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Bacterial populations as perfect gases: genomic integrity and diversification tensions in Helicobacter pylori

Key Points

  • The Gram-negative bacterium Helicobacter pylori is the predominant organism that colonizes the human stomach. In this article, the authors give their views on some of the genetic mechanisms that have allowed this organism to be so successful in this harsh environment.

  • The article focuses on the tensions between the opposing forces of maintaining genome integrity and increasing genome diversification in H. pylori. The stomach comprises various macroniches, which differ in anatomical location and therefore also in physiological properties. The authors propose that the tensions between integrity and diversification create a dynamic pool of genetic variants that is sufficiently genetically diverse to occupy many of the potential niches in the stomach. The authors draw an analogy with a perfect gas that can fill any volume.

  • The different mechanisms that H. pylori uses to generate its extraordinary diversity are reviewed, including diversity at the cellular level through inter-and intragenomic recombination, and diversity at the population level.

  • The mechanisms that control genome infidelity are then reviewed in detail. These include mismatch repair (absent from H. pylori), translesion synthesis, nucleotide excision repair, base excision repair and recombinational repair.

  • Finally, the role of restriction–modification systems in keeping the competing genotypes in balance is considered.


Microorganisms that persist in single hosts face particular challenges. Helicobacter pylori, an obligate bacterial parasite of the human stomach, has evolved a lifestyle that features interstrain competition and intraspecies cooperation, both of which involve horizontal gene transfer. Microbial species must maintain genomic integrity, yet H. pylori has evolved a complex nonlinear system for diversification that exists in dynamic tension with the mechanisms for ensuring fidelity. Here, we review these tensions and propose that they create a dynamic pool of genetic variants that is sufficiently genetically diverse to allow H. pylori to occupy all of the potential niches in the stomach.

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Figure 1: Bacterial mechanisms to control DNA damage.
Figure 2: Tensions between genomic integrity and diversification in Helicobacter pylori.
Figure 3: A model of the role of microbial variation in niche colonization.


  1. 1

    Falush, D. et al. Traces of human migrations in Helicobacter pylori populations. Science 299, 1582–1585 (2003). H. pylori is hypothesized to have colonized humans since their origins. Analysis of H. pylori variation, with a large number of informative sites, is used to elucidate details of human migration in this publication.

    CAS  PubMed  Google Scholar 

  2. 2

    Ghose, C. et al. East Asian genotypes of Helicobacter pylori strains in Amerindians provide evidence for its ancient human carriage. Proc. Natl Acad. Sci. USA 99, 15107–15111 (2002).

    CAS  PubMed  Google Scholar 

  3. 3

    Fox, J. G. The expanding genus of Helicobacter: pathogenic and zoonotic potential. Semin. Gastrointest. Dis. 8, 124–141 (1997).

    CAS  PubMed  Google Scholar 

  4. 4

    Mitchell, H. M. et al. Epidemiology of Helicobacter pylori in southern China: identification of early childhood as the critical period for acquisition. J. Infect. Dis. 166, 149–153 (1992).

    CAS  PubMed  Google Scholar 

  5. 5

    Perez-Perez, G. I. et al. Evidence that cagA+Helicobacter pylori strains are disappearing more rapidly than cagA strains. Gut 50, 295–298 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Rehnberg-Laiho, L. et al. Decreasing prevalence of Helicobacter antibodies in Finland, with reference to the decreasing incidence of gastric cancer. Epidemiol. Infect. 126, 37–42 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Granstrom, M., Tindberg, Y. & Blennow, M. Seroepidemiology of Helicobacter pylori infection in a cohort of children monitored from 6 months to 11 years of age. J. Clin. Microbiol. 35, 468–470 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Parsonnet, J. Helicobacter pylori: the size of the problem. Gut 43 (Suppl. 1), S6–S9 (1998).

    PubMed  PubMed Central  Google Scholar 

  9. 9

    Parsonnet, J. et al. Helicobacter pylori infection and gastric lymphoma. N. Engl. J. Med. 330, 1267–1271 (1994).

    CAS  Google Scholar 

  10. 10

    Peek, R. M. Jr. & Blaser, M. J. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nature Rev. Cancer 2, 28–37 (2002).

