Positive selection on MMP3 regulation has shaped heart disease risk

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1531-1539
Number of pages9
JournalCurrent Biology
Volume14
Issue number17
DOIs
StatePublished - Sep 7 2004

Fingerprint

heart diseases
Polymorphism
Coronary Disease
Heart Diseases
mutation
phenotypic variation
Genetic Drift
Mutation
Statistical tests
Genetic Selection
Nucleic Acid Regulatory Sequences
Transcription Initiation Site
Elasticity
Population Genetics
Public health
Mutation Rate
genetic polymorphism
Base Pairing
Thymidine
Haplotypes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

Rockman, M. V., Hahn, M. W., Soranzo, N., Loisel, D. A., Goldstein, D. B., & Wray, G. A. (2004). Positive selection on MMP3 regulation has shaped heart disease risk. Current Biology, 14(17), 1531-1539. https://doi.org/10.1016/j.cub.2004.08.051

Positive selection on MMP3 regulation has shaped heart disease risk. / Rockman, Matthew V.; Hahn, Matthew W.; Soranzo, Nicole; Loisel, Dagan A.; Goldstein, David B.; Wray, Gregory A.

In: Current Biology, Vol. 14, No. 17, 07.09.2004, p. 1531-1539.

Research output: Contribution to journalArticle

Rockman, MV, Hahn, MW, Soranzo, N, Loisel, DA, Goldstein, DB & Wray, GA 2004, 'Positive selection on MMP3 regulation has shaped heart disease risk', Current Biology, vol. 14, no. 17, pp. 1531-1539. https://doi.org/10.1016/j.cub.2004.08.051
Rockman MV, Hahn MW, Soranzo N, Loisel DA, Goldstein DB, Wray GA. Positive selection on MMP3 regulation has shaped heart disease risk. Current Biology. 2004 Sep 7;14(17):1531-1539. https://doi.org/10.1016/j.cub.2004.08.051
Rockman, Matthew V. ; Hahn, Matthew W. ; Soranzo, Nicole ; Loisel, Dagan A. ; Goldstein, David B. ; Wray, Gregory A. / Positive selection on MMP3 regulation has shaped heart disease risk. In: Current Biology. 2004 ; Vol. 14, No. 17. pp. 1531-1539.
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