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Natural selection has driven population differentiation in modern humans


The considerable range of observed phenotypic variation in human populations may reflect, in part, distinctive processes of natural selection and adaptation to variable environmental conditions. Although recent genome-wide studies have identified candidate regions under selection1,2,3,4,5, it is not yet clear how natural selection has shaped population differentiation. Here, we have analyzed the degree of population differentiation at 2.8 million Phase II HapMap single-nucleotide polymorphisms6. We find that negative selection has globally reduced population differentiation at amino acid–altering mutations, particularly in disease-related genes. Conversely, positive selection has ensured the regional adaptation of human populations by increasing population differentiation in gene regions, primarily at nonsynonymous and 5′-UTR variants. Our analyses identify a fraction of loci that have contributed, and probably still contribute, to the morphological and disease-related phenotypic diversity of current human populations.

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Figure 1: Consistent enrichment of nonsynonymous SNPs showing low degrees of population differentiation (FST).
Figure 2: Enrichment of nonsynonymous SNPs presenting low FST among low-frequency variants.
Figure 3: Imprints of negative selection in the human genome.
Figure 4: Imprints of positive selection in the human genome.
Figure 5: Enrichment of genic SNPs presenting high FST when matching for different allele frequency bins.


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We acknowledge the International HapMap Consortium and Perlegen Sciences for making available their datasets to the scientific community; J. Hey for providing the forward population genetics (FPG) simulation program; S. Sunyaev for help with Polyphen analyses; M. Przeworski, R. Nielsen and E. Heyer for helpful suggestions and discussion; and L. Abel, T. Bourgeron, J.L. Casanova, S. Jamain, K. McElreavey and O. Neyrolles for critical reading of the manuscript. Financial support was provided by Institut Pasteur, by the Centre National de la Recherche Scientifique (CNRS) and by an Agence Nationale de la Recherche (ANR) research grant (ANR-05-JCJC-0124-01). L.B.B. is supported by a “Fundação para a Ciência e a Tecnologia” fellowship (SFRH/BD/18580/2004), and E.P. by the Fondation pour la Recherche Médicale (FRM).

Author information




L.B.B., G.L., E.P. and L.Q.-M. conceived the study. The data analyses were primarily performed by L.B.B and G.L., with contributions from E.P. H.Q. performed the genotyping experiments. The paper was written primarily by L.B.B. and L.Q.-M., with contributions from G.L. and E.P.

Corresponding author

Correspondence to Lluís Quintana-Murci.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Note (PDF 1252 kb)

Supplementary Table 1

Exhaustive list of 582 genes containing at least one genic mutation showing signs of positive selection (XLS 203 kb)

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Barreiro, L., Laval, G., Quach, H. et al. Natural selection has driven population differentiation in modern humans. Nat Genet 40, 340–345 (2008).

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