201 tggacaagga attgaagaag ccactggtct cccccagaca gtagtctgtt 1261 ccagattcct ccagaaaact ctcctttaat ggagaggtgc ttcatatgtc 1321 tctgctggat aattcatctg gttttctggc aatgaatttc caagggaagt 1381 tcatggacag aaaaagaaag ggaaagatgg atcaatactt ccacctcagt 1441 tgcgatagct actccacttc agccaccatc catacttgaa atccggacca 116 gacgctctgt ccgaacggaa agcaccctgg ccgcggcgac agacggccca tccgccggtg ctcactgcgc agccgaggcg gcgcggcttc ggggacccgg gcagcagcgc taaagccaat ttaatacaga agttggacaa ttgatgttgc cagcaaattt atggctttgt aagattatct ataccgaaga gtacagagtc ataacccaga gtctaaggtg taaagtatct tggctttgtt aaaattttat 1501 1561 1621 1681 1741 1801 1861 1921 1981 2041 2101 2161 2221 2281 2341 2401 2461 2521 2581 2641 2701 2761 2821 2881 2941 3100 3061 3121 3181 3241 3301 3361 3421 3481 3541 3601 3661 3721 3781 3841 3901 3961 4021 4081 4141 4201 4261 4321 4381 4441 4501 4561 4621 4681 4741 4801 4861 4921 4981 5041 5101 5161 5221 5281 5341 5401 5461 ctttagaacc tgttttagga tgcagctgat tggcatgata tgcacgcctg aacagatgag taccactgga cttaccacta aagcaaggac tatttatctc caacgaatct tactatcctg tcacccaggg aggcattgat ttctggtgag agattcttta tctgaactca ccaaaagcaa agttaatggc gcaagaccca ctacaaatct tgtattacca atccccatac aaaccaaaag tggggccgtg gcagtacaat tttaaatgaa tcttcagcca attcctgtaa gattatggaa tgcatgctat ttaaaaatgg gtggtgaggt atcagggaaa acagtaaaaa caaagttaga gttaaaataa ctgtttcatc atataaagta gtttcctaaa actttcttca agttgtttct atgtctttcc cctcaacagt tgatgatagt aattgcaaga taaattgtct tataaatttc taagattgca ttgtatagat gtccatacct ttctaagaaa acatagttcg aataggcaaa aaatgacacc cgcccaaact caagtgattc cctgtagtcc aggttgcagg tccaaaaaaa aaaatggctt tgtagaatca gcatgaggta aaccttttat ataaattgtt agttataaaa aaaatgtatc aaacacaaac tatactgaag atgctttatt gttttccggc ctttataaaa gaaggaacag gaagctgtgt aggactaaaa tctctcaatc tatcctgctt atgaatgaat aaacatgagc ctctttcaag tttgaagaca gttgacttca agtaagtctc agctgtatgg gtagtagtgg atgtttgaaa caacaatata gaaatggatt caacattcca cccactactt catggattaa tcgatgtatc ccagtactgc acatatccag cttcatcatc ttccaagccc aaataaaact tcacaattat tatcaaaatt accgtctaca ctaagattct taaaatactt gaactaaact atggtttggt taagtgcctc ttctttttct tccaaccaat ggtaaaaggg agactataaa aaattatttc gttttcagaa tgaatgttgc agctttattt ttaaaaactg gcttcttaga gatagcaagg ataatgaaca tatatatgca tcaagtaatg tttaccttca ttaatcaccc atcttttatt ggagtgcagt tcttgcctca tagctactcg gccaagatcg aaaatacaat cggacaaaat atttaagtgt tctaaggatt tataagtctt tagtggaaaa ttaaaagttt taagaataat tagacttcac cagagctgtg gtgccgagtc ttcttacaaa atggaagacc agcatttacg tgtatgaggc atggcactag ctagttccct caagtacttc gcagaaattg aaattgacca atagtaaaaa tcagacacat gagacattga ccttcatacc tacaggaaca agccacagca attggaactc atgtctttac ctatgcctta aatgtacaga ctagtttaga atccacagtc agtgccagcc caggccaaca ctgaattaaa cgtcagaagc aattttgacc gtcactgttg tccaaaccaa acatatacta tttcacatta tttaaattag tgagttttga agtttttcct gctttttata acattttttt tttttaaatt tttcattaat caaataatga tgttgctatg ttaattatta gaaataaata aatgtgaaaa ctagcttttt ttttagacct acagtggaaa tttggtgcaa aaattatttg cttaatttgt aatccaactg aactttaggt taccaacttt cttttttttt ggcacaatct gcctcccgag ggaggctgag ccccactgca