Originally published as Genetics Published Articles Ahead of Print on September 7, 2009.

Genetics, Vol. 183, 1065-1077, November 2009, Copyright © 2009
doi:10.1534/genetics.109.107722

Population Differentiation as an Indicator of Recent Positive Selection in Humans: An Empirical Evaluation

Yali Xue^*,1, Xuelong Zhang^*,,1, Ni Huang^*, Allan Daly^*, Christopher J. Gillson^*,2, Daniel G. MacArthur^*, Bryndis Yngvadottir^*, Alexandra C. Nica^*, Cara Woodwark^*, Yuan Chen, Donald F. Conrad^*, Qasim Ayub^*, S. Qasim Mehdi, Pu Li and Chris Tyler-Smith^*,3

^* The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, United Kingdom, Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, United Kingdom and Sindh Institute of Urology and Transplantation, Karachi 74200, Pakistan

³ Corresponding author: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, United Kingdom.
E-mail: cts{at}sanger.ac.uk

We have evaluated the extent to which SNPs identified by genomewide surveys as showing unusually high levels of population differentiation in humans have experienced recent positive selection, starting from a set of 32 nonsynonymous SNPs in 27 genes highlighted by the HapMap1 project. These SNPs were genotyped again in the HapMap samples and in the Human Genome Diversity Project–Centre d'Etude du Polymorphisme Humain (HGDP–CEPH) panel of 52 populations representing worldwide diversity; extended haplotype homozygosity was investigated around all of them, and full resequence data were examined for 9 genes (5 from public sources and 4 from new data sets). For 7 of the genes, genotyping errors were responsible for an artifactual signal of high population differentiation and for 2, the population differentiation did not exceed our significance threshold. For the 18 genes with confirmed high population differentiation, 3 showed evidence of positive selection as measured by unusually extended haplotypes within a population, and 7 more did in between-population analyses. The 9 genes with resequence data included 7 with high population differentiation, and 5 showed evidence of positive selection on the haplotype carrying the nonsynonymous SNP from skewed allele frequency spectra; in addition, 2 showed evidence of positive selection on unrelated haplotypes. Thus, in humans, high population differentiation is (apart from technical artifacts) an effective way of enriching for recently selected genes, but is not an infallible pointer to recent positive selection supported by other lines of evidence.

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