RT Journal Article SR Electronic T1 Severe infections emerge from the microbiome by adaptive evolution JF bioRxiv FD Cold Spring Harbor Laboratory SP 116681 DO 10.1101/116681 A1 Bernadette C. Young A1 Chieh-Hsi Wu A1 N. Claire Gordon A1 Kevin Cole A1 James R. Price A1 Elian Liu A1 Anna E. Sheppard A1 Sanuki Perera A1 Jane Charlesworth A1 Tanya Golubchik A1 Zamin Iqbal A1 Rory Bowden A1 Ruth C. Massey A1 John Paul A1 Derrick W. Crook A1 Timothy E. A. Peto A1 A. Sarah Walker A1 Martin J. Llewelyn A1 David H. Wyllie A1 Daniel J. Wilson YR 2017 UL http://biorxiv.org/content/early/2017/04/19/116681.abstract AB 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 accompany infection is unknown. We investigated de novo mutation in 1163 Staphylococcus aureus genomes from 105 infected patients with nose-colonization. We report that 72% of infections emerged from the microbiome, with infecting and nose-colonizing bacteria showing parallel adaptive differences. We found 2.8-to-3.6-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. Adaptive mutations in pathogenesis-associated genes were 3.1-fold enriched in infecting but not nose-colonizing bacteria. None of these signatures were observed in healthy carriers nor at the species-level, 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.One Sentence Summary Life-threatening S. aureus infections emerge from nose microbiome bacteria in association with repeatable adaptive evolution.