title: Highly heterogeneous mutation rates in the hepatitis C virus genome.
abstract: 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.
authors: Instituto Cavanilles de Biodiversidad y Biología Evolutiva and Institute for Integrative Systems Biology (I2SysBio), Universitat de València, 46980 Paterna, València, Spain.
authors: Ron
authors: 0000-0002-7612-4611
authors: R
authors: Geller
authors: Unitat de Genómica, Servei Central de Suport a la Investigació Experimental, Universitat de València, 46100 Burjassot, València, Spain.
authors: Úrsula
authors: Ú
authors: Estada
authors: Instituto Cavanilles de Biodiversidad y Biología Evolutiva and Institute for Integrative Systems Biology (I2SysBio), Universitat de València, 46980 Paterna, València, Spain.
authors: Joan B
authors: JB
authors: Peris
authors: Instituto Cavanilles de Biodiversidad y Biología Evolutiva and Institute for Integrative Systems Biology (I2SysBio), Universitat de València, 46980 Paterna, València, Spain.
authors: Iván
authors: I
authors: Andreu
authors: Instituto Cavanilles de Biodiversidad y Biología Evolutiva and Institute for Integrative Systems Biology (I2SysBio), Universitat de València, 46980 Paterna, València, Spain.
authors: Juan-Vicente
authors: JV
authors: Bou
authors: Instituto Cavanilles de Biodiversidad y Biología Evolutiva and Institute for Integrative Systems Biology (I2SysBio), Universitat de València, 46980 Paterna, València, Spain.
authors: Raquel
authors: R
authors: Garijo
authors: Instituto Cavanilles de Biodiversidad y Biología Evolutiva and Institute for Integrative Systems Biology (I2SysBio), Universitat de València, 46980 Paterna, València, Spain.
authors: José M
authors: JM
authors: Cuevas
authors: Regional Center for Biomedical Research, Universidad de Castilla-La Mancha, 02006 Albacete, Spain.
authors: Rosario
authors: R
authors: Sabariegos
authors: Regional Center for Biomedical Research, Universidad de Castilla-La Mancha, 02006 Albacete, Spain.
authors: Antonio
authors: A
authors: Mas
authors: Instituto Cavanilles de Biodiversidad y Biología Evolutiva and Institute for Integrative Systems Biology (I2SysBio), Universitat de València, 46980 Paterna, València, Spain.|Departament de Genètica, Universitat de València, 46100 Burjassot, València, Spain.
authors: Rafael
authors: R
authors: Sanjuán
mesh_terms: D014644:Genetic Variation; D016679:Genome, Viral; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D059645:Mutation Rate; D009711:Nucleotides; D012367:RNA, Viral; D012093:Replicon; D014779:Virus Replication / Q000235:genetics
chemical_list: D009711:Nucleotides; D012367:RNA, Viral