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

Matthew W. Hahn, Matthew V. Rockman, Nicole Soranzo, David B. Goldstein, Gregory A. Wray

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)867-877
Number of pages11
JournalGenetics
Volume167
Issue number2
DOIs
StatePublished - Jun 2004

Fingerprint

Factor VII
Population Genetics
Mutation
Pan paniscus
Alleles
Myocardial Infarction
Pongo
Gorilla gorilla
Population
Blood Coagulation Factors
Pan troglodytes
Papio
Genetic Selection
Genetic Promoter Regions
Gene Frequency
Single Nucleotide Polymorphism
Transcription Factors
Binding Sites
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the factor VII locus in humans. / Hahn, Matthew W.; Rockman, Matthew V.; Soranzo, Nicole; Goldstein, David B.; Wray, Gregory A.

In: Genetics, Vol. 167, No. 2, 06.2004, p. 867-877.

Research output: Contribution to journalArticle

Hahn, Matthew W. ; Rockman, Matthew V. ; Soranzo, Nicole ; Goldstein, David B. ; Wray, Gregory A. / Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the factor VII locus in humans. In: Genetics. 2004 ; Vol. 167, No. 2. pp. 867-877.
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