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Bottlenecks and broomsticks: the molecular evolution of Mycobacterium bovis

Key Points

  • The M. tuberculosis complex (with the exception of M. canettii) shows little evidence for the transfer and recombination of chromosomal genes. We discuss the remarkable consequences of this strict clonality, and show how selective sweeps and population bottlenecks can profoundly reduce the diversity of the population.

  • The clonality of this group of organisms has shaped the phylogeny of the M. tuberculosis complex and we suggest that they might best be described as a group of host-adapted ecotypes rather than species. Our analysis highlights the close sequence similarity of these ecotypes and the facility these organisms have for invading and establishing themselves in new mammalian hosts.

  • The history and molecular epidemiology of bovine tuberculosis in the British Isles is then reviewed. A test and slaughter programme was initially highly successful at reducing the incidence of disease but, since the 1980s (and in contrast to the rest of Europe), has failed to control an exponential increase in incidents.

  • The molecular epidemiology of bovine tuberculosis reveals that a single clonal complex of strains has come to dominate throughout the British Isles and is responsible for over 85% of the bovine tuberculosis in Great Britain. We suggest that the limited diversity of M. bovis in the British Isles is a result of a population bottleneck induced by more than 100 years of bovine tuberculosis control programmes, in particular the extensive test and slaughter regime. The recent dominance and exponential increase of a single clonal complex can best be explained by selection, and two possible selective advantages of the dominant clonal complex in the British Isles are discussed.

  • Finally, we show how an understanding of the population structure and molecular epidemiology of this disease has contributed to our appreciation of the role of cattle movement and badgers in the spread and maintenance of the disease, and we describe the practical application to the development of advanced techniques of diagnosis and vaccination.

Abstract

Mycobacterium bovis is the cause of tuberculosis in cattle and is a member of the Mycobacterium tuberculosis complex. In contrast to many other pathogenic bacterial species, there is little evidence for the transfer and recombination of genes between cells. The clonality of this group of organisms indicates that the population structure is dominated by reductions in diversity, caused either by population bottlenecks or selective sweeps as entire chromosomes become fixed in the population. We describe how these forces have shaped not only the phylogeny of this group but also, at a very local level, the population structure of Mycobacterium bovis in the British Isles. We also discuss the practical implications of applying this knowledge to understanding the spread of infection and the development of improved vaccines and diagnostic tests.

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Figure 1: The phylogenetically informative mutations in the lineage leading to Mycobacterium bovis.
Figure 2: The severe bottleneck in bovine tuberculosis in British cattle.
Figure 3: The geographical localization of Mycobacterium bovis genotypes in Great Britain.

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References

  1. Corbett, E. L. et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch. Intern. Med. 163, 1009–1021 (2003).

    Article  PubMed  Google Scholar 

  2. Raviglione, M. C., Snider, D. E. Jr. & Kochi, A. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 273, 220–226 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Dye, C., Scheele, S., Dolin, P., Pathania, V. & Raviglione, M. C. Consensus statement.Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 282, 677–686 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. WHO. Bulletin of the World Health Organisation. Int. J. Public Health 80, 426–523 (2002).

  5. Smith, N. H. et al. Ecotypes of the Mycobacterium tuberculosis complex. J. Theor. Biol. 239, 220–225 (2006). Identifies a series of clades in the animal-adapted lineage of the M. tuberculosis complex and suggests that these bacteria are best described as a series of host-adapted ecotypes rather than species.

    Article  PubMed  Google Scholar 

  6. Brosch, R. et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc. Natl Acad. Sci. USA 99, 3684–3689 (2002). A seminal manuscript that identifies the backbone phylogeny of the M. tuberculosis complex based on a series of informative deletions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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  PubMed  PubMed Central  Google Scholar 

  8. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Perna, N. T. et al. Genome sequence of enterohaemorrhagic Escherichia coli O157:H7. Nature 409, 529–533 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Li, W. H. & Sadler, L. A. Low nucleotide diversity in man. Genetics 129, 513–523 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature Genet. 22, 231–238 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Maynard Smith, J., Smith, N. H., O'Rourke, M. & Spratt, B. G. How clonal are bacteria? Proc. Natl Acad. Sci. USA 90, 4384–4388 (1993). An important insight into bacterial population genetics and structure. This manuscript shows how bacterial populations can range from the panmictic to the purely clonal.

