Global expansion of Mycobacterium tuberculosis lineage 4 shaped by colonial migration and local adaptation

Abstract

On the basis of population genomic and phylogeographic analyses of 1669 Mycobacterium tuberculosis lineage 4 (L4) genomes, we find that dispersal of L4 has been completely dominated by historical migrations out of Europe. We demonstrate an intimate temporal relationship between European colonial expansion into Africa and the Americas and the spread of L4 tuberculosis (TB). Markedly, in the age of antibiotics, mutations conferring antimicrobial resistance overwhelmingly emerged locally (at the level of nations), with minimal cross-border transmission of resistance. The latter finding was found to reflect the relatively recent emergence of these mutations, as a similar degree of local restriction was observed for susceptible variants emerging on comparable time scales. The restricted international transmission of drug-resistant TB suggests that containment efforts at the level of individual countries could be successful.

Fig. 1. Sampling overview and phylogeography of the global L4 dataset.

In the map, sampled countries are colored by continent, and sample sizes are indicated. In the temporal phylogeny, branches are colored to match the most likely geographic location inferred using BASTA. MDR clusters identified in the dataset are highlighted with black background shading. A large black asterisk highlights the branch leading to the DS6_Quebec clade that was used to assess robustness of dating analyses, whereas yellow dots indicate independent introductions of the KZN ancestor to South Africa and South America (see main text for details).

Fig. 2. Within-country diversity as assessed by mean pairwise SNP distances (only including well-sampled countries).

Vertical dashed lines indicate median values. Embedded pie charts summarize sublineage distribution within each country. The Simpsons diversity index (1-D) was calculated at the level of subspecies and the estimate indicated in the top of each county panel (where higher values correspond to increased diversity).

Fig. 3. L4 migration.

(A) Heatmap summarizing the overall migration load between continents as inferred in BASTA. (B) Temporal overview of L4 migration out of Europe. The establishment of strains of interest discussed in the text is highlighted. As the exact timing of the first American migrations was uncertain, the mean of the first three inferred migration events to each of the two subcontinents is reported as an approximation of the earliest migration events to the Americas. (C) Out-of-Europe migration to Southeast Asia, Africa, and South America over time. The plots also show within-continent migration/transmission in the receiving continents to illustrate the relative importance of repeated L4 import on continental L4 load over time. SE, southeast.

Fig. 4. Transmission of resistance.

(Top) Independent emergence of AMR over time based on the age of nodes where resistance mutations were inferred to have emerged. (Middle) Inferred cross-border transmission of the descendants of susceptible and resistant ancestors as a function of node age. The size of the dots indicates the number of inferred cross-continental migration events occurring among ancestors of each node. Individual dots are colored by the drug to which they cause resistance. (Bottom) The number of descendants divided by node age for inferred nodes with or without resistance mutations as a proxy for transmissibility.