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Genomic insights into tuberculosis

Nature Reviews Genetics volume 15, pages 307–320 (2014)Cite this article

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Key Points

  • It was once thought that Mycobacterium tuberculosis in humans arose as a zoonosis, perhaps from Mycobacterium bovis that infected domesticated cattle. Genome sequencing has reversed this view and revealed that M. bovis and related animal ecotypes are likely to be derived from a human-adapted mycobacterium. Moreover, a molecular clock analysis based on sequence from smooth tubercle bacilli and M. tuberculosis has led to the hypothesis that human-infecting M. tuberculosis may have existed as far back as 2.8 million years ago.

  • Whole-genome sequencing (WGS) and analyses of hundreds of M. tuberculosis strains have resulted in a detailed phylogeny and a potential scenario for the emergence of human tuberculosis. According to this scenario, human-infecting mycobacteria arose in Africa and spread with early human migrations out of Africa. Subsequent human population expansion resulted in a concurrent growth of the M. tuberculosis population and its phylogeographical structuring.

  • Unlike most bacteria, M. tuberculosis does not seem to undergo lateral gene transfer or substantial genome rearrangement. Recent reports have documented the first large-scale duplications in M. tuberculosis, all of which affect the same large genomic regions. However, apart from this example, M. tuberculosis seems to evolve primarily through sequential chromosomal mutations.

  • The rate of genome evolution has implications for the ongoing emergence of drug resistance. WGS has been used to establish the mutation rate of M. tuberculosis. Surprisingly, the mutation rate does not seem to differ between active and latent disease. Although the mutation rate for M. tuberculosis is thought to be lower than most bacteria, sequencing of patient isolates has revealed that mutations causing resistance to many drugs can be acquired multiple times by different isolates and even multiple times within the same patient. Moreover, differences in mutation rates between different M. tuberculosis lineages have been linked to differences in the rate of drug resistance acquisition in the laboratory.

  • Although it was once thought that all drug resistance mutations would result in a competitive fitness cost relative to susceptible strains, studies have now demonstrated that clinical strains frequently harbour mutations with low or no fitness cost and that the fitness cost of other mutations can be offset by compensatory mutations.

  • Combining genome sequencing technologies with other whole-cell assay technologies is enabling the study of M. tuberculosis at a comprehensive molecular systems level. A recent systems analysis of the regulatory network of M. tuberculosis on the basis of chromatin immunoprecipitation followed by sequencing (ChIP–seq) revealed complex regulatory interactions that may coordinate different adaptions to the host environment. The data also reveal that transcription factor binding in bacteria is more diverse than previously appreciated.

  • A successful M. tuberculosis infection requires an immune response that is sufficient to establish a granuloma but that is not robust enough to result in sterilization. A emerging picture is that M. tuberculosis has evolved over a long evolutionary history to specifically interact with the human immune system in order to orchestrate this balance. One striking piece of evidence for this is the observation from WGS that antigens in M. tuberculosis are highly conserved.

Abstract

Prevalent since pre-history, human tuberculosis — caused by the pathogen Mycobacterium tuberculosis — remains a major source of death worldwide. Moreover, increasing drug resistance poses the threat of disease resurgence. However, the expanding application of genomic techniques is providing new avenues for combating this old foe. Whole-genome sequencing, comparative genomics and systems biology are generating new insights into the origins and ongoing evolution of M. tuberculosis, as well as the molecular basis for its pathogenicity. These have important implications for our perspective of the disease, development of new drugs and vaccines, and treatment of patients using existing therapeutics.

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Figure 1: Evolutionary relationship between selected mycobacteria and members of the Mycobacterium tuberculosis complex.
Figure 2: Hypothesized evolutionary scenario for Mycobacterium tuberculosis and selected archaeological evidence.
Figure 3: Host–pathogen interactions.

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Acknowledgements

The author thanks E. Azizi, A. Earl and B. Birren for their input and assistance. This project has been funded in whole or in part with Federal funds from the US National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Department of Health and Human Services, under Contract Number HHSN272200800059C, and a grant from the Massachusetts Life Sciences Foundation.

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  1. Department of Biomedical Engineering, Bioinformatics program and National Emerging Infectious Diseases Laboratory, Boston University, 34 Cummington Mall 1002, Boston, 02215, Massachusetts

    James E. Galagan

  2. Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    James E. Galagan

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Detailed phylogenetic trees. (PDF 219 kb)

Glossary

Active disease

A Mycobacterium tuberculosis infection associated with clinical symptoms of tuberculosis.

Granuloma

An organized nodule of inflammatory cells that is associated with a range of diseases, including tuberculosis. A tuberculosis granuloma consists of a core of infected macrophages surrounded by phagocytes that are enclosed in a mantle of lymphocytes and a fibrous cuff.

Professional pathogen

An organism adapted for a pathogenic lifestyle.

IS6110 repeat sequence

An insertion element specific to the Mycobacterium tuberculosis complex.

Spoligotyping

A PCR-based method for genotyping Mycobacterium tuberculosis strains on the basis of the presence or absence of clustered regularly interspaced short palindromic repeat (CRISPR) spacer sequences.

D1 deletion

A genomic region deleted specifically in Mycobacterium tuberculosis relative to the M. tuberculosis complex.

Zoonotic transmission

The transmission of an animal disease to humans.

Smooth tubercle bacilli

(STBs). Mycobacteria that show a smooth colony morphology on culture media.

Pulse-field gel electrophoresis

A technique for separating large DNA molecules in a gel matrix using a modulating electric field.

Pre-Columbian

Pertaining to the time period before the arrival of Christopher Columbus in the Americas.

Molecular clock

A method for dating divergence between species based on the hypothesis of a constant rate of molecular change over time in selectively neutral DNA sequences.

Clonal expansion

A population that arises from a single cell through cell replication without lateral gene transfer.

Genetic bottleneck

A reduction in genetic diversity of a species as a result of a large decrease in population size.

Multiple-drug resistant

(MDR). Pertaining to tuberculosis that is resistant to at least the first-line drugs isoniazid and rifampicin.

Extensively drug resistant

(XDR). Pertaining to tuberculosis that is resistant to both isoniazid and rifampicin, to a fluoroquinolone and to at least one of the three injectable second-line drugs amikacin, capreomycin or kanamycin.

Homoplasy

Identical character states (for example, the same nucleotide in a DNA sequence) that are not the result of common ancestry (that is, not homologous) but that arose independently in different ancestors by convergent mutations.

Latent disease

A Mycobacterium tuberculosis infection that does not have any clinical symptoms.

Reactivated disease

A Mycobacterium tuberculosis infection that has progressed from latent to active disease.

Selective sweeps

Reductions in genetic variation due to strong selection for advantageous alleles.

Purifying selection

(Also known as negative selection). The removal of deleterious alleles.

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Galagan, J. Genomic insights into tuberculosis. Nat Rev Genet 15, 307–320 (2014). https://doi.org/10.1038/nrg3664

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