The mutational landscape of Staphylococcus aureus during colonisation

Staphylococcus aureus is an important human pathogen but is primarily a commensal of the human nose and skin. Survival during colonisation is likely one of the major drivers of S. aureus evolution. Here we use a genome-wide mutation enrichment approach to analyse a genomic dataset of 3,060 S. aureus isolates from 791 individuals to show that despite limited within-host genetic diversity, an excess of protein-altering mutations can be found in genes encoding key metabolic pathways, in regulators of quorum-sensing and in known antibiotic targets. Nitrogen metabolism and riboflavin synthesis are the metabolic processes with strongest evidence of adaptation. Further evidence of adaptation to nitrogen availability was revealed by enrichment of mutations in the assimilatory nitrite reductase and urease, including mutations that enhance growth with urea as the sole nitrogen source. Inclusion of an additional 4,090 genomes from 802 individuals revealed eight additional genes including sasA/sraP, pstA, and rsbU with signals adaptive variation that warrant further characterisation. Our study provides the most comprehensive picture to date of the heterogeneity of adaptive changes that occur in the genomes of S. aureus during colonisation, revealing the likely importance of nitrogen metabolism, loss of quorum sensing and antibiotic resistance for successful human colonisation. ### Competing Interest Statement The authors have declared no competing interest.