How clonal is Staphylococcus aureus? - PubMed (original) (raw)

. 2003 Jun;185(11):3307-16.

doi: 10.1128/JB.185.11.3307-3316.2003.

Jessica E Cooper, Hajo Grundmann, D Ashley Robinson, Mark C Enright, Tony Berendt, Sharon J Peacock, John Maynard Smith, Michael Murphy, Brian G Spratt, Catrin E Moore, Nicholas P J Day

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How clonal is Staphylococcus aureus?

Edward J Feil et al. J Bacteriol. 2003 Jun.

Abstract

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.

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Figures

FIG. 1.

FIG. 1.

Identification of clonal complexes. BURST analysis was used to assign clonal complexes within the Oxford isolate collection. Splits graphs are also shown for each major clonal complex, generated by Splitstree version 3.1 (no splits graphs are shown for the minor groups). For the major clonal complexes, the predicted clonal ancestors are shown in the central ring, SLVs are shown in the middle (solid) ring, and double-locus variants are shown in the outer (dashed) ring. Individual relationships between some STs are shown as a solid line (single-locus difference) or a dashed line (double-locus difference). The values in parentheses are the numbers of isolates of a given ST when more than one example of an ST was observed.

FIG. 2.

FIG. 2.

Sequence diversity versus allelic diversity. The average number of nucleotide differences per locus (excluding those loci that do not differ) was calculated (y axis) for all pairwise comparisons of the 75 S. aureus STs (squares) and for the 575 S. pneumoniae STs (diamonds). These averages were computed separately for all pairwise comparisons differing at one, two, three, four, five, six, or all seven loci (x axis). There is a clear positive trend between the number of nucleotide differences in nonidentical alleles and the number of allelic differences (i.e., time since divergence) within the S. aureus data, suggesting that recombination has not been sufficiently frequent to overwhelm the stepwise accumulation of diversification through de novo point mutation. However, this trend is not noted within the data from S. pneumoniae.

FIG. 3.

FIG. 3.

Unrooted Bayesian tree of the concatenated sequences of the 75 different STs of S. aureus. The tree was constructed by using MrBayes version 2.01 (14); six different substitution rates were estimated with site-specific rate variation. Four Markov chains were run for 1,000,000 generations, and the tree was saved (with branch lengths) every 100 generations, resulting in 10,000 trees. These trees were imported into PAUP* 4.0b10 (33), and the first 2,000 trees were discarded as burn-in. A 50% majority rule consensus tree was computed from these trees, and the posterior probability given on each branch is a percentage of these trees supporting each node. All the major clonal complexes are enclosed within dashed rings; singletons or minor groups represented by more than five strains are boxed. With the exception of ST188 the individual STs within each major clonal complex are not labeled.

FIG. 4.

FIG. 4.

ML trees. Trees are shown for each MLST gene (a) and for the concatenated sequences of all seven genes (b), with a sample of 25 diverse STs. Each tree was computed by using the HKY85 model of nucleotide substitution, with the α parameter (describing the shape of the gamma distribution of rate variation with eight discrete categories) and the Ti/Tv ratio optimized during tree construction. Despite the presence of multiple inconsistencies between these trees, there is evidence for a conserved division, which is marked with an arrow in each tree. STs belonging to one side of this division (group 1) are given in white on a black background. There are some exceptions to this division, particularly at the arcC locus (see text). The branching order of the concatenated tree (b) is very similar to Fig. 3, which was computed by a Bayesian approach, the main difference being the positions of ST17 and ST59.

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