title: A population genetics study of the familial Mediterranean fever gene: evidence of balancing selection under an overdominance regime.
abstract: Familial Mediterranean Fever (FMF) is a recessively inherited systemic autoinflammatory disease caused by mutations in the MEFV gene. The frequency of different disease alleles is extremely high in multiple populations from the Mediterranean region, suggesting heterozygote advantage. Here, we characterize the sequence variation and haplotype structure of the MEFV 3' gene region (from exon 5 to the 3' UTR) in seven human populations. In non-African populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with two common haplotypes separated by deep branches. These features are suggestive of balancing selection having acted on this region to maintain one or more selected alleles. In line with this finding, an excess of heterozygotes was observed in Europeans and Asians, suggesting an overdominance regime. Our data, together with the earlier demonstration that the MEFV exon 10 has been subjected to episodic positive selection over primate evolution, provide evidence for an adaptive role of nucleotide variation in this gene region. Our data suggest that further studies aimed at clarifying the role of MEFV variants might benefit from the integration of molecular evolutionary and functional analyses.
authors.affiliation: Scientific Institute IRCCS E. Medea, Bioinformatic Laboratory, Bosisio Parini (LC), Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fumagalli
authors.forename: R
authors.initials: R
authors.lastname: Cagliani
authors.forename: U
authors.initials: U
authors.lastname: Pozzoli
authors.forename: S
authors.initials: S
authors.lastname: Riva
authors.forename: G P
authors.initials: GP
authors.lastname: Comi
authors.forename: G
authors.initials: G
authors.lastname: Menozzi
authors.forename: N
authors.initials: N
authors.lastname: Bresolin
authors.forename: M
authors.initials: M
authors.lastname: Sironi
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000276:immunology; D005091:Exons; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000276:immunology; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D002679:Pan troglodytes / Q000235:genetics; D000071198:Pyrin; D012641:Selection, Genetic
chemical_list: D020413:3' Untranslated Regions; D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; D000071198:Pyrin