Molecular and Functional Bases of Selection against a Mutation Bias in an RNA Virus
de la Higuera, Ignacio (Centro de Biología Molecular Severo Ochoa)
Ferrer-Orta, Cristina (Institut de Biologia Molecular de Barcelona)
de Ávila, Ana Isabel (Centro de Biología Molecular Severo Ochoa)
Perales Viejo, Celia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Sierra, Macarena (Centro de Biología Molecular Severo Ochoa)
Singh, Kamalendra (Christopher S. Bond Life Sciences Center, University of Missouri)
Sarafianos, Stefan G. (Christopher S. Bond Life Sciences Center, University of Missouri)
Dehouck, Yves (Machine Learning Group, Université Libre de Bruxelles (ULB))
Bastolla, Ugo (Centro de Biología Molecular Severo Ochoa)
Verdaguer, Nuria (Institut de Biologia Molecular de Barcelona)
Domingo, Esteban (Centro de Biología Molecular Severo Ochoa)
Universitat Autònoma de Barcelona

Date:	2017
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.
Grants:	Ministerio de Economía y Competitividad BIO2011-24333 Ministerio de Economía y Competitividad BIO2014-54588-P Ministerio de Economía y Competitividad MDM-2014-0435
Note:	Altres ajuts: Work in Madrid was supported by grants [BFU2011-23604, SAF2014-52400-R, S2013/ABI-2906 (PLATESA from Comunidad de Madrid/FEDER)] and Fundación R. Areces and grant BFU2012-40020 to U.B. CIBERehd is funded by Instituto de Salud Carlos III.[...] X-ray data were collected at ALBA Synchrotron (Cerdanyola de Valles, Spain) XALOC beamline with the collaboration of ALBA staff. Financial support was provided by ALBA. C.P. is supported by the Miguel Servet program of the Instituto de Salud Carlos III (CP14/00121) cofinanced by the European Regional Development Fund (ERDF). The kinetic studies at the University of Missouri were partially supported by grant [AI076119] (National Institute of Health, USA) to S.G.S.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Antiviral resistance ; Fitness ; Lethal mutagenesis ; Foot-and-mouth disease virus ; 5-fluorouracil ; Protein folding stability
Published in:	Genome biology and evolution, Vol. 9 (may 2017) , p. 1212-1228, ISSN 1759-6653

DOI: 10.1093/gbe/evx075
PMID: 28460010

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