Rapid, fine-scale genomic diversification of methicillin resistance in S. epidermidis colonizing neonatal human hosts

Staphylococcus epidermidis is a common skin commensal, a major cause of hospital-acquired infections, and a reservoir of antibiotic resistance genes for pathogenic Staphylococcus aureus, suggesting that its genomic diversity and evolution have important consequences for human health. Previous genome-wide comparisons reveal that S. epidermidis has an open pan-genome with substantial within-species variability in gene content, suggesting that the gain and loss of new genes is an important driving force underlying its genomic evolution. Nonetheless, it remains unclear how rapidly such gene content variability arises in S. epidermidis after colonizing human hosts, and which genes evolve most rapidly on short timescales. Here, we demonstrate that fine-scale gene content diversity evolves rapidly and reproducibly across multiple S. epidermidis lineages colonizing neonatal human hosts. By surveying the evolutionary histories of thousands of genes across hundreds of S. epidermidis isolates, we identify genes in the SCCmec island, including the penicillin binding protein mecA, as the most evolutionarily labile. Consistent with previous work, evolution of genes in the SCCmec island occurs via conservative site-specific recombination of regions flanked by short direct repeats. However, distinct repeats mediate recombination, even within a given lineage. This repeat diversity gives rise to patient-specific structural variants in the SCCmec island with different levels of resistance to beta-lactam antibiotics. Overall, our results demonstrate that S. epidermidis evolves rapidly following colonization of a new human host.