title: Dominant role of nucleotide substitution in the diversification of serotype 3 pneumococci over decades and during a single infection.
abstract: Streptococcus pneumoniae of serotype 3 possess a mucoid capsule and cause disease associated with high mortality rates relative to other pneumococci. Phylogenetic analysis of a complete reference genome and 81 draft sequences from clonal complex 180, the predominant serotype 3 clone in much of the world, found most sampled isolates belonged to a clade affected by few diversifying recombinations. However, other isolates indicate significant genetic variation has accumulated over the clonal complex's entire history. Two closely related genomes, one from the blood and another from the cerebrospinal fluid, were obtained from a patient with meningitis. The pair differed in their behaviour in a mouse model of disease and in their susceptibility to antimicrobials, with at least some of these changes attributable to a mutation that up-regulated the patAB efflux pump. This indicates clinically important phenotypic variation can accumulate rapidly through small alterations to the genotype.
authors.affiliation: Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom ; Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Croucher
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Mitchell
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Gould
authors.forename: Donald
authors.initials: D
authors.lastname: Inverarity
authors.forename: Lars
authors.initials: L
authors.lastname: Barquist
authors.forename: Theresa
authors.initials: T
authors.lastname: Feltwell
authors.forename: Maria C
authors.initials: MC
authors.lastname: Fookes
authors.forename: Simon R
authors.initials: SR
authors.lastname: Harris
authors.forename: Janina
authors.initials: J
authors.lastname: Dordel
authors.forename: Susannah J
authors.initials: SJ
authors.lastname: Salter
authors.forename: Sarah
authors.initials: S
authors.lastname: Browall
authors.forename: Helena
authors.initials: H
authors.lastname: Zemlickova
authors.forename: Julian
authors.initials: J
authors.lastname: Parkhill
authors.forename: Staffan
authors.initials: S
authors.lastname: Normark
authors.forename: Birgitta
authors.initials: B
authors.lastname: Henriques-Normark
authors.forename: Jason
authors.initials: J
authors.lastname: Hinds
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Bentley
mesh_terms: D000818:Animals; D014644:Genetic Variation; D016680:Genome, Bacterial; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008581:Meningitis / Q000097:blood / Q000134:cerebrospinal fluid / Q000382:microbiology; D051379:Mice; D009154:Mutation; D010802:Phylogeny; D012703:Serotyping; D013296:Streptococcus pneumoniae / Q000235:genetics* / Q000472:pathogenicity