Letter | Published:

Genome-wide detection and characterization of positive selection in human populations

Nature 449, 913–918 (18 October 2007) | Download Citation

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Abstract

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2)1. We used ‘long-range haplotype’ methods, which were developed to identify alleles segregating in a population that have undergone recent selection2, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus3, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation4,5, in Europe; and EDAR and EDA2R, both involved in development of hair follicles6, in Asia.

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Acknowledgements

P.C.S. is funded by a Burroughs Wellcome Career Award in the Biomedical Sciences and has been funded by the Damon Runyon Cancer Fellowship and the L’Oreal for Women in Science Award. We thank A. Schier, B. Voight, R. Roberts, M. Kreiger, A. Abzhanov, D. Degusta, M. Burnette, E. Lieberman, M. Daly, D. Altshuler, D. Reich, D. Lieberman and I. Woods for helpful discussions on our analysis and results. We also thank L. Ziaugra, D. Tabbaa and T. Rachupka for experimental assistance. This work was funded in part by grants from the National Human Genome Research Institute (to E.S.L.) and from the Broad Institute of MIT and Harvard.

Author Contributions P.C.S., P.V., B.F. and E.S.L. initiated the project. P.V., B.F. and P.C.S. developed key software. P.C.S., P.V., B.F., S.F.S., J.L., E.H., C.C., X.X., E.B., S.A.McC. and R.G. performed analysis. P.C.S., E.B. and E.H. performed experiments. P.C.S., E.S.L., P.V. and S.F.S. wrote the manuscript.

Author information

    • Pardis C. Sabeti
    •  & Patrick Varilly

    These authors contributed equally to this work.

Affiliations

  1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02139, USA

    • Pardis C. Sabeti
    • , Patrick Varilly
    • , Ben Fry
    • , Jason Lohmueller
    • , Elizabeth Hostetter
    • , Chris Cotsapas
    • , Xiaohui Xie
    • , Elizabeth H. Byrne
    • , Steven A. McCarroll
    • , Stephen F. Schaffner
    •  & Eric S. Lander

  2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Chris Cotsapas
    •  & Steven A. McCarroll

  3. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Rachelle Gaudet

  4. Department of Biology, MIT, Cambridge, Massachusetts 02139, USA

    • Eric S. Lander

  5. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA

    • Eric S. Lander

  6. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Eric S. Lander

  7. The Scripps Research Institute, 10550 North Torrey Pines Road MEM275, La Jolla, California 92037, USA.

    • Kelly A. Frazer (Principal Investigator)
    •  & Sarah S. Murray

  8. Perlegen Sciences, 2021 Stierlin Court, Mountain View, California 94043, USA.

    • Dennis G. Ballinger
    • , David R. Cox
    • , David A. Hinds
    •  & Laura L. Stuve

  9. Baylor College of Medicine, Human Genome Sequencing Center, Department of Molecular and Human Genetics, 1 Baylor Plaza, Houston, Texas 77030, USA.

    • Richard A. Gibbs (Principal Investigator)
    • , John W. Belmont
    • , Suzanne M. Leal
    • , David A. Wheeler
    • , Donna Muzny
    • , Lynne Nazareth
    • , Erica Sodergren
    • , George M. Weinstock
    •  & Imtaz Yakub

  10. Affymetrix, 3420 Central Expressway, Santa Clara, California 95051, USA.

    • Andrew Boudreau
    • , Thomas D. Willis
    •  & Jean-François Olivier

  11. Pacific Biosciences, 1505 Adams Drive, Menlo Park, California 94025, USA.

    • Paul Hardenbol

  12. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.

    • Shiran Pasternak
    • , Lincoln D. Stein (Principal Investigator)
    • , Lalitha Krishnan
    • , Albert Vernon Smith
    •  & Marcela K. Tello-Ruiz

  13. The Broad Institute of Harvard and Massachusetts Institute of Technology, 1 Kendall Square, Cambridge, Massachusetts 02139, USA.

