• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of geneticsGeneticsCurrent IssueInformation for AuthorsEditorial BoardSubscribeSubmit a Manuscript
Genetics. Jan 2004; 166(1): 25–32.
PMCID: PMC1470718

Strong positive selection and recombination drive the antigenic variation of the PilE protein of the human pathogen Neisseria meningitidis.


The PilE protein is the major component of the Neisseria meningitidis pilus, which is encoded by the pilE/pilS locus that includes an expressed gene and eight homologous silent fragments. The silent gene fragments have been shown to recombine through gene conversion with the expressed gene and thereby provide a means by which novel antigenic variants of the PilE protein can be generated. We have analyzed the evolutionary rate of the pilE gene using the nucleotide sequence of two complete pilE/pilS loci. The very high rate of evolution displayed by the PilE protein appears driven by both recombination and positive selection. Within the semivariable region of the pilE and pilS genes, recombination appears to occur within multiple small sequence blocks that lie between conserved sequence elements. Within the hypervariable region, positive selection was identified from comparison of the silent and expressed genes. The unusual gene conversion mechanism that operates at the pilE/pilS locus is a strategy employed by N. meningitidis to enhance mutation of certain regions of the PilE protein. The silent copies of the gene effectively allow "parallelized" evolution of pilE, thus enabling the encoded protein to rapidly explore a large area of sequence space in an effort to find novel antigenic variants.