    CAS  Google Scholar 

  11. 11

    Peterson, W. L. Helicobacter pylori and peptic ulcer disease. N. Engl. J. Med. 324, 1043–1048 (1991).

    CAS  PubMed  Google Scholar 

  12. 12

    Suerbaum, S. & Michetti, P. Helicobacter pylori infection. N. Engl. J. Med. 347, 1175–1186 (2002).

    CAS  PubMed  Google Scholar 

  13. 13

    Bik, E. M. et al. Molecular analysis of the bacterial microbiota in the human stomach. Proc. Natl Acad. Sci. USA 103, 732–737 (2006).

    CAS  PubMed  Google Scholar 

  14. 14

    Go, M. F., Kapur, V., Graham, D. Y. & Musser, J. M. Population genetic analysis of Helicobacter pylori by multilocus enzyme electrophoresis: extensive allelic diversity and recombinational population structure. J. Bacteriol. 178, 3934–3938 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Achtman, M. et al. Recombination and clonal groupings within Helicobacter pylori from different geographical regions. Mol. Microbiol. 32, 459–470 (1999). The first study to use multilocus sequence typing to characterize H. pylori; demonstrates extensive recombination in weakly clonal groupings.

    CAS  PubMed  Google Scholar 

  16. 16

    Jiang, Q., Hiratsuka, K. & Taylor, D. E. Variability of gene order in different Helicobacter pylori strains contributes to genome diversity. Mol. Microbiol. 20, 833–842 (1996).

    CAS  PubMed  Google Scholar 

  17. 17

    Akopyanz, N., Bukanov, N. O., Westblom, T. U. & Berg, D. E. PCR-based RFLP analysis of DNA sequence diversity in the gastric pathogen Helicobacter pylori. Nucleic Acids Res. 20, 6221–6225 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Akopyanz, N., Bukanov, N. O., Westblom, T. U., Kresovich, S. & Berg, D. E. DNA diversity among clinical isolates of Helicobacter pylori detected by PCR-based RAPD fingerprinting. Nucleic Acids Res. 20, 5137–5142 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Wirth, T. et al. Sex and virulence in Escherichia coli: an evolutionary perspective. Mol. Microbiol. 60, 1136–1151 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Oh, J. D. et al. The complete genome sequence of a chronic atrophic gastritis Helicobacter pylori strain: evolution during disease progression. Proc. Natl Acad. Sci. USA 103, 9999–10004 (2006).

    CAS  PubMed  Google Scholar 

  21. 21

    Alm, R. A. & Trust, T. J. Analysis of the genetic diversity of Helicobacter pylori: the tale of two genomes. J. Mol. Med. 77, 834–846 (1999). This study catalogues the differences between the two sequenced H. pylori strains 26695 and J99, and notes the different types of variation that are present.

    CAS  PubMed  Google Scholar 

  22. 22

    Kansau, I. et al. Genotyping of Helicobacter pylori isolates by sequencing of PCR products and comparison with the RAPD technique. Res. Microbiol. 147, 661–669 (1996).

    CAS  PubMed  Google Scholar 

  23. 23

    Atherton, J. C. et al. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J. Biol. Chem. 270, 17771–17777 (1995).

    CAS  PubMed  Google Scholar 

  24. 24

    Aras, R. A., Kang, J., Tschumi, A. I., Harasaki, Y. & Blaser, M. J. Extensive repetitive DNA facilitates prokaryotic genome plasticity. Proc. Natl Acad. Sci. USA 100, 13579–13584 (2003). This study demonstrates the presence of extensive, non-randomly distributed repetitive chromosomal sequences in the H. pylori genome, which can undergo deletions and duplications, suggesting that this is a primary mechanism of generating diversity, in addition to intergenic recombination and point mutations. In silico analyses indicate that H. pylori is representative of other prokaryotic species with small genomes that have similarly extensive arrays of direct repeats.

    CAS  PubMed  Google Scholar 

  25. 25

    Salaun, L., Linz, B., Suerbaum, S. & Saunders, N. J. The diversity within an expanded and redefined repertoire of phase-variable genes in Helicobacter pylori. Microbiology 150, 817–830 (2004).

