Molecular and Functional Bases of Selection against a Mutation Bias in an RNA Virus

Genome Biol Evol. 2017 May 1;9(5):1212-1228. doi: 10.1093/gbe/evx075.


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.

Keywords: 5-fluorouracil; antiviral resistance; fitness; foot-and-mouth disease virus; lethal mutagenesis; protein folding stability.

MeSH terms

  • Amino Acid Substitution*
  • Cell Line
  • Fluorouracil / metabolism
  • Foot-and-Mouth Disease Virus / enzymology
  • Foot-and-Mouth Disease Virus / genetics*
  • Foot-and-Mouth Disease Virus / physiology
  • Genetic Fitness
  • Kinetics
  • Models, Molecular
  • Mutation*
  • Protein Folding
  • RNA-Dependent RNA Polymerase / genetics
  • RNA-Dependent RNA Polymerase / metabolism
  • Virus Replication


  • RNA-Dependent RNA Polymerase
  • Fluorouracil