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Fine-scale recombination rate differences between sexes, populations and individuals - Nature

  • ️Stefansson, Kari
  • ️Wed Oct 27 2010

Abstract

Meiotic recombinations contribute to genetic diversity by yielding new combinations of alleles. Recently, high-resolution recombination maps were inferred from high-density single-nucleotide polymorphism (SNP) data using linkage disequilibrium (LD) patterns that capture historical recombination events1,2. The use of these maps has been demonstrated by the identification of recombination hotspots2 and associated motifs3, and the discovery that the PRDM9 gene affects the proportion of recombinations occurring at hotspots4,5,6. However, these maps provide no information about individual or sex differences. Moreover, locus-specific demographic factors like natural selection7 can bias LD-based estimates of recombination rate. Existing genetic maps based on family data avoid these shortcomings8, but their resolution is limited by relatively few meioses and a low density of markers. Here we used genome-wide SNP data from 15,257 parent–offspring pairs to construct the first recombination maps based on directly observed recombinations with a resolution that is effective down to 10 kilobases (kb). Comparing male and female maps reveals that about 15% of hotspots in one sex are specific to that sex. Although male recombinations result in more shuffling of exons within genes, female recombinations generate more new combinations of nearby genes. We discover novel associations between recombination characteristics of individuals and variants in the PRDM9 gene and we identify new recombination hotspots. Comparisons of our maps with two LD-based maps inferred from data of HapMap populations of Utah residents with ancestry from northern and western Europe (CEU) and Yoruba in Ibadan, Nigeria (YRI) reveal population differences previously masked by noise and map differences at regions previously described as targets of natural selection.

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References

  1. McVean, G. A. et al. The fine-scale structure of recombination rate variation in the human genome. Science 304, 581–584 (2004)

    Article  ADS  CAS  Google Scholar 

  2. Myers, S., Bottolo, L., Freeman, C., McVean, G. & Donnelly, P. A fine-scale map of recombination rates and hotspots across the human genome. Science 310, 321–324 (2005)

    Article  ADS  CAS  Google Scholar 

  3. Myers, S., Freeman, C., Auton, A., Donnelly, P. & McVean, G. A common sequence motif associated with recombination hot spots and genome instability in humans. Nature Genet. 40, 1124–1129 (2008)

    Article  CAS  Google Scholar 

  4. Baudat, F. et al. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327, 836–840 (2010)

    Article  ADS  CAS  Google Scholar 

  5. Myers, S. et al. Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science 327, 876–879 (2010)

    Article  ADS  CAS  Google Scholar 

  6. Parvanov, E. D., Petkov, P. M. & Paigen, K. Prdm9 controls activation of mammalian recombination hotspots. Science 327, 835 (2010)

    Article  ADS  CAS  Google Scholar 

  7. O’Reilly, P. F., Birney, E. & Balding, D. J. Confounding between recombination and selection, and the Ped/Pop method for detecting selection. Genome Res. 18, 1304–1313 (2008)

    Article  Google Scholar 

  8. Kong, A. et al. A high-resolution recombination map of the human genome. Nature Genet. 31, 241–247 (2002)

    Article  CAS  Google Scholar 

  9. Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nature Genet. 40, 1068–1075 (2008)

    Article  CAS  Google Scholar 

  10. Kong, A. et al. Parental origin of sequence variants associated with complex diseases. Nature 462, 868–874 (2009)

    Article  ADS  CAS  Google Scholar 

  11. Dempster, A. P., Laird, N. M. & Rubin, D. B. Maximum likelihood from incomplete data via the EM algorithm. J. R. Stat. Soc. B 39, 1–38 (1977)

    MathSciNet  MATH  Google Scholar 

  12. The International HapMap Consortium A haplotype map of the human genome. Nature 437, 1299–1320 (2005)

    Article  ADS  Google Scholar 

  13. Lang, M. R., Patterson, L. B., Gordon, T. N., Johnson, S. L. & Parichy, D. M. Basonuclin-2 requirements for zebrafish adult pigment pattern development and female fertility. PLoS Genet. 5, e1000744 (2009)

    Article  Google Scholar 

  14. Broman, K. W., Murray, J. C., Sheffield, V. C., White, R. L. & Weber, J. L. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am. J. Hum. Genet. 63, 861–869 (1998)

    Article  CAS  Google Scholar 

  15. Kong, A. et al. Sequence variants in the RNF212 gene associate with genome-wide recombination rate. Science 319, 1398–1401 (2008)

    Article  ADS  CAS  Google Scholar 

  16. Akey, J. M. Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res. 19, 711–722 (2009)

    Article  CAS  Google Scholar 

  17. Stefansson, H. et al. A common inversion under selection in Europeans. Nature Genet. 37, 129–137 (2005)

    Article  CAS  Google Scholar 

  18. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Reich for discussion and suggestions.