ttttatttct atctctgagt tgaaaaaaat tagaccagag acataaacca taggcttttt gaaaagcaat aaaatcacgt 117 acctattggt cacgagaggc ccatatccga aaacaaccga agattatatc aaaacgaaat aaccaaccct tggaaaagac cctggctgcc aagtactgca gcaagataat gcctcaggat cagtgacttg gcagaatgaa cttaacggat ttcagattat cctacatcta acagctgtgt taaccaattc agacttacat tacacagaac gctggactac agattttgtc agccataata agaacctcag ggcattttta taacataaat cagacctttt ctggtttttg gacgtcagca attttaattt cagtcaagat ttctgggcac aaaatattct gctactggat atcatgttaa aaaagataat ctacctataa aatatctttc tcaggcatat tcgaaaaaat tgccttatgt taaaaatatt taccactctt atctgctgtt aattaagcaa ataatccttg ctatgtgttt agtattgtaa taagatattt tggggcttta cttaaagttg ttttttaatg actgtcctaa tttttttttt tggctcactg ttgctgggat gcaggagaat ctccagcctg tttacttttt tctgtgtatt ttgtctgaaa gtctagatta tttttgttac aatcatgaat attgtatatt taaacc tgtgatgcca tcaggttatc atgattaaga tggacttggg attgtaactc acgaagttgc tttcctgcca tctgctacca atgatgcaac ccttttgaaa actgcaccga gtgaactcat tacagcataa aaatttttca gaaatcctga caacagcaac gaacagcaac cagaagatga gtgcctttca gggatcagtc tttatttcct cctatgggga acttgtttac actcctcaga cacacccacg aacaagtttc aacactcaga cctgatttga gattaaatta agttcacatg ttgcttttag agaaagggtg cacaaaatat ctatttgaat tcttattagt cctctgcttt ctcagtgctt cactctagga tgcacacaaa tttaactcca aattatttat tgaaaaaatt aagacaatag tacctttatt aactgcaacc agcacccatt ataatatatt ttctcatatt tgagtgaatt gcagtttttc catactttat gtattaataa atatactgat catggacttt gagagagagt caacctctac tgcgggcatg agcctgaacc gcaatagacc ttagtaagtt ttcagtcaaa catttcataa atactctatt tctcttccac atgatgacaa tttatctata aaggaagaat agtttattca ctggagaaag tccagtctaa agagaccact cttttatgtt taatggatcc catccactct aagatgagtc acaacttttt tgggaaatga ttgctggagg tgaaaaacct gaaatgattt cgtatgtcca agtccttggc agcaacatca agcacatgca attgtccaca aagagttccc gtaatcagcc gttttgaacc aacttcctga catgttatgc tgggtcagat agaatggagt ctaccacaca catccagtgg gtttgtgaag gaggcattga aaaagggagt ctgccacgga acaaaacttt tatttctgtc tccccaaata tatctcagat tcctccttca tgtatatttt tattatttgt ctgcttacct tacataattt taaaagtaaa cacttaaatt gatatctcca ttgtttatta tcaatgtgta gtgttgactt tgaggagtgt gaatggtgca attttaaaaa caatgtgtct aaagacaacc cttcattacc caaaaagaaa cttactctgc ctcctgggtt gtggcgtgag tgggaatcgg gagctccgtc aatgtatata actttaaacc tttgtttcca tttacattta atgttactgg tcagttatac taaaataact Một số điểm đa hình đột biến gen CYP1A1 KEY PROPEP CHAIN FROM 11 TO 10 848 10 838 LENGTH DESCRIPTION BY SIMILARITY ARYL HYDROCARBON RECEPTOR (BY SIMILARITY) BASIC DOMAIN HELIX-LOOP-HELIX MOTIF (BY SIMILARITY) PAS PAS PAC GLN-RICH VAR_015516 VAR_9281 VAR_9282 VAR_015517 INCREASED SPECIFIC LIGAND BINDING ABOLISHED SPECIFIC LIGAND BINDING DNA_BIND DOMAIN 13 41 40 81 28 41 DOMAIN DOMAIN DOMAIN DOMAIN VARIANT VARIANT VARIANT VARIANT MUTAGEN MUTAGEN 111 275 348 517 554 570 786 381 381 181 342 386 640 517 554 570 786 381 381 71 68 39 41 P -> S R -> K V -> I M -> V V->A: V->D: MUTAGEN CONFLICT CONFLICT CONFLICT 381 191 340 807 381 191 341 848 V->L,G: E -> EG MI -> SD LNETYPAELNNINNTQT TTHLQPLHHPSEARPFPDLT SSGFL -> FK 118 NO EFFECT ON SPECIFIC LIGAND BINDING