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Myths and misconceptions: the origin and evolution of Mycobacterium tuberculosis

Abstract

Much effort has been spent trying to work out the origin and history of tuberculosis. Understanding these concepts could have important consequences for the development of vaccines and therapies that are effective against all strains of Mycobacterium tuberculosis. We discuss a series of misconceptions about the origin of both M. tuberculosis and the disease it causes that have arisen over the years, and identify a number of unanswered questions that could provide insight into both these areas.

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Figure 1: The phylogenetic history of the Mycobacterium tuberculosis complex.
Figure 2: The most detailed molecular phylogeny of the Mycobacterium tuberculosis complex to date.
Figure 3: Linear phylogenies.

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References

  1. Smith, N. H. et al. Ecotypes of the Mycobacterium tuberculosis complex. J. Theor. Biol. 239, 220–225 (2006).

    Article  Google Scholar 

  2. Smith, N. H., Gordon, S. V., de la Rua-Domenech, R., Clifton-Hadley, R. S. & Hewinson, R. G. Bottlenecks and broomsticks: the molecular evolution of Mycobacterium bovis. Nature Rev. Microbiol. 4, 670–681 (2006).

    Article  CAS  Google Scholar 

  3. Brosch, R. et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc. Natl Acad. Sci. USA 99, 3684–3689 (2002).

    Article  CAS  Google Scholar 

  4. van Soolingen, D. et al. A novel pathogenic taxon of the Mycobacterium tuberculosis complex, Canetti: characterization of an exceptional isolate from Africa. Int. J. Syst. Bacteriol. 47, 1236–1245 (1997).

    Article  CAS  Google Scholar 

  5. Niemann, S., Richter, E. & Rèusch-Gerdes, S. Biochemical and genetic evidence for the transfer of Mycobacterium tuberculosis subsp. caprae Aranaz et al. 1999 to the species Mycobacterium bovis Karlson and Lessel 1970 (Approved Lists 1980) as Mycobacterium bovis subsp. caprae comb. nov. Int. J. Syst. Evol. Microbiol. 52, 433–436 (2002).

  6. Supply, P. et al. Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area. Mol. Microbiol. 47, 529–538 (2003).

    Article  CAS  Google Scholar 

  7. Hershberg, R. et al. High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography. PLoS Biol. 6, e311 (2009).

    Article  Google Scholar 

  8. Gutierrez, M. C. et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLoS Pathog. 1, e5 (2005).

    Article  Google Scholar 

  9. Mostowy, S., Cousins, D., Brinkman, J., Aranaz, A. & Behr, M. A. Genomic deletions suggest a phylogeny for the Mycobacterium tuberculosis complex. J. Infect. Dis. 186, 74–80 (2002).

    Article  CAS  Google Scholar 

  10. Tsolaki, A. G. et al. Functional and evolutionary genomics of Mycobacterium tuberculosis: insights from genomic deletions in 100 strains. Proc. Natl Acad. Sci. USA 101, 4865–4870 (2004).

    Article  CAS  Google Scholar 

  11. Gagneux, S. & Small, P. M. Global phylogeography of Mycobacterium tuberculosis and implications for tuberculosis product development. Lancet Infect. Dis. 7, 328–337 (2007).

    Article  Google Scholar 

  12. Dye, C. Doomsday postponed? Preventing and reversing epidemics of drug-resistant tuberculosis. Nature Rev. Microbiol. 7, 81–87 (2009).

    Article  CAS  Google Scholar 

  13. Roumagnac, P. et al. Evolutionary history of Salmonella Typhi. Science 314, 1301–1304 (2006).

    Article  CAS  Google Scholar 

  14. Moodley, Y. et al. The peopling of the Pacific from a bacterial perspective. Science 323, 527–530 (2009).

    Article  CAS  Google Scholar 

  15. Diamond, J. Guns, Germs, and Steel: The Fates of Human Societies (W. W. Norton & Company, London, 1997).

    Google Scholar 

  16. Stead, W. W. The origin and erratic global spread of tuberculosis: how the past explains the present and is the key to the future. Clin. Chest Med. 18, 65–77 (1997).

