Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1β suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1β specifically in response to Y. pestis. Y. pestis-infected Mefv^M680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.

家族性地中海热（FMF）是由MEFV中的纯合或复合杂合功能获得性突变引起的自发性疾病，该突变编码炎性体蛋白pyrin。在多个地中海种群中，多种MEFV突变的杂合子携带者频率很高，表明它们具有选择优势。在2,313名土耳其人中，我们发现了与FMF相关突变侧接的单倍型纯合性，这表明FMF相关突变在进化上是积极的。1800年前，两个致病的吡喃变体独立出现。突变的吡喃与鼠疫耶尔森氏菌的亲和力较小毒力因子YopM较之野生型人大黄素，因此减弱了YopM诱导的白介素（IL）-1β抑制作用。相对于健康对照组，从患者的白细胞与FMF窝藏纯合的或杂合化合物突变和从无症状杂合子携带者响应于公布提高IL-1β特异性Y. 菌。Y.  pestis-感染MEFV ^{M680I / M680I} FMF敲入小鼠表现出IL-1依赖性相对于野生型增加的存活敲入小鼠。因此，呈正在地中海种群选择FMF突变共同赋予提高到电阻Y. 菌。