Author information

Authors and Affiliations

  1. deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland,

    Augustine Kong, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Gisli Masson, Asgeir Sigurdsson, Aslaug Jonasdottir, G. Bragi Walters, Adalbjorg Jonasdottir, Arnaldur Gylfason, Kari Th. Kristinsson, Sigurjon A. Gudjonsson, Michael L. Frigge, Agnar Helgason, Unnur Thorsteinsdottir & Kari Stefansson

  2. Department of Anthropology, University of Iceland, Sæmundargötu 2, 101 Reykjavik, Iceland,

    Agnar Helgason

  3. Faculty of Medicine, University of Iceland, Sæmundargötu 2, 101 Reykjavik, Iceland,

    Unnur Thorsteinsdottir & Kari Stefansson

Authors

  1. Augustine Kong

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  2. Gudmar Thorleifsson

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  3. Daniel F. Gudbjartsson

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  4. Gisli Masson

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  5. Asgeir Sigurdsson

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  6. Aslaug Jonasdottir

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  7. G. Bragi Walters

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  8. Adalbjorg Jonasdottir

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  9. Arnaldur Gylfason

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  10. Kari Th. Kristinsson

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  11. Sigurjon A. Gudjonsson

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  12. Michael L. Frigge

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  13. Agnar Helgason

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  14. Unnur Thorsteinsdottir

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  15. Kari Stefansson

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Contributions

A.K. and K.S. planned and directed the research. A.K. wrote the first draft of the paper and, with K.S., U.T. and A.H., wrote most of the final version. D.F.G. improved previous phasing procedures and, with G.M., made the recombination calls. G.T. created the maps and, with M.L.F., assisted A.K. in the analyses. U.T., Aslaug J., A.S., Adalbjorg J., K.T.K. and G.B.W. performed experiments providing information on sequences at the PRDM9 gene. A.G. did the variant imputations. G.M. and S.A.G. determined the locations and intensities of genomic features. A.H. assisted in the study on selection.

Corresponding authors

Correspondence to Augustine Kong or Kari Stefansson.

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Competing interests

The authors are all employees of deCode Genetics, a biotechnology company that provides genetic testing services, and own stocks or stock options in the company.

Additional information

The maps constructed in this study are available at http://www.decode.com/addendum.

Supplementary information

Supplementary Information

The file contains Supplementary Notes 1-10, Supplementary Tables 1-6, Supplementary Figures 1-4 with legends and additional references. (PDF 656 kb)

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Kong, A., Thorleifsson, G., Gudbjartsson, D. et al. Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467, 1099–1103 (2010). https://doi.org/10.1038/nature09525

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  • Received: 18 May 2010

  • Accepted: 14 September 2010

  • Published: 27 October 2010

  • Issue Date: 28 October 2010

  • DOI: https://doi.org/10.1038/nature09525

Editorial Summary

Recombination maps reveal differences between the sexes

High-resolution recombination maps serve many purposes in genetic research. The currently available maps, which use linkage disequilibrium patterns of high-density SNP (single nucleotide polymorphism) data from the HapMap project, have proved to be very useful. But they have some limitations; for instance, they do not provide information on differences in recombination characteristics between and within the sexes. A team at biopharmaceutical firm deCODE genetics in Reykjavik has used genome-wide SNP data from more than 15,000 parent–offspring pairs to construct the first recombination maps based on directly observed recombination events, providing resolution down to 10 kilobases. Their data reveal interesting recombination differences between the sexes. In males, for example, recombination tends to shuffle exons, whereas in females it generates new combinations of nearby genes. Comparisons of these maps with those based on linkage disequilibrium reveal previously unrecognized differences between populations in Europe, Africa and the United States.