Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the Factor VII locus in humans

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, bave 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 polymorphisins in six Old World populations for which we also have data front a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is clue 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.