Department of Biology, San Francisco State University, San Francisco, California, United States of America.
BC Centre for Excellence in HIV/AIDS, Vancouver, British Colombia, Canada.
PLoS Genet. 2022 May 2;18(5):e1010179. doi: 10.1371/journal.pgen.1010179. eCollection 2022 May.
Like many viruses, Hepatitis C Virus (HCV) has a high mutation rate, which helps the virus adapt quickly, but mutations come with fitness costs. Fitness costs can be studied by different approaches, such as experimental or frequency-based approaches. The frequency-based approach is particularly useful to estimate in vivo fitness costs, but this approach works best with deep sequencing data from many hosts are. In this study, we applied the frequency-based approach to a large dataset of 195 patients and estimated the fitness costs of mutations at 7957 sites along the HCV genome. We used beta regression and random forest models to better understand how different factors influenced fitness costs. Our results revealed that costs of nonsynonymous mutations were three times higher than those of synonymous mutations, and mutations at nucleotides A or T had higher costs than those at C or G. Genome location had a modest effect, with lower costs for mutations in HVR1 and higher costs for mutations in Core and NS5B. Resistance mutations were, on average, costlier than other mutations. Our results show that in vivo fitness costs of mutations can be site and virus specific, reinforcing the utility of constructing in vivo fitness cost maps of viral genomes.
像许多病毒一样，丙型肝炎病毒 (HCV) 具有很高的突变率，这有助于病毒快速适应，但突变伴随着适应度代价。适应度代价可以通过不同的方法来研究，例如实验或基于频率的方法。基于频率的方法特别适用于估计体内适应度代价，但这种方法在有大量宿主的深度测序数据时效果最佳。在这项研究中，我们应用基于频率的方法对来自 195 名患者的大型数据集进行了分析，并估计了 HCV 基因组中 7957 个位点的突变适应度代价。我们使用贝塔回归和随机森林模型来更好地理解不同因素如何影响适应度代价。我们的结果表明，非同义突变的代价是同义突变的三倍，而 A 或 T 核苷酸的突变代价高于 C 或 G 核苷酸的突变代价。基因组位置有一定的影响，HVR1 中的突变代价较低，而核心和 NS5B 中的突变代价较高。耐药突变的代价通常比其他突变高。我们的结果表明，体内突变的适应度代价可能具有特定的位置和病毒特异性，这增强了构建病毒基因组体内适应度代价图谱的实用性。
