Article | Published:

The landscape of recombination in African Americans

Nature volume 476, pages 170175 (11 August 2011) | Download Citation

Abstract

Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value < 10−245). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution.

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Acknowledgements

We are grateful to the participants who donated DNA samples, to D. Altshuler, J. Buard, K. Bryc, J. Kovacs, B. de Massy, G. McVean, B. Pasaniuc and S. Sankararaman for conversations and critiques, and to A. Auton for facilitating analysis of the 1000 Genomes Project data. Analysis was supported by the Wellcome Trust and NIH grants HL084107 and GM091332. CARe was supported by a contract from the National Heart, Lung and Blood Institute (HHSN268200960009C) to create a phenotype and genotype database for dissemination to the biomedical research community. Eight parent studies contributed phenotypic data and DNA samples through the Broad Institute (N01-HC-65226): the Atherosclerosis Risk in Communities study (ARIC), the Cleveland Family Study (CFS), the Coronary Artery Risk Development in Young Adults study (CARDIA), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA) study, the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS) and the Sleep Heart Health Study (SHHS). Support for CARe also came from the individual research institutions, investigators, field staff and study participants. Individual funding information is available at http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx. All genome-wide genotyping of samples from the Children’s Hospital of Pennsylvania (CHOP) was supported by an Institutional Development Award to the Center for Applied Genomics from the Children’s Hospital of Philadelphia, a research award from the Landenberger Foundation and the Cotswold Foundation. We thank all study participants and the staff at the Center for Applied Genomics for performing the genotyping. The African American Breast Cancer Consortium (AABCC) was supported by a DoD Breast Cancer Research Program Era of Hope Scholar Award to C.A.H. and the Norris Foundation, and by grants to the component studies: MEC (CA63464, CA54281); CARE (HD33175); WCHS (CA100598, DAMD 170100334, Breast Cancer Research Foundation); SFBC (CA77305, DAMD 17966071); CBCS (CA58223, ES10126), PLCO (NCI Intramural Research Program); NHBS (CA100374); WFBC (R01-CA73629); and CPS-II (the American Cancer Society). The African American Prostate Cancer Consortium (AAPCC) was supported by grants CA63464, CA54281, CA1326792, CA148085 and HG004726, and by grants to the component studies: PLCO (NCI Intramural Research Program), LAAPC (Cancer Research Fund 99-00524V-10258), both MEC and LAAPC (PC35139, DP000807); MDA (CA68578, CA140388, ES007784, DAMD W81XWH0710645); GECAP (ES011126); CaP Genes (CA88164); IPCG (W81XWH0710122); DCPC (GM08016, DAMD W81XWH0710203, DAMD W81XWH0610066); and SCCS (CA092447, CA68485). The African American Lung Cancer Consortium (AALCC) was supported by grants CA060691, CA87895, PC35145 and CA22453, CA68578, CA140388, ES007784, ES06717, CA55769, CA127219, CA1116460S1, CA1116460, CA121197, CA141716, CA121197S2, CPRIT RP100443, CA148127, DAMD W81XWH0710645, University Cancer Foundation, Duncan Family institute, Center for Community, Implementation and Dissemination Research Core, and by grants to the component studies: PLCO and the Maryland Studies (NCI Intramural Research Program), LAAPC (Cancer Research Fund 99-00524V-10258), and both MEC and LAAPC (PC35139, DP000807).

Author information

Author notes

    • David Reich
    •  & Simon R. Myers

    These authors contributed equally to this work.

Affiliations

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

    • Anjali G. Hinch
    •  & Simon R. Myers
  2. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Arti Tandon
    • , Nick Patterson
    • , Nadin Rohland
    •  & David Reich
  3. Deptartment of Genetics, Harvard Medical School, New Research Building, 77 Ave. Louis Pasteur, Boston, Massachusetts 02115, USA.

    • Arti Tandon
    • , Nadin Rohland
    •  & David Reich
  4. Department of Statistics, Oxford University, 1 South Parks Road, Oxford OX1 3TG, UK.

