PT - JOURNAL ARTICLE AU - Bernadette C. Young AU - Chieh-Hsi Wu AU - N. Claire Gordon AU - Kevin Cole AU - James R. Price AU - Elian Liu AU - Anna E. Sheppard AU - Sanuki Perera AU - Jane Charlesworth AU - Tanya Golubchik AU - Zamin Iqbal AU - Rory Bowden AU - Ruth C. Massey AU - John Paul AU - Derrick W. Crook AU - Timothy E. A. Peto AU - A. Sarah Walker AU - Martin J. Llewelyn AU - David H. Wyllie AU - Daniel J. Wilson TI - Severe infections emerge from the microbiome by adaptive evolution AID - 10.1101/116681 DP - 2017 Jan 01 TA - bioRxiv PG - 116681 4099 - http://biorxiv.org/content/early/2017/04/19/116681.short 4100 - http://biorxiv.org/content/early/2017/04/19/116681.full 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.