Highly heterogeneous mutation rates in the hepatitis C virus genome

• Published in: Nature microbiology Vol. 1; no. 7; p. 16045
• Main Authors: Geller, Ron, Estada, Úrsula, Peris, Joan B., Andreu, Iván, Bou, Juan-Vicente, Garijo, Raquel, Cuevas, José M., Sabariegos, Rosario, Mas, Antonio, Sanjuán, Rafael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.04.2016; Nature Publishing Group
• Subjects: 631/181/735; 631/208/325/2483; 631/326/596/1905; Base composition; Biomedical and Life Sciences; Drug resistance; Genetic diversity; Genetic load; Genetic Variation; Genome, Viral; Genomes; Genotype; Hepacivirus - genetics; Hepatitis; Hepatitis C; Hepatitis C - virology; High-Throughput Nucleotide Sequencing; Humans; Infectious Diseases; Life Sciences; Medical Microbiology; Microbiology; Mutation; Mutation Rate; Mutation rates; Natural selection; Nucleotides; Parasitology; Replicon; RNA viruses; RNA, Viral; Transversion; Virology; Virus Replication - genetics
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/nmicrobiol.2016.45

Spontaneous mutations are the ultimate source of genetic variation and have a prominent role in evolution. RNA viruses such as hepatitis C virus (HCV) have extremely high mutation rates, but these rates have been inferred from a minute fraction of genome sites, limiting our view of how RNA viruses create diversity. Here, by applying high-fidelity ultradeep sequencing to a modified replicon system, we scored >15,000 spontaneous mutations, encompassing more than 90% of the HCV genome. This revealed >1,000-fold differences in mutability across genome sites, with extreme variations even between adjacent nucleotides. We identify base composition, the presence of high- and low-mutation clusters and transition/transversion biases as the main factors driving this heterogeneity. Furthermore, we find that mutability correlates with the ability of HCV to diversify in patients. These data provide a site-wise baseline for interrogating natural selection, genetic load and evolvability in HCV, as well as for evaluating drug resistance and immune evasion risks. High fidelity, ultra-deep sequencing of a modified replicon system revealed >1000-fold differences in mutation rate across the hepatitis C virus genome, with extreme variation even between adjacent nucleotides.