Local adaptation in populations of Mycobacterium tuberculosis endemic to the Indian Ocean Rim

Abstract

Background: Lineage 1 (L1) and 3 (L3) are two lineages of the Mycobacterium tuberculosis complex (MTBC) causing tuberculosis (TB) in humans. L1 and L3 are prevalent around the rim of the Indian Ocean, the region that accounts for most of the world's new TB cases. Despite their relevance for this region, L1 and L3 remain understudied. Methods: We analyzed 2,938 L1 and 2,030 L3 whole genome sequences originating from 69 countries. We reconstructed the evolutionary history of these two lineages and identified genes under positive selection. Results: We found a strongly asymmetric pattern of migration from South Asia toward neighboring regions, highlighting the historical role of South Asia in the dispersion of L1 and L3. Moreover, we found that several genes were under positive selection, including genes involved in virulence and resistance to antibiotics. For L1 we identified signatures of local adaptation at the esxH locus, a gene coding for a secreted effector that targets the human endosomal sorting complex, and is included in several vaccine candidates. Conclusions: Our study highlights the importance of genetic diversity in the MTBC, and sheds new light on two of the most important MTBC lineages affecting humans.

Keywords: Mycobacterium tuberculosis; adaptation; coevolution.

Figure 1.. Results of the biogeography analysis: L1.

a) Heatmap indicating the origin of the 2,061 L1 strains included in the dataset used for the biogeography analysis. b) The geographic regions used in the biogeography analysis of L1. c) Results of PASTML (compressed tree), the color code follow the legend of panel ( b), the size of the circles is proportional to the number of tips, and the size of the arrows is proportional to the number of times the pattern of migration was observed on the tree. This plot excluded nodes that represented less than three strains. The same plot including all nodes can be found as Extended Data File 1. d) Tree obtained with the Mascot analysis; the branches are colored following the legend in panel ( b) and represent the inferred ancestral region with the largest posterior probability. e) Representation of the relative effective population sizes (circles) and migration rates (lines connecting circles) estimated by Mascot. Lines representing migration rates are colored based on the region of origin (interpreted forward in time). For example, the dark blue line connecting the dark blue circle with the red circle represents the forward migration rate between South Asia and East Africa, which is the largest migration rate estimated by Mascot. The parameter estimates are reported in Extended Data Table 2.

Figure 2.. Results of the biogeography analysis: L3.

a) Heatmap indicating the origin of 1,021 L3 strains included in the dataset used for the biogeography analysis. b) The geographic regions used in the biogeography analysis of L3. c) Results of PASTML (compressed tree), the color code follow the legend of panel (b), the size of the circles is proportional to the number of tips, and the size of the arrows is proportional to the number of times the pattern of migration was observed on the tree. This plot excluded nodes that represent less than three strains, the same plot including all nodes can be found as Extended Data File 3. d) Tree obtained with the Mascot analysis; the branches are colored following the legend in panel (b) and represent the inferred ancestral region with the largest posterior probability. e) Representation of the relative effective population sizes (circles) and migration rates (lines connecting circles) estimated by Mascot. Lines representing migration rates are colored based on the region of origin (interpreted forward in time). The effective population size of South Asia was estimated to be much larger than the one of East Africa. Additionally, the forward migration rate between South Asia and East Africa was much larger than the one in the opposite direction. The parameter estimates are reported in Extended Data Table 2.

Figure 3.. The hypervariable epitope at the N terminus of esxH (aa 1–18).

The ancestral epitope is reported in top position, the derived haplotypes are reported below: mutations that were present in more than one lineage are highlighted in yellow, haplotypes that were found exclusively in L1, L2 or L4 are highlighted in pink, blue and red, respectively. Asterisks indicate the position inferred to be under positive selection by PAML: * posterior probability > 0.95: ** posterior probability > 0.99. The table on the right reports for each lineage the number of strains harboring the corresponding haplotype, and between parentheses, the number of independent parallel occurrences of the mutations as inferred by PAUP.