Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
J Mol Biol. 2018 Apr 13;430(8):1098-1115. doi: 10.1016/j.jmb.2018.02.009. Epub 2018 Feb 18.
The fitness effects of synonymous mutations can provide insights into biological and evolutionary mechanisms. We analyzed the experimental fitness effects of all single-nucleotide mutations, including synonymous substitutions, at the beginning of the influenza A virus hemagglutinin (HA) gene. Many synonymous substitutions were deleterious both in bulk competition and for individually isolated clones. Investigating protein and RNA levels of a subset of individually expressed HA variants revealed that multiple biochemical properties contribute to the observed experimental fitness effects. Our results indicate that a structural element in the HA segment viral RNA may influence fitness. Examination of naturally evolved sequences in human hosts indicates a preference for the unfolded state of this structural element compared to that found in swine hosts. Our overall results reveal that synonymous mutations may have greater fitness consequences than indicated by simple models of sequence conservation, and we discuss the implications of this finding for commonly used evolutionary tests and analyses.
同义突变的适应度效应可以为生物和进化机制提供深入的了解。我们分析了流感 A 病毒血凝素 (HA) 基因起始处所有单核苷酸突变，包括同义替换，在大量竞争和单独分离的克隆中的实验适应度效应。对一组单独表达的 HA 变体的蛋白质和 RNA 水平的研究表明，多种生化特性有助于观察到的实验适应度效应。我们的结果表明，HA 段病毒 RNA 中的一个结构元件可能会影响适应度。对人类宿主中自然进化序列的检查表明，与在猪宿主中发现的相比，该结构元件更倾向于展开状态。我们的总体结果表明，同义突变的适应度后果可能比简单的序列保守性模型所表明的更为严重，我们讨论了这一发现对常用的进化测试和分析的影响。