    Article  CAS  Google Scholar 

  17. Wolfe, N. D., Dunavan, C. P. & Diamond, J. Origins of major human infectious diseases. Nature 447, 279–283 (2007).

    Article  CAS  Google Scholar 

  18. Gordon, S. V. et al. Identification of variable regions in the genomes of tubercle bacilli using bacterial artificial chromosome arrays. Mol. Microbiol. 32, 643–655 (1999).

    Article  CAS  Google Scholar 

  19. Baker, L., Brown, T., Maiden, M. C. & Drobniewski, F. Silent nucleotide polymorphisms and a phylogeny for Mycobacterium tuberculosis. Emerg. Infect. Dis. 10, 1568–1577 (2004).

    Article  CAS  Google Scholar 

  20. Filliol, I. et al. Global phylogeny of Mycobacterium tuberculosis based on single nucleotide polymorphism (SNP) analysis: insights into tuberculosis evolution, phylogenetic accuracy of other DNA fingerprinting systems, and recommendations for a minimal standard SNP set. J. Bacteriol. 188, 759–772 (2006).

    Article  CAS  Google Scholar 

  21. Brosch, R., Pym, A. S., Gordon, S. V. & Cole, S. T. The evolution of mycobacterial pathogenicity: clues from comparative genomics. Trends Microbiol. 9, 452–458 (2001).

    Article  CAS  Google Scholar 

  22. Gutacker, M. M. et al. Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms: resolution of genetic relationships among closely related microbial strains. Genetics 162, 1533–1543 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Gutacker, M. M. et al. Single-nucleotide polymorphism-based population genetic analysis of Mycobacterium tuberculosis strains from 4 geographic sites. J. Infect. Dis. 193, 121–128 (2006).

    Article  CAS  Google Scholar 

  24. Mostowy, S. & Behr, M. A. The origin and evolution of Mycobacterium tuberculosis. Clin. Chest Med. 26, 207–216 (2005).

    Article  Google Scholar 

  25. Mostowy, S. et al. Revisiting the evolution of Mycobacterium bovis. J. Bacteriol. 187, 6386–6395 (2005).

    Article  CAS  Google Scholar 

  26. Garnier, T. et al. The complete genome sequence of Mycobacterium bovis. Proc. Natl Acad. Sci. USA 100, 7877–7882 (2003).

    Article  CAS  Google Scholar 

  27. Gibbons, A. American Association of Physical Anthropologists meeting. Tuberculosis jumped from humans to cows, not vice versa. Science 320, 608 (2008).

    Article  CAS  Google Scholar 

  28. de Jong, B. C. et al. Clinical presentation and outcome of tuberculosis patients infected by M. africanum versus M. tuberculosis. Int. J. Tuberc. Lung Dis. 11, 450–456 (2007).

    CAS  PubMed  Google Scholar 

  29. Niobe-Eyangoh, S. N. et al. Genetic biodiversity of Mycobacterium tuberculosis complex strains from patients with pulmonary tuberculosis in Cameroon. J. Clin. Microbiol. 41, 2547–2553 (2003).

    Article  Google Scholar 

  30. Meyer, C. G. et al. Pulmonary tuberculosis: virulence of Mycobacterium africanum and relevance in HIV co-infection. Tuberculosis (Edinb.) 88, 482–489 (2008).

    Article  Google Scholar 

  31. O'Brien, D. J., Schmitt, S. M., Fitzgerald, S. D., Berry, D. E. & Hickling, G. J. Managing the wildlife reservoir of Mycobacterium bovis: the Michigan, USA, experience. Vet. Microbiol. 112, 313–323 (2006).

    Article  Google Scholar 

  32. Zanella, G. et al. Mycobacterium bovis in wildlife in France. J. Wildl. Dis. 44, 99–108 (2008).

    Article  Google Scholar 

  33. Sreevatsan, S. et al. Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proc. Natl Acad. Sci. USA 94, 9869–9874 (1997).

    Article  CAS  Google Scholar 

  34. Kapur, V., Whittam, T. S. & Musser, J. M. Is Mycobacterium tuberculosis 15,000 years old? J. Infect. Dis. 170, 1348–1349 (1994).

