维基百科

全基因组测序

完全確定某生物的基因組的過程

全基因组测序（Whole genome sequencing，WGS）是将一个生物的基因组完整（或接近完整）测序的流程。1990年代起陆续有生物的基因组被完整测序，最早被测序完成的生物为流感嗜血杆菌（1995年），1996年首次有真核生物（酿酒酵母）被完整测序。2014年以后全基因组测序逐渐开始被用于临床用途[2][3][4]，以病人基因组信息决定其疗法，即个性化医疗[5]。2000年全基因体测序技术获《科学》期刊选为该年的年度突破（英语：Breakthrough of the Year）[6]。

霰弹枪测序法的流程图
显示基因测序结果的电泳图谱（英语：Electropherogram）[1]

历史

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流感嗜血杆菌为第一个被全基因组测序的生物
 
秀丽隐杆线虫为第一个被全基因组测序的多细胞生物（动物）
 
拟南芥为第一个被全基因组测序的植物

1977年，弗雷德里克·桑格的团队将ΦX174噬菌体（英语：Phi X 174）的基因组完整测序，长5368bp，是第一个被完整测序的基因组[7][8][9]。1990年代起测序技术逐渐成熟，开始被用于测序生物的完整基因组[10]。第一个被完整测序的生物为流感嗜血杆菌，共长183万bp，于1995年由霰弹枪测序法完成[11]，随后有其他细菌与古菌的基因组陆续被以相同方法测序。真核生物的基因组大小则大的多，因此测序较为困难，1996年酿酒酵母的基因组测序完成，约长1200万bp，为第一个被完整测序的真核生物[12]；1998年秀丽隐杆线虫的基因组被完整测序，为第一个完成测序的多细胞真核生物[13]。真核生物测序的方式除使用霰弹枪测序法外，还用到了细菌人工染色体（BAC）、酵母菌人工染色体（YAC）等基因文库[14]。



1999年人类22号染色体（最短的常染色体）被测序发表[15]；2000年黑腹果蝇的基因组被完整测序，为第二种被完整测序的动物[16]，同年拟南芥的基因组测序也告完成，是第一个被完整测序的植物[17]。2001年人类基因组计划发表人类基因组的测序草图（draft）[18]，2003年宣告真染色质的序列皆测序完成[19][20]，2021年发表测序程度达“完整”的基因组[21][22]；2002年小鼠的基因组也被测序发表[23]。目前已有上千种生物的基因组被完整测序。2005年起桑格测序等传统的测序方法逐渐被Illumina染料测序（英语：Illumina dye sequencing）、焦磷酸测序、SMRT测序（英语：Single-molecule real-time sequencing）与奈米孔洞测序等次世代测序（英语：Massive parallel sequencing）（NGS）技术取代（但仍使用霰弹枪测序法的策略，将基因组打碎成许多片段后分别完成测序，再进行组装）。[24][25]

商业化

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2001年至2019年一次人类全基因组测序的费用变化

已有许多公司尝试将全基因组测序商业化以作研究或临床用途[26]，包括Illumina[27]、Knome（英语：Knome）[28]、Sequenom（英语：Sequenom）[29]、454生物科学[30]、Pacific Biosciences（英语：Pacific Biosciences）[31]、Complete Genomics（英语：Complete Genomics）[32]、Helicos Biosciences（英语：Helicos Biosciences）[33]、GE Global Research（英语：GE Global Research）（通用电气的研发部门）、Affymetrix（英语：Affymetrix）、IBM、Intelligent Bio-Systems[34]、Life Technologies、Oxford Nanopore Technologies（英语：Oxford Nanopore Technologies）[35]与华大基因等[36][37][38]。2010年代晚期全基因组测序一次约要价1000美元，许多公司正试图将成本进一步降低[39]，2017年华大基因的全基因组测序收费已降为一人600美元[40]，2019年Veritas Genetics（英语：Veritas Genetics）也将费用降至一人599美元[41]

应用

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全基因组关联分析（GWAS）的结果（曼哈顿图（英语：Manhattan plot））示意图