    PubMed  Google Scholar 

  26. 26

    Kang, J., Iovine, N. M. & Blaser, M. J. A paradigm for direct stress-induced mutagenesis in prokaryotes. FASEB J. in the press. In this paper, DNA damage, in the form of oxidative stress and reactive nitrogen species, is demonstrated to increase point mutations, deletions and recombination in H. pylori , which lacks an SOS response. For H. pylori , this provides an alternative strategy for generating variation and increasing adaptive potential. Direct DNA damage, by promoting deletions in non-randomly distributed repetitive elements, is hypothesized to increase mutations in potentially beneficial genetic loci.

  27. 27

    Kalia, A. et al. Evolutionary dynamics of insertion sequences in Helicobacter pylori. J. Bacteriol. 186, 7508–7520 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Hofler, C., Fischer, W., Hofreuter, D. & Haas, R. Cryptic plasmids in Helicobacter pylori: putative functions in conjugative transfer and microcin production. Int. J. Med. Microbiol. 294, 141–148 (2004).

    PubMed  Google Scholar 

  29. 29

    Hofreuter, D. & Haas, R. Characterization of two cryptic Helicobacter pylori plasmids: a putative source for horizontal gene transfer and gene shuffling. J. Bacteriol. 184, 2755–2766 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Xu, Q., Morgan, R. D., Roberts, R. J. & Blaser, M. J. Identification of type II restriction and modification systems in Helicobacter pylori reveals their substantial diversity among strains. Proc. Natl Acad. Sci. USA 97, 9671–9676 (2000). H. pylori strains possess numerous type II restriction-modification systems. This study demonstrates strain-specific variation in identity and activity of restriction endonucleases among H. pylori strains.

    CAS  PubMed  Google Scholar 

  31. 31

    Takata, T. et al. Phenotypic and genotypic variation in methylases involved in type II restriction-modification systems in Helicobacter pylori. Nucleic Acids Res. 30, 2444–2452 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Kong, H. et al. Functional analysis of putative restriction-modification system genes in the Helicobacter pylori J99 genome. Nucleic Acids Res. 28, 3216–3223 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Kobayashi, I., Nobusato, A., Kobayashi-Takahashi, N. & Uchiyama, I. Shaping the genome — restriction-modification systems as mobile genetic elements. Curr. Opin. Genet. Dev. 9, 649–656 (1999).

    CAS  PubMed  Google Scholar 

  34. 34

    Pride, D. T. & Blaser, M. J. Identification of horizontally acquired genetic elements in Helicobacter pylori and other prokaryotes using oligonucleotide difference analyses. Genome Lett. 1, 2–15 (2002).

    CAS  Google Scholar 

  35. 35

    Aras, R. A., Small, A. J., Ando, T. & Blaser, M. J. Helicobacter pylori interstrain restriction-modification diversity prevents genome subversion by chromosomal DNA from competing strains. Nucleic Acids Res. 30, 5391–5397 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Ando, T. et al. Restriction-modification system differences in Helicobacter pylori are a barrier to interstrain plasmid transfer. Mol. Microbiol. 37, 1052–1065 (2000). Although H. pylori is naturally competent, barriers to transformation between plasmids from unrelated strains exist. This study hypothesizes that H. pylori restriction-modification systems exist to limit genetic exchange, allowing for 'polyploidy' in the stomach of a colonized host.

    CAS  PubMed  Google Scholar 

  37. 37

    Wang, G., Humayun, M. Z. & Taylor, D. E. Mutation as an origin of genetic variability in Helicobacter pylori. Trends Microbiol. 7, 488–493 (1999).

    CAS  PubMed  Google Scholar 

  38. 38

    Bjorkholm, B. et al. Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori. Proc. Natl Acad. Sci. USA 98, 14607–14612 (2001).

    CAS  PubMed  Google Scholar 

  39. 39

    Suerbaum, S. et al. Free recombination within Helicobacter pylori. Proc. Natl Acad. Sci. USA 95, 12619–12624 (1998). H. pylori , although clonal over short time periods, has a panmictic population structure, and undergoes recombination at a much higher frequency than other species.

    CAS  PubMed  Google Scholar 

  40. 40

    Israel, D. A., Lou, A. S. & Blaser, M. J. Characteristics of Helicobacter pylori natural transformation. FEMS Microbiol. Lett. 186, 275–280 (2000).

