Nature Genetics
27, 318 - 321 (2001)
doi:10.1038/85893
Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid statesPhilip Schaner1, Neil Richards2, Anish Wadhwa2, Ivona Aksentijevich4, Daniel Kastner4, Priscilla Tucker3
& Deborah Gumucio21
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA. 2
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA. 3
Museum of Zoology and Department of Biology, University of Michigan, Ann Arbor, Michigan, USA. 4
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Correspondence should be addressed to Deborah Gumucio dgumucio@umich.eduFamilial Mediterranean fever (FMF; MIM 249100) is an autosomal recessive disease characterized by recurrent attacks of fever with synovial, pleural or peritoneal inflammation1. The disease is caused by mutations in the gene encoding the pyrin protein2,
3,
4. Human population studies have revealed extremely high allele frequencies for several different pyrin mutations, leading to the conclusion that the mutant alleles confer a selective advantage5,
6,
7. Here we examine the ret finger protein (rfp) domain (which contains most of the disease-causing mutations) of pyrin during primate evolution. Amino acids that cause human disease are often present as wild type in other species. This is true at positions 653 (a novel mutation), 680, 681, 726, 744 and 761. For several of these human mutations, the mutant represents the reappearance of an ancestral amino acid state. Examination of lineage-specific dN/dS ratios revealed a pattern consistent with the signature of episodic positive selection. Our data, together with previous human population studies, indicate that selective pressures may have caused functional evolution of pyrin in humans and other primates.
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