    • Fuli Yu
    • , Stacey B. Gabriel (Project Leader)
    • , Rachel Barry
    • , Brendan Blumenstiel
    • , Amy Camargo
    • , Matthew Defelice
    • , Maura Faggart
    • , Mary Goyette
    • , Supriya Gupta
    • , Jamie Moore
    • , Huy Nguyen
    • , Robert C. Onofrio
    • , Melissa Parkin
    • , Jessica Roy
    • , Erich Stahl
    • , Ellen Winchester
    • , Liuda Ziaugra
    • , David Altshuler (Principal Investigator)
    • , Mark J. Daly (Project Leader)
    • , Paul I. W. de Bakker
    • , Jeff Barrett
    • , Yves R. Chretien
    • , Julian Maller
    • , Steve McCarroll
    • , Nick Patterson
    • , Alkes Price
    • , Daniel J. Richter
    • , Pardis Sabeti
    • , Richa Saxena
    • , Stephen F. Schaffner
    • , Patrick Varilly
    • , Chris Spencer
    • , Bruce W. Birren
    •  & Mark J. Daly

  14. Beijing Genomics Institute, Chinese Academy of Sciences, Beijing 100300, China.

    • Huanming Yang (Principal Investigator)
    • , Changqing Zeng (Principal Investigator)
    • , Yang Gao
    • , Haoran Hu
    • , Weitao Hu
    • , Chaohua Li
    • , Wei Lin
    • , Siqi Liu
    • , Hao Pan
    • , Xiaoli Tang
    • , Jian Wang
    • , Wei Wang
    • , Jun Yu
    • , Bo Zhang
    • , Qingrun Zhang
    • , Hongbin Zhao
    • , Hui Zhao
    • , Jun Zhou
    •  & Changqing Zeng

  15. Massachusetts General Hospital and Harvard Medical School, Simches Research Center, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

    • David Altshuler (Principal Investigator)
    • , Mark J. Daly (Project Leader)
    • , Paul I. W. de Bakker
    • , Jeff Barrett
    • , Julian Maller
    • , Steve McCarroll
    • , Shaun Purcell
    • , Richa Saxena
    •  & Mark J. Daly

  16. Chinese National Human Genome Center at Beijing, 3-707 N. Yongchang Road, Beijing Economic-Technological Development Area, Beijing 100176, China.

    • Yan Shen (Principal Investigator)
    •  & Zhijian Yao

  17. Chinese National Human Genome Center at Shanghai, 250 Bi Bo Road, Shanghai 201203, China.

    • Wei Huang (Principal Investigator)
    • , Xun Chu
    • , Yungang He
    • , Yangfan Liu
    • , Yayun Shen
    • , Weiwei Sun
    • , Haifeng Wang
    • , Yi Wang
    • , Ying Wang
    • , Xiaoyan Xiong
    •  & Liang Xu

  18. Fudan University and CAS-MPG Partner Institute for Computational Biology, School of Life Sciences, SIBS, CAS, Shanghai, 201203, China.

    • Li Jin

  19. The Chinese University of Hong Kong, Department of Biochemistry, The Croucher Laboratory for Human Genetics, 6/F Mong Man Wai Building, Shatin, Hong Kong.

    • Mary M. Y. Waye (Principal Investigator)
    •  & Stephen K. W. Tsui

  20. Hong Kong University of Science and Technology, Department of Biochemistry and Applied Genomics Center, Clear Water Bay, Knowloon, Hong Kong.

    • Hong Xue
    •  & J. Tze-Fei Wong

  21. Illumina, 9885 Towne Centre Drive, San Diego, California 92121, USA.

    • Luana M. Galver (Project Leader)
    • , Jian-Bing Fan
    • , Kevin Gunderson
    • , Stéphanie Roumy
    •  & Arthur L. Holden

  22. Complete Genomics, 658 North Pastoria Avenue, Sunnyvale, California 94085, USA.

    • Arnold R. Oliphant

  23. Prognosys Biosciences, 4215 Sorrento Valley Boulevard, Suite 105, San Diego, California 92121, USA.

    • Mark S. Chee (Principal Investigator)

  24. McGill University and Génome Québec Innovation Centre, 740 Dr Penfield Avenue, Montréal, Québec H3A 1A4, Canada.

    • Alexandre Montpetit (Project Leader)
    • , Fanny Chagnon
    • , Vincent Ferretti
    • , Martin Leboeuf
    • , Michael S. Phillips
    •  & Andrei Verner

  25. University of Montréal, The Public Law Research Centre (CRDP), PO Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada.

    • Clémentine Sallée
    •  & Bartha M. Knoppers

  26. Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Suite 500, Toronto, Ontario, M5G 1L7, Canada.

    • Thomas J. Hudson (Principal Investigator)

  27. University of California, San Francisco, Cardiovascular Research Institute, 513 Parnassus Avenue, Box 0793, San Francisco, California 94143, USA.

    • Pui-Yan Kwok
    • , Dongmei Cai
    • , Ludmila Pawlikowska
    •  & Ming Xiao

  28. Washington University School of Medicine, Department of Genetics, 660 S. Euclid Avenue, Box 8232, St Louis, Missouri 63110, USA.