    Article  Google Scholar 

  15. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. 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  PubMed  PubMed Central  Google Scholar 

  18. 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  PubMed  PubMed Central  Google Scholar 

  19. 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  PubMed  Google Scholar 

  20. 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 

  21. 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  PubMed  Google Scholar 

  22. 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  PubMed  PubMed Central  Google Scholar 

  23. 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  PubMed  PubMed Central  Google Scholar 

  24. Maynard Smith, J. & Smith, N. H. Detecting recombination from gene trees. Mol. Biol. Evol. 15, 590–599 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Smith, N. H., Beltran, P. & Selander, R. K. Recombination of Salmonella phase 1 flagellin genes generates new serovars. J. Bacteriol. 172, 2209–2216 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Barcus, V. A. & Murray, N. E. in Population Genetics of Bacteria (52nd SGM Symposium) (eds Baumbergs, S. et al.) 31–58 (Cambridge Univ. Press, Cambridge, 1995).

    Google Scholar 

  27. 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  PubMed  Google Scholar 

  28. 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  PubMed  Google Scholar 

  29. Mahairas, G. G., Sabo, P. J., Hickey, M. J., Singh, D. C. & Stover, C. K. Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis. J. Bacteriol. 178, 1274–1282 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gordon, S. V. et al. Genomics of Mycobacterium bovis. Tuberculosis (Edinb) 81, 157–163 (2001).

    Article  CAS  Google Scholar 

  31. Behr, M. A. et al. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284, 1520–1523 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  33. 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  PubMed  PubMed Central  Google Scholar 

  34. Mostowy, S. et al. Genomic analysis distinguishes Mycobacterium africanum. J. Clin. Microbiol. 42, 3594–3599 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cohan, F. M. What are bacterial species? Annu. Rev. Microbiol. 56, 457–487 (2002). Explains the ecotype concept for identifying bacterial populations with similar properties to eukaryotic species.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rad, M. E. et al. Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family. Emerg. Infect. Dis. 9, 838–845 (2003).

    Article  CAS  PubMed Central  Google Scholar 

  39. Lopez, B. et al. A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes. Clin. Exp. Immunol. 133, 30–37 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Glynn, J. R., Whiteley, J., Bifani, P. J., Kremer, K. & van Soolingen, D. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg. Infect. Dis. 8, 843–849 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhang, M. et al. Enhanced capacity of a widespread strain of Mycobacterium tuberculosis to grow in human macrophages. J. Infect. Dis. 179, 1213–1217 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Reed, M. B. et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431, 84–87 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Atwood, K. C. & Ryan, F. J. Periodic selection in Escherichia coli. Proc. Natl Acad. Sci. USA 37, 146–155 (1951).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

  45. Caballero, A. Developments in the prediction of effective population size. Heredity 73, 657–679 (1994).

    Article  PubMed  Google Scholar 

  46. Mayr, E. Animal Species and Evolution (Harvard Univ. Press, Cambridge, Massachusetts, 1963).

    Book  Google Scholar 

  47. Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge Univ. Press, Cambridge, 1983).

    Book  Google Scholar 

  48. 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  PubMed  Google Scholar 

  49. Tweddle, N. E. & Livingstone, P. Bovine tuberculosis control and eradication programs in Australia and New Zealand. Vet. Microbiol. 40, 23–39 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. de Kantor, I. N. & Ritacco, V. An update on bovine tuberculosis programmes in Latin American and Caribbean countries. Vet. Microbiol. 112, 111–118 (2006).

