Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans

Nature Genetics volume 45, pages 1176–1182 (2013)Cite this article

Subjects

Abstract

Tuberculosis caused 20% of all human deaths in the Western world between the seventeenth and nineteenth centuries and remains a cause of high mortality in developing countries. In analogy to other crowd diseases, the origin of human tuberculosis has been associated with the Neolithic Demographic Transition, but recent studies point to a much earlier origin. We analyzed the whole genomes of 259 M. tuberculosis complex (MTBC) strains and used this data set to characterize global diversity and to reconstruct the evolutionary history of this pathogen. Coalescent analyses indicate that MTBC emerged about 70,000 years ago, accompanied migrations of anatomically modern humans out of Africa and expanded as a consequence of increases in human population density during the Neolithic period. This long coevolutionary history is consistent with MTBC displaying characteristics indicative of adaptation to both low and high host densities.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The genome-based phylogeny of MTBC mirrors that of human mitochondrial genomes.
Figure 2: Out-of-Africa and Neolithic expansion of MTBC.
Figure 3: Neolithic expansion and spread of MTBC lineage 2 Beijing strains in East Asia.
Figure 4: Time-dependent decay of substitution rates in bacteria based on whole-genome data sets.

Accession codes

Primary accessions

European Nucleotide Archive

Sequence Read Archive

References

  1. Wilson, L.G. Commentary: medicine, population, and tuberculosis. Int. J. Epidemiol. 34, 521–524 (2005).

    Article  PubMed  Google Scholar 

  2. World Health Organization. The Global Plan to STOP TB 2011–2015 (World Health Organization, Geneva, 2011).

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Diamond, J. Guns, Germs, and Steel: The Fates of Human Societies 496 (W.W. Norton & Company, New York, 1999).

  5. Blaser, M.J. & Kirschner, D. The equilibria that allow bacterial persistence in human hosts. Nature 449, 843–849 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Berg, G. The prognosis of open pulmonary tuberculosis: a clinical-statistical analysis. J. Am. Med. Assoc. 114, 1954–1955 (1940).

    Google Scholar 

  7. Barry, C.E. III et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat. Rev. Microbiol. 7, 845–855 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hershberg, R. et al. High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography. PLoS Biol. 6, e311 (2008).

    Article  PubMed  PubMed Central  CAS  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  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. 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 

  14. Firdessa, R. et al. Mycobacterial lineages causing pulmonary and extrapulmonary tuberculosis in Ethiopia. Emerg. Infect. Dis. 19, 460–463 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Namouchi, A., Didelot, X., Schöck, U., Gicquel, B. & Rocha, E.P.C. After the bottleneck: genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection. Genome Res. 22, 721–734 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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 

  17. Comas, I. & Gagneux, S. The past and future of tuberculosis research. PLoS Pathog. 5, e1000600 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Behar, D.M. et al. A “Copernican” reassessment of the human mitochondrial DNA tree from its root. Am. J. Hum. Genet. 90, 675–684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Drummond, A.J., Ho, S.Y.W., Phillips, M.J. & Rambaut, A. Relaxed phylogenetics and dating with confidence. PLoS Biol. 4, e88 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Bos, K.I. et al. A draft genome of Yersinia pestis from victims of the Black Death. Nature 478, 506–510 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mutreja, A. et al. Evidence for several waves of global transmission in the seventh cholera pandemic. Nature 477, 462–465 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Morelli, G. et al. Yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity. Nat. Genet. 42, 1140–1143 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Djelouadji, Z., Raoult, D. & Drancourt, M. Palaeogenomics of Mycobacterium tuberculosis: epidemic bursts with a degrading genome. Lancet Infect. Dis. 11, 641–650 (2011).

    Article  PubMed  Google Scholar 

  24. Ford, C.B. et al. Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat. Genet. 43, 482–486 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Walker, T.M. et al. Whole-genome sequencing to delineate Mycobacterium tuberculosis outbreaks: a retrospective observational study. Lancet Infect. Dis. 13, 137–146 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Morelli, G. et al. Microevolution of Helicobacter pylori during prolonged infection of single hosts and within families. PLoS Genet. 6, e1001036 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Ho, S.Y.W. et al. Time-dependent rates of molecular evolution. Mol. Ecol. 20, 3087–3101 (2011).

