title: Evolutionary dynamics of Staphylococcus aureus during progression from carriage to disease.
abstract: Whole-genome sequencing offers new insights into the evolution of bacterial pathogens and the etiology of bacterial disease. Staphylococcus aureus is a major cause of bacteria-associated mortality and invasive disease and is carried asymptomatically by 27% of adults. Eighty percent of bacteremias match the carried strain. However, the role of evolutionary change in the pathogen during the progression from carriage to disease is incompletely understood. Here we use high-throughput genome sequencing to discover the genetic changes that accompany the transition from nasal carriage to fatal bloodstream infection in an individual colonized with methicillin-sensitive S. aureus. We found a single, cohesive population exhibiting a repertoire of 30 single-nucleotide polymorphisms and four insertion/deletion variants. Mutations accumulated at a steady rate over a 13-mo period, except for a cluster of mutations preceding the transition to disease. Although bloodstream bacteria differed by just eight mutations from the original nasally carried bacteria, half of those mutations caused truncation of proteins, including a premature stop codon in an AraC-family transcriptional regulator that has been implicated in pathogenicity. Comparison with evolution in two asymptomatic carriers supported the conclusion that clusters of protein-truncating mutations are highly unusual. Our results demonstrate that bacterial diversity in vivo is limited but nonetheless detectable by whole-genome sequencing, enabling the study of evolutionary dynamics within the host. Regulatory or structural changes that occur during carriage may be functionally important for pathogenesis; therefore identifying those changes is a crucial step in understanding the biological causes of invasive bacterial disease.
authors.affiliation: Experimental Medicine Division, Nuffield Department of Clinical Medicine,  University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU,  United Kingdom.
authors.forename: Bernadette C
authors.initials: BC
authors.lastname: Young
authors.forename: Tanya
authors.initials: T
authors.lastname: Golubchik
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Batty
authors.forename: Rowena
authors.initials: R
authors.lastname: Fung
authors.forename: Hanna
authors.initials: H
authors.lastname: Larner-Svensson
authors.forename: Antonina A
authors.initials: AA
authors.lastname: Votintseva
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Miller
authors.forename: Heather
authors.initials: H
authors.lastname: Godwin
authors.forename: Kyle
authors.initials: K
authors.lastname: Knox
authors.forename: Richard G
authors.initials: RG
authors.lastname: Everitt
authors.forename: Zamin
authors.initials: Z
authors.lastname: Iqbal
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rimmer
authors.forename: Madeleine
authors.initials: M
authors.lastname: Cule
authors.forename: Camilla L C
authors.initials: CL
authors.lastname: Ip
authors.forename: Xavier
authors.initials: X
authors.lastname: Didelot
authors.forename: Rosalind M
authors.initials: RM
authors.lastname: Harding
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.forename: Tim E
authors.initials: TE
authors.lastname: Peto
authors.forename: Derrick W
authors.initials: DW
authors.lastname: Crook
authors.forename: Rory
authors.initials: R
authors.lastname: Bowden
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
mesh_terms: D001499:Bayes Theorem; D016000:Cluster Analysis; D018450:Disease Progression; D019143:Evolution, Molecular; D017353:Gene Deletion; D014644:Genetic Variation; D016680:Genome, Bacterial; D006801:Humans; D008712:Methicillin / Q000494:pharmacology; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000235:genetics*; D013997:Time Factors
chemical_list: D008712:Methicillin