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Evidence of widespread selection on standing variation in Europe at height-associated SNPs

Nature Genetics volume 44, pages 1015–1019 (2012)Cite this article

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Abstract

Strong signatures of positive selection at newly arising genetic variants are well documented in humans1,2,3,4,5,6,7,8, but this form of selection may not be widespread in recent human evolution9. Because many human traits are highly polygenic and partly determined by common, ancient genetic variation, an alternative model for rapid genetic adaptation has been proposed: weak selection acting on many pre-existing (standing) genetic variants, or polygenic adaptation10,11,12. By studying height, a classic polygenic trait, we demonstrate the first human signature of widespread selection on standing variation. We show that frequencies of alleles associated with increased height, both at known loci and genome wide, are systematically elevated in Northern Europeans compared with Southern Europeans (P < 4.3 × 10−4). This pattern mirrors intra-European height differences and is not confounded by ancestry or other ascertainment biases. The systematic frequency differences are consistent with the presence of widespread weak selection (selection coefficients ∼10−3–10−5 per allele) rather than genetic drift alone (P < 10−15).

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Figure 1: Mean allele frequency difference of height SNPs, matched SNPs and genome-wide SNPs between Northern- and Southern-European populations.
Figure 2: Within-family analyses of height and the Northern-predominant alleles across the genome.

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Acknowledgements

The authors would like to thank E.L. Altmaier, K.E. Samocha, S.R. Grossman, G. Coop, other attendees of the Biology of Genomes 2011 conference, B.F. Voight, M. McCarthy, P. Visscher and other members of the Reich and Hirschhorn labs for their discussions and helpful comments. We gratefully thank the GIANT consortium and particularly the members of the height working group for making unpublished association data available. We thank the MIGen consortium for making allele frequency data available. This research was conducted using data and resources from the FHS of the National Heart, Lung, and Blood Institute of the US National Institutes of Health and Boston University School of Medicine based on analyses by FHS investigators participating in the SNP Health Association Resource project. This work was supported by the National Heart, Lung and Blood Institute's FHS (contract no. N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (contract no. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This work was also supported by a graduate research fellowship from the National Science Foundation (to C.W.K.C.), the March of Dimes (6-FY09-507 to J.N.H.) and the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK075787 to J.N.H.).

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Author notes

  1. Michael C Turchin and Charleston WK Chiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Genetics, Children's Hospital Boston, Boston, Massachusetts, USA

    Michael C Turchin, Charleston WK Chiang, Cameron D Palmer & Joel N Hirschhorn

  2. Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA

    Michael C Turchin, Charleston WK Chiang, Cameron D Palmer & Joel N Hirschhorn

  3. Program in Genomics, Children's Hospital Boston, Boston, Massachusetts, USA

    Michael C Turchin, Charleston WK Chiang, Cameron D Palmer & Joel N Hirschhorn

  4. Metabolism Initiative, Broad Institute, Cambridge, Massachusetts, USA

    Michael C Turchin, Charleston WK Chiang, Cameron D Palmer & Joel N Hirschhorn

  5. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA

    Michael C Turchin, Charleston WK Chiang, Cameron D Palmer, Sriram Sankararaman, David Reich & Joel N Hirschhorn

  6. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Charleston WK Chiang, Sriram Sankararaman, David Reich & Joel N Hirschhorn

Authors
  1. Michael C Turchin
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  4. Sriram Sankararaman
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  6. Joel N Hirschhorn
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Consortia

Genetic Investigation of ANthropometric Traits (GIANT) Consortium

Contributions

M.C.T., C.W.K.C., C.D.P., S.S., D.R. and J.N.H. conceived of and designed the experiments; M.C.T. and C.D.P. performed the analyses; M.C.T., C.W.K.C. and J.N.H. interpreted the data; C.W.K.C., C.D.P., D.R. and the GIANT Consortium contributed materials; M.C.T., C.W.K.C. and J.N.H. wrote the paper with input from all coauthors.

Corresponding author

Correspondence to Joel N Hirschhorn.

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The authors declare no competing financial interests.

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Turchin, M., Chiang, C., Palmer, C. et al. Evidence of widespread selection on standing variation in Europe at height-associated SNPs. Nat Genet 44, 1015–1019 (2012). https://doi.org/10.1038/ng.2368

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