Mycobacterium tuberculosis (Mtb) is a member of the Mtb complex (MTBC), which comprises pathogenic bacteria that cause tuberculosis (TB) in humans and animals[1]. Mtb is a clonal pathogen proposed to have co-evolved with its human host for millennia[2]. This long-term adaptation of the bacterium to its human host has enabled it to become a highly efficient pathogen, still ranking as the leading cause of death from a single infectious agent today. Tuberculosis is accompanied by lung pain, sweating, and severe weight loss. Without treatment, TB often results in death. The latest WHO TB report mentions 10.6 million new cases and 1.3 million TB deaths in 2022[3].
A robust classification of Mtb strains into evolutionarily meaningful sub-lineages is important both for taxonomic purposes and because sub-lineages can differ in virulence or antibiotic resistance[4]. Mtb was first classified into three principal genetic groups in 1997, based on two neutral single nucleotide substitutions (SNSs) in the antibiotic resistance genes katG (codon 463) and gyrA (codon 95)[5]. Since then, several studies have attempted higher-resolution classification, using large genomic deletions, spoligotyping and SNSs[6]. There are currently nine recognized MTBC lineages (L1–9): Indo-Oceanic (L1), East-Asian (L2), East-African-Indian (L3), Euro-American (L4), West-Africa 1 (L5), West-Africa 2 (L6), Ethiopian (L7), Central-Africa (L8), and Eastern-Africa (L9). Among these, the most common lineage on the planet is L4. A collection belonging to L4 was sequenced and further classified into ten sub-lineages, distinguished as generalists (globally distributed) and specialists (geographically restricted) based on the ecological niche they occupy[7].
The fumarate reductase locus, which is present in all Mtb-associated phylotype species, contains (i) the genes frdA, frdB, frdC, and frdD encoding a fumarate reductase; and (ii) the genes encoding a transcriptional regulator, MmpS6 and MmpL6 representing a putative transmembrane transporter that belong to the MmpS/MmpL membrane protein family. Almost all Mtb strains investigated showed a deletion of the Mtb-specific deletion region 1 (TbD1) region, characterized by the deletion of the mmpS6 gene and truncation of the adjacent mmpL6 gene. The presence or absence of the TbD1 region was used to define strains that had deleted this region (ΔTbD1) as “modern” Mtb strains, whereas TbD1-intact Mtb strains were defined as “ancestral” Mtb strains. The presence or absence of the TbD1-region emerged as a powerful marker for differentiating Mtb strains within the MTBC. Mtb L2, L3, and L4 specifically represented “modern” ΔTbD1 Mtb strains, and all other lineages and clades of the MTBC represented “ancestral” TbD1-intact MTBC strains. It was found that the deletion of mmpS6 and part of the mmpL6 gene generated a fitness advantage for the strains under certain conditions of oxidative stress and during hypoxia[8]. This suggests that the deletion of the TbD1 region in a common ancestor of L2, L3, and L4 Mtb strains might have contributed to the wide distribution and global spread of strains belonging to these “modern”.
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[2] Comas I A, Coscolla M, Luo T, et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans[J]. Nature Genetics, 2013, 45(10): 1176-U311.
[3] WHO. Global Tuberculosis Report 2023[EB/OL]. https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023/tb-disease-burden/1-1-tb-incidence
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[8] Bottai D, Frigui W, Sayes F, et al. TbD1 deletion as a driver of the evolutionary success of modern epidemic Mycobacterium tuberculosis lineages[J]. Nat Commun, 2020, 11(1): 684.