Gene conversion is a key driver of diversity hotspots in Mycobacterium tuberculosis antigens and virulence-associated loci
5 affiliations
- 1Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115
- 2Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215
- 3Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
- 4Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA 01655
- 5Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114
Abstract
Despite the long-held view of Mycobacterium tuberculosis (Mtb) as a genetically conserved pathogen, many genomic regions remain poorly resolved due to high sequence homology and repetitive content. Using complete genome assemblies generated from long-read sequencing of 151 globally representative clinical isolates, we comprehensively analyzed genome-wide patterns of genetic diversity and evolution across the Mtb genome. Our analysis uncovers pronounced diversity hotspots within paralogous regions (PRs) generated by recurrent gene conversion between homologous genes. In many cases, these hotspots exhibit more than an order of magnitude greater genetic diversity than the rest of the Mtb genome, which is otherwise characterized by remarkably low variation. Mutations within these regions display clustered substitution patterns, excess paralog-matching variants, and distinct mutational spectra consistent with ongoing gene conversion. Our analysis identifies over 300 individual gene conversion events (GCEs) distributed throughout the Mtb phylogeny. These GCEs occur predominantly within gene families associated with virulence and host–pathogen interactions, including the PE, PPE, and ESX families. Several of the most pronounced diversity hotspots occur in antigens encoded within PRs. Among these, the vaccine candidate PPE18 harbors mutations in validated epitope sequences and predicted alterations in HLA-II binding. Together, these findings demonstrate that gene conversion actively shapes antigenic and virulence-associated diversity in Mtb.
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BibTeX
@article{marin2026gene,
title = {{Gene conversion is a key driver of diversity hotspots in Mycobacterium tuberculosis antigens and virulence-associated loci}},
author = {Maximillian G. Marin and Natalia Quinones-Olvera and Hu Jin and Michael A. Harris and Brendan M. Jeffrey and Alex Rosenthal and Kenan C. Murphy and Christopher M. Sassetti and Heng Li and Maha R. Farhat},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2607261123},
url = {https://doi.org/10.1073/pnas.2607261123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Gene conversion is a key driver of diversity hotspots in Mycobacterium tuberculosis antigens and virulence-associated loci
AU - Maximillian G. Marin
AU - Natalia Quinones-Olvera
AU - Hu Jin
AU - Michael A. Harris
AU - Brendan M. Jeffrey
AU - Alex Rosenthal
AU - Kenan C. Murphy
AU - Christopher M. Sassetti
AU - Heng Li
AU - Maha R. Farhat
PY - 2026
DA - 2026/10/21
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2607261123
UR - https://doi.org/10.1073/pnas.2607261123
AB - Despite the long-held view of Mycobacterium tuberculosis (Mtb) as a genetically conserved pathogen, many genomic regions remain poorly resolved due to high sequence homology and repetitive content. Using complete genome assemblies generated from long-read sequencing of 151 globally representative clinical isolates, we comprehensively analyzed genome-wide patterns of genetic diversity and evolution across the Mtb genome. Our analysis uncovers pronounced diversity hotspots within paralogous regions (PRs) generated by recurrent gene conversion between homologous genes. In many cases, these hotspots exhibit more than an order of magnitude greater genetic diversity than the rest of the Mtb genome, which is otherwise characterized by remarkably low variation. Mutations within these regions display clustered substitution patterns, excess paralog-matching variants, and distinct mutational spectra consistent with ongoing gene conversion. Our analysis identifies over 300 individual gene conversion events (GCEs) distributed throughout the Mtb phylogeny. These GCEs occur predominantly within gene families associated with virulence and host–pathogen interactions, including the PE, PPE, and ESX families. Several of the most pronounced diversity hotspots occur in antigens encoded within PRs. Among these, the vaccine candidate PPE18 harbors mutations in validated epitope sequences and predicted alterations in HLA-II binding. Together, these findings demonstrate that gene conversion actively shapes antigenic and virulence-associated diversity in Mtb.
SN - 0027-8424
SN - 1091-6490
ER -