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

Journal name:
Nature Genetics
Volume:
44,
Pages:
1015–1019
Year published:
DOI:
doi:10.1038/ng.2368
Received
Accepted
Published online

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).

At a glance

Figures

  1. Mean allele frequency difference of height SNPs, matched SNPs and genome-wide SNPs between Northern- and Southern-European populations.
    Figure 1: Mean allele frequency difference of height SNPs, matched SNPs and genome-wide SNPs between Northern- and Southern-European populations.

    (a) Mean frequency difference of the height-increasing alleles from 139 known height SNPs (solid red line) compared to that of 10,000 sets of randomly drawn SNPs matched by average Northern- and Southern-European allele frequencies to the known height SNPs on a per-SNP basis (purple dashed line). Blue dashed line, expected mean difference for matched SNPs (x = 0); NEur, Northern European; SEur, Southern European; AF, allele frequency. (b) Mean frequency difference of the height-increasing allele for sets of 500 independent (r2 < 0.1) SNPs across the genome, sorted by GIANT height-association P value. Red line, curve of best fit; purple dashed line, genome-wide mean frequency difference; blue dashed line, expected mean difference (y = 0).

  2. Within-family analyses of height and the Northern-predominant alleles across the genome.
    Figure 2: Within-family analyses of height and the Northern-predominant alleles across the genome.

    (a) Average regression coefficients of height versus number of Northern-predominant (N>S) alleles for sets of 500 SNPs sorted by GIANT height-association P value. Red line, curve of best fit; purple dashed line, curve of best fit for the GIANT effect sizes; blue dashed line, expected difference (y = 0). (b) Running averages of the regression coefficients (red and black circles; black indicates <0.01% of permuted values) sorted by GIANT height-association P value. Gray circles, running averages from 1,000 analyses where phenotypes were permuted within sibships; blue dashed line, expected running average (y = 0).

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Author information

  1. These authors contributed equally to this work.

    • Michael C Turchin &
    • Charleston WK Chiang

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

Consortia

  1. Genetic Investigation of ANthropometric Traits (GIANT) Consortium

  2. A full list of members and institutions is provided in the Supplementary Note.

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.

Competing financial interests

The authors declare no competing financial interests.

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Supplementary information

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  1. Supplementary Text and Figures (4M)

    Supplementary Tables 1–13, Supplementary Figures 1–10 and Supplementary Note

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