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RESEARCH PRODUCT
Highly heterogeneous mutation rates in the hepatitis C virus genome.
Rosario SabariegosJosé M. CuevasJuan-vicente BouIván AndreuAntonio MasRon GellerRaquel GarijoRafael SanjuánJoan B. PerisUrsula Estadasubject
0301 basic medicineMicrobiology (medical)Mutation rateGenotypeHepatitis C virusImmunologyGenome ViralHepacivirusBiologymedicine.disease_causeVirus ReplicationApplied Microbiology and BiotechnologyMicrobiologyGenome03 medical and health sciencesMutation RateMolecular evolutionGenetic variationGeneticsmedicineHumansTransversionGenetics030102 biochemistry & molecular biologyNucleotidesGenetic VariationHigh-Throughput Nucleotide SequencingCell BiologyResistance mutationHepatitis C030104 developmental biologyViral replicationRNA ViralReplicondescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-04-18 | Nature microbiology |