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 the first in-depth analysis of the ancient East African Indian 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 4,939 pan-susceptible strains and find 30 new genetically distinct clades that we validate in a dataset of 4,645 independent isolates. We characterize sub-lineage geographic distributions and demonstrate a consistent geographically restricted and unrestricted pattern for 20 groups, including three groups of Lineage 1. We assess the transmissibility of the four major lineages by examining the distribution of terminal branch lengths across the M. tuberculosis phylogeny and identify evidence supporting higher transmissibility in Lineages 2 and 4 than 3 and 1 on a global scale. We define a robust expanded barcode of 95 single nucleotide substitutions (SNS) that allows for the rapid identification of 69 Mtb sub-lineages and 26 additional internal groups. Our results paint a higher resolution picture of the Mtb phylogeny and biogeography.

Population structure, biogeography and transmissibility of Mycobacterium tuberculosis