Evolution of Smooth Tubercle Bacilli PE and PE_PGRS Genes: Evidence for a Prominent Role of Recombination and Imprint of Positive Selection

Abstract

BackgroundPE and PE_PGRS are two mycobateria-restricted multigene families encoding membrane associated and secreted proteins that have expanded mainly in the pathogenic species, notably the Mycobacterium tuberculosis complex (MTBC). Several lines of evidence attribute to PE and PE_PGRS genes critical roles in mycobacterial pathogenicity. To get more insight into the nature of these genes, we sought to address their evolutionary trajectories in the group of smooth tubercle bacilli (STB), the putative ancestor of the clonal MTBC.Methodology/Principal FindingsBy focussing on six polymorphic STB PE/PE_PGRS genes, we demonstrate significant incongruence among single gene genealogies and detect strong signals of recombination using various approaches. Coalescent-based estimation of population recombination and mutation rates (ρ and θ, respectively) indicates that the two mechanisms are of roughly equal importance in generating diversity (ρ/θ = 1.457), a finding in a marked contrast to house keeping genes (HKG) whose evolution is chiefly brought about by mutation (ρ/θ = 0.012). In comparison to HKG, we found 15 times higher mean rate of nonsynonymous substitutions, with strong evidence of positive selection acting on PE_PGRS62 (dN/dS = 1.42), a gene that has previously been shown to be essential for mycobacterial survival in macrophages and granulomas. Imprint of positive selection operating on specific amino acid residues or along branches of PE_PGRS62 phylogenetic tree was further demonstrated using maximum likelihood- and covarion-based approaches, respectively. Strikingly, PE_PGR62 proved highly conserved in present-day MTBC strains.Conclusions/SignificanceOverall the data indicate that, in STB, PE/PE_PGRS genes have undergone a strong diversification process that is speeded up by recombination, with evidence of positive selection. The finding that positive selection involved an essential PE_PGRS gene whose sequence appears to be driven to fixation in present-day MTBC strains lends further support to the critical role of PE/PE_PGRS genes in the evolution of mycobacterial pathogenicity.

Phylogeny to function: PE/PPE protein evolution and impact on Mycobacterium tuberculosis pathogenicity

“…In contrast, an in silico examination of all H37Rv genes suggested that one sublineage IV ppe gene and three sublineage V pe_pgrs genes displayed positive selection (Zhang et al ., ). Interestingly, the pe_pgrs62 V gene shows relatively little sequence variation, suggestive of purifying selection acting upon this gene (Namouchi et al ., ). The reason for such discrepant findings is unclear but could be related to small sample size and biased gene selection.…”

The Enigmatic PE/PPE Multigene Family of Mycobacteria and Tuberculosis Vaccination

“…Expansion of the PE/PPE families may have provided the genes needed for adaptation of M. tuberculosis to the human host (18, 19, 20). Remarkably, almost nothing is known about host cell receptors for PE/PPE ligands with the exception of interactions with Toll-like receptor 2 (TLR2), which is discussed below.…”

SMRT Genome Assembly Corrects Reference Errors, Resolving the Genetic Basis of Virulence inMycobacterium tuberculosis

“…Since its publication in 2008 [5], several studies have used the whole genome [8, 36, 41–46] of H37RaJH, or the reported differences between H37RaJH and H37Rv [47] in their analyses. Our improved assembly changes the implications of several of these in silico analyses.…”