    CAS  PubMed  Google Scholar 

  41. 41

    Hofreuter, D., Odenbreit, S. & Haas, R. Natural transformation competence in Helicobacter pylori is mediated by the basic components of a type IV secretion system. Mol. Microbiol. 41, 379–391 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Baltrus, D. A. & Guillemin, K. Multiple phases of competence occur during the Helicobacter pylori growth cycle. FEMS Microbiol. Lett. 255, 148–155 (2006).

    CAS  PubMed  Google Scholar 

  43. 43

    Kuipers, E. J. et al. Quasispecies development of Helicobacter pylori observed in paired isolates obtained years apart from the same host. J. Infect. Dis. 181, 273–282 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Israel, D. A. et al. Helicobacter pylori genetic diversity within the gastric niche of a single human host. Proc. Natl Acad. Sci. USA 98, 14625–14630 (2001).

    CAS  PubMed  Google Scholar 

  45. 45

    Kersulyte, D., Chalkauskas, H. & Berg, D. E. Emergence of recombinant strains of Helicobacter pylori during human infection. Mol. Microbiol. 31, 31–43 (1999). This study demonstrates recombination occuring in vivo during persistent H. pylori colonization of human hosts.

    CAS  PubMed  Google Scholar 

  46. 46

    Falush, D. et al. Recombination and mutation during long-term gastric colonization by Helicobacter pylori: estimates of clock rates, recombination size, and minimal age. Proc. Natl Acad. Sci. USA 98, 15056–15061 (2001). Frequent and very extensive recombination between H. pylori strains during colonization contributes to its panmictic population structure.

    CAS  PubMed  Google Scholar 

  47. 47

    Wirth, T. et al. Distinguishing human ethnic groups by means of sequences from Helicobacter pylori: lessons from Ladakh. Proc. Natl Acad. Sci. USA 101, 4746–4751 (2004).

    CAS  PubMed  Google Scholar 

  48. 48

    Aras, R. A., Takata, T., Ando, T., van der Ende, A. & Blaser, M. J. Regulation of the HpyII restriction-modification system of Helicobacter pylori by gene deletion and horizontal reconstitution. Mol. Microbiol. 42, 369–382 (2001).

    CAS  PubMed  Google Scholar 

  49. 49

    Ghose, C., Perez-Perez, G. I., van Doorn, L. J., Dominguez-Bello, M. G. & Blaser, M. J. High frequency of gastric colonization with multiple Helicobacter pylori strains in Venezuelan subjects. J. Clin. Microbiol. 43, 2635–2641 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Pride, D. T. & Blaser, M. J. Concerted evolution between duplicated genetic elements in Helicobacter pylori. J. Mol. Biol. 316, 629–642 (2002).

    CAS  PubMed  Google Scholar 

  51. 51

    Steinhauer, D. A. & Holland, J. J. Rapid evolution of RNA viruses. Annu. Rev. Microbiol. 41, 409–433 (1987).

    CAS  PubMed  Google Scholar 

  52. 52

    Webb, G. F. & Blaser, M. J. Dynamics of bacterial phenotype selection in a colonized host. Proc. Natl Acad. Sci. USA 99, 3135–3140 (2002).

    CAS  PubMed  Google Scholar 

  53. 53

    Tomb, J. F. et al. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388, 539–547 (1997).

    CAS  Google Scholar 

  54. 54

    Schofield, M. J. & Hsieh, P. DNA mismatch repair: molecular mechanisms and biological function. Annu. Rev. Microbiol. 57, 579–608 (2003).

    CAS  PubMed  Google Scholar 

  55. 55

    Michel, B., Grompone, G., Flores, M. J. & Bidnenko, V. Multiple pathways process stalled replication forks. Proc. Natl Acad. Sci. USA 101, 12783–12788 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Hanawalt, P. C. Controlling the efficiency of excision repair. Mutat. Res. 485, 3–13 (2001).

    CAS  PubMed  Google Scholar 

  57. 57

    Miller, J. H. Spontaneous mutators in bacteria: insights into pathways of mutagenesis and repair. Annu. Rev. Microbiol. 50, 625–643 (1996).

