title: Meningococcal genetic variation mechanisms viewed through comparative analysis of serogroup C strain FAM18.
abstract: The bacterium Neisseria meningitidis is commonly found harmlessly colonising the mucosal surfaces of the human nasopharynx. Occasionally strains can invade host tissues causing septicaemia and meningitis, making the bacterium a major cause of morbidity and mortality in both the developed and developing world. The species is known to be diverse in many ways, as a product of its natural transformability and of a range of recombination and mutation-based systems. Previous work on pathogenic Neisseria has identified several mechanisms for the generation of diversity of surface structures, including phase variation based on slippage-like mechanisms and sequence conversion of expressed genes using information from silent loci. Comparison of the genome sequences of two N. meningitidis strains, serogroup B MC58 and serogroup A Z2491, suggested further mechanisms of variation, including C-terminal exchange in specific genes and enhanced localised recombination and variation related to repeat arrays. We have sequenced the genome of N. meningitidis strain FAM18, a representative of the ST-11/ET-37 complex, providing the first genome sequence for the disease-causing serogroup C meningococci; it has 1,976 predicted genes, of which 60 do not have orthologues in the previously sequenced serogroup A or B strains. Through genome comparison with Z2491 and MC58 we have further characterised specific mechanisms of genetic variation in N. meningitidis, describing specialised loci for generation of cell surface protein variants and measuring the association between noncoding repeat arrays and sequence variation in flanking genes. Here we provide a detailed view of novel genetic diversification mechanisms in N. meningitidis. Our analysis provides evidence for the hypothesis that the noncoding repeat arrays in neisserial genomes (neisserial intergenic mosaic elements) provide a crucial mechanism for the generation of surface antigen variants. Such variation will have an impact on the interaction with the host tissues, and understanding these mechanisms is important to aid our understanding of the intimate and complex relationship between the human nasopharynx and the meningococcus.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom. sdb@sanger.ac.uk
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Bentley
authors.forename: George S
authors.initials: GS
authors.lastname: Vernikos
authors.forename: Lori A S
authors.initials: LA
authors.lastname: Snyder
authors.forename: Carol
authors.initials: C
authors.lastname: Churcher
authors.forename: Claire
authors.initials: C
authors.lastname: Arrowsmith
authors.forename: Tracey
authors.initials: T
authors.lastname: Chillingworth
authors.forename: Ann
authors.initials: A
authors.lastname: Cronin
authors.forename: Paul H
authors.initials: PH
authors.lastname: Davis
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Holroyd
authors.forename: Kay
authors.initials: K
authors.lastname: Jagels
authors.forename: Mark
authors.initials: M
authors.lastname: Maddison
authors.forename: Sharon
authors.initials: S
authors.lastname: Moule
authors.forename: Ester
authors.initials: E
authors.lastname: Rabbinowitsch
authors.forename: Sarah
authors.initials: S
authors.lastname: Sharp
authors.forename: Louise
authors.initials: L
authors.lastname: Unwin
authors.forename: Sally
authors.initials: S
authors.lastname: Whitehead
authors.forename: Michael A
authors.initials: MA
authors.lastname: Quail
authors.forename: Mark
authors.initials: M
authors.lastname: Achtman
authors.forename: Bart
authors.initials: B
authors.lastname: Barrell
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Saunders
authors.forename: Julian
authors.initials: J
authors.lastname: Parkhill
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics; D001482:Base Composition / Q000235:genetics; D015321:Gene Rearrangement; D005798:Genes, Bacterial; D014644:Genetic Variation; D006801:Humans; D038542:Neisseria meningitidis, Serogroup C / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D026801:Synteny / Q000235:genetics
chemical_list: D001426:Bacterial Proteins