Population genomics of skin Staphylococcus reveals disease-associated restructuring of species and strain diversity

Whole genome sequences of microbial isolates are essential to link microbial diversity to population and community ecology, because metagenomics alone cannot resolve strain-level variation, particularly in complex and mobile genetic elements that confer strain-specific traits such as virulence. We cultured and whole-genome sequenced 2,920 Staphylococcus isolates from healthy subjects and patients with Darier’s disease and congenital ichthyosis. Our results show that disease imposes selection at the species level, while strain populations within those species diversify across individuals in a manner consistent with ecological drift, resulting in increased interpersonal heterogeneity of strain composition. Despite this variability, strain populations converged on shared functional traits, suggesting constraints imposed by the disease environment. We further examined key functional elements of clinical and ecological relevance, including the agr quorum sensing system, the mobile genetic element SCCmec that carries methicillin resistance, and CRISPR/Cas systems, contextualizing these features both within isolate population structure and the surrounding microbial community using metagenomic data. We found disease-dependent enrichment of virulence genes, striking species-specific phylogenetic sorting of agr variants, unexpected modularity of previously undocumented SCCmec elements in diseased skin, and links between phages in the microbiota and CRISPR spacers in the isolate genomes. Taken together, our integrated, large-scale analysis of isolate genomics and metagenomics reveals that skin disease restructures staphylococcal strain populations through combined effects of selection, drift, and functional constraint.