    CAS  PubMed  Google Scholar 

  58. 58

    Humbert, O., Prudhomme, M., Hakenbeck, R., Dowson, C. G. & Claverys, J. P. Homeologous recombination and mismatch repair during transformation in Streptococcus pneumoniae: saturation of the Hex mismatch repair system. Proc. Natl Acad. Sci. USA 92, 9052–9056 (1995).

    CAS  PubMed  Google Scholar 

  59. 59

    Eppinger, M., Baar, C., Raddatz, G., Huson, D. H. & Schuster, S. C. Comparative analysis of four Campylobacterales. Nature Rev. Microbiol. 2, 872–885 (2004).

    CAS  Google Scholar 

  60. 60

    Guerry, P. et al. Phase variation of Campylobacter jejuni 81–176 lipooligosaccharide affects ganglioside mimicry and invasiveness in vitro. Infect. Immun. 70, 787–793 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Prendergast, M. M. et al. In vivo phase variation and serologic response to lipooligosaccharide of Campylobacter jejuni in experimental human infection. Infect. Immun. 72, 916–922 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Rocha, E. P. & Blanchard, A. Genomic repeats, genome plasticity and the dynamics of Mycoplasma evolution. Nucleic Acids Res. 30, 2031–2042 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Rosengarten, R. & Wise, K. S. Phenotypic switching in mycoplasmas: phase variation of diverse surface lipoproteins. Science 247, 315–318 (1990).

    CAS  PubMed  Google Scholar 

  64. 64

    Rayssiguier, C., Thaler, D. S. & Radman, M. The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch-repair mutants. Nature 342, 396–401 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Tippin, B., Pham, P. & Goodman, M. F. Error-prone replication for better or worse. Trends Microbiol. 12, 288–295 (2004).

    CAS  PubMed  Google Scholar 

  66. 66

    Tenaillon, O., Taddei, F., Radmian, M. & Matic, I. Second-order selection in bacterial evolution: selection acting on mutation and recombination rates in the course of adaptation. Res. Microbiol. 152, 11–16 (2001).

    CAS  PubMed  Google Scholar 

  67. 67

    Kang, J. & Blaser, M. J. UvrD helicase suppresses recombination and DNA damage-induced deletions. J. Bacteriol. 188, 6224–6234 (2006).

    PubMed  PubMed Central  Google Scholar 

  68. 68

    Abril, N., Roldan-Arjona, T., Prieto-Alamo, M. J., van Zeeland, A. A. & Pueyo, C. Mutagenesis and DNA repair for alkylation damages in Escherichia coli K-12. Environ. Mol. Mutagen. 19, 288–296 (1992).

    CAS  PubMed  Google Scholar 

  69. 69

    Grossman, L. & Yeung, A. T. The UvrABC endonuclease system of Escherichia coli — a view from Baltimore. Mutat. Res. 236, 213–221 (1990).

    CAS  PubMed  Google Scholar 

  70. 70

    Sancar, A. DNA excision repair. Annu. Rev. Biochem. 65, 43–81 (1996).

    CAS  Google Scholar 

  71. 71

    Normark, S., Nilsson, C., Normark, B. H. & Hornef, M. W. Persistent infection with Helicobacter pylori and the development of gastric cancer. Adv. Cancer Res. 90, 63–89 (2003).

    PubMed  Google Scholar 

  72. 72

    Makarova, K. S., Aravind, L., Grishin, N. V., Rogozin, I. B. & Koonin, E. V. A DNA repair system specific for thermophilic Archaea and bacteria predicted by genomic context analysis. Nucleic Acids Res. 30, 482–496 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Mongodin, E. F. et al. Gene transfer and genome plasticity in Thermotoga maritima, a model hyperthermophilic species. J. Bacteriol. 187, 4935–4944 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Smeets, L. C. et al. Molecular patchwork: chromosomal recombination between two Helicobacter pylori strains during natural colonization. Infect. Immun. 71, 2907–2910 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Huang, S., Kang, J. & Blaser, M. J. Antimutator role of mutY glycosylase in Helicobacter pylori. J. Bacteriol. 188, 6224–6234 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    O'Rourke, E. J. et al. A novel 3-methyladenine DNA glycosylase from Helicobacter pylori defines a new class within the endonuclease III family of base excision repair glycosylases. J. Biol. Chem. 275, 20077–20083 (2000).

