Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Dec 16;6(12):e311.
doi: 10.1371/journal.pbio.0060311.

High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography

Ruth Hershberg  1 , Mikhail Lipatov, Peter M Small, Hadar Sheffer, Stefan Niemann, Susanne Homolka, Jared C Roach, Kristin Kremer, Dmitri A Petrov, Marcus W Feldman, Sebastien Gagneux
Affiliations

High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography

Ruth Hershberg et al. PLoS Biol. .

Abstract

Mycobacterium tuberculosis infects one third of the human world population and kills someone every 15 seconds. For more than a century, scientists and clinicians have been distinguishing between the human- and animal-adapted members of the M. tuberculosis complex (MTBC). However, all human-adapted strains of MTBC have traditionally been considered to be essentially identical. We surveyed sequence diversity within a global collection of strains belonging to MTBC using seven megabase pairs of DNA sequence data. We show that the members of MTBC affecting humans are more genetically diverse than generally assumed, and that this diversity can be linked to human demographic and migratory events. We further demonstrate that these organisms are under extremely reduced purifying selection and that, as a result of increased genetic drift, much of this genetic diversity is likely to have functional consequences. Our findings suggest that the current increases in human population, urbanization, and global travel, combined with the population genetic characteristics of M. tuberculosis described here, could contribute to the emergence and spread of drug-resistant tuberculosis.

PubMed Disclaimer

Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Maximum Parsimony Phylogeny of M. tuberculosis Complex Using 89 Concatenated Gene Sequences in 108 Strains
The branches are colored according to the main lineages defined previously based on our genomic deletion analysis, except for the animal-adapted strains, which are indicated in orange. The main clades are labeled according to their dominance in particular geographic areas. The branch leading to M. canettii has been truncated in the figure because of the large numbers of changes that separate this hypothesized outgroup from the rest of the phylogeny (Table S4). Ancient and modern strain lineages are indicated. The green and brown lineages correspond to strains traditionally known as M. africanum [21].
Figure 2
Figure 2. Frequency of Pairwise Genetic Distances Among 108 Strains of the MTBC
Pairwise comparisons of genetic distances between human-adapted strains are indicated in yellow, those between animal-adapted strains in blue, and those between human- and animal-adapted strains in red. For better illustration, the frequencies of genetic distances in the animal-to-animal strain comparisons and the animal-to-human strain comparisons were multiplied by 20 and 3, respectively. However, for the statistical analysis (see main text), the actual frequencies were used.
Figure 3
Figure 3. Frequency Distribution of Nonsynonymous Mutations, Synonymous Mutations, and Genomic Deletions in MTBC Strains
For each site that underwent a mutation within MTBC we observed two states: the derived (or mutated) state, and the ancestral state. For synonymous and nonsynonymous mutations we deduced the ancestral state based on the sequence of the outgroup strain M. canettii. For the genomic deletions (originally described in [44]), the ancestral state is the non-deleted state and the deleted state is derived. The frequencies depicted here are those of the mutated states. All three types of mutations show similar frequency distributions, which suggests that most nonsynonymous mutations and deletions are not slightly deleterious but rather selectively neutral within MTBC. Blue, nonsynonymous mutations; red, synonymous mutations; yellow, genomic deletions.
Figure 4
Figure 4. Out-Of-And-Back-To-Africa Scenario for the Evolutionary History of Human-Adapted MTBC
(A) Global human population size during the last 50,000 y. The letters above the graph indicate the time periods corresponding to (B), (C), and (D), respectively (data source: http://en.wikipedia.org/wiki/Image:Population_curve.svg). (B) Hypothesized migration out of Africa of ancient lineages of MTBC. Colored arrows correspond to the six main human-adapted MTBC lineages shown in Figure 1. The hypothesized common ancestor of the three modern lineages (in red, purple, and blue) is indicated in black. (C) Recent increase of global human population. Each dark grey dot corresponds to 1 million people (data source: http://www.pbs.org/wgbh/nova/worldbalance/numb-nf.html). The population increase was strongest in Western Europe, India, and East Asia (Figure S3). These three geographic regions are each associated with one of the three modern MTBC lineages (red, purple, and blue). Recent human migration, trade, and conquest have promoted global spread of these modern MTBC lineages. (D) The human population has reached 6 billion. The distribution of the six main human-adapted MTBC lineages we observe today is shown (colors correspond to Figures 1 and S2; based on data from [19,21]).
Figure 5
Figure 5. Correlations between Genetic and Geographic Distances in Ancient and Modern MTBC Strains
To determine the route by which human-adapted MTBC strains were globally dispersed, we sought correlations between genetic and geographic distances in ancient (A) and modern (B) MTBC strains. The shortest distances between geographic locations via water routes (pink diamonds) or continental waypoints (i.e., land routes; blue squares) are plotted against the corresponding genetic distances expressed as the number of SNPs. In ancient strains, the correlation using either route was highly statistically significant (p < 0.0001 for both), but the correlation using land routes was slightly stronger. By contrast in modern strains the correlation using water routes was stronger and more statistically significant compared with land routes (p < 0.0001 and p = 0.05, respectively). Significant p values and r2 between 0 and 1 for all four analyses support the association between MTBC dispersal and human migration, which is consistent with early spread of MTBC out of Africa. The relative magnitude of r 2 for land routes versus water routes suggests that spread of ancient strains occurred over land (i.e., through ancient human migration) and modern strains over water (i.e., through recent historical migration, trade, and conquest).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Raviglione MC, Smith IM. XDR tuberculosis–implications for global public health. N Engl J Med. 2007;356:656–659. - PubMed
    1. Young DB, Perkins MD, Duncan K, Barry CE. Confronting the scientific obstacles to global control of tuberculosis. J Clin Invest. 2008;118:1255–1265. - PMC - PubMed
    1. Gagneux S, Small PM. Molecular evolution of mycobacteria. In: Kaufmann SH, Rubin E, editors. Handbook of tuberculosis. Weinheim: Wiley VCH; 2008.
    1. Smith T. A comparative study of bovine tubercle bacilli and of human bacilli from sputum. J Exp Med. 1898;3:451–511. - PMC - PubMed
    1. Garnier T, Eiglmeier K, Camus JC, Medina N, Mansoor H, et al. The complete genome sequence of Mycobacterium bovis . Proc Natl Acad Sci U S A. 2003;100:7877–7882. - PMC - PubMed

Publication types