title: Phylogenetic evidence for frequent positive selection and recombination in the meningococcal surface antigen PorB.
abstract: Previous estimates of rates of synonymous (d(S)) and nonsynonymous (d(N)) substitution among Neisseria meningitidis gene sequences suggested that the surface loops of the variable outer membrane protein PorB were under only weak selection pressure from the host immune response. These findings were consistent with studies indicating that PorB variants were not always protective in immunological and microbiological assays and questioned the suitability of this protein as a vaccine component. PorB, which is expressed at high levels on the surface of the meningococcus, has been implicated in mechanisms of pathogenesis and has also been used as a typing target in epidemiological investigations. In this work, using more precise estimates of selection pressures and recombination rates, we have shown that some residues in the surface loops of PorB are under very strong positive selection, as great as that observed in human immunodeficiency virus-1 surface glycoproteins, whereas amino acids within the loops and the membrane-spanning regions of the protein are under purifying selection, presumably because of structural constraints. Congruence tests showed that recombination occurred at a rate that was not sufficient to erase all phylogenetic similarity and did not greatly bias selection analysis. Homology models of PorB structure indicated that many strongly selected sites encoded residues that were predicted to be exposed to host immune responses, implying that this protein is under strong immune selection and requires further examination as a potential vaccine candidate. These data show that phylogenetic inference can be used to complement immunological and biochemical data in the choice of vaccine candidates.
authors.affiliation: The Peter Medawar Building for Pathogen Research and Department of Zoology, University of Oxford, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Urwin
authors.forename: Edward C
authors.initials: EC
authors.lastname: Holmes
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fox
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Derrick
authors.forename: Martin C J
authors.initials: MC
authors.lastname: Maiden
mesh_terms: D000595:Amino Acid Sequence; D000940:Antigenic Variation; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics*; D000954:Antigens, Surface / Q000737:chemistry / Q000235:genetics*; D019143:Evolution, Molecular; D005798:Genes, Bacterial; D022401:Meningococcal Vaccines / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009345:Neisseria meningitidis / Q000235:genetics* / Q000276:immunology*; D010802:Phylogeny; D018272:Porins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D011487:Protein Conformation; D011995:Recombination, Genetic; D012641:Selection, Genetic
chemical_list: D000942:Antigens, Bacterial; D000954:Antigens, Surface; D022401:Meningococcal Vaccines; D018272:Porins; C057699:porin protein, Neisseria