Dormancy regulon reduction was pivotal to the evolution of Mycobacterium tuberculosis
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.
Authors
- Nitin S. Baliga (ORCID: https://orcid.org/0000-0001-9157-5974)
- Phan Vuong Khac Thai
- Rita M. McCall (ORCID: https://orcid.org/0000-0001-5076-2909)
- Megan J. Maher (ORCID: https://orcid.org/0000-0003-0848-9640)
- Liam K. Harold (ORCID: https://orcid.org/0000-0002-7570-7348)
- Chen‐Yi Cheung (ORCID: https://orcid.org/0000-0002-5850-0919)
- Nguyễn Thụy Thương Thương (ORCID: https://orcid.org/0000-0001-8733-692X)
- Matthew Silcocks (ORCID: https://orcid.org/0000-0002-1527-5168)
- Evan Pepper-Tunick (ORCID: https://orcid.org/0000-0002-3841-9099)
- Stephanie L. Neville (ORCID: https://orcid.org/0000-0002-7298-9335)
- Sarah J. Dunstan (ORCID: https://orcid.org/0000-0001-7873-933X)
- Maxine Caws (ORCID: https://orcid.org/0000-0002-9109-350X)
- Chris Greening (ORCID: https://orcid.org/0000-0001-7616-0594)
- Christopher A. McDevitt (ORCID: https://orcid.org/0000-0003-1596-4841)
- Aleix Canalda-Baltrons (ORCID: https://orcid.org/0000-0001-8366-7377)
- David Edwards (ORCID: https://orcid.org/0000-0003-2964-8620)
- Thomas R. Hawn (ORCID: https://orcid.org/0000-0003-2368-3185)
- Kathryn E. Holt (ORCID: https://orcid.org/0000-0003-3949-2471)
- Xuling Chang (ORCID: https://orcid.org/0000-0001-7471-4768)
- James P. Lingford (ORCID: https://orcid.org/0000-0003-1980-3949)
- Matthew B. McNeil (ORCID: https://orcid.org/0000-0001-7747-7745)
- Christopher D. Rae
- William J. Jowsey
- Gregory M. Cook
Institutions
- Biotechnology Institute (US)
- Queensland University of Technology (AU)
- The University of Melbourne (AU)
- National University of Singapore (SG)
- Liverpool School of Tropical Medicine (GB)
- University of Washington (US)
- Australian Regenerative Medicine Institute (AU)
- Institute for Systems Biology (US)
- University of Oxford (GB)
- London School of Hygiene & Tropical Medicine (GB)
- Peter Doherty Institute (AU)
- Oxford University Clinical Research Unit (VN)
- National University Health System (SG)
- Viet Duc Hospital (VN)
- Hospital for Tropical Diseases (VN)
- Monash University (AU)
- University of Otago (NZ)
- University of California, Berkeley (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-13
- DOI
- https://doi.org/10.1038/s41467-026-71566-x
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council