Publications [#231605] of Gregory A. Wray

Papers Published

1. Rockman, MV; Hahn, MW; Soranzo, N; Loisel, DA; Goldstein, DB; Wray, GA, Positive selection on MMP3 regulation has shaped heart disease risk., Current biology : CB, vol. 14 no. 17 (September, 2004), pp. 1531-1539, ISSN 0960-9822 [15341739], [doi]
   (last updated on 2024/04/19)

   Abstract:
   

   Background

   The evolutionary forces of mutation, natural selection, and genetic drift shape the pattern of phenotypic variation in nature, but the roles of these forces in defining the distributions of particular traits have been hard to disentangle. To better understand the mechanisms contributing to common variation in humans, we investigated the evolutionary history of a functional polymorphism in the upstream regulatory region of the MMP3 gene. This single base pair insertion/deletion variant, which results in a run of either 5 or 6 thymidines 1608 bp from the transcription start site, alters transcription factor binding and influences levels of MMP3 mRNA and protein. The polymorphism contributes to variation in arterial traits and to the risk of coronary heart disease and its progression.

   Results

   Phylogenetic and population genetic analysis of primate sequences indicate that the binding site region is rapidly evolving and has been a hot spot for mutation for tens of millions of years. We also find evidence for the action of positive selection, beginning approximately 24,000 years ago, increasing the frequency of the high-expression allele in Europe but not elsewhere. Positive selection is evident in statistical tests of differentiation among populations and haplotype diversity within populations. Europeans have greater arterial elasticity and suffer dramatically fewer coronary heart disease events than they would have had this selection not occurred.

   Conclusions

   Locally elevated mutation rates and strong positive selection on a cis-regulatory variant have shaped contemporary phenotypic variation and public health.