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.

FIG. 1.

Distribution of the percentage of codon regions under adaptive evolution along the genome of FMDV for serotypes. (A) Plot of the percentages of codons under adaptive evolution in the different proteins of FMDV. Different serotypes are color coded. (B) Comparison of the mean percentages of codon regions under adaptive evolution in each serotype between structural proteins and nonstructural proteins.

FIG. 2.

Genomic distribution of nucleotide substitutions per synonymous site (d_S). (A) Average d_S variation along the FMDV genome. This distribution was highly heterogeneous when we compared structural proteins with nonstructural proteins (separated in the plot by a dashed line). The median of d_S for structural proteins (indicated by a blue horizontal bar) is qualitatively higher than that for nonstructural proteins (indicated by an orange horizontal bar). The difference between the mean d_S values between structural and nonstructural proteins is significant at the 5% significance level (box in the upper right corner of the plot). (B) Comparison of the distribution of d_S values between southern African serotypes (blue bars) and non-SAT serotypes (red bars) along the genome. These values are qualitatively greater in the SATs compared to the other serotypes along the genome. This difference is mainly due to more relaxed constraints on synonymous sites of structural (S) proteins compared to nonstructural proteins (NS) in the SAT serotypes (box in the upper right corner of the plot).

FIG. 3.

Phylogenetic distribution of the percentages of SDMs in each serotype. Horizontal bars represent the genome of FMDV. Horizontal bars in the lineage leading to each serotype as well as in the tip of each serotype indicate percentages of SDMs in the ancestral serotype lineage and within serotypes, respectively. The percentages of SDMs are normalized along the genome and phylogeny and are therefore comparable between serotypes, between proteins, and even between temporal sampling in the phylogeny (ancestral versus terminal distributions). The normalized percentages of SDMs are color coded, as is the serotype group according to the average percentage of SDMs observed per serotype.

FIG. 4.

Comparison of the percentage of slightly deleterious mutations between SAT and non-SAT serotypes in structural (a) and nonstructural (b) proteins. Percentages have been normalized along genomes and phylogenies so as to make them comparable. (a) Black bars refer to the percentage of SDMs identified in the lineages leading to the ancestors of serotypes (root of serotype), whereas gray bars refer to those percentages within serotypes (terminal branches). Standard errors have been averaged for root and terminal lineages.