Article révisé par les pairs
Résumé : The 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 themutagen 5-fluorouracil (FU) through a single polymerase substitution that prevents an excess of A to Gand U to C transitions evoked by FU on thewild-type foot-and-mouth disease virus, while maintaining the same level ofmutant spectrumcomplexity. 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 itwas associatedwith structural modifications at theN-terminal region and motif B of the viral polymerase. Predictions of the effect ofmutations 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 lethalmutagenesis-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.

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