    Article  PubMed  Google Scholar 

  51. Ryan, T. J. et al. Advances in understanding disease epidemiology and implications for control and eradication of tuberculosis in livestock: the experience from New Zealand. Vet. Microbiol. 112, 211–219 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. 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  PubMed  Google Scholar 

  53. Nishi, J. S., Shury, T. & Elkin, B. T. Wildlife reservoirs for bovine tuberculosis (Mycobacterium bovis) in Canada: strategies for management and research. Vet. Microbiol. 112, 325–338 (2006).

    Article  PubMed  Google Scholar 

  54. Michel, A. L. et al. Wildlife tuberculosis in South African conservation areas: implications and challenges. Vet. Microbiol. 112, 91–100 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Hewinson, R. G., Vordermeier, H. M., Smith, N. H. & Gordon, S. V. Recent advances in our knowledge of Mycobacterium bovis: a feeling for the organism. Vet. Microbiol. 112, 127–139 (2006).

    Article  PubMed  Google Scholar 

  56. Reviriego Gordejo, F. J. & Vermeersch, J. P. Towards eradication of bovine tuberculosis in the European Union. Vet. Microbiol. 112, 101–109 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Pavlik, I. The experience of new European Union Member States concerning the control of bovine tuberculosis. Vet. Microbiol. 112, 221–230 (2006).

    Article  PubMed  Google Scholar 

  58. DEFRA. Animal Health 2005. The report of the Chief Veterinary Officer DEFRA Animal Health [online], http://www.defra.gov.uk/animalh/cvo/report/2005/index.htm (2006).

  59. Abernethy, D. A. et al. The Northern Ireland programme for the control and eradication of Mycobacterium bovis. Vet. Microbiol. 112, 231–237 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Moore, S. I. & Good, M. The tuberculosis eradication programme in Ireland: a review of scientific and policy advances since 1988. Vet. Microbiol. 112, 239–251 (2006).

    Article  Google Scholar 

  61. Good, M. Bovine tuberculosis eradication in Ireland. Irish Vet. J. 59, 154–160 (2006).

    Google Scholar 

  62. Donnelly, C. A. et al. Positive and negative effects of widespread badger culling on tuberculosis in cattle. Nature 439, 843–846 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Griffin, J. M. et al. The impact of badger removal on the control of tuberculosis in cattle herds in Ireland. Prev. Vet. Med. 67, 237–266 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Mairtin, D. O., Williams, D. H., Griffin, J. M., Dolan, L. A. & Eves, J. A. The effect of a badger removal programme on the incidence of tuberculosis in an Irish cattle population. Prev. Vet. Med. 34, 47–56 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. de la Rua-Domenech, R. Human Mycobacterium bovis infection in the United Kingdom: incidence, risks, control measures and review of the zoonotic aspects of bovine tuberculosis. Tuberculosis (Edinb) 86, 77–109 (2006). An in-depth review of the history and impact of bovine tuberculosis in the United Kingdom.

