Diversification of the Staphylococcal Cassette Chromosome Through Distinct Mechanisms of Horizontal Transfer

The staphylococcal cassette chromosome mec (SCCmec) is a mobile genetic element that carries the mecA gene conferring resistance to beta-lactam antibiotics. While SCCmec is widely disseminated in Staphylococcus aureus, its diversity and evolutionary history across different taxonomic scales have not been investigated in detail. To elucidate the mechanisms governing the diversification of SCCmec, we carried out the largest systematic analysis of SCCmec to date. We focused on the Staphylococcaceae family, which is the primary cellular host of SCCmec. We scanned 2,556 complete genomes, representing 75 species and 8 genera within Staphylococcaceae. For this, we developed SCCeeker, a tailored pipeline to detect SCCmec across a large-scale genomic dataset. We uncovered 1,419 candidate SCCmec regions in 3 of 5 Mammaliicoccus species and 32 of 54 Staphylococcus species. SCCmec-carrying species are not more cladistically related than those without the SCCmec. The present study reveals that the evolution of SCCmec locus is driven by multiple mechanisms of horizontal transfer: transposition of insertion sequences IS1272 and IS6/IS431, transfer of entire cassette or fragments of it, cassettes carried by putative plasmids, formation of chimeric cassettes, and recombination of homologous sequences. The multimodal shuffling of SCCmec elements creates a genetically diverse cassette pool and sheds light on the independent evolution of mobile elements and the origins of SCCmec.