Pervasive within-host recombination and epistasis as major determinants of the molecular evolution of the foot-and-mouth disease virus capsid

Autoři: Luca Ferretti aff001;  Eva Pérez-Martín aff001;  Fuquan Zhang aff001;  François Maree aff003;  Lin-Mari de Klerk-Lorist aff003;  Louis van Schalkwykc aff003;  Nicholas D. Juleff aff001;  Bryan Charleston aff001;  Paolo Ribeca aff001
Působiště autorů: The Pirbright Institute, Woking, Surrey, United Kingdom aff001;  Current address: Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom aff002;  South Africa Department of Microbiology and Plant Pathology, University of Pretoria, Pretoria, South Africa aff003;  Onderstepoort Veterinary Institute-Transboundary Animal Diseases Programme (OVI-TADP), Onderstepoort, Gauteng, South Africa aff004
Vyšlo v časopise: Pervasive within-host recombination and epistasis as major determinants of the molecular evolution of the foot-and-mouth disease virus capsid. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008235
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008235


Although recombination is known to occur in foot-and-mouth disease virus (FMDV), it is considered only a minor determinant of virus sequence diversity. Analysis at phylogenetic scales shows inter-serotypic recombination events are rare, whereby recombination occurs almost exclusively in non-structural proteins. In this study we have estimated recombination rates within a natural host in an experimental setting. African buffaloes were inoculated with a SAT-1 FMDV strain containing two major viral sub-populations differing in their capsid sequence. This population structure enabled the detection of extensive within-host recombination in the genomic region coding for structural proteins and allowed recombination rates between the two sub-populations to be estimated. Quite surprisingly, the effective recombination rate in VP1 during the acute infection phase turns out to be about 0.1 per base per year, i.e. comparable to the mutation/substitution rate. Using a high-resolution map of effective within-host recombination in the capsid-coding region, we identified a linkage disequilibrium pattern in VP1 that is consistent with a mosaic structure with two main genetic blocks. Positive epistatic interactions between co-evolved variants appear to be present both within and between blocks. These interactions are due to intra-host selection both at the RNA and protein level. Overall our findings show that during FMDV co-infections by closely related strains, capsid-coding genes recombine within the host at a much higher rate than expected, despite the presence of strong constraints dictated by the capsid structure. Although these intra-host results are not immediately translatable to a phylogenetic setting, recombination and epistasis must play a major and so far underappreciated role in the molecular evolution of the virus at all scales.

Klíčová slova:

Alleles – DNA recombination – Epistasis – Foot and mouth disease – Linkage disequilibrium – Recombinant proteins – Viral packaging – Buffaloes


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