Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell Host Microbe. 2012 Nov 15;12(5):623-32. doi: 10.1016/j.chom.2012.10.008.
RNA viruses exist as dynamic and diverse populations shaped by constant mutation and selection. Yet little is known about how the mutant spectrum contributes to virus evolvability and pathogenesis. Because several codon choices are available for a given amino acid, a central question concerns whether viral sequences have evolved to optimize not only the protein coding consensus, but also the DNA/RNA sequences accessible through mutation. Here we directly test this hypothesis by comparing wild-type poliovirus to synthetic viruses carrying re-engineered capsid sequences with hundreds of synonymous mutations. Strikingly, such rewiring of the population's mutant network reduced its robustness and attenuated the virus in an animal model of infection. We conclude that the position of a virus in sequence space defines its mutant spectrum, evolutionary trajectory, and pathogenicity. This organizing principle for RNA virus populations confers tolerance to mutations and facilitates replication and spread within the dynamic host environment.
RNA 病毒作为动态且多样化的群体而存在，其受到持续的突变和选择的影响。然而，人们对于突变谱如何影响病毒的可进化性和发病机制知之甚少。由于给定的氨基酸有几种密码子可供选择，一个核心问题是病毒序列是否已经进化到不仅优化蛋白质编码共识，而且还优化通过突变可获得的 DNA/RNA 序列。在这里，我们通过将野生型脊髓灰质炎病毒与携带数百个同义突变的合成病毒进行比较，直接检验了这一假设。令人惊讶的是，这种对群体突变网络的重新布线降低了其稳健性，并在感染的动物模型中减弱了病毒。我们得出结论，病毒在序列空间中的位置决定了其突变谱、进化轨迹和致病性。这种 RNA 病毒群体的组织原则赋予了对突变的耐受性，并促进了在动态宿主环境中的复制和传播。
