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. 2021 Oct 20;12(1):6099.
doi: 10.1038/s41467-021-26248-1.

Population structure, biogeography and transmissibility of Mycobacterium tuberculosis

Luca Freschi  1 , Roger Vargas Jr  2   3 , Ashaque Husain  4 , S M Mostofa Kamal  5 , Alena Skrahina  6 , Sabira Tahseen  7 , Nazir Ismail  8   9 , Anna Barbova  10 , Stefan Niemann  11 , Daniela Maria Cirillo  12 , Anna S Dean  13 , Matteo Zignol  13 , Maha Reda Farhat  14   15
Affiliations

Population structure, biogeography and transmissibility of Mycobacterium tuberculosis

Luca Freschi et al. Nat Commun. .

Abstract

Mycobacterium tuberculosis is a clonal pathogen proposed to have co-evolved with its human host for millennia, yet our understanding of its genomic diversity and biogeography remains incomplete. Here we use a combination of phylogenetics and dimensionality reduction to reevaluate the population structure of M. tuberculosis, providing an in-depth analysis of the ancient Indo-Oceanic Lineage 1 and the modern Central Asian Lineage 3, and expanding our understanding of Lineages 2 and 4. We assess sub-lineages using genomic sequences from 4939 pan-susceptible strains, and find 30 new genetically distinct clades that we validate in a dataset of 4645 independent isolates. We find a consistent geographically restricted or unrestricted pattern for 20 groups, including three groups of Lineage 1. The distribution of terminal branch lengths across the M. tuberculosis phylogeny supports the hypothesis of a higher transmissibility of Lineages 2 and 4, in comparison with Lineages 3 and 1, on a global scale. We define an expanded barcode of 95 single nucleotide substitutions that allows rapid identification of 69 M. tuberculosis sub-lineages and 26 additional internal groups. Our results paint a higher resolution picture of the M. tuberculosis phylogeny and biogeography.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Phylogenetic tree reconstruction of lineage 1 (binary tree).
Gray circles define splits where the FST (fixation index) calculated using the descendants of the two children nodes is greater than 0.33. The sub-lineages are defined by colored areas (blue: sub-lineages already described in the literature; green: sub-lineages described here; purple: internal sub-lineages). Source data are provided as a Source Data file.
Fig. 2
Fig. 2. Phylogenetic tree reconstruction of lineage 3 (binary tree).
Gray circles define splits where the FST (fixation index) calculated using the descendants of the two children nodes is greater than 0.33. The sub-lineages are defined by colored areas (green: sub-lineages described here; purple: internal sub-lineages). Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Phylogenetic tree reconstruction of lineage 2 (binary tree).
Gray circles define splits where the FST (fixation index) calculated using the descendants of the two children nodes is greater than 0.33. The sub-lineages are defined by colored areas (blue: sub-lineages already described in the literature; green: sub-lineages described here; purple: internal sub-lineages). Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Phylogenetic tree reconstruction of lineage 4 (binary tree).
Gray circles define splits where the FST (fixation index) calculated using the descendants of the two children nodes is greater than 0.33. The sub-lineages are defined by colored areas (blue: sub-lineages already described in the literature; green: sub-lineages described here; purple: internal sub-lineages). Source data are provided as a Source Data file.
Fig. 5
Fig. 5. Histogram of the Simpson diversity index calculated for sub-lineages of lineages 1–4.
A data set of 17,432 isolates from 74 countries was used to perform this analysis. Yellow triangles designate the Simpson diversity index values of sub-lineages designated as geographically restricted by Stucki et al. Light gray circles designate the Simpson diversity index values of sub-lineages designated as geographically unrestricted by Stucki et al. Source data are provided as a Source Data file.
Fig. 6
Fig. 6. Geographic distribution of internal sub-lineage 1.1.3.i1.
Colors represent the percentage of 1.1.3.i1 strains isolated in a given country with respect to all lineage 1 strains isolated in such country. Source data are provided as a Source Data file.
Fig. 7
Fig. 7. Geographic distribution of internal sub-lineage 1.1.1.1.
Colors represent the percentage of 1.1.1.1 strains isolated in a given country with respect to all lineage 1 strains isolated in such country. Source data are provided as a Source Data file.
Fig. 8
Fig. 8. Geographic distribution of internal sub-lineage 1.1.2.
Colors represent the percentage of 1.1.2 strains isolated in a given country with respect to all lineage 1 strains isolated in such country. Source data are provided as a Source Data file.
Fig. 9
Fig. 9. Distributions of terminal branch lengths for the four global Mtb lineages (L1–L4).
Two-sided Wilcoxon rank sum tests were performed to test that two distributions were significantly different. Medians: 6.2 × 10−5 (L4), 8.2 × 10−5 (L2), 10.2 × 10−5 (L3), 17.5 × 10−5 (L1). Comparisons: L1 vs L2, L3 or L4 (p-value < 2.2 × 10−16); L2 vs L3 (p-value = 3.6 × 10−6), L2 vs L4 (p-value < 2.2 × 10−16); L3 vs L4 (p-value < 2.2 × 10−16). Description of the distributions (L1: n = 739, Min: 0.5 × 10−5, 1st Quartile: 6.7 × 10−5, Median: 17.5 × 10−5, 3rd Quartile: 28 × 10−5, Max: 120 × 10−5; L2: n = 2193, Min: 0.7 × 10−5, 1st Quartile: 5.3 × 10−5, Median: 8.2 × 10−5, 3rd Quartile: 12 × 10−5, Max: 110 × 10−5; L3: n = 1103, Min: 0.5 × 10−5, 1st Quartile: 4.5 × 10−5, Median: 10.2 × 10−5, 3rd Quartile: 20 × 10−5, Max: 80 × 10−5; L4: n = 5514, Min: 0.2 × 10−5, 1st Quartile: 2.6 × 10−5, Median: 6.2 × 10−5, 3rd Quartile: 13 × 10−5, Max: 70 × 10−5). Source data are provided as a Source Data file.
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