Journal Article

Dormancy regulon reduction was pivotal to the evolution of Mycobacterium tuberculosis

Chang, Xuling, McNeil, Matthew B., Maher, Megan J., Lingford, James P., McCall, Rita M., Cox, Jeffery S., Holt, Kathryn E., Cheung, Chen-Yi, Canalda-Baltrons, Aleix, Rae, Christopher D., Caws, Maxine, Greening, Chris, Cook, Gregory M., Pepper-Tunick, Evan, Thuong, Nguyen Thuy Thuong, Edwards, David, Thai, Phan Vuong Khac, McDevitt, Christopher A., Neville, Stephanie L., Jowsey, William J., Silcocks, Matthew, Hawn, Thomas R., Baliga, Nitin S., Dunstan, Sarah J., Harold, Liam K.

2026

Overview

Phenotypically agnostic screens for positive selection in pathogen populations provide a means of pinpointing genes and regulatory regions involved in adaptation to the local environment or host population. We screened a large ( n  = 2506) collection of Vietnamese Mycobacterium tuberculosis ( Mtb ) isolates, finding targets of selection to be lineage-specific, and encompass diverse functions, including dormancy ( Rv0080 ), zinc homeostasis ( zur ), and virulence (ESX-1 structure). Extending our screen to the wider Mtb complex (MTBC) phylogeny demonstrated Rv0080 to display an extraordinarily dynamic evolutionary history, acquiring premature stop codons or putative functional mutations on branches upstream of 8 of the 10 human-adapted lineages, and undergoing positive selection in the remaining 2. Lineage 1, which is one of two such lineages retaining the ancestral Rv0080 sequence, displays a rate of selection for this gene (dN/dS=9.37) exceeding any other in the Mtb genome, save a transcription factor linked to its expression ( Rv0042c ; dN/dS=11.02). Deletion of Rv0080 ’s M. smegmatis orthologue confers a survival advantage in hypoxic conditions, as does the evolution of nonsense or missense mutations on an ancestral Rv0080 background. We show the dormancy survival regulon experienced recurrent episodes of reductive evolution across the MTBC phylogeny, illuminating a novel mechanism via which it adapted to human populations. Mycobacterium tuberculosis owes its success partly to its ability to enter a ‘dormant’, non-replicative state, reactivating years or even decades after initial infection. In this work, authors find that a key alteration in a gene involved in this dormancy response has evolved, or is evolving, in parallel in human-adapted lineages across the globe.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/23 / 38/91 / 631/181/2474 / 631/181/457 / 631/181/757 / 631/208/325/2482 / 631/250/255/1856 / Antibiotics / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / Codons / Datasets / Dormancy / Drug resistance / Evolution / Evolution, Molecular / Gene Expression Regulation, Bacterial / Genes / Homeostasis / Human populations / Humanities and Social Sciences / Humans / Hypoxia / Missense mutation / multidisciplinary / Mutation / Mycobacterium tuberculosis / Mycobacterium tuberculosis - genetics / Mycobacterium tuberculosis - physiology / Phylogeny / Populations / Positive selection / Ratios / Regulatory sequences / Regulon - genetics / Science / Science (multidisciplinary) / Survival / Tuberculosis / Virulence