    CAS  PubMed  Google Scholar 

  77. 77

    Giraud, A. et al. Costs and benefits of high mutation rates: adaptive evolution of bacteria in the mouse gut. Science 291, 2606–2608 (2001).

    CAS  PubMed  Google Scholar 

  78. 78

    Funchain, P. et al. The consequences of growth of a mutator strain of Escherichia coli as measured by loss of function among multiple gene targets and loss of fitness. Genetics 154, 959–970 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    de Visser, J. A. The fate of microbial mutators. Microbiology 148, 1247–1252 (2002).

    CAS  PubMed  Google Scholar 

  80. 80

    Trobner, W. & Piechocki, R. Selection against hypermutability in Escherichia coli during long term evolution. Mol. Gen. Genet. 198, 177–178 (1984).

    CAS  PubMed  Google Scholar 

  81. 81

    McGlynn, P. & Lloyd, R. G. Recombinational repair and restart of damaged replication forks. Nature Rev. Mol. Cell Biol. 3, 859–870 (2002).

    CAS  Google Scholar 

  82. 82

    Cox, M. M. et al. The importance of repairing stalled replication forks. Nature 404, 37–41 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Maisnier-Patin, S., Nordstrom, K. & Dasgupta, S. Replication arrests during a single round of replication of the Escherichia coli chromosome in the absence of DnaC activity. Mol. Microbiol. 42, 1371–1382 (2001).

    CAS  PubMed  Google Scholar 

  84. 84

    Kowalczykowski, S. C. Initiation of genetic recombination and recombination-dependent replication. Trends Biochem. Sci. 25, 156–165 (2000).

    CAS  Google Scholar 

  85. 85

    Brendel, V., Brocchieri, L., Sandler, S. J., Clark, A. J. & Karlin, S. Evolutionary comparisons of RecA-like proteins across all major kingdoms of living organisms. J. Mol. Evol. 44, 528–541 (1997).

    CAS  PubMed  Google Scholar 

  86. 86

    McGlynn, P. & Lloyd, R. G. Genome stability and the processing of damaged replication forks by RecG. Trends Genet. 18, 413–419 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    McGlynn, P. & Lloyd, R. G. Action of RuvAB at replication fork structures. J. Biol. Chem. 276, 41938–41944 (2001).

    CAS  PubMed  Google Scholar 

  88. 88

    Pinto, A. V. et al. Suppression of homologous and homeologous recombination by the bacterial MutS2 protein. Mol. Cell 17, 113–120 (2005).

    CAS  PubMed  Google Scholar 

  89. 89

    Kang, J., Huang, S. & Blaser, M. J. Structural and functional divergence of MutS2 from bacterial MutS1 and eukaryotic MSH4-MSH5 homologs. J. Bacteriol. 187, 3528–3537 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Kirschner, D. E. & Blaser, M. J. The dynamics of Helicobacter pylori infection of the human stomach. J. Theor. Biol. 176, 281–290 (1995).

    CAS  PubMed  Google Scholar 

  91. 91

    Blaser, M. J. & Kirschner, D. Dynamics of Helicobacter pylori colonization in relation to the host response. Proc. Natl Acad. Sci. USA 96, 8359–8364 (1999).

    CAS  PubMed  Google Scholar 

  92. 92

    Majewski, J. Sexual isolation in bacteria. FEMS Microbiol. Lett. 199, 161–169 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Redfield, R. J. Do bacteria have sex? Nature Rev. Genet. 2, 634–639 (2001).

    CAS  Google Scholar 

  94. 94

    Kondrashov, F. A. & Kondrashov, A. S. Multidimensional epistasis and the disadvantage of sex. Proc. Natl Acad. Sci. USA 98, 12089–12092 (2001).

    CAS  PubMed  Google Scholar 

  95. 95

    Zahrt, T. C. & Maloy, S. Barriers to recombination between closely related bacteria: MutS and RecBCD inhibit recombination between Salmonella typhimurium and Salmonella typhi. Proc. Natl Acad. Sci. USA 94, 9786–9791 (1997).

    CAS  PubMed  Google Scholar 

  96. 96

    Xu, Q., Stickel, S., Roberts, R. J., Blaser, M. J. & Morgan, R. D. Purification of the novel endonuclease, Hpy188I, and cloning of its restriction-modification genes reveal evidence of its horizontal transfer to the Helicobacter pylori genome. J. Biol. Chem. 275, 17086–17093 (2000).

