Genome-Wide Identification of Susceptibility Alleles for Viral Infections through a Population Genetics Approach

Viruses have exerted a constant and potent selective pressure on human genes throughout evolution. We utilized the marks left by selection on allele frequency to identify viral infection-associated allelic variants. Virus diversity (the number of different viruses in a geographic region) was used to measure virus-driven selective pressure. Results showed an excess of variants correlated with virus diversity in genes involved in immune response and in the biosynthesis of glycan structures functioning as viral receptors; a significantly higher than expected number of variants was also seen in genes encoding proteins that directly interact with viral components. Genome-wide analyses identified 441 variants significantly associated with virus-diversity; these are more frequently located within gene regions than expected, and they map to 139 human genes. Analysis of functional relationships among genes subjected to virus-driven selective pressure identified a complex network enriched in viral products-interacting proteins. The novel approach to the study of infectious disease epidemiology presented herein may represent an alternative to classic genome-wide association studies and provides a large set of candidate susceptibility variants for viral infections.

在人类演化的整个历程中，病毒始终对人类基因施加着持续且强效的选择压力。本研究利用选择作用于等位基因频率所留下的印记，来识别与病毒感染相关的等位基因变异体。研究采用病毒多样性（即某一地理区域内存在的不同病毒种类数）作为病毒驱动选择压力的衡量指标。分析结果显示，在参与免疫应答以及构成病毒受体的聚糖结构生物合成的基因中，与病毒多样性相关的变异体数量超出预期；此外，在编码直接与病毒组分相互作用的蛋白质的基因中，变异体数量同样显著高于预期水平。全基因组分析共鉴定出441个与病毒多样性显著相关的变异体；这些变异体在基因区域内的分布频率高于随机预期，且对应到139个人类基因。对受病毒驱动选择压力的基因之间的功能关联进行分析，发现了一个富集了与病毒产物相互作用蛋白的复杂网络。本文所提出的这种用于传染病流行病学研究的新方法，可作为经典全基因组关联研究的替代方案，同时为病毒感染研究提供了大量候选易感变异体。