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Human Molecular Genetics Advance Access published online on May 22, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl134
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received April 7, 2006
Revised May 17, 2006
Accepted May 17, 2006

Article

TRPV6 Exhibits Unusual Patterns of Polymorphism and Divergence in Worldwide Populations

Joshua M. Akey 1 *, Willie J. Swanson 2, Jennifer Madeoy 2, Michael Eberle 2, and Mark D. Shriver 3

1 Department of Genome Sciences, University of Washington, 1705 NE Pacific St., Box 357730, HSB J-279, Seattle, WA. 98195-7730
2 Department of Genome Sciences, University of Washington, Seattle, Washington
3 Department of Anthropology, Pennsylvania State University, State College, Pennsylvania

* To whom correspondence should be addressed.
Joshua M. Akey, E-mail: akeyj{at}u.washington.edu


  Abstract

A striking footprint of positive selection was recently identified on chromosome 7q34-35 that spans at least 115 kb and encompasses four known genes (KEL, TRPV5, TRPV6, EPHB6). The signature of selection was observed in only one of the two populations analyzed suggesting the action of geographically restricted selective pressures. However, as only two populations were analyzed it remains unknown whether the signature of selection extends to additional populations. To address this issue and begin to dissect the evolutionary history of this region in more detail, we performed an in-depth population genetic analysis on TRPV6, which is a calcium permeable ion channel thought to mediate the rate-limiting step of dietary calcium absorption. We demonstrate that the rate of TRPV6 protein evolution is significantly accelerated in the human lineage, but only for a haplotype comprised of three non-synonymous SNPs (C157R, M378V, and M681T) that are nearly fixed for the derived alleles in non-African populations. Interestingly, we found that these three non-synonymous SNPs have high posterior probabilities for being targets of positive selection and are therefore strong candidates for mediating the population specific signatures of selection in this region. In addition, we resequenced the exons corresponding to the C157R, M378V, and M681T polymorphisms in 90 geographically diverse individuals and characterized their global allele frequency distribution by genotyping them in 1064 individuals from 52 populations. These data strongly suggest that the TRPV6 haplotype defined by the derived alleles at C157R, M378V, and M681T conferred a selective advantage that varied spatially, and perhaps temporally, during human history.


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