Abstract

A small number of high-burden countries account for the majority of tuberculosis cases worldwide. Detailed data are lacking from these regions. To explore the evolutionary history of Mycobacterium tuberculosis in China—the country with the third highest tuberculosis burden—we analysed a countrywide collection of 4,578 isolates. Little genetic diversity was detected, with 99.4% of the bacterial population belonging to lineage 2 and three sublineages of lineage 4. The deeply rooted phylogenetic positions and geographic restriction of these four genotypes indicate that their populations expanded in situ following a small number of introductions to China. Coalescent analyses suggest that these bacterial subpopulations emerged in China around 1,000 years ago, and expanded in parallel from the twelfth century onwards, and that the whole population peaked in the late eighteenth century. More recently, sublineage L2.3, which is indigenous to China and exhibited relatively high transmissibility and extensive global dissemination, came to dominate the population dynamics of M. tuberculosis in China. Our results indicate that historical expansion of four M. tuberculosis strains shaped the current tuberculosis epidemic in China, and highlight the long-term genetic continuity of the indigenous M. tuberculosis population.

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Data availability

Sequencing reads have been submitted to the European Nucleotide Archive (EMBL-EBI) under study accession PRJEB23157. The geographic information for individual isolates is listed in Supplementary Table 3. The analysis scripts used in this study are available online at GitHub (https://github.com/StopTB/China_TB_Evolutionary_History).

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Acknowledgements

We thank T. M. Walker for sharing the geographic information of 3,651 MTBC isolates of multiple continents origin. We also thank Y.-X. Fu and X. Liu for advice on effective population size calculation and fruitful discussions, and D. Brites and C. Wang for help with clarifying technical details of data analysis during this work. This work was supported by the Natural Science Foundation of China (91631301 and 81661128043 to Q.G. and 81701975 to Q.L.). C.S.P. was supported by the National Institutes of Health (grant 1R01AI113287-01A1). S.G. was supported by the Swiss National Science Foundation (grants IZRJZ3_164171, 310030_166687, IZLSZ3_170834 and CRSII5_177163). This work was also supported by MINECO research grant SAF2016-77346-R (to I.C.), the European Research Council (638553-TB-ACCELERATE to I.C.), the National Science and Technology Major Project of China (2017ZX10201302 to Q.G., 2018ZX10103001 to Y.Z.), the Sanming Project of Medicine in Shenzhen (SZSM201611030 to Q.G.), JSGG20170413142559220 (to Q.G.), and National Basic Research programme of China (2014CB744403 to Y.Z.).

Author information

Author notes

  1. These authors contributed equally: Aijing Ma, Lanhai Wei.

Affiliations

  1. Key Laboratory of Medical Molecular Virology, Ministry of Education and Health, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China

    • Qingyun Liu
    • , Qi Jiang
    • , Mingyu Gan
    • , Tianyu Zuo
    • , Mei Liu
    • , Chongguang Yang
    •  & Qian Gao
  2. Shenzhen Center for Chronic Disease Control, Shenzhen, China

    • Qingyun Liu
    • , Qi Jiang
    • , Mingyu Gan
    •  & Qian Gao
  3. National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China

    • Aijing Ma
    • , Yang Zhou
    •  & Yanlin Zhao
  4. State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    • Lanhai Wei
    • , Hong-Xiang Zheng
    •  & Li Jin
  5. National Tuberculosis Clinical Laboratory, Beijing Key Laboratory for Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China

    • Yu Pang
  6. The Institute of TB Control, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China

    • Beibei Wu
  7. West China School of Basic Medical Sciences and Forensic Medicines, Sichuan University, Chengdu, China

    • Tao Luo
  8. Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University, New Haven, CT, USA

    • Chongguang Yang
  9. Institute of Biomedicine of Valencia, CSIC and CIBER in Epidemiology and Public Health, Valencia, Spain

    • Iñaki Comas
  10. Swiss Tropical and Public Health Institute, Basel, Switzerland

    • Sebastien Gagneux
  11. University of Basel, Basel, Switzerland

    • Sebastien Gagneux
  12. Department of Medicine, Division of Infectious Diseases, University of Wisconsin-Madison, Madison, WI, USA

    • Caitlin S. Pepperell
  13. Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA

    • Caitlin S. Pepperell

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Contributions

Q.L., Y.Z., C.S.P. and Q.G. designed and implemented the study. Y.P., B.W., Y.Z. and Q.G. collected and contributed the MTBC isolates analysed in this study. Q.L., A.M. and Y.Z. conducted the SNP genotyping work. M.L. and C.Y. conducted the MIRU-VNTR typing and analysis. Q.L., T.L., M.G. and T.Z. analysed the sequencing reads and performed the genetic analysis. L.W., H.-X.Z. and L.J. participated in the analysis of integrating tuberculosis history with Chinese human population history. Q.J. performed the statistical analysis. Q.L., I.C., S.G., C.S.P. and Q.G. drafted the manuscript. All authors critically reviewed and approved the final version of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Yanlin Zhao or Caitlin S. Pepperell or Qian Gao.

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