在生医研究中，全基因组测序可被用于全基因组关联分析（GWAS）以寻找基因组中与特定疾病相关的单核苷酸多态性（SNP）位点[42]。

全基因组测序在医疗上也有很大的应用价值，2009年Illumina即推出了用于临床医疗的全基因组分析套件，供医师在不知病人病因、传统疗法均效果不彰时使用[43]。因近年来全基因组测序的费用大幅下降，其应用潜力也大幅增加。2011年布莱根妇女医院与哈佛医学院创立了Genomes2People（G2P）计划，旨在将基因测序整合进临床医疗[44]。

伦理争议

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人类全基因组测序可能伴随一些伦理议题，此技术虽有诊断出疾病的潜力[45]，但也有造成基因歧视（英语：Genetic discrimination）、隐私外泄（特别是未成年人的隐私[46]）与心理上负面影响之风险[47]。另外当一个人接受全基因组测序时，除了自己基因组的信息外，还可能得知其近亲的基因组信息，进而推得他们过去、现在或未来的健康状况[48]，因此接受测序者是否应与近亲分享测序的结果也是一伦理议题，若其带有一与某疾病相关的突变，却不愿与近亲分享此信息，则医疗人员可能面临预防医疗与病人隐私的两难[45]。科学研究中的全基因组测序也可能有隐私外泄的疑虑，因学术研究发表时通常需要将病人的基因型的信息发表到公开数据库，此信息虽为匿名，但在疾病或突变相当罕见的情况下仍有可能使病人被认出[45]。

被全基因组测序的名人

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最早被全基因组测序完成的人是克莱格·凡特[49][50][51]与詹姆斯·杜威·沃森[52][53][54]，于2007年完成（覆盖度（英语：Coverage (genetics)）分别为7.5与7.4），2008年又有一名匿名的中国汉族人（覆盖度为36）[55]、尼日利亚约鲁巴人（覆盖度为30）[56]、荷兰的女性遗传学家玛乔琳·克里克（为首位基因组被完整测序的女性，覆盖度7至8）[57][58]与一高加索人种的白血病女性患者基因组被测序完成[59]。史蒂夫·乔布斯为最早被全基因组测序的20人之一，有消息指其花费高达10万美元[60]。截至2012年6月共有69个人接近完整的基因组序列数据向大众公开[61]。2013年11月有一西班牙家庭在接受23andMe与华大基因测序后，将全家的全基因组序列以知识共享公有领域授权条款公开，是第一个公开的家族全基因组序列数据[62]。

