Simple sequence repeats power Staphylococcus aureus adaptation

Understanding Staphylococcus aureus adaptation is foundational for addressing the challenges posed by this pathogen. Using evolutionary convergence analysis on 7099 S. aureus genomes we uncovered frequent, reversible loss-of-function (LoF) mutations caused by simple sequence repeats (SSRs). Functional assays showed SSRs are potent, length-dependent switches that activate and deactivate genes, a mechanism exemplified by frequent LoF mutations in mutL (DNA mismatch repair) that causes a hypermutator phenotype. Analysis of over 600 episodes of human S. aureus colonisation and infection confirmed laboratory findings and showed that mutL SSR hypermutability behaves like a phase-variable evolutionary capacitor that unlocks subsequent adaptive SSR variations. We also experimentally demonstrate that SSRs facilitate foreign DNA uptake (hsdR restriction endonuclease) and lead to gentamicin-resistant small colony variants that are known to cause persistent infections (menF menadione biosynthesis). Furthermore, the phenomenon is widespread, with 27 of 29 diverse human microbiome samples harbouring S. aureus with distinct SSR subpopulations, indicative of niche-specific adaptations. Thus, SSRs are potent reservoirs of previously unrecognized S. aureus genetic heterogeneity that confer rapid adaptive capacity, including in antigens targeted by past vaccine trials. A deeper understanding of SSR evolutionary trajectories has the potential to improve treatments and to anticipate S. aureus responses to new therapies.