Scientific Institute IRCCS E. Medea, Bioinformatic Laboratory, Bosisio Parini (LC), Italy.
Genes Immun. 2009 Dec;10(8):678-86. doi: 10.1038/gene.2009.59. Epub 2009 Aug 13.
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.
家族性地中海热（FMF）是一种由 MEFV 基因突变引起的隐性遗传性全身炎症性疾病。来自地中海地区的多个群体的不同疾病等位基因的频率极高，提示杂合子优势。在这里，我们描述了 MEFV 3'基因区域（从外显子 5 到 3'UTR）在七个人类群体中的序列变异和单倍型结构。在非非洲人群中，我们观察到高水平的核苷酸变异、中间频率等位基因的过剩、种群分化的减少以及两个常见单倍型之间存在深分支的谱系。这些特征表明，平衡选择作用于该区域以维持一个或多个选择的等位基因。与这一发现一致的是，在欧洲人和亚洲人中观察到杂合子过剩，表明存在超显性机制。我们的数据，以及先前证明 MEFV 外显子 10 在灵长类动物进化过程中经历了间歇性正选择，为该基因区域核苷酸变异的适应性作用提供了证据。我们的数据表明，进一步阐明 MEFV 变异体作用的研究可能受益于分子进化和功能分析的整合。
