Pervasive within-host recombination and epistasis as major determinants of the molecular evolution of the Foot-and-Mouth Disease Virus capsid
Pervasive within-host recombination and epistasis as major determinants of the molecular evolution of the Foot-and-Mouth Disease Virus capsid
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普遍的宿主内重组和上位性是口蹄疫病毒衣壳分子进化的主要决定因素
DOI：
10.1101/271239
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Ferretti L
中科院分区：
文献类型：
--
作者：
Ferretti L
尽管重组已知发生在口蹄疫病毒（FMDV）中，但它被认为只是病毒序列多样性的一个次要决定因素。系统发育尺度的分析表明，血清型间重组事件很少见，重组几乎只发生在非结构蛋白中。在这项研究中，我们在实验环境中估计了自然宿主内的重组率。非洲水牛接种了 SAT-1 FMDV 毒株，该毒株含有衣壳序列不同的两个主要病毒亚群。这种群体结构使得能够检测编码结构蛋白的基因组区域中广泛的宿主内重组，并允许估计两个亚群体之间的重组率。令人惊讶的是，急性感染阶段 VP1 的有效重组率约为每年每个碱基 0.1 次，即与突变/取代率相当。利用衣壳编码区有效宿主内重组的高分辨率图谱，我们确定了 VP1 中的连锁不平衡模式，该模式与具有两个主要遗传块的镶嵌结构一致。共同进化变体之间的正上位相互作用似乎存在于块内和块之间。这些相互作用是由于 RNA 和蛋白质水平上的宿主内选择所致。总体而言，我们的研究结果表明，在密切相关菌株共同感染 FMDV 期间，尽管存在衣壳结构所规定的强烈限制，但衣壳编码基因在宿主内的重组率远高于预期。尽管这些宿主内结果不能立即转化为系统发育环境，但重组和上位性必须在病毒各个尺度的分子进化中发挥重要且迄今为止未被充分认识的作用。
Although recombination is known to occur in foot-and-mouth disease virus (FMDV), it is considered only a minor determinant of virus sequence diversity. Analysis at phylogenetic scales shows inter-serotypic recombination events are rare, whereby recombination occurs almost exclusively in non-structural proteins. In this study we have estimated recombination rates within a natural host in an experimental setting. African buffaloes were inoculated with a SAT-1 FMDV strain containing two major viral sub-populations differing in their capsid sequence. This population structure enabled the detection of extensive within-host recombination in the genomic region coding for structural proteins and allowed recombination rates between the two sub-populations to be estimated. Quite surprisingly, the effective recombination rate in VP1 during the acute infection phase turns out to be about 0.1 per base per year, i.e. comparable to the mutation/substitution rate. Using a high-resolution map of effective within-host recombination in the capsid-coding region, we identified a linkage disequilibrium pattern in VP1 that is consistent with a mosaic structure with two main genetic blocks. Positive epistatic interactions between co-evolved variants appear to be present both within and between blocks. These interactions are due to intra-host selection both at the RNA and protein level. Overall our findings show that during FMDV co-infections by closely related strains, capsid-coding genes recombine within the host at a much higher rate than expected, despite the presence of strong constraints dictated by the capsid structure. Although these intra-host results are not immediately translatable to a phylogenetic setting, recombination and epistasis must play a major and so far underappreciated role in the molecular evolution of the virus at all scales.