    Article  Google Scholar 

  66. Gibson, A. L. et al. Molecular epidemiology of disease due to Mycobacterium bovis in humans in the United Kingdom. J. Clin. Microbiol. 42, 431–434 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Maiden, M. C. et al. Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc. Natl Acad. Sci. USA 95, 3140–3145 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fang, Z., Morrison, N., Watt, B., Doig, C. & Forbes, K. J. IS6110 transposition and evolutionary scenario of the direct repeat locus in a group of closely related Mycobacterium tuberculosis strains. J. Bacteriol. 180, 2102–2109 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Warren, R. M. et al. Microevolution of the direct repeat region of Mycobacterium tuberculosis: implications for interpretation of spoligotyping data. J. Clin. Microbiol. 40, 4457–4465 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kremer, K. et al. Use of variable-number tandem-repeat typing to differentiate Mycobacterium tuberculosis Beijing family isolates from Hong Kong and comparison with IS6110 restriction fragment length polymorphism typing and spoligotyping. J. Clin. Microbiol. 43, 314–320 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gibson, A., Brown, T., Baker, L. & Drobniewski, F. Can 15-locus mycobacterial interspersed repetitive unit-variable-number tandem repeat analysis provide insight into the evolution of Mycobacterium tuberculosis? Appl. Environ. Microbiol. 71, 8207–8213 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Frothingham, R. & Meeker-O'Connell, W. A. Genetic diversity in the Mycobacterium tuberculosis complex based on variable numbers of tandem DNA repeats. Microbiology 144, 1189–1196 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Smith, N. H. et al. The population structure of Mycobacterium bovis in Great Britain: clonal expansion. Proc. Natl Acad. Sci. USA 100, 15271–15275 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Haddad, N. et al. Spoligotype diversity of Mycobacterium bovis strains isolated in France from 1979 to 2000. J. Clin. Microbiol. 39, 3623–3632 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Skuce, R. A. et al. Discrimination of isolates of Mycobacterium bovis in Northern Ireland on the basis of variable numbers of tandem repeats (VNTRs). Vet. Rec. 157, 501–504 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Crow, J. F. & Kimura, M. An Introduction to Population Genetics Theory (Harper & Row, New York, 1970).

    Google Scholar 

  77. Commission Decision 2001/26/EC of 27 December 2000, amending for the fourth time Decision 1999/467/EC establishing the officially tuberculosis-free status of bovine herds of certain Member States or regions of Member States. 11 January 2001. Official Journal of the European Union L006 13–19 (2000).

  78. Wahlund, S. Zusammensetzung von Population und Korrelationserscheinung vom Standpunkt der Vererbungslehre aus betrachtet. Hereditas 11, 65–106 (1928) (in German).

    Article  Google Scholar 

  79. Haddad, N., Masselot, M. & Durand, B. Molecular differentiation of Mycobacterium bovis isolates. Review of main techniques and applications. Res. Vet. Sci. 76, 1–18 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Cataldi, A. A. et al. The genotype of the principal Mycobacterium bovis in Argentina is also that of the British Isles: did bovine tuberculosis come from Great Britain? Rev. Argent. Microbiol. 34, 1–6 (2002).

    CAS  PubMed  Google Scholar 

  81. Njanpop-Lafourcade, B. M. et al. Molecular typing of Mycobacterium bovis isolates from Cameroon. J. Clin. Microbiol. 39, 222–227 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Koonin, E. V., Makarova, K. S., Grishin, N. V., Wolf, Y. I. in Prokaryotic Diversity (66th SGM symposium) (eds Logan, N. A., Lappin-Scott, H. M. & Oyston, P. C. F) 39–64, (Cambridge Univ. Press, 2006).

    Book  Google Scholar 

  83. Gopal, R., A. Goodchild, G. Hewinson, R., de la Rua-Domenech, R. & Clifton-Hadley, R. Introduction of bovine tuberculosis from bought-in cattle in Northeast England. Vet. Record. (in the press).

  84. Krebs, J. R. Independent Scientific Review Group Report (Ministry of Agriculture, Fisheries and Food, UK,1997).

    Google Scholar 

  85. Clifton-Hadley, R. S. et al. in Proceedings of the Society for Veterinary Epidemiology and Preventive Medicine (eds Thrusfield, M. V. & Goodall, E. A.) 15–27 (Ennis, County Clare, 1998).

    Google Scholar 

  86. Woodroffe, R. et al. Spatial association of Mycobacterium bovis infection in cattle and badgers Meles meles. J. Appl. Ecol. 42, 852–862 (2005).

    Article  Google Scholar 

  87. Ewer, K. et al. Antigen mining with iterative genome screens identifies novel diagnostics for the Mycobacterium tuberculosis complex. Clin. Vaccine Immunol. 13, 90–97 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cockle, P. J. et al. Identification of novel Mycobacterium tuberculosis antigens with potential as diagnostic reagents or subunit vaccine candidates by comparative genomics. Infect. Immun. 70, 6996–7003 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Inwald, J. et al. Microarray-based comparative genomics: genome plasticity in Mycobacterium bovis. Comp. Funct. Genom. 3, 342–344 (2002).

