TY - JOUR
T1 - TRPV6 exhibits unusual patterns of polymorphism and divergence in worldwide populations
AU - Akey, Joshua M.
AU - Swanson, Willie J.
AU - Madeoy, Jennifer
AU - Eberle, Michael
AU - Shriver, Mark D.
N1 - Funding Information:
We thank Dayna Akey for critical reading of the manuscript and providing valuable comments. J.M.A. is supported in part by a Pilot and Feasibility Award from the Clinical Nutrition Research Unit at the University of Washington and the NSF (DEB-0512279).
PY - 2006/7
Y1 - 2006/7
N2 - 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 defined by 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.
AB - 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 defined by 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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U2 - 10.1093/hmg/ddl134
DO - 10.1093/hmg/ddl134
M3 - Article
C2 - 16717058
AN - SCOPUS:33745279634
SN - 0964-6906
VL - 15
SP - 2106
EP - 2113
JO - Human molecular genetics
JF - Human molecular genetics
IS - 13
ER -