Shifts in the Selection-Drift Balance Drive the Evolution and Epidemiology of Foot-and-Mouth Disease Virus

Abstract

Foot-and-mouth disease virus (FMDV) is the causative agent of an acute vesicular disease affecting wild and domesticated animals. Despite the economic burden of the disease and all efforts to eradicate it, FMD outbreaks continue to emerge unexpectedly in developed and developing countries. Correlation of the mutational dynamics of the virus with its epidemiology remains unexplored. Analysis of 103 complete genomes representing the seven serotypes shows the important role that selection plays in the genomic evolution of viral isolates for serotypes. We identified selection and relaxed constraints due to genetic drift through analyses of synonymous sites. Finally, we investigated interactions between mutations that showed coevolving patterns and analyzed, based on protein structures, slightly deleterious and compensatory mutational dynamics. Specifically, we demonstrate that structurally exposed capsid proteins present a greater number of adaptive mutations and relaxed selection than nonstructural proteins. Such events have been magnified during the evolution of the southern African virus types (SATs). These shifts in selection-drift balance have generated the great antigenic and genetic diversity observed for SAT serotypes and that are responsible for epizootics on the continent of Africa. The high number of slightly deleterious and compensatory mutations in SAT serotypes in structural proteins is testament to such balance plasticity. The significant accumulation of these coevolving mutations in African serotypes supports their contribution in generating adaptive immune-escaping mutants and in establishing persistent infections. The reverse of this pattern in nonstructural proteins reveals the neutral fixation of mutations in the more widely spread and commonly studied Euro-Asiatic serotypes.

Genomics and outbreaks: foot and mouth disease

“…Therefore, the monitoring of past viral population kinetics and evolutionary dynamics of FMDV can inform and drive the guidance of regional and countrylevel control policies. While major serotypic determinants reside within the genomic region encoding VP1, a number of studies have looked at comparative genomics of FMDV using both individual components of the FMDV genome (46,66), and on a genome-wide level, exploring genetic relationships between individual serotypes (53,67,68).…”

Determination of common genetic variants within the non-structural proteins of foot-and-mouth disease viruses isolated in sub-Saharan Africa

“…The FMDV genome exhibits a quasispecies nature like many RNA viruses as a result genetic drift due to error prone replication and recombination occurs (Domingo et al, 1992;Eigen, 1996;Heath et al, 2006;Holland and Domingo, 1998). Only limited numbers of non-deleterious mutations can occur in regions of functional conservation in the non-structural proteins like the 2A, 2B, 2C, 3A, 3C pro and 3D pol of FMDV (Tully and Fares, 2009). This preserves both the integrity of structure and function especially of the major enzymes, like the RDRP (Domingo et al, 1990(Domingo et al, , 1992.…”

Identifying Coevolutionary Patterns in Human Leukocyte Antigen (Hla) Molecules

“…However, if two coevolving residues are distant in the structure, it may be hard to tell. To determine if a compensatory relationship exists between any pairs of distantly located amino acid sites identified by our analyses as coevolving, we followed an approach previously described (Tully and Fares 2009). Briefly, for each one of the amino acid sites we draw spheres of 4Å radius.…”