    Article  CAS  Google Scholar 

  90. 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  PubMed  PubMed Central  Google Scholar 

  91. Kremer, K. et al. Comparison of methods based on different molecular epidemiological markers for typing of Mycobacterium tuberculosis complex strains: interlaboratory study of discriminatory power and reproducibility. J. Clin. Microbiol. 37, 2607–2618 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Durr, P. A., Clifton-Hadley, R. S. & Hewinson, R. G. Molecular epidemiology of bovine tuberculosis. II. Applications of genotyping. Rev. Sci. Tech. 19, 689–701 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Kamerbeek, J. et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J. Clin. Microbiol. 35, 907–914 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. van Embden, J. D. et al. Genetic variation and evolutionary origin of the direct repeat locus of Mycobacterium tuberculosis complex bacteria. J. Bacteriol. 182, 2393–2401 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Groenen, P. M., Bunschoten, A. E., van Soolingen, D. & van Embden, J. D. Nature of DNA polymorphism in the direct repeat cluster of Mycobacterium tuberculosis; application for strain differentiation by a novel typing method. Mol. Microbiol. 10, 1057–1065 (1993).

    Article  CAS  PubMed  Google Scholar 

  96. Jeffreys, A. J., Wilson, V. & Thein, S. L. Individual-specific 'fingerprints' of human DNA. Nature 316, 76–79 (1985).

    Article  CAS  PubMed  Google Scholar 

  97. Monaghan, M. L., Doherty, M. L., Collins, J. D., Kazda, J. F. & Quinn, P. J. The tuberculin test. Vet. Microbiol. 40, 111–124 (1994).

    Article  CAS  PubMed  Google Scholar 

  98. Gilbert, M. et al. Cattle movements and bovine tuberculosis in Great Britain. Nature 435, 491–496 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Costello, E. et al. Study of restriction fragment length polymorphism analysis and spoligotyping for epidemiological investigation of Mycobacterium bovis infection. J. Clin. Microbiol. 37, 3217–3222 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Selander, R. K. et al. Methods of multilocus enzyme electrophoresis for bacterial population genetics and systematics. Appl. Environ. Microbiol. 51, 873–884 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank past and present members of the Tuberculosis Research Group, Tuberculosis Epidemiology Group and the Tuberculosis Diagnostics Group at VLA Weybridge for their data, advice and discussion, and members of the Centre for the Study of Evolution, University of Sussex, UK, for discussion and critical reading of the manuscript. In particular, we should like to thank D. Lamb for all her help. We should also like to thank our friends and colleagues from the Republic of Ireland, Northern Ireland and France for their continuing help and collaboration. Our work is funded by the Department of Environment, Food and Rural Affairs, Great Britain.

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Correspondence to R. Glyn Hewinson.

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DATABASES

Entrez Genome Project

Escherichia coli

Mycobacterium bovis

Mycobacterium microti

Mycobacterium tuberculosis

FURTHER INFORMATION

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Glossary

Recombination

In bacterial population genetics, recombination is the transfer of a segment of chromosomal DNA from one strain to another. Referred to as 'sex' in bacteria because recombination breaks the linkage between alleles at different loci.

Population bottleneck

A severe reduction in population size that generally leads to a loss of genetic variation by population sampling. During the bottleneck, drift can further homogenize the population.

Selective sweep

(Periodic selection). Process by which a new favourable mutation sweeps to fixation in a population and purges variation at, or around, the selected locus (sexual population) or for the entire chromosome (clonal population). For a clonal bacterial population the entire chromosome is taken to fixation with the driven locus (chromosomal hitch-hiking), and the only variation left in the population accumulates by mutation during the selective sweep.