    Article  PubMed  Google Scholar 

  28. Holt, K.E. et al. Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe. Nat. Genet. 44, 1056–1059 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Croucher, N.J. et al. Rapid pneumococcal evolution in response to clinical interventions. Science 331, 430–434 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Harris, S.R. et al. Evolution of MRSA during hospital transmission and intercontinental spread. Science 327, 469–474 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Soares, P. et al. Correcting for purifying selection: an improved human mitochondrial molecular clock. Am. J. Hum. Genet. 84, 740–759 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Soares, P. et al. The expansion of mtDNA haplogroup L3 within and out of Africa. Mol. Biol. Evol. 29, 915–927 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Rasmussen, M. et al. An Aboriginal Australian genome reveals separate human dispersals into Asia. Science 334, 94–98 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Henn, B.M., Cavalli-Sforza, L.L. & Feldman, M.W. The great human expansion. Proc. Natl. Acad. Sci. USA 109, 17758–17764 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Stewart, J.R. & Stringer, C.B. Human evolution out of Africa: the role of refugia and climate change. Science 335, 1317–1321 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Jin, L. & Su, B. Natives or immigrant: modern human origins in East Asia. Nat. Rev. Genet. 1, 126–133 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Bellwood, P. & Oxenham, M. The Neolithic Demographic Transition and its Consequences 13–34 (Springer, New York, 2008).

  38. Gignoux, C.R., Henn, B.M. & Mountain, J.L. Rapid, global demographic expansions after the origins of agriculture. Proc. Natl. Acad. Sci. USA 108, 6044–6049 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Parwati, I., van Crevel, R. & van Soolingen, D. Possible underlying mechanisms for successful emergence of the Mycobacterium tuberculosis Beijing genotype strains. Lancet Infect. Dis. 10, 103–111 (2010).

    Article  PubMed  Google Scholar 

  40. Barton, L. et al. Agricultural origins and the isotopic identity of domestication in northern China. Proc. Natl. Acad. Sci. USA 106, 5523–5528 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Atkinson, Q.D., Gray, R.D. & Drummond, A.J. mtDNA variation predicts population size in humans and reveals a major Southern Asian chapter in human prehistory. Mol. Biol. Evol. 25, 468–474 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Wei, W. et al. A calibrated human Y-chromosomal phylogeny based on resequencing. Genome Res. 23, 388–395 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hamilton, M.J., Milne, B.T., Walker, R.S., Burger, O. & Brown, J.H. The complex structure of hunter-gatherer social networks. Proc. Biol. Sci. 274, 2195–2202 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Linz, B. et al. An African origin for the intimate association between humans and Helicobacter pylori. Nature 445, 915–918 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Littman, D.R. & Pamer, E.G. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 10, 311–323 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Perry, S. et al. Infection with Helicobacter pylori is associated with protection against tuberculosis. PLoS ONE 5, e8804 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. de Jong, B.C. et al. Progression to active tuberculosis, but not transmission, varies by Mycobacterium tuberculosis lineage in The Gambia. J. Infect. Dis. 198, 1037–1043 (2008).

    Article  PubMed  Google Scholar 

  48. Martineau, A.R. et al. Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa. Proc. Natl. Acad. Sci. USA 108, 19013–19017 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Barnes, I., Duda, A., Pybus, O.G. & Thomas, M.G. Ancient urbanization predicts genetic resistance to tuberculosis. Evolution 65, 842–848 (2011).

    Article  PubMed  Google Scholar 

  50. Ramachandran, S. et al. Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa. Proc. Natl. Acad. Sci. USA 102, 15942–15947 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Quail, M.A. et al. A large genome center 's improvements to the Illumina sequencing system. Nature Methods 5, 1005–1010 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Comas, I. et al. Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat. Genet. 42, 498–503 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li, H., Ruan, J. & Durbin, R. Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 18, 1851–1858 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li, H. & Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26, 589–595 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Li, H. et al. The sequence alignment/map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    PubMed  PubMed Central  Google Scholar 

  56. Larkin, M.A. et al. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948 (2007).

    CAS  PubMed  Google Scholar 

  57. Hall, T.A. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp. Ser. 41, 95–98 (1999).

    CAS  Google Scholar 

  58. Lemey, P., Rambaut, A., Drummond, A.J. & Suchard, M.A. Bayesian phylogeography finds its roots. PLoS Comput. Biol. 5, e1000520 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Yu, Y., Harris, A.J. & He, X. S-DIVA (Statistical Dispersal-Vicariance Analysis): a tool for inferring biogeographic histories. Mol. Phylogenet. Evol. 56, 848–850 (2010).

    Article  PubMed  Google Scholar 

  60. Parker, J., Rambaut, A. & Pybus, O.G. Correlating viral phenotypes with phylogeny: accounting for phylogenetic uncertainty. Infect. Genet. Evol. 8, 239–246 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D. Behar and S. Rosset for providing the mitochondrial genome sequences and C. Gignoux for advice on the mitochondrial Neolithic data set, N. Mistry (The Foundation for Medical Research) for providing bacterial strains and C. Dye, F. Balloux and L. Weinert for comments on the manuscript. This work was supported by the MRC UK (grants U.1175.02.002.00015.01 to S.G. and U117581288 to D.Y.), the Swiss National Science Foundation (PP0033-119205 to S.G.), the US National Institutes of Health (AI090928 and HHSN266200700022C to S.G.), the Leverhulme-Royal Society Africa Award (AA080019 to S.G.) and the Natural Science Foundation of China (grant 91231115 to Q.G.). DNA sequencing was partially supported by core funding of the Wellcome Trust (grant 098051) and by a Framework Programme 7 project of the European Community (SysteMTb HEALTH-F4-2010-241587 to D.Y.). I.C. is supported by European Union funding from the Marie Curie Framework Programme 7 actions (project 272086) and project BFU2011-24112 from the Ministerio de Economía y Competitividad (Spain).