    • Yunli Song
    •  & Simon R. Myers
  5. Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Cameron D. Palmer
    •  & Joel N. Hirschhorn
  6. Divisions of Endocrinology and Genetics and Program in Genomics, Children’s Hospital Boston, Massachusetts 02115, USA.

    • Cameron D. Palmer
    •  & Joel N. Hirschhorn
  7. Department of Preventive Medicine and Department of Pathology, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.

    • Gary K. Chen
    • , Graham Casey
    • , Sue A. Ingles
    • , Michael F. Press
    • , Brian E. Henderson
    •  & Christopher A. Haiman
  8. Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90089, USA.

    • Kai Wang
  9. Center for Applied Genomics, The Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

    • Kai Wang
    • , Joseph Glessner
    • , Brendan Keating
    •  & Hakon Hakonarson
  10. Jackson Heart Study Coordinating Center, Jackson State University, 350 W. Woodrow Wilson Ave., Suite 701, Jackson, Mississippi 39213, USA.

    • Sarah G. Buxbaum
    •  & Ermeg L. Akylbekova
  11. Department of Medicine, University of Mississippi Medical Center, 2500 N. State St., Jackson, Mississippi 39216, USA.

    • Ermeg L. Akylbekova
    • , Solomon Musani
    •  & Herman A. Taylor Jr
  12. Department of Thoracic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.

    • Melinda C. Aldrich
  13. Division of Epidemiology in the Department of Medicine, Vanderbilt Epidemiology Center; and the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.

    • Melinda C. Aldrich
    • , William J. Blot
    • , Qiuyin Cai
    • , Sandra L. Deming
    • , Lisa B. Signorello
    •  & Wei Zheng
  14. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

    • Christine B. Ambrosone
  15. Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

    • Christopher Amos
    • , Margaret Spitz
    •  & Xifeng Wu
  16. The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.

    • Elisa V. Bandera
  17. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.

    • Sonja I. Berndt
    • , Neil Caporaso
    • , Margaret A. Tucker
    • , Regina G. Ziegler
    •  & Stephen J. Chanock
  18. Division of Cancer Etiology, Department of Population Science, Beckman Research Institute, City of Hope, California 91010, USA.

    • Leslie Bernstein
  19. International Epidemiology Institute, Rockville, Maryland 20850, USA.

    • William J. Blot
    •  & Lisa B. Signorello
  20. Karmanos Cancer Institute and Department of Oncology, Wayne State University of Medicine, Detroit, Michigan 48201, USA.

    • Cathryn H. Bock
    •  & Ann G. Schwartz
  21. Human Genetics Center and Division of Epidemiology, University of Texas at Houston, 1200 Herman Pressler St., Houston, Texas 77030, USA.

    • Eric Boerwinkle
  22. Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118 and Framingham Heart Study, Framingham, Massachusetts 01702, USA.

    • L. Adrienne Cupples
  23. Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.

    • W. Ryan Diver
    •  & Michael J. Thun
  24. Department of Biostatistical Sciences, Wake Forest University School of Medicine WC-2326, Medical Center Blvd., Winston Salem, North Carolina 27157, USA.

    • Jasmin Divers
  25. Institute of Molecular Medicine and Division of Epidemiology, School of Public Health, University of Texas Health Sciences Center at Houston, 1825 Pressler Street, Houston, Texas 77030, USA.

    • Myriam Fornage
  26. Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.

    • Elizabeth M. Gillanders
    •  & Krista A. Zanetti
  27. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.

    • Curtis C. Harris
    •  & Krista A. Zanetti
  28. Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.

    • Jennifer J. Hu
    •  & Jorge L. Rodriguez-Gil
  29. James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institutions, Baltimore, Maryland 21287, USA.

    • William Isaacs
  30. Cancer Prevention Institute of California, Fremont, California 94538; and Stanford University School of Medicine and Stanford Cancer Center, Stanford, California 94305, USA.

    • Esther M. John
  31. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, Maryland 21205, USA.

    • W. H. Linda Kao
  32. Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607, USA.

    • Rick A. Kittles
  33. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.

