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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The International Haplotype Map Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Carlson, C.S. et al. Genomic regions exhibiting positive selection identified from dense genotype data. Genome Res. 15, 1553–1565 (2005).
Sabeti, P.C. et al. Genome-wide detection and characterization of positive selection in human populations. Nature 449, 913–918 (2007).
Voight, B.F., Kudaravalli, S., Wen, X. & Pritchard, J.K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006).
Williamson, S.H. et al. Localizing recent adaptive evolution in the human genome. PLoS Genet. 3, e90 (2007).
Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).
Tishkoff, S.A. et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat. Genet. 39, 31–40 (2007).
Hamblin, M.T. & Di Rienzo, A. Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. Am. J. Hum. Genet. 66, 1669–1679 (2000).
Weir, C.L. & Cockerham, C.C. Estimating F-statistics for the analysis of population structure. Evolution 38, 1358–1370 (1984).
Excoffier, L., Smouse, P.E. & Quattro, J.M. Analysis of molecular variance inferred from metric distances among DNA haplotypes: application to human mitochondrial DNA restriction data. Genetics 131, 479–491 (1992).
Nielsen, R. Molecular signatures of natural selection. Annu. Rev. Genet. 39, 197–218 (2005).
Akey, J.M., Zhang, G., Zhang, K., Jin, L. & Shriver, M.D. Interrogating a high-density SNP map for signatures of natural selection. Genome Res. 12, 1805–1814 (2002).
Weir, B.S., Cardon, L.R., Anderson, A.D., Nielsen, D.M. & Hill, W.G. Measures of human population structure show heterogeneity among genomic regions. Genome Res. 15, 1468–1476 (2005).
Clark, A.G., Hubisz, M.J., Bustamante, C.D., Williamson, S.H. & Nielsen, R. Ascertainment bias in studies of human genome-wide polymorphism. Genome Res. 15, 1496–1502 (2005).
Hinds, D.A. et al. Whole-genome patterns of common DNA variation in three human populations. Science 307, 1072–1079 (2005).
Ramensky, V., Bork, P. & Sunyaev, S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002).
Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22, 231–238 (1999).
Williamson, S.H. et al. Simultaneous inference of selection and population growth from patterns of variation in the human genome. Proc. Natl. Acad. Sci. USA 102, 7882–7887 (2005).
Kelley, J.L., Madeoy, J., Calhoun, J.C., Swanson, W. & Akey, J.M. Genomic signatures of positive selection in humans and the limits of outlier approaches. Genome Res. 16, 980–989 (2006).
McVean, G. & Spencer, C.C. Scanning the human genome for signals of selection. Curr. Opin. Genet. Dev. 16, 624–629 (2006).
Sabeti, P.C. et al. Positive natural selection in the human lineage. Science 312, 1614–1620 (2006).
Teshima, K.M., Coop, G. & Przeworski, M. How reliable are empirical genomic scans for selective sweeps? Genome Res. 16, 702–712 (2006).
Sabeti, P.C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).
Monreal, A.W. et al. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat. Genet. 22, 366–369 (1999).
Mou, C., Jackson, B., Schneider, P., Overbeek, P.A. & Headon, D.J. Generation of the primary hair follicle pattern. Proc. Natl. Acad. Sci. USA 103, 9075–9080 (2006).
Cockburn, I.A. et al. A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc. Natl. Acad. Sci. USA 101, 272–277 (2004).
Meyre, D. et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat. Genet. 37, 863–867 (2005).
Di Rienzo, A. & Hudson, R.R. An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet. 21, 596–601 (2005).
Drake, J.A. et al. Conserved noncoding sequences are selectively constrained and not mutation cold spots. Nat. Genet. 38, 223–227 (2006).
Williamson, S. & Orive, M.E. The genealogy of a sequence subject to purifying selection at multiple sites. Mol. Biol. Evol. 19, 1376–1384 (2002).
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).
About this article
Cite this article
Barreiro, L., Laval, G., Quach, H. et al. Natural selection has driven population differentiation in modern humans. Nat Genet 40, 340–345 (2008). https://doi.org/10.1038/ng.78
The Journal of Poultry Science (2021)
Molecular Genetics & Genomic Medicine (2021)
Scanning the human genome for “signatures” of positive selection: Transformative opportunities and ethical obligations
Evolutionary Anthropology: Issues, News, and Reviews (2021)
Global climate change, diet, and the complex relationship between human host and microbiome: Towards an integrated picture
No association of GSTP1 rs1695 polymorphism with amyotrophic lateral sclerosis: A case-control study in the Brazilian population
PLOS ONE (2021)