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Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states

Abstract

Familial 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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Figure 1: Portions of the protein sequence alignment of primate and non-primate rfp domains (for the entire alignment, see Web Fig. A).
Figure 2: History of amino acid change at four positions.
Figure 3: Maximum likelihood analysis using the 'free ratio' model.

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Acknowledgements

We thank D. Mindell, W. Brown and M. Goodman for helpful comments on the manuscript. P.S. acknowledges Training Grant support from the University of Michigan's Training Program in Organogenesis, NIH T32-HD07505. D.G. is grateful to the University of Michigan Biomedical Research Council for a Research Partnership Grant supporting this work.

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Correspondence to Deborah Gumucio.

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Schaner, P., Richards, N., Wadhwa, A. et al. Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states. Nat Genet 27, 318–321 (2001). https://doi.org/10.1038/85893

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