Department of Biological Science, University of Idaho.
Institute for Modeling Collaboration and Innovation, University of Idaho.
Genome Biol Evol. 2021 Feb 3;13(2). doi: 10.1093/gbe/evaa214.
Natural selection acting on synonymous mutations in protein-coding genes influences genome composition and evolution. In viruses, introducing synonymous mutations in genes encoding structural proteins can drastically reduce viral growth, providing a means to generate potent, live-attenuated vaccine candidates. However, an improved understanding of what compositional features are under selection and how combinations of synonymous mutations affect viral growth is needed to predictably attenuate viruses and make them resistant to reversion. We systematically recoded all nonoverlapping genes of the bacteriophage ΦX174 with codons rarely used in its Escherichia coli host. The fitness of recombinant viruses decreases as additional deoptimizing mutations are made to the genome, although not always linearly, and not consistently across genes. Combining deoptimizing mutations may reduce viral fitness more or less than expected from the effect size of the constituent mutations and we point out difficulties in untangling correlated compositional features. We test our model by optimizing the same genes and find that the relationship between codon usage and fitness does not hold for optimization, suggesting that wild-type ΦX174 is at a fitness optimum. This work highlights the need to better understand how selection acts on patterns of synonymous codon usage across the genome and provides a convenient system to investigate the genetic determinants of virulence.
自然选择作用于蛋白质编码基因中的同义突变会影响基因组组成和进化。在病毒中，引入编码结构蛋白的基因中的同义突变会极大地降低病毒的生长速度，为生成有效、活减毒疫苗提供了可能。然而，需要更好地了解哪些组成特征受到选择的影响，以及同义突变的组合如何影响病毒的生长速度，以便能够有把握地减毒病毒并使其具有抗回复突变的能力。我们系统地用大肠杆菌中很少使用的密码子重新编码了噬菌体 ΦX174 的所有非重叠基因。尽管重组病毒的适应性随着基因组中附加的去优化突变而降低，但并非总是呈线性关系，也不是在所有基因中都一致。组合去优化突变可能会比组成突变的效应大小所预期的减少更多或更少的病毒适应性，我们指出了理清相关组成特征的困难。我们通过优化相同的基因来检验我们的模型，发现密码子使用与适应性之间的关系不适用于优化，这表明野生型 ΦX174 处于适应性最优状态。这项工作强调了需要更好地了解选择如何作用于基因组中同义密码子使用模式的必要性，并提供了一个方便的系统来研究毒力的遗传决定因素。
