Staphylococcus aureus is an important human pathogen and represents a growing public health burden owing to the emergence and spread of antibiotic-resistant clones, particularly within the hospital environment. Despite this, basic questions about the evolution and population biology of the species, particularly with regard to the extent and impact of homologous recombination, remain unanswered. We address these issues through an analysis of sequence data obtained from the characterization by multilocus sequence typing (MLST) of 334 isolates of S. aureus, recovered from a well-defined population, over a limited time span. We find no significant differences in the distribution of multilocus genotypes between strains isolated from carriers and those from patients with invasive disease; there is, therefore, no evidence from MLST data, which index variation within the stable "core" genome, for the existence of hypervirulent clones of this pathogen. Examination of the sequence changes at MLST loci during clonal diversification shows that point mutations give rise to new alleles at least 15-fold more frequently than does recombination. This contrasts with the naturally transformable species Neisseria meningitidis and Streptococcus pneumoniae, in which alleles change between 5-and 10-fold more frequently by recombination than by mutation. However, phylogenetic analysis suggests that homologous recombination does contribute toward the evolution of this species over the long term. Finally, we note a striking excess of nonsynonymous substitutions in comparisons between isolates belonging to the same clonal complex compared to isolates belonging to different clonal complexes, suggesting that the removal of deleterious mutations by purifying selection may be relatively slow.Staphylococcus aureus is a gram-positive pathogen responsible for a wide range of human disease, including septicemia; endocarditis and pneumonia; and wound, bone, and joint infections. Although the vast majority of infections by S. aureus result in asymptomatic carriage, this species nevertheless represents a serious public health burden, particularly in the hospital setting, where clones resistant to methicillin and other classes of antibiotics are endemic and insensitivity to vancomycin is on the increase. Although S. aureus is considered to be an opportunistic pathogen, it is possible that certain clones are more prone to cause invasive disease than are others, due to the presence of virulence factors that increase their chance of gaining access to normally sterile sites. Although many putative virulence factors have been identified in the S. aureus genome (17), the differences in pathogenic potential between naturally occurring isolates remain largely unaddressed.The extent to which homologous recombination contributes to the emergence and subsequent diversification of clones is also at present unclear, although this question has important implications both for the choice of the most appropriate typing strategy for effective epidemiological surveilla...

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The accessory gene regulator (agr) locus influences the expression of many virulence genes in the human pathogen Staphylococcus aureus. Four allelic groups of agr, which generally inhibit the regulatory activity of each other, have been identified within the species. Interference in virulence gene expression caused by different agr groups has been suggested to be a mechanism for isolating bacterial populations and a fundamental basis for subdividing the species. To test the hypothesis that the species is phylogenetically structured according to agr groups, we mapped agr groups onto a clone phylogeny inferred from partial sequences of 14 genes from 27 genetically diverse strains. Shimodaira-Hasegawa and parametric bootstrap tests rejected the hypotheses that the species is subdivided into three or five monophyletic agr groups but failed to reject the hypothesis that the species is subdivided into two groups that each consist of multiple clonal complexes and multiple agr groups. Additional evidence for agr recombination is found from clustered polymorphisms in complete agr sequences. However, agr recombination has not occurred frequently or randomly through time, because the topology and branch lengths of the clone phylogeny are reflected within each agr group. To account for these observations, we propose a new evolutionary model that involves a genetically polymorphic ancestral population of S. aureus that horizontally transferred agr groups between two subspecies groups near the time that these subspecies groups diverged.The accessory gene regulator (agr) locus of Staphylococcus aureus encodes a two-component signal transduction system that leads to down-regulation of surface proteins and up-regulation of secreted proteins during in vitro growth (32). A role for agr in virulence has been demonstrated by the attenuated virulence of agr mutants in different animal infection models (4, 6). The agr locus consists of the divergently transcribed P2 and P3 operons (reviewed in references 30 and 31). The P2 operon consists of the genes agrB, agrD, agrC, and agrA. In essence, AgrB activity leads to secretion of the autoinducing pheromone, AgrD, which binds to and activates the histidine kinase receptor, AgrC, which subsequently activates the response regulator, AgrA. The P3 operon consists of the regulatory effector molecule of the agr system, RNAIII, and the gene encoding delta-hemolysin, hld. Interestingly, amino acid changes within the AgrD pheromone can cause inhibition of agr activity. Four allelic groups of agr have been characterized in S. aureus (numbered I to IV) that generally induce agr activity within a group and inhibit agr activity between groups (21, 23). The inhibitory activity of these agr groups represents a form of bacterial interference that affects virulence gene expression (23).It has been proposed that the inhibitory activity of agr groups may serve to isolate bacterial populations and facilitate the evolution of new strains or even species (31). This notion has been perpetuated by the observation...