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Molecular and functional bases of selection against a mutation bias in an RNA virus

AuthorsHiguera, Ignacio de la ; Ferrer-Orta, Cristina ; Ávila, Ana Isabel de; Perales, Celia ; Sierra, Macarena; Singh, Kamalendra; Sarafianos, Stefan G.; Dehouck, Yves; Bastolla, Ugo ; Verdaguer, Núria ; Domingo, Esteban
KeywordsAntiviral resistance
Lethal mutagenesis
Foot-and-mouth disease virus
Protein folding stability
Issue Date1-May-2017
PublisherOxford University Press
CitationGenome biology and evolution 9(5): 1212–1228 (2017)
AbstractThe selective pressures acting on viruses that replicate under enhanced mutation rates are largely unknown. Here, we describe resistance of foot-and-mouth disease virus to the mutagen 5-fluorouracil (FU) through a single polymerase substitution that prevents an excess of A to G and U to C transitions evoked by FU on the wild-type foot-and-mouth disease virus, while maintaining the same level of mutant spectrum complexity. The polymerase substitution inflicts upon the virus a fitness loss during replication in absence of FU but confers a fitness gain in presence of FU. The compensation of mutational bias was documented by in vitro nucleotide incorporation assays, and it was associated with structural modifications at the N-terminal region and motif B of the viral polymerase. Predictions of the effect of mutations that increase the frequency of G and C in the viral genome and encoded polymerase suggest multiple points in the virus life cycle where the mutational bias in favor of G and C may be detrimental. Application of predictive algorithms suggests adverse effects of the FU-directed mutational bias on protein stability. The results reinforce modulation of nucleotide incorporation as a lethal mutagenesis-escape mechanism (that permits eluding virus extinction despite replication in the presence of a mutagenic agent) and suggest that mutational bias can be a target of selection during virus replication
Publisher version (URL)http://dx.doi.org/10.1093/gbe/evx075
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