参见

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参考文献

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  1. ^ Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. Chapter 8. Molecular biology of the cell 5th. New York: Garland Science. 2008: 550. ISBN 978-0-8153-4106-2. 
  2. ^ Gilissen. Genome sequencing identifies major causes of severe intellectual disability. Nature. July 2014, 511 (7509): 344–7. Bibcode:2014Natur.511..344G. PMID 24896178. S2CID 205238886. doi:10.1038/nature13394. 
  3. ^ Nones, K; Waddell, N; Wayte, N; Patch, AM; Bailey, P; Newell, F; Holmes, O; Fink, JL; Quinn, MC; et al. Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. Nature Communications. 2014-10-29, 5: 5224. Bibcode:2014NatCo...5.5224N. PMC 4596003  . PMID 25351503. doi:10.1038/ncomms6224. 
  4. ^ van El, CG; Cornel, MC; Borry, P; Hastings, RJ; Fellmann, F; Hodgson, SV; Howard, HC; Cambon-Thomsen, A; Knoppers, BM; Meijers-Heijboer, H; Scheffer, H; Tranebjaerg, L; Dondorp, W; de Wert, GM. Whole-genome sequencing in health care. Recommendations of the European Society of Human Genetics. European Journal of Human Genetics. June 2013,. 21 Suppl 1: S1–5. PMC 3660957  . PMID 23819146. doi:10.1038/ejhg.2013.46. 
  5. ^ Mooney, Sean. Progress towards the integration of pharmacogenomics in practice. Human Genetics. Sep 2014, 134 (5): 459–65. PMC 4362928  . PMID 25238897. doi:10.1007/s00439-014-1484-7. 
  6. ^ Elizabeth Pennisi. BREAKTHROUGH OF THE YEAR. Genomics Comes of Age. Science. 2000, 290 (5500): 2220–2221. PMID 11188701. S2CID 82676530. doi:10.1126/science.290.5500.2220. 
  7. ^ A History of Genome Sequencing. MB&B 447b3 (747b3) BIOINFORMATICS, Yale University. [2021-12-20]. （原始内容存档于2022-05-01）. 
  8. ^ Brownlee, George G. Frederick Sanger CBE CH OM. 13 August 1918 – 19 November 2013. Biographical Memoirs of Fellows of the Royal Society. 2015, 61: 437–466. doi:10.1098/rsbm.2015.0013  . 
  9. ^ Sanger F, Air GM, Barrell BG, Brown NL, Coulson AR, Fiddes CA, et al. Nucleotide sequence of bacteriophage phi X174 DNA. Nature. February 1977, 265 (5596): 687–95. Bibcode:1977Natur.265..687S. PMID 870828. S2CID 4206886. doi:10.1038/265687a0. 
  10. ^ al.], Bruce Alberts ... [et. Molecular biology of the cell 5th. New York: Garland Science. 2008: 551. ISBN 978-0-8153-4106-2. 
  11. ^ Fleischmann, R.; Adams, M.; White, O; Clayton, R.; Kirkness, E.; Kerlavage, A.; Bult, C.; Tomb, J.; Dougherty, B.; Merrick, J.; al., e. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science. 1995-07-28, 269 (5223): 496–512. Bibcode:1995Sci...269..496F. PMID 7542800. doi:10.1126/science.7542800. 
  12. ^ Goffeau, A.; Barrell, B. G.; Bussey, H.; Davis, R. W.; Dujon, B.; Feldmann, H.; Galibert, F.; Hoheisel, J. D.; Jacq, C.; Johnston, M.; Louis, E. J.; Mewes, H. W.; Murakami, Y.; Philippsen, P.; Tettelin, H.; Oliver, S. G. Life with 6000 Genes. Science. 1996-10-25, 274 (5287): 546–567. Bibcode:1996Sci...274..546G. PMID 8849441. S2CID 16763139. doi:10.1126/science.274.5287.546. （原始内容存档 (PDF)于2016-03-07）. 
  13. ^ The C. elegans Sequencing Consortium. Genome Sequence of the Nematode C. elegans: A Platform for Investigating Biology. Science. 1998-12-11, 282 (5396): 2012–2018. Bibcode:1998Sci...282.2012.. PMID 9851916. doi:10.1126/science.282.5396.2012. 
