Components of Selection in the Evolution of the Influenza Virus: Linkage Effects Beat Inherent Selection

The influenza virus is an important human pathogen, with a rapid rate of evolution in the human population. The rate of homologous recombination within genes of influenza is essentially zero. As such, where two alleles within the same gene are in linkage disequilibrium, interference between alleles will occur, whereby selection acting upon one allele has an influence upon the frequency of the other. We here measured the relative importance of selection and interference effects upon the evolution of influenza. We considered time-resolved allele frequency data from the global evolutionary history of the haemagglutinin gene of human influenza A/H3N2, conducting an in-depth analysis of sequences collected since 1996. Using a model that accounts for selection-caused interference between alleles in linkage disequilibrium, we estimated the inherent selective benefit of individual polymorphisms in the viral population. These inherent selection coefficients were in turn used to calculate the total selective effect of interference acting upon each polymorphism, considering the effect of the initial background upon which a mutation arose, and the subsequent effect of interference from other alleles that were under selection. Viewing events in retrospect, we estimated the influence of each of these components in determining whether a mutant allele eventually fixed or died in the global viral population. Our inherent selection coefficients, when combined across different regions of the protein, were consistent with previous measurements of dN/dS for the same system. Alleles going on to fix in the global population tended to be under more positive selection, to arise on more beneficial backgrounds, and to avoid strong negative interference from other alleles under selection. However, on average, the fate of a polymorphism was determined more by the combined influence of interference effects than by its inherent selection coefficient.

流感病毒（influenza virus）是一类重要的人类病原体，在人群中具有极快的进化速率。流感病毒基因内部的同源重组（homologous recombination）速率几乎为零。因此，当同一基因内的两个等位基因（allele）处于连锁不平衡（linkage disequilibrium）状态时，等位基因间会发生干扰效应：即作用于某一等位基因的选择压力会影响另一等位基因的频率。本研究定量评估了选择效应与干扰效应对流感病毒进化的相对重要性。我们选取了人类甲型流感病毒A/H3N2型血凝素（haemagglutinin）基因的全球进化时间分辨等位基因频率数据集，对1996年以来收集的病毒序列展开了深入分析。我们采用了能够考量连锁不平衡等位基因间选择引发干扰的模型，估算了病毒种群中单个多态性位点（polymorphism）的固有选择优势。随后，结合突变产生时的初始遗传背景效应，以及后续受选择的其他等位基因带来的干扰效应，基于这些固有选择系数（selective coefficient）计算了作用于每个多态性位点的总干扰选择效应。通过回溯性分析进化事件，我们估算了这两类效应在决定突变等位基因最终能否在全球病毒种群中固定或消亡时的影响权重。将蛋白质不同区域的固有选择系数整合后，我们的结果与此前针对同一系统测得的dN/dS值相一致。最终在全球病毒种群中固定的等位基因，往往处于更强的正向选择压力下，诞生于更有益的遗传背景，且能够规避来自其他受选择等位基因的强烈负向干扰。不过平均而言，多态性位点的演化命运更多由干扰效应的综合影响所决定，而非其自身的固有选择系数。