Signatures of demographic history and natural selection in the human MHC loci
Diogo Meyer 1*, Richard M Single 2, Steven J Mack 3, Henry A Erlich 3 and Glenys Thomson 4
1 University of São Paulo
2 University of Vermont
3 Roche Molecular Systems, USA and Children's Hospital Oakland Research Institute
4 University of California at Berkeley
* To whom correspondence should be addressed. E-mail: diogo{at}ib.usp.br.
Submitted on November 18, 2005
Revised on January 15, 2006
Accepted on 30 April 2006
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Abstract |
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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 the present study we address this challenge using data from a diverse set of human populations at 6 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 by demographic factors alone. For several populations linkage disequilibrium (LD) among HLA loci was higher than that between similarly spaced microsatellites, also indicating the role of selection. 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. Based on 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.
Key Words:
HLA, MHC, balancing selection, demography, linkage disequilibrium
