Originally published as Genetics Published Articles Ahead of Print on May 23, 2005.

Genetics, Vol. 170, 1181-1187, July 2005, Copyright © 2005
doi:10.1534/genetics.104.037077

Effects of Natural Selection on Interpopulation Divergence at Polymorphic Sites in Human Protein-Coding Loci

Austin L. Hughes^*,1, Bernice Packer^,, Robert Welch^,, Andrew W. Bergen, Stephen J. Chanock^, and Meredith Yeager^,

^* Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208
Intramural Research Support Program, SAIC-Frederick, NCI-FCRDC, Frederick, Maryland 21702
Core Genotyping Facility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4605
Section on Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Gaithersburg, Maryland 20892-4605

¹ Corresponding author: Department of Biological Sciences, University of South Carolina, Coker Life Sciences Bldg., 700 Sumter St., Columbia, SC 29208.
E-mail: austin{at}biol.sc.edu

To develop new strategies for searching for genetic associations with complex human diseases, we analyzed 2784 single-nucleotide polymorphisms (SNPs) in 396 protein-coding genes involved in biological processes relevant to cancer and other complex diseases, with respect to gene diversity within samples of individuals representing the three major historic human populations (African, European, and Asian) and with respect to interpopulation genetic distance. Reduced levels of both intrapopulation gene diversity and interpopulation genetic distance were seen in the case of SNPs located within the 5'-UTR and at nonsynonymous SNPs, causing radical changes to protein structure. Reduction of gene diversity at SNP loci in these categories was evidence of purifying selection acting at these sites, which in turn causes a reduction in interpopulation divergence. By contrast, a small number of SNP sites in these categories revealed unusually high genetic distances between the two most diverged populations (African and Asian); these loci may have historically been subject to divergent selection pressures.

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