    Article  CAS  Google Scholar 

  35. Maynard Smith, J. & Haigh, J. The hitch-hiking effect of a favourable gene. Genet. Res. 23, 23–35 (1974).

    Article  Google Scholar 

  36. Hershkovitz, I. et al. Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean. PLoS ONE 3, e3426 (2008).

    Article  Google Scholar 

  37. Crubezy, E., Legal, L., Fabas, G., Dabernat, H. & Ludes, B. Pathogeny of archaic mycobacteria at the emergence of urban life in Egypt (3400 BC). Infect. Genet. Evol. 6, 13–21 (2006).

    Article  Google Scholar 

  38. Donoghue, H. D. et al. Tuberculosis: from prehistory to Robert Koch, as revealed by ancient DNA. Lancet Infect. Dis. 4, 584–592 (2004).

    Article  CAS  Google Scholar 

  39. Achtman, M. Evolution, population structure, and phylogeography of genetically monomorphic bacterial pathogens. Annu. Rev. Microbiol. 62, 53–70 (2008).

    Article  CAS  Google Scholar 

  40. Hartl, D. & Clark, A. Principles of Population Genetics (Sinauer Associates, Sunderland, Massachusetts, 2007).

    Google Scholar 

  41. Frothingham, R. Evolutionary bottlenecks in the agents of tuberculosis, leprosy, and paratuberculosis. Med. Hypotheses 52, 95–99 (1999).

    Article  CAS  Google Scholar 

  42. Rosas-Magallanes, V. et al. Horizontal transfer of a virulence operon to the ancestor of Mycobacterium tuberculosis. Mol. Biol. Evol. 23, 1129–1135 (2006).

    Article  CAS  Google Scholar 

  43. Huard, R. C. et al. Novel genetic polymorphisms that further delineate the phylogeny of the Mycobacterium tuberculosis complex. J. Bacteriol. 188, 4271–4287 (2006).

    Article  CAS  Google Scholar 

  44. Tanaka, M. M. Evidence for positive selection on Mycobacterium tuberculosis within patients. BMC Evol. Biol. 4, 31 (2004).

    Article  Google Scholar 

  45. Hughes, A. L., Friedman, R. & Murray, M. Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis. Emerg. Infect. Dis. 8, 1342–1346 (2002).

    Article  CAS  Google Scholar 

  46. Wirth, T. et al. Origin, spread and demography of the Mycobacterium tuberculosis complex. PLoS Pathog. 4, e1000160 (2008).

    Article  Google Scholar 

  47. Ho, S. Y. & Larson, G. Molecular clocks: when times are a-changin'. Trends Genet. 22, 79–83 (2006).

    Article  CAS  Google Scholar 

  48. Woolfit, M. & Bromham, L. Increased rates of sequence evolution in endosymbiotic bacteria and fungi with small effective population sizes. Mol. Biol. Evol. 20, 1545–1555 (2003).

    Article  CAS  Google Scholar 

  49. Bromham, L. & Penny, D. The modern molecular clock. Nature Rev. Genet. 4, 216–224 (2003).

    Article  CAS  Google Scholar 

  50. Rocha, E. P. et al. Comparisons of dN/dS are time dependent for closely related bacterial genomes. J. Theor. Biol. 239, 226–235 (2006).

    Article  CAS  Google Scholar 

  51. Mokrousov, I. et al. Origin and primary dispersal of the Mycobacterium tuberculosis Beijing genotype: clues from human phylogeography. Genome Res. 15, 1357–1364 (2005).

    Article  CAS  Google Scholar 

  52. Hirsh, A. E., Tsolaki, A. G., DeRiemer, K., Feldman, M. W. & Small, P. M. Stable association between strains of Mycobacterium tuberculosis and their human host populations. Proc. Natl Acad. Sci. USA 101, 4871–4876 (2004).

    Article  CAS  Google Scholar 

  53. Mokrousov, I. Genetic geography of Mycobacterium tuberculosis Beijing genotype: a multifacet mirror of human history? Infect. Genet. Evol. 8, 777–785 (2008).

    Article  CAS  Google Scholar 

  54. Deshayes, C. et al. Detecting the molecular scars of evolution in the Mycobacterium tuberculosis complex by analyzing interrupted coding sequences. BMC Evol. Biol. 8, 78 (2008).