  14. ^ Alberts, Bruce. Molecular Biology of the Cell 5th. New York: Garland Science. 2008: 552. ISBN 978-0-8153-4106-2. 
  15. ^ Dunham, I. The DNA sequence of human chromosome 22. Nature. December 1999, 402 (6761): 489–495. Bibcode:1999Natur.402..489D. PMID 10591208. doi:10.1038/990031  . 
  16. ^ Adams MD; Celniker SE; Holt RA; et al. The Genome Sequence of Drosophila melanogaster. Science. 2000-03-24, 287 (5461): 2185–2195. Bibcode:2000Sci...287.2185.. CiteSeerX 10.1.1.549.8639  . PMID 10731132. doi:10.1126/science.287.5461.2185. 
  17. ^ The Arabidopsis Genome Initiative. Analysis of the genome sequence of the flowering plant Arabidopsis thaliana. Nature. 2000-12-14, 408 (6814): 796–815. Bibcode:2000Natur.408..796T. PMID 11130711. doi:10.1038/35048692  . 
  18. ^ Venter JC; Adams MD; Myers EW; et al. The Sequence of the Human Genome. Science. 2001-02-16, 291 (5507): 1304–1351. Bibcode:2001Sci...291.1304V. PMID 11181995. doi:10.1126/science.1058040  . 
  19. ^ Human Genome Project Completion: Frequently Asked Questions. National Human Genome Research Institute (NHGRI). [2021-12-10]. （原始内容存档于2019-04-09）. 
  20. ^ International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004-09-07, 431 (7011): 931–945. Bibcode:2004Natur.431..931H. PMID 15496913. doi:10.1038/nature03001  . 
  21. ^ CHM13 T2T v1.1 – Genome – Assembly – NCBI. www.ncbi.nlm.nih.gov. [2021-06-16]. （原始内容存档于2021-05-29）. 
  22. ^ Genome List – Genome – NCBI. www.ncbi.nlm.nih.gov. [2021-06-16]. （原始内容存档于2015-02-20）. 
  23. ^ Waterston RH; Lindblad-Toh K; Birney E; et al. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002-10-31, 420 (6915): 520–562. Bibcode:2002Natur.420..520W. PMID 12466850. doi:10.1038/nature01262  . 
  24. ^ Mukhopadhyay R. DNA sequencers: the next generation. Anal. Chem. February 2009, 81 (5): 1736–40. PMID 19193124. doi:10.1021/ac802712u. 
  25. ^ Kwong, JC; McCallum, N; Sintchenko, V; Howden, BP. Whole genome sequencing in clinical and public health microbiology.. Pathology. April 2015, 47 (3): 199–210. PMC 4389090  . PMID 25730631. doi:10.1097/pat.0000000000000235. 
  26. ^ Article : Race to Cut Whole Genome Sequencing Costs Genetic Engineering & Biotechnology News — Biotechnology from Bench to Business. Genengnews.com. [2009-02-23]. （原始内容存档于2006-10-17）. 
  27. ^ Whole Genome Sequencing Costs Continue to Drop. Eyeondna.com. [2009-02-23]. （原始内容存档于2009-03-25）. 
  28. ^ Harmon, Katherine. Genome Sequencing for the Rest of Us. Scientific American. 2010-06-28 [2010-08-13]. （原始内容存档于2011-03-19）. 
  29. ^ San Diego/Orange County Technology News. Sequenom to Develop Third-Generation Nanopore-Based Single Molecule Sequencing Technology. Freshnews.com. [2009-02-24]. （原始内容存档于2008-12-05）. 
  30. ^ Article : Whole Genome Sequencing in 24 Hours Genetic Engineering & Biotechnology News — Biotechnology from Bench to Business. Genengnews.com. [2009-02-23]. （原始内容存档于2006-10-17）. 
  31. ^ Pacific Bio lifts the veil on its high-speed genome-sequencing effort. VentureBeat. 2008-02-10 [2009-02-23]. （原始内容存档于2009-02-20）. 
  32. ^ Bio-IT World. Bio-IT World. 2008-10-06 [2009-02-23]. （原始内容存档于2009-02-17）. 
  33. ^ With New Machine, Helicos Brings Personal Genome Sequencing A Step Closer. Xconomy. 2008-04-22 [2011-01-28]. （原始内容存档于2011-01-02）. 
