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Título

Rare haplotype load as marker for lethal mutagenesis

AutorGregori, Josep; Soria, María Eugenia; Gallego, Isabel CSIC ORCID; Guerrero-Murillo, Mercedes; Esteban, Juan Ignacio; Quer, Josep; Perales, Celia CSIC ORCID; Domingo, Esteban CSIC ORCID
Fecha de publicación3-oct-2018
EditorPublic Library of Science
CitaciónPLoS ONE 13 (2018)
ResumenRNA viruses replicate with a template-copying fidelity, which lies close to an extinction threshold. Increases of mutation rate by nucleotide analogues can drive viruses towards extinction. This transition is the basis of an antiviral strategy termed lethal mutagenesis. We have introduced a new diversity index, the rare haplotype load (RHL), to describe NS5B (polymerase) mutant spectra of hepatitis C virus (HCV) populations passaged in absence or presence of the mutagenic agents favipiravir or ribavirin. The increase in RHL is more prominent in mutant spectra whose expansions were due to nucleotide analogues than to multiple passages in absence of mutagens. Statistical tests for paired mutagenized versus non-mutagenized samples with 14 diversity indices show that RHL provides consistently the highest standardized effect of mutagenic treatment difference for ribavirin and favipiravir. The results indicate that the enrichment of viral quasispecies in very low frequency minority genomes can serve as a robust marker for lethal mutagenesis. The diagnostic value of RHL from deep sequencing data is relevant to experimental studies on enhanced mutagenesis of viruses, and to pharmacological evaluations of inhibitors suspected to have a mutagenic activity.
URIhttp://hdl.handle.net/10261/181647
DOI10.1371/journal.pone.0204877
Identificadoresdoi: 10.1371/journal.pone.0204877
issn: 1932-6203
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