Author information

Author notes

  1. Mireia Coscolla and Tao Luo: These authors contributed equally to this work.

  2. Douglas Young and Sebastien Gagneux: These authors jointly directed this work.

Authors and Affiliations

  1. Genomics and Health Unit, Centre for Public Health Research (CSISP-FISABIO), Valencia, Spain

    Iñaki Comas

  2. CIBER (Centros de Investigación Biomédica en Red) in Epidemiology and Public Health, Barcelona, Spain

    Iñaki Comas

  3. Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland

    Mireia Coscolla, Sonia Borrell, Bijaya Malla & Sebastien Gagneux

  4. University of Basel, Basel, Switzerland

    Mireia Coscolla, Sonia Borrell, Bijaya Malla & Sebastien Gagneux

  5. Key Laboratory of Medical Molecular Virology, Institutes of Biomedical Sciences and Institute of Medical Microbiology, Shanghai Medical College, Fudan University, Shanghai, China

    Tao Luo & Qian Gao

  6. Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria, Australia

    Kathryn E Holt

  7. Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia

    Kathryn E Holt

  8. Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California, USA

    Midori Kato-Maeda

  9. Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    Julian Parkhill, Stephen Bentley & Simon R Harris

  10. TB Research Group, Veterinary Laboratories Agency, Weybridge, New Haw and Addlestone, UK

    Stefan Berg

  11. Department of Infectious Disease, King's College London, London, UK

    Guy Thwaites

  12. Centre for Clinical Infection and Diagnostics Research, King's College London, London, UK

    Guy Thwaites

  13. Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana

    Dorothy Yeboah-Manu

  14. Department of Respiratory Medicine, Homerton University Hospital, London, UK

    Graham Bothamley

  15. Department of Tuberculosis Control, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China

    Jian Mei

  16. Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Lanhai Wei

  17. Molecular Mycobacteriology, Research Center Borstel, Borstel, Germany

    Stefan Niemann

  18. Institute for Epidemiology, Schleswig-Holstein University Hospital, Kiel, Germany

    Roland Diel

  19. Armauer Hansen Research Institute, Addis Ababa, Ethiopia

    Abraham Aseffa

  20. Medical Research Council (MRC) National Institute for Medical Research, Mill Hill, London, UK

    Douglas Young

  21. Department of Medicine, Imperial College London, London, UK

    Douglas Young

  22. Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK

    Douglas Young

Authors
  1. Iñaki Comas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mireia Coscolla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tao Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sonia Borrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathryn E Holt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Midori Kato-Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julian Parkhill
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bijaya Malla
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stefan Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Guy Thwaites
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dorothy Yeboah-Manu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Graham Bothamley
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jian Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Lanhai Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Stephen Bentley
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Simon R Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Stefan Niemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Roland Diel
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Abraham Aseffa
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Qian Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Douglas Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Sebastien Gagneux
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I.C., Q.G., D.Y. and S.G. designed and supervised the study. M.C., S. Borrell, K.E.H., M.K.-M., J.P., B.M., S. Berg, G.T., D.Y.-M., G.B., J.M., L.W., S.R.H., S.N., R.D., A.A., Q.G. and S.G. provided MTBC strains and/or reagents. J.P., S. Bentley and S.R.H. contributed to the genome sequencing. I.C., M.C. and T.L. analyzed the data. I.C., M.C., T.L., S. Borrell, K.E.H., J.P., S. Berg, G.T., D.Y.-M., S. Bentley, S.R.H., S.N., A.A., Q.G., D.Y. and S.G. contributed to the manuscript writing. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Iñaki Comas, Qian Gao or Sebastien Gagneux.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10, Supplementary Table 7 and Supplementary Note (PDF 2301 kb)

Supplementary Table 1

List of mycobacterial strains used in this study (XLSX 34 kb)

Supplementary Table 2

Variable single nucleotide positions in the 219 MTBC dataset (excluding outgroup) (XLSX 2760 kb)

Supplementary Table 3

Accession number and haplogroup of the 4,955 human mitochondrial (mtDNA) genomes reference dataset (XLSX 104 kb)

Supplementary Table 4

MTBC strains and human mtDNA genomes used to test for the statistical association (XLSX 13 kb)

Supplementary Table 5

Accession number, haplogroup and prehistoric period of the 423 human mtDNA genomes obtained from Gignoux et al. 2011 (XLSX 17 kb)

Supplementary Table 6

Accession number and haplogroup of the human mtDNA genomes used for the analysis of the Neolithic in East Asia (XLSX 12 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Comas, I., Coscolla, M., Luo, T. et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet 45, 1176–1182 (2013). https://doi.org/10.1038/ng.2744

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2744

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing