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

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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.

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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.

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European Nucleotide Archive

Sequence Read Archive

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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).

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Authors and Affiliations

Authors

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.

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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)

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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

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