Genome graphs reveal the importance of structural variation in Mycobacterium tuberculosis evolution and drug resistance

Aleix Canalda-Baltrons, Matthew Silcocks, Michael B. Hall, Derrick Theys, Xuling Chang 常戌灵, Linda T. Viberg, Norelle L. Sherry, Lachlan Coin and Sarah J. Dunstan ()
Additional contact information
Aleix Canalda-Baltrons: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Department of Infectious Diseases
Matthew Silcocks: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Department of Infectious Diseases
Michael B. Hall: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology
Derrick Theys: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Department of Infectious Diseases
Xuling Chang 常戌灵: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Department of Infectious Diseases
Linda T. Viberg: Melbourne Health at the Peter Doherty Institute for Infection and Immunity, Victorian Infectious Diseases Reference Laboratory
Norelle L. Sherry: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Microbiological Diagnostic Unit Public Health Laboratory (MDU PHL)
Lachlan Coin: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology
Sarah J. Dunstan: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Department of Infectious Diseases

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Structural variants (SVs) are increasingly recognized as key drivers of bacterial evolution, yet their role has not been explored thoroughly. This is due to limitations in traditional short-read sequencing and linear reference-based analyses, which can miss complex structural changes. Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), remains a major global health concern. In this study, we harness long-read sequencing technologies and genome graph tools to construct a Mtb pangenome reference graph (PRG) from 859 high-quality, diverse, long-read assemblies. To enable accurate genotyping of SVs leveraging the PRG, we developed miniwalk, a tool that outperforms a traditional linear genome-based approach in precision for SV detection. We characterize patterns of structural variation genome-wide, revealing a virulence-associated ESX-5 deletion to be recurrent across the phylogeny, and fixed in a sub-lineage of L4. Systematic screens for additional genes that are recurrently affected by SVs implicated those related to metal homeostasis, including a copper exporter fixed in the widely distributed L1.2.1 sub-lineage. Lastly, we genotyped 41,134 isolates and found SVs putatively associated with resistance to various first and second-line drugs. These findings underscore the broader role of SVs in shaping Mtb diversity, highlighting their importance in both understanding evolution and designing strategies to combat drug-resistant TB.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65779-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65779-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65779-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().