Molecular and Functional Bases of Selection against a Mutation Bias in an RNA Virus. (1st May 2017)

• Record Type: Journal Article
• Authors: de la Higuera, Ignacio; Ferrer-Orta, Cristina; de Ávila, Ana I.; Perales, Celia; Sierra, Macarena; Singh, Kamalendra; Sarafianos, Stefan G.; Dehouck, Yves; Bastolla, Ugo; Verdaguer, Nuria; Domingo, Esteban
• Is Part Of: Genome biology and evolution. Volume 9:Number 5(2017:May)
• Page Start: 1212
• Page End: 1228
• Publication Date: 2017-05-01
• Subjects: antiviral resistance -- fitness -- lethal mutagenesis -- foot-and-mouth disease virus -- 5-fluorouracil -- protein folding stability; Genomics -- Periodicals; Genes -- Periodicals; 572.8605
• DOI: 10.1093/gbe/evx075
• Languages: English
• ISSNs: 1759-6653

Abstract

Abstract : 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.