5n95

Publication Abstract from PubMed

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 (FMDV) 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 FMDV, 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 suggest 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.

Molecular and functional bases of selection against a mutation bias in an RNA virus.,de la Higuera I, Ferrer-Orta C, de Avila AI, Perales C, Sierra M, Singh K, Sarafianos SG, Dehouck Y, Bastolla U, Verdaguer N, Domingo E Genome Biol Evol. 2017 Apr 27. doi: 10.1093/gbe/evx075. PMID:28460010^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.