  34. ^ Whole genome sequencing costs continue to fall: $300 million in 2003, $1 million 2007, $60,000 now, $5000 by year end. Nextbigfuture.com. 2008-03-25 [2011-01-28]. （原始内容存档于2010-12-20）. 
  35. ^ Han Cao's nanofluidic chip could cut DNA sequencing costs dramatically. Technology Review. （原始内容存档于2011-03-29）. 
  36. ^ Julia Karow. BGI Launches Desktop Sequencer in China; Plans to Register Platform With CFDA. GenomeWeb. 2015-10-26 [2018-12-02]. （原始内容存档于2018-12-02）. 
  37. ^ BGI Launches New Desktop Sequencer in China, Registers Larger Version With CFDA. 360Dx. GenomeWeb. 2016-11-11 [2018-12-02]. （原始内容存档于2020-09-19）. 
  38. ^ Monica Heger. BGI Launches New Sequencer as Customers Report Data From Earlier Instruments. GenomeWeb. 2018-10-26 [2018-12-02]. （原始内容存档于2021-10-09）. 
  39. ^ Sarah Neville. Cheaper DNA sequencing unlocks secrets of rare diseases. Financial Times. 2018-03-05 [2018-12-02]. （原始内容存档于2020-08-19）. 
  40. ^ Megan Molteni. A Chinese Genome Giant Sets Its Sights on the Ultimate Sequencer. Wired. 2017-05-18 [2018-12-02]. （原始内容存档于2021-08-10）. 
  41. ^ Andrews, Joe. 23andMe competitor Veritas Genetics slashes price of whole genome sequencing 40% to $600. CNBC. 2019-07-01 [2019-09-02]. （原始内容存档于2022-02-24）. 
  42. ^ Yano, K; Yamamoto, E; Aya, K; Takeuchi, H; Lo, PC; Hu, L; Yamasaki, M; Yoshida, S; Kitano, H; Hirano, K; Matsuoka, M. Genome-wide association study using whole-genome sequencing rapidly identifies new genes influencing agronomic traits in rice.. Nature Genetics. August 2016, 48 (8): 927–34. PMID 27322545. S2CID 22427006. doi:10.1038/ng.3596. 
  43. ^ Abbott, Phil. US clinics quietly embrace whole-genome sequencing : Nature News. Nature. 2010 [2016-11-11]. doi:10.1038/news.2010.465. （原始内容存档于2017-04-16）. 
  44. ^ Genomes2People: A Roadmap for Genomic Medicine. www.frontlinegenomics.com. [2018-04-29]. （原始内容存档于2017-02-14）. 
  45. ^ 45.0 45.1 45.2 Sijmons, R.H.; Van Langen, I.M. A clinical perspective on ethical issues in genetic testing. Accountability in Research: Policies and Quality Assurance. 2011, 18 (3): 148–162. Bibcode:2013ARPQ...20..143D. PMID 21574071. S2CID 24935558. doi:10.1080/08989621.2011.575033. 
  46. ^ Borry, P.; Evers-Kiebooms, G.; Cornel, MC; Clarke, A; Dierickx, K; Public Professional Policy Committee (PPPC) of the European Society of Human Genetics (ESHG)（英语：European Society of Human Genetics）. Genetic testing in asymptomatic minors Background considerations towards ESHG Recommendations. Eur J Hum Genet. 2009, 17 (6): 711–9. PMC 2947094  . PMID 19277061. doi:10.1038/ejhg.2009.25. 
  47. ^ Ayday E; De Cristofaro E; Hubaux JP; Tsudik G. The Chills and Thrills of Whole Genome Sequencing. 2015. arXiv:1306.1264   [cs.CR]. 
  48. ^ McGuire, Amy, L; Caulfield, Timothy. Science and Society: Research ethics and the challenge of whole-genome sequencing. Nature Reviews Genetics. 2008, 9 (2): 152–156. PMC 2225443  . PMID 18087293. doi:10.1038/nrg2302. 
  49. ^ Wade, Nicholas. In the Genome Race, the Sequel Is Personal. New York Times. 2007-09-04 [2009-02-22]. （原始内容存档于2009-04-11）. 
  50. ^ Ledford, Heidi. Access : All about Craig: the first 'full' genome sequence. Nature. 2007, 449 (7158): 6–7. Bibcode:2007Natur.449....6L. PMID 17805257. doi:10.1038/449006a  . 