    • Daniel C. Koboldt
    • , Raymond D. Miller
    •  & Patricia Taillon-Miller

  29. University of Hong Kong, Genome Research Centre, 6/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong.

    • Lap-Chee Tsui (Principal Investigator)
    • , William Mak
    • , You Qiang Song
    • , Paul K. H. Tam
    •  & Pak C. Sham

  30. University of Tokyo, Institute of Medical Science, 4-6-1 Sirokanedai, Minatoku, Tokyo 108-8639, Japan.

    • Yusuke Nakamura (Principal Investigator)

  31. RIKEN SNP Research Center, 1-7-22 Suehiro-cho, Tsurumi-ku Yokohama, Kanagawa 230-0045, Japan.

    • Yusuke Nakamura (Principal Investigator)
    • , Takahisa Kawaguchi
    • , Takuya Kitamoto
    • , Takashi Morizono
    • , Atsushi Nagashima
    • , Yozo Ohnishi
    • , Akihiro Sekine
    • , Toshihiro Tanaka
    • , Tatsuhiko Tsunoda
    • , Tatsuhiko Tsunoda (Principal Investigator)
    •  & Todd A Johnson

  32. Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Panos Deloukas (Project Leader)
    • , Christine P. Bird
    • , Marcos Delgado
    • , Emmanouil T. Dermitzakis
    • , Rhian Gwilliam
    • , Sarah Hunt
    • , Don Powell
    • , Barbara E. Stranger
    • , Pamela Whittaker
    • , Jane Rogers (Principal Investigator)
    • , John Burton
    • , Nigel P. Carter
    • , Christopher M. Clee
    • , Mark Griffiths
    • , Matthew C. Jones
    • , Kirsten McLay
    • , Robert W. Plumb
    • , Mark T. Ross
    • , Sarah K. Sims
    •  & David L. Willey

  33. University of Cambridge, Department of Oncology, Cambridge CB1 8RN, UK.

    • Jonathan Morrison

  34. Solexa, Chesterford Research Park, Little Chesterford, nr Saffron Walden, Essex CB10 1XL, UK.

    • David R. Bentley (Principal Investigator)

  35. Columbia University, 500 West 120th Street, New York, New York 10027, USA.

    • Itsik Pe’er

  36. University of Leicester, Department of Genetics, Leicester LE1 7RH, UK.

    • Gudmundur A. Thorisson

  37. Johns Hopkins University School of Medicine, McKusick-Nathans Institute of Genetic Medicine, Broadway Research Building, Suite 579, 733 N. Broadway, Baltimore, Maryland 21205, USA.

    • Aravinda Chakravarti
    • , Peter E. Chen
    • , David J. Cutler
    • , Carl S. Kashuk
    •  & Shin Lin

  38. University of Michigan, Center for Statistical Genetics, Department of Biostatistics, 1420 Washington Heights, Ann Arbor, Michigan 48109, USA.

    • Gonçalo R. Abecasis (Principal Investigator)
    • , Weihua Guan
    • , Yun Li
    •  & Zhaohui Steve Qin

  39. International Epidemiology Institute, 1455 Research Boulevard, Suite 550, Rockville, Maryland 20850, USA.

    • Heather M. Munro

  40. Center for Biomolecular Science and Engineering, Engineering 2, Suite 501, Mail Stop CBSE/ITI, UC Santa Cruz, Santa Cruz, California 95064, USA.

    • Daryl J. Thomas

  41. University of Oxford, Department of Statistics, 1 South Parks Road, Oxford OX1 3TG, UK.

    • Gilean McVean (Project Leader)
    • , Adam Auton
    • , Leonardo Bottolo
    • , Niall Cardin
    • , Susana Eyheramendy
    • , Colin Freeman
    • , Jonathan Marchini
    • , Simon Myers
    •  & Peter Donnelly

  42. University of Chicago, Department of Statistics, 5734 S. University Avenue, Eckhart Hall, Room 126, Chicago, Illinois 60637, USA.

    • Matthew Stephens

  43. Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.

    • Lon R. Cardon (Principal Investigator)

  44. University of Oxford/Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.

    • Geraldine Clarke
    • , David M. Evans
    •  & Andrew P. Morris

  45. University of Washington Department of Biostatistics, Box 357232, Seattle, Washington 98195, USA.

    • Bruce S. Weir

  46. US National Institutes of Health, National Human Genome Research Institute, 50 South Drive, Bethesda, Maryland 20892, USA.

