Assessing <i>in vivo</i> mutation frequencies and creating a high-resolution genome-wide map of fitness costs of Hepatitis C virus

Abstract Like many viruses, Hepatitis C Virus (HCV) has a high nutation 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 virus specific, reinforcing the utility of constructing in vivo fitness cost maps of viral genomes. Author Summary Understanding how viruses evolve within patients is important for combatting viral diseases, yet studying viruses within patients is difficult. Laboratory experiments are often used to understand the evolution of viruses, in place of assessing the evolution in natural populations (patients), but the dynamics will be different. In this study, we aimed to understand the within-patient evolution of Hepatitis C virus, which is an RNA virus that replicates and mutates extremely quickly, by taking advantage of high-throughput next generation sequencing. Here, we describe the evolutionary patterns of Hepatitis C virus from 195 patients: We analyzed mutation frequencies and estimated how costly each mutation was. We also assessed what factors made a mutation more costly, including the costs associated with drug resistance mutations. We were able to create a genome-wide fitness map of within-patient mutations in Hepatitis C virus which proves that, with technological advances, we can deepen our understanding of within-patient viral evolution, which can contribute to develop better treatments and vaccines.

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