British Isles

The British Isles contain two states, the United Kingdom of Great Britain and Northern Ireland (referred to as the UK) and the Republic of Ireland.

Clonal complex

A group of bacterial strains derived from a recent common ancestor that share many alleles at various phylogenetically informative loci. A clonal complex generally includes the ancestral genotype and strains with minor variation. This definition is highly subjective. Here, a clonal complex is defined in terms of strains bearing closely related spoligotype patterns.

Strain

A single isolate of any bacterial population and any laboratory induced variants thereof. All types of the vaccine isolate BCG are considered to be a single strain even though many variants of the original isolate exist in laboratories throughout the world.

Index of association

A fairly blunt tool to detect linkage disequilibrium, and therefore recombination, in a sample of allele frequencies from a population. Applied by Maynard Smith and others to show that bacterial populations can range from the panmictic to the clonal.

Linkage disequilibrium

The condition in which the frequency of a particular haplotype for two loci is significantly different from that expected under random mating. For a population in linkage equilibrium the expected frequency is the product of observed allelic frequencies at each locus. For haploid bacteria if the type of allele at one locus predicts the type of allele at another locus then the loci are in linkage disequilibrium.

Homoplasy

An identical mutation or similar characteristic found in phylogenetically unrelated lineages. Homoplasic mutations are not identical by descent from the common ancestor, and in bacteria can be generated by either repeated, independent mutation or by recombination.

Variable number tandem repeat analysis

(VNTR). VNTR analysis of strains of the M. tuberculosis complex is a method to detect variation in the number of repeat units found at a series of chromosomally dispersed mini-satellite loci. The VNTR genotype of a strain is represented as a string of integers reflecting the number of repeats detected at each locus.

Ecotype

The bacterial ecotype concept suggests that bacterial ecotypes have the following properties: they occupy distinct niches; selective sweeps limit the diversity in each ecotype; and the diversity between ecotypes is free to increase.

Spoligotype

The spoligotype is determined using a PCR and hybridization method to measure allelic variation in the direct repeat region of strains of the M. tuberculosis complex.

Clade

For the M. tuberculosis complex, a clade is informally used to describe the group of organisms descended from an ancestral cell without change in the major phylogenetically informative markers. A clade can contain more than one ecotype. This definition differs from the cladistic definition of a clade that would include all descendents of a recent common ancestor.

Founder effect

The reduction in diversity caused by population sampling as a small group of organisms establish themselves in a new ecological niche (host) or geographical region. During the founding of the new population, selective sweeps and drift in a small population can further reduce diversity.

Non-synonymous mutation

A single nucleotide mutation in a coding region that alters the encoded amino acid. By contrast, a synonymous mutation does not result in an amino-acid replacement.

Great Britain

Collectively, England, Scotland and Wales are known as Great Britain.

Single intradermal comparative cervical test

(SICCT). Also known as the tuberculin test, SICCT is an immunological method used to detect cattle infected with M. bovis, and is an integral part of the 'test and slaughter' protocol.

Pasteurization

A method of heating food to reduce the number of pathogenic organisms present. Pasteurization of milk is the major barrier to the transmission of bovine tuberculosis from cattle to humans.

Multilocus sequence typing

A portable and easier-to-use replacement for multilocus enzyme electrophoresis (MLEE) for identifying genotypic variation in prokaryotic populations. Multilocus sequence typing identifies allelic mismatches in the nucleotide sequence of a small number of housekeeping genes to identify sequence types.

Wahlund effect

The increase in heterozygocity observed after the mixing of two previously isolated sexual eukaryotic populations. In a similar manner, for bacterial populations the observed allelic diversity of a locus can be artificially inflated if a population sample contains strains from two populations that are geographically or phylogenetically separated.

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Smith, N., Gordon, S., de la Rua-Domenech, R. et al. Bottlenecks and broomsticks: the molecular evolution of Mycobacterium bovis. Nat Rev Microbiol 4, 670–681 (2006). https://doi.org/10.1038/nrmicro1472

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