    • James C. Mullikin

  47. US National Institutes of Health, National Library of Medicine, National Center for Biotechnology Information, 8600 Rockville Pike, Bethesda, Maryland 20894, USA.

    • Stephen T. Sherry
    •  & Michael Feolo

  48. University of Chicago, Department of Medicine, Section of Genetic Medicine, 5801 South Ellis, Chicago, Illinois 60637, USA.

    • Andrew Skol

  49. Beijing Normal University, 19 Xinjiekouwai Street, Beijing 100875, China.

    • Houcan Zhang

  50. Health Sciences University of Hokkaido, Ishikari Tobetsu Machi 1757, Hokkaido 061-0293, Japan.

    • Ichiro Matsuda (Principal Investigator)

  51. Shinshu University School of Medicine, Department of Medical Genetics, Matsumoto 390-8621, Japan.

    • Yoshimitsu Fukushima

  52. United Nations Educational, Scientific and Cultural Organization (UNESCO Bangkok), 920 Sukhumwit Road, Prakanong, Bangkok 10110, Thailand.

    • Darryl R. Macer

  53. University of Tsukuba, Eubios Ethics Institute, PO Box 125, Tsukuba Science City 305-8691, Japan.

    • Eiko Suda

  54. Howard University, National Human Genome Center, 2216 6th Street, NW, Washington, District of Columbia 20059, USA.

    • Charles N. Rotimi (Principal Investigator)
    •  & Charmaine D. M. Royal

  55. University of Ibadan College of Medicine, Ibadan, Oyo State, Nigeria.

    • Clement A. Adebamowo
    • , Ike Ajayi
    • , Toyin Aniagwu
    • , Chibuzor Nkwodimmah
    •  & Isaac F. Adewole

  56. Case Western Reserve University School of Medicine, Department of Bioethics, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.

    • Patricia A. Marshall

  57. University of Utah, Eccles Institute of Human Genetics, Department of Human Genetics, 15 North 2030 East, Salt Lake City, Utah 84112, USA.

    • Mark F. Leppert (Principal Investigator)
    • , Missy Dixon
    •  & Andy Peiffer

  58. Chinese Academy of Social Sciences, Institute of Philosophy/Center for Applied Ethics, 2121, Building 9, Caoqiao Xinyuan 3 Qu, Beijing 100067, China.

    • Renzong Qiu

  59. Genetic Interest Group, 4D Leroy House, 436 Essex Road, London N130P, UK.

    • Alastair Kent

  60. Kyoto University, Institute for Research in Humanities and Graduate School of Biostudies, Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan.

    • Kazuto Kato

  61. Nagasaki University Graduate School of Biomedical Sciences, Department of Human Genetics, Sakamoto 1-12-4, Nagasaki 852-8523, Japan.

    • Norio Niikawa

  62. University of Oklahoma, Department of Anthropology, 455 W. Lindsey Street, Norman, Oklahoma 73019, USA.

    • Morris W. Foster

  63. Vanderbilt University, Center for Genetics and Health Policy, 507 Light Hall, Nashville, Tennessee 37232, USA.

    • Ellen Wright Clayton

  64. Wellcome Trust, 215 Euston Road, London NW1 2BE, UK.

    • Jessica Watkin
    • , Ruth Jamieson
    •  & John Stewart

  65. Washington University School of Medicine, Genome Sequencing Center, Box 8501, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA.

    • David Altshuler (Principal Investigator)
    • , Richard K. Wilson
    •  & Lucinda L. Fulton

  66. Chinese Academy of Sciences, 52 Sanlihe Road, Beijing 100864, China.

    • Zhu Chen
    • , Hua Han
    •  & Le Kang

  67. Genome Canada, 150 Metcalfe Street, Suite 2100, Ottawa, Ontario K2P 1P1, Canada.

    • Martin Godbout
    •  & Karen Kennedy

  68. McGill University, Office of Technology Transfer, 3550 University Street, Montréal, Québec H3A 2A7, Canada.

    • John C. Wallenburg

  69. Génome Québec, 630, boulevard René-Lévesque Ouest, Montréal, Québec H3B 1S6, Canada.

    • Paul L'Archevêque
    •  & Guy Bellemare

  70. Ministry of Education, Culture, Sports, Science, and Technology, 3-2-2 Kasumigaseki, Chiyodaku, Tokyo 100-8959, Japan.