    Article  Google Scholar 

  55. Stinear, T. P. et al. Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. Genome Res. 18, 729–741 (2008).

    Article  CAS  Google Scholar 

  56. Rogall, T., Wolters, J., Flohr, T. & Bottger, E. C. Towards a phylogeny and definition of species at the molecular level within the genus Mycobacterium. Int. J. Syst. Bacteriol. 40, 323–330 (1990).

    Article  CAS  Google Scholar 

  57. Becq, J. et al. Contribution of horizontally acquired genomic islands to the evolution of the tubercle bacilli. Mol. Biol. Evol. 24, 1861–1871 (2007).

    Article  CAS  Google Scholar 

  58. Maynard Smith, J. The Evolution of Sex (Cambridge Univ. Press, UK, 1978).

    Google Scholar 

  59. Gagneux, S. et al. Variable host–pathogen compatibility in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 103, 2869–2873 (2006).

    Article  CAS  Google Scholar 

  60. Flores, L. et al. Large sequence polymorphisms classify Mycobacterium tuberculosis strains with ancestral spoligotyping patterns. J. Clin. Microbiol. 45, 3393–3395 (2007).

    Article  CAS  Google Scholar 

  61. Arnold, C., Thorne, N., Underwood, A., Baster, K. & Gharbia, S. Evolution of short sequence repeats in Mycobacterium tuberculosis. FEMS Microbiol. Lett. 256, 340–346 (2006).

    Article  CAS  Google Scholar 

  62. Mathema, B., Kurepina, N. E., Bifani, P. J. & Kreiswirth, B. N. Molecular epidemiology of tuberculosis: current insights. Clin. Microbiol. Rev. 19, 658–685 (2006).

    Article  CAS  Google Scholar 

  63. Ahmed, N., Dobrindt, U., Hacker, J. & Hasnain, S. E. Genomic fluidity and pathogenic bacteria: applications in diagnostics, epidemiology and intervention. Nature Rev. Microbiol. 6, 387–394 (2008).

    Article  CAS  Google Scholar 

  64. Banu, S. et al. Genotypic analysis of Mycobacterium tuberculosis in Bangladesh and prevalence of the Beijing strain. J. Clin. Microbiol. 42, 674–682 (2004).

    Article  CAS  Google Scholar 

  65. Gutierrez, M. C. et al. Predominance of ancestral lineages of Mycobacterium tuberculosis in India. Emerg. Infect. Dis. 12, 1367–1374 (2006).

    Article  CAS  Google Scholar 

  66. Dos Vultos, T. et al. Evolution and diversity of clonal bacteria: the paradigm of Mycobacterium tuberculosis. PLoS ONE 3, e1538 (2008).

    Article  Google Scholar 

  67. Cole, S. T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998).

    Article  CAS  Google Scholar 

  68. Fleischmann, R. D. et al. Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J. Bacteriol. 184, 5479–5490 (2002).

    Article  CAS  Google Scholar 

  69. de Jong, B. C. et al. Mycobacterium africanum: a new opportunistic pathogen in HIV infection? AIDS 19, 1714–1715 (2005).

    Article  Google Scholar 

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Acknowledgements

We thank A. Armes for her help. This work was supported in part by the European Community's FP7 Programme under grant agreement number 201762, the Institut Pasteur (PTR 202 and 314) and the UK Department for Environment, Food and Rural Affairs.

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Correspondence to Noel H. Smith.

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DATABASES

Entrez Genome Project

Helicobacter pylori

Mycobacterium avium subsp. paratuberculosis

Mycobacterium leprae

Mycobacterium marinum

Mycobacterium smegmatis

Mycobacterium tuberculosis

Mycobacterium ulcerans

Salmonella enterica subsp. enterica serovar Typhi

FURTHER INFORMATION

Mbovis.org

Microbial Sequencing Centres

Wellcome Trust Sanger Institute

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Smith, N., Hewinson, R., Kremer, K. et al. Myths and misconceptions: the origin and evolution of Mycobacterium tuberculosis. Nat Rev Microbiol 7, 537–544 (2009). https://doi.org/10.1038/nrmicro2165

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