title: Within-host evolution of Staphylococcus aureus during asymptomatic carriage.
abstract: BACKGROUND
  Staphylococcus aureus is a major cause of healthcare associated mortality, but like many important bacterial pathogens, it is a common constituent of the normal human body flora. Around a third of healthy adults are carriers. Recent evidence suggests that evolution of S. aureus during nasal carriage may be associated with progression to invasive disease. However, a more detailed understanding of within-host evolution under natural conditions is required to appreciate the evolutionary and mechanistic reasons why commensal bacteria such as S. aureus cause disease. Therefore we examined in detail the evolutionary dynamics of normal, asymptomatic carriage. Sequencing a total of 131 genomes across 13 singly colonized hosts using the Illumina platform, we investigated diversity, selection, population dynamics and transmission during the short-term evolution of S. aureus.
  
  
  RESULTS
  We characterized the processes by which the raw material for evolution is generated: micro-mutation (point mutation and small insertions/deletions), macro-mutation (large insertions/deletions) and the loss or acquisition of mobile elements (plasmids and bacteriophages). Through an analysis of synonymous, non-synonymous and intergenic mutations we discovered a fitness landscape dominated by purifying selection, with rare examples of adaptive change in genes encoding surface-anchored proteins and an enterotoxin. We found evidence for dramatic, hundred-fold fluctuations in the size of the within-host population over time, which we related to the cycle of colonization and clearance. Using a newly-developed population genetics approach to detect recent transmission among hosts, we revealed evidence for recent transmission between some of our subjects, including a husband and wife both carrying populations of methicillin-resistant S. aureus (MRSA).
  
  
  CONCLUSIONS
  This investigation begins to paint a picture of the within-host evolution of an important bacterial pathogen during its prevailing natural state, asymptomatic carriage. These results also have wider significance as a benchmark for future systematic studies of evolution during invasive S. aureus disease.
authors: Department of Statistics, University of Oxford, Oxford, Oxfordshire, United Kingdom.
authors: Tanya
authors: T
authors: Golubchik
authors: Elizabeth M
authors: EM
authors: Batty
authors: Ruth R
authors: RR
authors: Miller
authors: Helen
authors: H
authors: Farr
authors: Bernadette C
authors: BC
authors: Young
authors: Hanna
authors: H
authors: Larner-Svensson
authors: Rowena
authors: R
authors: Fung
authors: Heather
authors: H
authors: Godwin
authors: Kyle
authors: K
authors: Knox
authors: Antonina
authors: A
authors: Votintseva
authors: Richard G
authors: RG
authors: Everitt
authors: Teresa
authors: T
authors: Street
authors: Madeleine
authors: M
authors: Cule
authors: Camilla L C
authors: CL
authors: Ip
authors: Xavier
authors: X
authors: Didelot
authors: Timothy E A
authors: TE
authors: Peto
authors: Rosalind M
authors: RM
authors: Harding
authors: Daniel J
authors: DJ
authors: Wilson
authors: Derrick W
authors: DW
authors: Crook
authors: Rory
authors: R
authors: Bowden
mesh_terms: D000328:Adult; D058345:Asymptomatic Infections; D002353:Carrier State; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D006801:Humans; D054643:INDEL Mutation; D009666:Nose / Q000382:microbiology; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections / Q000382:microbiology* / Q000635:transmission; D013211:Staphylococcus aureus / Q000235:genetics*
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