    CAS  PubMed  Google Scholar 

  97. 97

    Henderson, I. R., Owen, P. & Nataro, J. P. Molecular switches — the ON and OFF of bacterial phase variation. Mol. Microbiol. 33, 919–932 (1999).

    CAS  Google Scholar 

  98. 98

    Hosaka, Y. et al. Characterization of pKU701, a 2.5-kb plasmid, in a Japanese Helicobacter pylori isolate. Plasmid 47, 193–200 (2002).

    CAS  PubMed  Google Scholar 

  99. 99

    Eisen, J. A. & Hanawalt, P. C. A phylogenomic study of DNA repair genes, proteins, and processes. Mutat. Res. 435, 171–213 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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This work was supported in part by the National Institutes of Health, the Senior Scholar Award in Infectious Diseases from the Ellison Medical Foundation, and the Diane Belfer Program for Human Microbial Ecology.

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Corresponding author

Correspondence to Martin J. Blaser.

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Competing interests

The authors declare no competing financial interests.

Related links

Related links


Entrez Genome Project

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H.pylori MLST database



(Random amplification of polymorphic DNA). A marker system that relies on the use of short PCR primers.


(Multilocus sequence typing). A method for the genotypic characterization of bacteria, using the allelic mismatches of a small number (usually seven) of housekeeping genes. Designed as a tool in molecular epidemiology and used for recognizing distinct strains within named species.


A nucleotide change that does not alter the amino acid that is encoded.


The quality of being a chimera. In genetics, a chimera refers to a gene mosaic, composed of distinct genetic sequences from two or more strains.

Restriction-modification (RM) system

A bacterial mechanism of defence against invasion by foreign DNA (for example, bacteriophage). Comprises genes that encode a restriction enzyme and a modification methylase.


The ability of bacteria to take up extracellular DNA.


The uptake and incorporation of exogenous, 'naked' DNA directly from the environment.


Characterized by a lack of restriction in genetic exchange in a population; all individuals within the species population are potential recombination partners.

Linkage equilibrium

The situation when the association between two loci is random.


An identical mutation or similar characteristic found in phylogenetically unrelated lineages. In bacteria, homoplasic mutations can be generated by either repeated, independent mutation or by recombination.

Slip-strand mispairing

Tandem direct repeats can pair incorrectly during DNA replication. For example, 'slippage' between the template and newly synthesized DNA strands during replication can result in pairing between, for example, the third repeat unit on the new strand and the fourth repeat on the template strand. Such mispairing results in a change in the number of repeats in the newly synthesized strand compared with the template DNA.


Closely related, non-identical genomes subjected to ongoing mutation, recombination, competition and selection.

Mismatch repair

A process of DNA repair in which a mispaired region of a DNA duplex is excised and replaced by resynthesis using the remaining strand as a template.

Nucleotide excision repair

The replacement of nucleotides that are altered by large chemical additions or crosslinks through the excision of a short, single-stranded segment containing the damage.

Recombinational repair

A repair process that uses recombination enzymes to remove a DNA lesion and repair the patch by strand exchange.

Base excision repair

The excision and repair of bases that have been altered by small chemical modifications.

Translesion synthesis

A type of specialized DNA synthesis, in which translesion polymerases can synthesize past lesions in the complementary strand that would normally block standard polymerases. Once the lesion is overcome, standard polymerases replace the less accurate translesion enzymes.

SOS response

The bacterial response to DNA damage. The SOS response is regulated by the LexA and RecA proteins and involves the expression of a network of >40 genes, including several DNA-repair enzymes.

Mutator phenotype

A bacterial strain with hyper-recombination is referred to as a mutator.

Second-order selection

Selection for organisms with mutator alleles, which have increased adaptive potential and genetic variability.

Holliday junction

An intermediate stage in genetic recombination that is formed when the strands of two double-stranded DNA molecules exchange partners.

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Kang, J., Blaser, M. Bacterial populations as perfect gases: genomic integrity and diversification tensions in Helicobacter pylori. Nat Rev Microbiol 4, 826–836 (2006).

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