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/2017/03/14/116681.short
4100  - http://biorxiv.org/content/early/2017/03/14/116681.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 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.