Overall Genome Structure

The size of the sequenced S. aureus genomes varies from 2.800 Mbp to 2.903 Mbp, encoding 2565-2721 proteins (Table9.1) [14-17]. It has been calculated that approx. 75% of the genome is conserved among all S. aureus isolates representing the core genome [18]. This part of the genome encodes housekeeping functions such as factors involved in central metabolism. In addition, some virulence-associated factors are expressed by almost all isolates: protein A (spa), a-toxin (hla), clumping factor (clfAB), aureolysin (aur), lipase (lip), fibrinogen binding protein A (fnbA), coagulase (coa), superoxide dismutase (sodM), and the intercellular adhe-sin (ica) [19]. Besides comparing whole genome sequences, DNA microarray technology has been used to define the genetic diversity of S. aureus isolates of different origin [18, 20, 21]. Fitzgerald et al. examined the extent and types of genetic diversity in S. aureus using a collection of strains representing the most abundant lineages identified by multilocus enzyme electrophoresis (MLEE) [18]. In that study, the core of the genome found in all strains encompasses 2198 open reading frames (ORFs), representing 78% of all ORFs. Most of the dispensable genes were clustered in 18 regions of difference (RDs) that contained elements related to pathogenicity islands, phages, plasmids, transposons, and insertion sequences. Ten of these regions encode virulence factors or antibiotic resistance determinants. These results underscore the great degree of diversity in S. aureus. Interestingly, several RDs vary extensively in gene content and size, suggesting that multiple deletions and integration and recombination events have occurred during the evolution of the strains. In a similar approach, the genetic diversity between strains of different origins including sepsis isolates, wound isolates, isolates from mucoviscidosis (cystic fibrosis) patients, and carrier isolates from the nose were compared [22]. Here, it was found that 14 RDs were scattered throughout the genome. These regions encompass the mecA genomic island, the pathogenicity and genomic islands SaPIn1, SaPIn2, SaPIn3, a phage region (0 315), the capsule gene cluster, and cluster of genes of unknown function. Interestingly, the differences between the strains were almost completely restricted to these regions; the sequences outside of these regions were highly conserved. For some of the regions putative mobility factors like integrases, transposases, and IS elements could be identified, but for others the reasons for the great extent of variations remains unknown. The clustering of genes/ORFs which are absent in different isolates suggests a common mechanism for genome stability and flexibility. Apart from integration and excision of staphylococcal phages (see below), the processes leading to small or large genome variations are less understood. For some pathogenicity islands (SaPIn2 and SaPInbov) genetic transfer has been experimentally demonstrated, revealing a phage-like mechanism [23-25]. In addition, IS elements like IS256 confer recombination events leading to gene deletion, inversion, and integration [26].

Several multilocus sequencing (MLST) studies were performed to analyze clonal structures of S. aureus. Interestingly, clinical isolates have a highly clonal population structure. For example, 87% of strains in hospitals and the community belong to 11 clonal complexes (CCs) [27]. Furthermore, MLST has been employed to analyze clonal relationships of MRSA. Here, it became evident that the SCCmec genomic island was introduced in only five clonal complexes [28]. Moreover, MLST analysis of the seven sequenced S. aureus strains has shown that six strains are closely related (COL, 8325, N315, Mu50, MW2, MSSA476). Only the strain MRSA252 belongs to an unrelated sequence type (ST) [29]. Importantly, this strain is a representative of the EMRSA-16 clonal group, the cause of 50% of the MRSA infections in the UK and one of the predominant clones spreading in the USA [30, 31].

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