Abstract
We identified and examined a candidate gene for local directional selection in Europeans, TRPV6, and conclude that selection has acted on standing genetic variation at this locus, creating parallel soft sweep events in humans. A novel modification of the extended haplotype homozygosity (EHH) test was utilized, which compares EHH for a single allele across populations, to investigate the signature of selection at TRPV6 and neighboring linked loci in published data sets for Europeans, Asians and African-Americans, as well as in newly-obtained sequence data for additional populations. We find that all non-African populations carry a signature of selection on the same haplotype at the TRPV6 locus. The selective footprints, however, are significantly differentiated between non-African populations and estimated to be younger than an ancestral population of non-Africans. The possibility of a single selection event occurring in an ancestral population of non-Africans was tested by simulations and rejected. The putatively-selected TRPV6 haplotype contains three candidate sites for functional differences, namely derived non-synonymous substitutions C157R, M378V and M681T. Potential functional differences between the ancestral and derived TRPV6 proteins were investigated by cloning the ancestral and derived forms, transfecting cell lines, and carrying out electrophysiology experiments via patch clamp analysis. No statistically-significant differences in biophysical channel function were found, although one property of the protein, namely Ca2+ dependent inactivation, may show functionally relevant differences between the ancestral and derived forms. Although the reason for selection on this locus remains elusive, this is the first demonstration of a widespread parallel selection event acting on standing genetic variation in humans, and highlights the utility of between population EHH statistics.
Highlights
With the advent of large, publicly-available data sets, the completion of many mammalian genome sequences, and large-scale genotyping resources, there has been much effort in attempting to identify loci which have potentially been under selection in the entire human species, or locally in specific human populations [1,2,3,4,5,6,7,8,9,10,11]
Time since Selection We identified TRPV6 as a putative target of local selection by implementing a genome scan based on two summary statistics of the sequence data (Figure S1), analogous to that performed previously [6]
A drastic reduction in diversity was identified at the TRPV6 locus (Figure S2) and at the neighboring loci EPHB6, TRPV5 and KEL
Summary
With the advent of large, publicly-available data sets, the completion of many mammalian genome sequences, and large-scale genotyping resources, there has been much effort in attempting to identify loci which have potentially been under selection in the entire human species, or locally in specific human populations [1,2,3,4,5,6,7,8,9,10,11]. TPRV6 is the primary route of dietary calcium uptake, and has previously been identified as a candidate for local selection in two other studies [1,8] These studies both used the SeattleSNPs data base, consisting at the time of full sequence data for over 130 genes in twenty-four individuals of African American decent and twenty-three individuals of European decent. Both studies identified putative selected genes by comparing the empirical data to simulated data that was based on an assumed demographic history. The date of selection in Europeans was estimated to be around 10,000 years before present, suggesting that TRPV6 may have coevolved with lactose tolerance [13] as fresh milk is a major source of calcium in European populations
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