Bioinformatic Lab, Scientific Institute Istituto di Ricovero e Cura a Carattere Scientifico E. Medea, Bosisio Parini, Lecco, Italy.
Mol Biol Evol. 2010 Nov;27(11):2555-66. doi: 10.1093/molbev/msq141. Epub 2010 Jun 10.
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.
人类的螺旋酶结构域蛋白 1（IFIH1）基因诱导干扰素编码了一种涉及抗病毒固有免疫的双链 RNA 传感器，这表明该基因是病毒驱动选择压力的一个可能靶点。值得注意的是，IFIH1 也在自身免疫中发挥作用，因为该基因的常见和罕见多态性与 1 型糖尿病（T1D）有关。我们分析了人类群体中 IFIH1 的进化历史。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），并且基因受到了局部选择压力的影响。具体来说，欧洲和亚洲的定向选择导致了一种携带衍生 His460 等位基因的常见 IFIH1 单倍型的传播。该变体改变了螺旋酶结构域中一个高度保守的精氨酸残基，可能赋予了病毒识别的改变特异性。另一种常见的单倍型由于最近的正选择而在南美人中高频传播。先前的研究表明，一部分自身免疫性疾病的风险等位基因可能在人类中得以保留，因为它们赋予了对抗感染的选择优势。然而，IFIH1 并非如此，因为群体遗传分化和单倍型分析表明，T1D 易感性等位基因表现为中性或近乎中性的多态性。我们的研究结果表明，IFIH1 中的变体赋予了对不同病毒感染的不同易感性，并深入了解了过去感染的适应性与现代人群中自身免疫易感性之间的关系。
