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

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

Author information

1
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.
2
Christopher S. Bond Life Sciences Center and Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Columbia, Missouri.
3
Institut de Biologia Molecular de Barcelona (CSIC), Parc Científic de Barcelona, Barcelona, Spain.
4
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
5
Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, Barcelona, Spain.
6
Machine Learning Group, Université Libre de Bruxelles (ULB), Brussels, Belgium.

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.

KEYWORDS:

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

PMID:
28460010
PMCID:
PMC5433387
DOI:
10.1093/gbe/evx075
[Indexed for MEDLINE]
Free PMC Article

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