Population Genetic and Phylogenetic Evidence for Positive Selection on Regulatory Mutations at the Factor VII Locus in HumansSequence data from this article have been deposited with the EMBL/GenBank Data Libraries under accession nos. AY493422, AY493423, AY493424, AY493425, AY493426, AY493427, AY493428, AY493429, AY493430, AY493431, AY493432, AY493433.

Author:

Hahn Matthew W1,Rockman Matthew V1,Soranzo Nicole2,Goldstein David B2,Wray Gregory A1

Affiliation:

1. Department of Biology, Duke University, Durham, North Carolina 27708

2. Department of Biology, University College London, London WC1E 6BT, United Kingdom

Abstract

Abstract The abundance of cis-regulatory polymorphisms in humans suggests that many may have been important in human evolution, but evidence for their role is relatively rare. Four common polymorphisms in the 5′ promoter region of factor VII (F7), a coagulation factor, have been shown to affect its transcription and protein abundance both in vitro and in vivo. Three of these polymorphisms have low-frequency alleles that decrease expression of F7 and may provide protection against myocardial infarction (heart attacks). The fourth polymorphism has a minor allele that increases the level of transcription. To look for evidence of natural selection on the cis-regulatory variants flanking F7, we genotyped three of the polymorphisms in six Old World populations for which we also have data from a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is due to a large increase in frequency of the high-expression variant in Singaporean Chinese. Further characterization of a Japanese population shows that at least part of the increase in frequency of the high-expression allele is found in other East Asian populations. In addition, to examine interspecific patterns of selection we sequenced the homologous 5′ noncoding region in chimpanzees, bonobos, a gorilla, an orangutan, and a baboon. Analysis of these data reveals an excess of fixed differences within transcription factor binding sites along the human lineage. Our results thus further support the hypothesis that regulatory mutations have been important in human evolution.

Publisher

Oxford University Press (OUP)

Subject

Genetics

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