Population Genetics of IFIH1: Ancient Population Structure, Local Selection, and Implications for Susceptibility to Type 1 Diabetes
Population Genetics of IFIH1: Ancient Population Structure, Local Selection, and Implications for Susceptibility to Type 1 Diabetes
复制标题
DOI：
10.1093/molbev/msq141
复制
发表时间：
2010-11-01
影响因子：
10.7
通讯作者：
Sironi, Manuela
中科院分区：
文献类型：
--
作者：
Fumagalli, Matteo;Cagliani, Rachele;Sironi, Manuela
人干扰素与解旋酶C结构域1(IFIH1)基因编码的双链RNA传感器参与了对病毒的天然免疫，这表明该基因可能是病毒驱动的选择压力的靶标。值得注意的是，IFIH1也在自身免疫中发挥作用，因为该基因常见和罕见的多态与1型糖尿病(T1D)有关。我们分析了IFIH1在人类群体中的进化史。结果表明，两个主要的IFIH1单倍型分支起源于非洲大陆的祖先群体结构(或平衡选择)，局部选择压力对该基因产生了作用。具体地说，欧洲和亚洲的定向选择导致了携带衍生的His460等位基因的常见IFIH1单倍型的传播。这种变异改变了解旋酶结构域中高度保守的精氨酸残基，可能在病毒识别中赋予了改变的特异性。由于最近的积极选择，一种替代的常见单倍型在南美人中出现的频率很高。之前的研究表明，自身免疫性疾病的部分风险等位基因可能在人类身上保持不变，因为它们赋予了对抗感染的选择性优势。但IFIH1并非如此，因为群体遗传分化和单倍型分析表明，T1D易感等位基因表现为中性或接近中性的多态。我们的发现表明，IFIH1的变异赋予了对不同病毒感染的不同易感性，并提供了对现代人群中对过去感染的适应与自身免疫易感性之间的关系的洞察。
The human interferon induced with helicase C domain 1 (IFIH1) gene encodes a sensor of double-strand RNA involved in innate immunity against viruses, indicating that this gene is a likely target of virus-driven selective pressure. Notably, IFIH1 also plays a role in autoimmunity, as common and rare polymorphisms in this gene have been associated with type 1 diabetes (T1D). We analyzed the evolutionary history of IFIH1 in human populations. Results herein suggest that two major IFIH1 haplotype clades originated from ancestral population structure (or balancing selection) in the African continent and that local selective pressures have acted on the gene. Specifically, directional selection in Europe and Asia resulted in the spread of a common IFIH1 haplotype carrying a derived His460 allele. This variant changes a highly conserved arginine residue in the helicase domain, possibly conferring altered specificity in viral recognition. An alternative common haplotype has swept to high frequency in South Americans as a result of recent positive selection. Previous studies suggested that a portion of risk alleles for autoimmune diseases could have been maintained in humans as they conferred a selective advantage against infections. This is not the case for IFIH1, as population genetic differentiation and haplotype analyses indicated that the T1D susceptibility alleles behaved as neutral or nearly neutral polymorphisms. Our findings suggest that variants in IFIH1 confer different susceptibility to diverse viral infections and provide insight into the relationship between adaptation to past infection and predisposition to autoimmunity in modern populations.