  51. ^ Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, Walenz BP, Axelrod N, Huang J, Kirkness EF, Denisov G, Lin Y, MacDonald JR, Pang AW, Shago M, Stockwell TB, Tsiamouri A, Bafna V, Bansal V, Kravitz SA, Busam DA, Beeson KY, McIntosh TC, Remington KA, Abril JF, Gill J, Borman J, Rogers YH, Frazier ME, Scherer SW, Strausberg RL, Venter JC. The diploid genome sequence of an individual human. PLOS Biol. September 2007, 5 (10): e254. PMC 1964779  . PMID 17803354. doi:10.1371/journal.pbio.0050254  . 
  52. ^ Wade, Wade. DNA pioneer Watson gets own genome map. International Herald Tribune. 2007-06-01 [2009-02-22]. （原始内容存档于2008-09-27）. 
  53. ^ Wade, Nicholas. Genome of DNA Pioneer Is Deciphered. New York Times. 2007-05-31 [2009-02-21]. （原始内容存档于2011-06-20）. 
  54. ^ Wheeler DA; Srinivasan M; Egholm M; Shen Y; Chen L; McGuire A; He W; Chen YJ; Makhijani V; Roth GT; Gomes X; Tartaro K; Niazi F; Turcotte CL; Irzyk GP; Lupski JR; Chinault C; Song XZ; Liu Y; Yuan Y; Nazareth L; Qin X; Muzny DM; Margulies M; Weinstock GM; Gibbs RA; Rothberg JM. The complete genome of an individual by massively parallel DNA sequencing. Nature. 2008, 452 (7189): 872–6. Bibcode:2008Natur.452..872W. PMID 18421352. doi:10.1038/nature06884  . 
  55. ^ Wang J; Wang, Wei; Li, Ruiqiang; Li, Yingrui; Tian, Geng; Goodman, Laurie; Fan, Wei; Zhang, Junqing; Li, Jun; Zhang, Juanbin, Juanbin; Guo, Yiran, Yiran; Feng, Binxiao, Binxiao; Li, Heng, Heng; Lu, Yao, Yao; Fang, Xiaodong, Xiaodong; Liang, Huiqing, Huiqing; Du, Zhenglin, Zhenglin; Li, Dong, Dong; Zhao, Yiqing, Yiqing; Hu, Yujie, Yujie; Yang, Zhenzhen, Zhenzhen; Zheng, Hancheng, Hancheng; Hellmann, Ines, Ines; Inouye, Michael, Michael; Pool, John, John; Yi, Xin, Xin; Zhao, Jing, Jing; Duan, Jinjie, Jinjie; Zhou, Yan, Yan; et al. The diploid genome sequence of an Asian individual. Nature. 2008, 456 (7218): 60–65. Bibcode:2008Natur.456...60W. PMC 2716080  . PMID 18987735. doi:10.1038/nature07484. 
  56. ^ Bentley DR; Balasubramanian S; et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008, 456 (7218): 53–9. Bibcode:2008Natur.456...53B. PMC 2581791  . PMID 18987734. doi:10.1038/nature07517. 
  57. ^ Coats, Christopher. Dr. Marjolein Kriek, First Woman to Have Her DNA Sequence Determined. 2009-12-27 [2012-01-03]. （原始内容存档于2021-08-13）. 
  58. ^ First Female DNA Sequenced. ScienceDaily. 2008-05-26. （原始内容存档于2021-02-05）. 
  59. ^ Ley TJ; Mardis ER; Ding L; Fulton B; McLellan MD; Chen K; Dooling D; Dunford-Shore BH; McGrath S; Hickenbotham M; Cook L; Abbott R; Larson DE; Koboldt DC; Pohl C; Smith S; Hawkins A; Abbott S; Locke D; Hillier LW; Miner T; Fulton L; Magrini V; Wylie T; Glasscock J; Conyers J; Sander N; Shi X; Osborne JR; et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008, 456 (7218): 66–72. Bibcode:2008Natur.456...66L. PMC 2603574  . PMID 18987736. doi:10.1038/nature07485. 
  60. ^ Lohr, Steve. New Book Details Jobs's Fight Against Cancer. The New York Times. 2011-10-20. （原始内容存档于2017-09-28）. 
  61. ^ Complete Human Genome Sequencing Datasets to its Public Genomic Repository. （原始内容存档于2012-06-10）. 
  62. ^ Corpas, Manuel; Cariaso, Mike; Coletta, Alain; Weiss, David; Harrison, Andrew P; Moran, Federico; Yang, Huanming. A Complete Public Domain Family Genomics Dataset. 2013-11-12. bioRxiv 10.1101/000216  . 

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