    • Laurence N. Kolonel
    •  & Loic Le Marchand
  34. Department of Medicine, Division of Allergy, Pulmonary and Critical Care, 6100 Medical Center East, Vanderbilt University Medical Center, Nashville, Tennessee 37232-8300, USA.

    • Emma Larkin
  35. Department of Health Disparities Research, Division of OVP, Cancer Prevention and Population Sciences, and Center for Community Implementation and Dissemination Research, Duncan Family Institute, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

    • Lorna H. McNeill
  36. Department of Epidemiology, Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Robert C. Millikan
    •  & Sarah Nyante
  37. Department of Urology, Northwestern University, Chicago, Illinois 60611, USA.

    • Murphy
  38. Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan 48202, USA.

    • Christine Neslund-Dudas
    •  & Benjamin A. Rybicki
  39. Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, 6701 Rockledge Drive, Bethesda, Maryland 20892, USA.

    • George J. Papanicolaou
  40. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology & Health Services, University of Washington; Group Health Research Institute; Group Health Cooperative; 1730 Minor Ave., Seattle, Washington 98101, USA.

    • Bruce M. Psaty
  41. Department of Epidemiology, University of Washington, Box 357236 Seattle, Washington 98195, USA.

    • Alex P. Reiner
  42. Center for Public Health Genomics, University of Virginia, West Complex Room 6111, Charlottesville, Virginia 22908, USA.

    • Stephen S. Rich
  43. Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, California 90048, USA.

    • Jerome I. Rotter
  44. Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

    • Sara S. Strom
    •  & Yuko Yamamura
  45. Core Genotype Facility, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland 20877, USA.

    • Zhaoming Wang
  46. University of California San Francisco, San Francisco, California 94158, USA.

    • John K. Wiencke
    •  & Margaret Wrensch
  47. Institute for Human Genetics, Departments of Epidemiology and Biostatistics and Urology, University of California, San Francisco, San Francisco, California 94158, USA.

    • John S. Witte
  48. Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Wolstein Research Building, Cleveland, Ohio 4106, USA.

    • Xiaofeng Zhu
  49. Brigham and Women’s Hospital, Department of Medicine, Division of Sleep Medicine, 75 Francis Street, Boston, Massachusetts 02115, USA.

    • Susan Redline
  50. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Joel N. Hirschhorn
  51. Jackson State University, 1400 Lynch Street, Jackson, Mississippi 39217, USA.

    • Herman A. Taylor Jr
  52. Tougaloo College, 500 West County Line Road, Tougaloo, Mississippi 39174, USA.

    • Herman A. Taylor Jr
  53. Departments of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Alkes L. Price
  54. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    • Hakon Hakonarson
  55. Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State St., Jackson, Mississippi 39216, USA.

    • James G. Wilson

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Contributions

D.R. and S.R.M. conceived the study. A.G.H., A.T., N.P., Y.S., N.R., C.D.P., G.K.C., K.W., S.G.B., D.R. and S.R.M. performed analyses. N.R. performed the experimental work (genotyping of polymorphisms at PRDM9). A.G.H., N.P., J.N.H., B.E.H., H.A.T. Jr, A.L.P., H.H., S.J.C., C.A.H., J.G.W., D.R. and S.R.M. coordinated the study. A.G.H., D.R. and S.R.M. wrote the paper. N.R., C.D.P., G.K.C., K.W., S.G.B., S.R., J.N.H., B.E.H., H.A.T. Jr, H.H., S.J.C., C.A.H., J.G.W., D.R. and all the alphabetically listed authors contributed to sample collection and generation of SNP array data. All authors contributed to revision and review of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David Reich.

Crossover rate estimates for the AA map can be found at http://www.well.ox.ac.uk/~anjali/AAmap/. We also provide estimates of uncertainty for the map based on samples from the MCMC. Association testing results for each SNP are available from the authors on request.

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    Supplementary Information

    The file contains Supplementary Notes 1-6, Supplementary Tables 1-2 and Supplementary Figures 1-11 with legends.

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DOI

https://doi.org/10.1038/nature10336

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