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

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discussion about the paper. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Scientific Institute IRCCS E. Medea, Bioinformatic Laboratory, Bosisio Parini (LC), Italy M Fumagalli, R Cagliani, U

Pozzoli, S Riva, G Menozzi, N Bresolin & M Sironi * Department of Bioengineering, Politecnico di Milano, Milan, Italy M Fumagalli * Department of Neurological Sciences, Dino Ferrari

Centre, University of Milan, IRCCS Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, Milan, Italy G P Comi & N Bresolin Authors * M Fumagalli View author

publications You can also search for this author inPubMed Google Scholar * R Cagliani View author publications You can also search for this author inPubMed Google Scholar * U Pozzoli View

author publications You can also search for this author inPubMed Google Scholar * S Riva View author publications You can also search for this author inPubMed Google Scholar * G P Comi View

author publications You can also search for this author inPubMed Google Scholar * G Menozzi View author publications You can also search for this author inPubMed Google Scholar * N Bresolin

View author publications You can also search for this author inPubMed Google Scholar * M Sironi View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to M Sironi. ADDITIONAL INFORMATION Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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M., Cagliani, R., Pozzoli, U. _et al._ A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime. _Genes Immun_ 10,

678–686 (2009). https://doi.org/10.1038/gene.2009.59 Download citation * Received: 12 February 2009 * Revised: 25 June 2009 * Accepted: 08 July 2009 * Published: 13 August 2009 * Issue Date:

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balancing selection * heterozygote advantage