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Originally published as Genetics Published Articles Ahead of Print on May 15, 2006.

Genetics, Vol. 173, 2121-2142, August 2006, Copyright © 2006
doi:10.1534/genetics.105.052837

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Signatures of Demographic History and Natural Selection in the Human Major Histocompatibility Complex Loci

Diogo Meyer*,1,2, Richard M. Single{dagger},1, Steven J. Mack{ddagger},§, Henry A. Erlich{ddagger},§ and Glenys Thomson**

* Departamento de Genética e Evolução, Universidade de São Paulo, São Paulo, SP 05608-900, Brazil, {dagger} Department of Mathematics and Statistics, University of Vermont, Burlington, Vermont 05401, {ddagger} Children's Hospital Oakland Research Institute, Oakland, California 94609, § Department of Human Genetics, Roche Molecular Systems, Berkeley, California 94501 and ** Department of Integrative Biology, University of California, Berkeley, California 94720

2 Corresponding author: Departamento de Genética e Biologia Evolutiva, Universidade de São Paulo, Rua do Matão, 277, São Paulo, SP 05608-900, Brazil.
E-mail: diogo{at}ib.usp.br

Many lines of evidence show that several HLA loci have experienced balancing selection. However, distinguishing among demographic and selective explanations for patterns of variation observed with HLA genes remains a challenge. In this study we address this issue using data from a diverse set of human populations at six classical HLA loci and, employing a comparative genomics approach, contrast results for HLA loci to those for non-HLA markers. Using a variety of analytic methods, we confirm and extend evidence for selection acting on several HLA loci. We find that allele frequency distributions for four of the six HLA loci deviate from neutral expectations and show that this is unlikely to be explained solely by demographic factors. Other features of HLA variation are explained in part by demographic history, including decreased heterozygosity and increased LD for populations at greater distances from Africa and a similar apportionment of genetic variation for HLA loci compared to putatively neutral non-HLA loci. On the basis of contrasts among different HLA loci and between HLA and non-HLA loci, we conclude that HLA loci bear detectable signatures of both natural selection and demographic history.






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Copyright © 2006 by the Genetics Society of America.