title: Genomic Analysis of the Evolution and Global Spread of Hyper-invasive Meningococcal Lineage 5.
abstract: BACKGROUND
  The predominant model for bacterial pandemics is the emergence of a virulent variant that diversifies as it spreads in human populations. We investigated a 40-year meningococcal disease pandemic caused by the hyper-invasive ET-5/ST-32 complex.
  
  
  METHODS
  A global collection ofNeisseria meningitidisisolates dating from 1969 to 2008 was whole genome sequenced (WGS) and analysed using a gene-by-gene approach at http://pubmlst.org/neisseria.
  
  
  RESULTS
  Analysis of WGS data identified a 'Lineage 5 pan genome' of 1940 genes, 1752 (92%) of which were present in all isolates (Lineage 5 'core genome'). Genetic diversity, which was mostly generated by horizontal gene transfer, was unevenly distributed in the genome; however, genealogical analysis of diverse and conserved core genes, accessory genes, and antigen encoding genes, robustly identified a star phylogeny with a number of sub-lineages. Most European and American isolates belonged to one of two closely related sub-lineages, which had diversified before the identification of the pandemic in the 1970s. A third, genetically more diverse sub-lineage, was associated with Asian isolates. Several isolates had acquired DNA from the related gonococcus.
  
  
  CONCLUSIONS
  These data were inconsistent with a single point of origin followed by pandemic spread, rather suggesting that the sub-lineages had diversified and spread by asymptomatic transmission, with multiple distinct strains causing localised hyperendemic outbreaks.
authors.affiliation: Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.
authors.forename: Odile B
authors.initials: OB
authors.lastname: Harrison
authors.affiliation: Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Bray
authors.affiliation: Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.
authors.forename: Martin C J
authors.initials: MC
authors.lastname: Maiden
authors.affiliation: WHO Collaborating Centre for Reference and Research on Meningococci, Norwegian Institute of Public health, P.O. Box 4404 Nydalen, NO-0403 Oslo, Norway ; Department of Community Medicine, Faculty of Medicine, University of Oslo, P.O. Box 1130 Blindern, NO-0318 Oslo, Norway.
authors.forename: Dominique A
authors.initials: DA
authors.lastname: Caugant
keywords: Evolution; Genome sequencing; Neisseria meningitidis; Serogroup B