Molecular and Functional Bases of Selection against a Mutation Bias in an RNA Virus.
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 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.
['de la Higuera|Ignacio|I|', 'Ferrer-Orta|Cristina|C|', 'de Ávila|Ana I|AI|', 'Perales|Celia|C|', 'Sierra|Macarena|M|', 'Singh|Kamalendra|K|', 'Sarafianos|Stefan G|SG|', 'Dehouck|Yves|Y|', 'Bastolla|Ugo|U|', 'Verdaguer|Nuria|N|', 'Domingo|Esteban|E|']
D019943:Amino Acid Substitution D002460:Cell Line D005472:Fluorouracil D029544:Foot-and-Mouth Disease Virus D056084:Genetic Fitness D007700:Kinetics D008958:Models, Molecular D009154:Mutation D017510:Protein Folding D012324:RNA-Dependent RNA Polymerase D014779:Virus Replication
foot-and-mouth disease virus 5-fluorouracil fitness antiviral resistance lethal mutagenesis protein folding stability