  71. Ministry of Science and Technology of the People's Republic of China, 15 B. Fuxing Road, Beijing 100862, China.

    • Koji Saeki
    • , Hongguang Wang
    • , Daochang An
    • , Hongbo Fu
    • , Qing Li
    •  & Zhen Wang

  72. The Human Genetic Resource Administration of China, b7, Zaojunmiao, Haidian District, Beijing 100081, China.

  73. US National Institutes of Health, National Human Genome Research Institute, 5635 Fishers Lane, Bethesda, Maryland 20892, USA.

    • Renwu Wang
    • , Lisa D. Brooks
    • , Jean E. McEwen
    • , Mark S. Guyer
    • , Vivian Ota Wang
    • , Jane L. Peterson
    •  & Lynn F. Zacharia

  74. US National Institutes of Health, Office of Behavioral and Social Science Research, 31 Center Drive, Bethesda, Maryland 20892, USA.

    • Vivian Ota Wang

  75. Novartis Pharmaceuticals Corporation, Biomarker Development, One Health Plaza, East Hanover, New Jersey 07936, USA.

    • Michael Shi

  76. US National Institutes of Health, Office of Technology Transfer, 6011 Executive Boulevard, Rockville, Maryland 20852, USA.

    • Jack Spiegel

  77. University of Maryland School of Law, 500 W. Baltimore Street, Baltimore, Maryland 21201, USA.

    • Lawrence M. Sung

  78. US National Institutes of Health, National Human Genome Research Institute, 31 Center Drive, Bethesda, Maryland 20892, USA.

    • Francis S. Collins

Consortia

  1. The International HapMap Consortium

    Lists of participants and affiliations appear at the end of the paper.

    Genotyping centres: Perlegen Sciences

    Baylor College of Medicine and ParAllele BioScience

    Beijing Genomics Institute

    Broad Institute of Harvard and Massachusetts Institute of Technology

    Chinese National Human Genome Center at Beijing

    Chinese National Human Genome Center at Shanghai

    Chinese University of Hong Kong

    Hong Kong University of Science and Technology

    Illumina

    McGill University and Génome Québec Innovation Centre

    University of California at San Francisco and Washington University

    University of Hong Kong

    University of Tokyo and RIKEN

    Wellcome Trust Sanger Institute

    Analysis groups: Broad Institute

    Cold Spring Harbor Laboratory

    Johns Hopkins University School of Medicine

    University of Michigan

    University of Oxford

    University of Oxford, Wellcome Trust Centre for Human Genetics

    RIKEN

    US National Institutes of Health

    US National Institutes of Health National Center for Biotechnology Information

    Community engagement/public consultation and sample collection groups: Beijing Normal University and Beijing Genomics Institute

    Health Sciences University of Hokkaido, Eubios Ethics Institute and Shinshu University

    Howard University and University of Ibadan

    University of Utah

    Ethical, legal and social issues: Chinese Academy of Social Sciences

    Genetic Interest Group

    Kyoto University

    Nagasaki University

    University of Ibadan School of Medicine

    University of Montréal

    University of Oklahoma

    Vanderbilt University

    Wellcome Trust

    SNP discovery: Baylor College of Medicine

    Broad Institute of Harvard and Massachusetts Institute of Technology

    Washington University

    Wellcome Trust Sanger Institute

    Scientific management: Chinese Academy of Sciences

    Genome Canada

    Génome Québec

    Japanese Ministry of Education, Culture, Sports, Science and Technology

    Ministry of Science and Technology of the People’s Republic of China

    The Human Genetic Resource Administration of China

    The SNP Consortium

    US National Institutes of Health

    Wellcome Trust

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Competing interests

The authors declare no competing financial interests.

Supplementary information

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  1. 1.

    Supplementary Information

    The file contains Supplementary Methods, Supplementary Figures S1-S10 with Legends and Supplementary Tables 1-11.  Supplementary Methods give details of LRH, iHS, XP-EHH, and localization analysis, including simulations and power calculations, Sweep software, ruling out confounders and details of identification of functional elements in the top candidates.  Supplementary Tables illustrate power calculations for LRH, iHS, and XP-EHH, candidate regions and polymorphisms found from several analysis, fraction of SNPs predicted to be in the HapMap and dbSNP, as well as locations of copy number variants in the top candidates.   Supplementary Figures show schematic of localization heuristic, power of LRH, iHS, and XP-EHH, top XP-EHH candidate,. localization of signal in LCT region, conservation, protein sequence and structure prediction, global variation, and examination of copy number variants for SLC24A5 and EDAR.

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https://doi.org/10.1038/nature06250

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