Full Text

The Full Text of this article is available as a PDF (113K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Smith JM. Analyzing the mosaic structure of genes. J Mol Evol. 1992 Feb;34(2):126–129. [PubMed]
  • Moxon ER, Rainey PB, Nowak MA, Lenski RE. Adaptive evolution of highly mutable loci in pathogenic bacteria. Curr Biol. 1994 Jan 1;4(1):24–33. [PubMed]
  • Nassif X. Interaction mechanisms of encapsulated meningococci with eucaryotic cells: what does this tell us about the crossing of the blood-brain barrier by Neisseria meningitidis? Curr Opin Microbiol. 1999 Feb;2(1):71–77. [PubMed]
  • Nei M, Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol. 1986 Sep;3(5):418–426. [PubMed]
  • Nielsen R, Yang Z. Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics. 1998 Mar;148(3):929–936. [PMC free article] [PubMed]
  • Noormohammadi AH, Markham PF, Kanci A, Whithear KG, Browning GF. A novel mechanism for control of antigenic variation in the haemagglutinin gene family of mycoplasma synoviae. Mol Microbiol. 2000 Feb;35(4):911–923. [PubMed]
  • Olsen GJ, Matsuda H, Hagstrom R, Overbeek R. fastDNAmL: a tool for construction of phylogenetic trees of DNA sequences using maximum likelihood. Comput Appl Biosci. 1994 Feb;10(1):41–48. [PubMed]
  • Parge HE, Forest KT, Hickey MJ, Christensen DA, Getzoff ED, Tainer JA. Structure of the fibre-forming protein pilin at 2.6 A resolution. Nature. 1995 Nov 2;378(6552):32–38. [PubMed]
  • Aho EL, Keating AM, McGillivray SM. A comparative analysis of pilin genes from pathogenic and nonpathogenic Neisseria species. Microb Pathog. 2000 Feb;28(2):81–88. [PubMed]
  • Parkhill J, Achtman M, James KD, Bentley SD, Churcher C, Klee SR, Morelli G, Basham D, Brown D, Chillingworth T, et al. Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491. Nature. 2000 Mar 30;404(6777):502–506. [PubMed]
  • Anisimova Maria, Nielsen Rasmus, Yang Ziheng. Effect of recombination on the accuracy of the likelihood method for detecting positive selection at amino acid sites. Genetics. 2003 Jul;164(3):1229–1236. [PMC free article] [PubMed]
  • Perry AC, Nicolson IJ, Saunders JR. Neisseria meningitidis C114 contains silent, truncated pilin genes that are homologous to Neisseria gonorrhoeae pil sequences. J Bacteriol. 1988 Apr;170(4):1691–1697. [PMC free article] [PubMed]
  • Brayton Kelly A, Palmer Guy H, Lundgren Anna, Yi Jooyoung, Barbet Anthony F. Antigenic variation of Anaplasma marginale msp2 occurs by combinatorial gene conversion. Mol Microbiol. 2002 Mar;43(5):1151–1159. [PubMed]
  • Felsenstein J. Evolutionary trees from DNA sequences: a maximum likelihood approach. J Mol Evol. 1981;17(6):368–376. [PubMed]
  • Rahman M, Källström H, Normark S, Jonsson AB. PilC of pathogenic Neisseria is associated with the bacterial cell surface. Mol Microbiol. 1997 Jul;25(1):11–25. [PubMed]
  • Forest KT, Bernstein SL, Getzoff ED, So M, Tribbick G, Geysen HM, Deal CD, Tainer JA. Assembly and antigenicity of the Neisseria gonorrhoeae pilus mapped with antibodies. Infect Immun. 1996 Feb;64(2):644–652. [PMC free article] [PubMed]
  • Rudel T, Scheurerpflug I, Meyer TF. Neisseria PilC protein identified as type-4 pilus tip-located adhesin. Nature. 1995 Jan 26;373(6512):357–359. [PubMed]
  • Gibbs CP, Reimann BY, Schultz E, Kaufmann A, Haas R, Meyer TF. Reassortment of pilin genes in Neisseria gonorrhoeae occurs by two distinct mechanisms. Nature. 1989 Apr 20;338(6217):651–652. [PubMed]
  • Sarubbi FA, Jr, Sparling PF. Transfer of antibiotic resistance in mixed cultures of Neisseria gonorrhoeae. J Infect Dis. 1974 Dec;130(6):660–663. [PubMed]
  • Goodman SD, Scocca JJ. Identification and arrangement of the DNA sequence recognized in specific transformation of Neisseria gonorrhoeae. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6982–6986. [PMC free article] [PubMed]
  • Segal E, Hagblom P, Seifert HS, So M. Antigenic variation of gonococcal pilus involves assembly of separated silent gene segments. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2177–2181. [PMC free article] [PubMed]
  • Grassly NC, Holmes EC. A likelihood method for the detection of selection and recombination using nucleotide sequences. Mol Biol Evol. 1997 Mar;14(3):239–247. [PubMed]
  • Seifert HS. Questions about gonococcal pilus phase- and antigenic variation. Mol Microbiol. 1996 Aug;21(3):433–440. [PubMed]
  • Haas R, Meyer TF. The repertoire of silent pilus genes in Neisseria gonorrhoeae: evidence for gene conversion. Cell. 1986 Jan 17;44(1):107–115. [PubMed]
  • Seifert HS, Ajioka RS, Marchal C, Sparling PF, So M. DNA transformation leads to pilin antigenic variation in Neisseria gonorrhoeae. Nature. 1988 Nov 24;336(6197):392–395. [PubMed]
  • Haas R, Veit S, Meyer TF. Silent pilin genes of Neisseria gonorrhoeae MS11 and the occurrence of related hypervariant sequences among other gonococcal isolates. Mol Microbiol. 1992 Jan;6(2):197–208. [PubMed]
  • Sparling PF. Genetic transformation of Neisseria gonorrhoeae to streptomycin resistance. J Bacteriol. 1966 Nov;92(5):1364–1371. [PMC free article] [PubMed]
  • Suzuki Y, Gojobori T. A method for detecting positive selection at single amino acid sites. Mol Biol Evol. 1999 Oct;16(10):1315–1328. [PubMed]
  • Hamrick TS, Dempsey JA, Cohen MS, Cannon JG. Antigenic variation of gonococcal pilin expression in vivo: analysis of the strain FA1090 pilin repertoire and identification of the pilS gene copies recombining with pilE during experimental human infection. Microbiology. 2001 Apr;147(Pt 4):839–849. [PubMed]
  • Suzuki Y, Gojobori T, Nei M. ADAPTSITE: detecting natural selection at single amino acid sites. Bioinformatics. 2001 Jul;17(7):660–661. [PubMed]
  • Tettelin H, Saunders NJ, Heidelberg J, Jeffries AC, Nelson KE, Eisen JA, Ketchum KA, Hood DW, Peden JF, Dodson RJ, et al. Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Science. 2000 Mar 10;287(5459):1809–1815. [PubMed]
  • Howell-Adams B, Seifert HS. Molecular models accounting for the gene conversion reactions mediating gonococcal pilin antigenic variation. Mol Microbiol. 2000 Sep;37(5):1146–1158. [PubMed]
  • Jiggins Francis M, Hurst Gregory D D, Yang Ziheng. Host-symbiont conflicts: positive selection on an outer membrane protein of parasitic but not mutualistic Rickettsiaceae. Mol Biol Evol. 2002 Aug;19(8):1341–1349. [PubMed]
  • Urwin Rachel, Holmes Edward C, Fox Andrew J, Derrick Jeremy P, Maiden Martin C J. Phylogenetic evidence for frequent positive selection and recombination in the meningococcal surface antigen PorB. Mol Biol Evol. 2002 Oct;19(10):1686–1694. [PubMed]
  • Zhang JR, Norris SJ. Genetic variation of the Borrelia burgdorferi gene vlsE involves cassette-specific, segmental gene conversion. Infect Immun. 1998 Aug;66(8):3698–3704. [PMC free article] [PubMed]
  • Yang Z, Nielsen R, Goldman N, Pedersen AM. Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics. 2000 May;155(1):431–449. [PMC free article] [PubMed]

Articles from Genetics are provided here courtesy of Genetics Society of America


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...