Abstract
Bacteria responsible for the greatest global mortality colonize the human microbiome far more frequently than they cause severe infections. Whether mutation and selection within the microbiome precipitate infection is unknown. To address this question, we investigated de novo mutation in 1163 Staphylococcus aureus genomes from 105 infected patients with nose-colonization. We report that 72% of the infections emerged from the microbiome, with infecting and nose-colonizing bacteria showing systematic adaptive differences. We found 3.6-fold, 2.9-fold and 2.8-fold enrichments of protein-altering variants in genes responding to rsp, which regulates surface antigens and toxicity; agr, which regulates quorum-sensing, toxicity and abscess formation; and host-derived antimicrobial peptides, respectively. These adaptive signatures were not observed in healthy carriers and differed from prevailing species-level signals of selection, suggesting disease-associated, short-term, within-host selection pressures. Our results show that infection, like a cancer of the microbiome, emerges through spontaneous adaptive evolution, raising new possibilities for diagnosis and treatment.