Authors
Chitale, P., Ocke, E., Odom, A. R., Fan, H., Henoch, A., Vasco, K., Fogarty, E. C., Grady, C., Lemenze, A. D., Kumar, P., Manning, S., Eren, A. M., Johnson, W. E., Alland, D.
Abstract
Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB), a global disease with diverse clinical and microbiological manifestations. Studies into the biological causes of this phenotypic diversity have been largely limited to a few reference strains. A pangenome approach is likely to provide new insights. Pangenomic tuberculosis studies have been limited the availability of only fragmented genome sequences and error-prone reference genomes. We used a de novo assembly pipeline that generates extremely complete and accurate whole genome sequences to generate 50 closed Mtb genomes across all seven major lineages. We identified 3,377 core gene clusters and 379 accessory clusters. Analysis showed multi-copy core clusters were largely due to gene fragmentation (76%), paralogs (12%), nearly identical gene duplications (4%), or combinations (8%). Sixteen hypervariable regions (HVRs) were identified, including novel paralogs and variable PE/PPE genes. We consolidated these findings into a Pangenome Gene Reference Resource (PGRR) for precision alignment. Our study demonstrates the closed nature of the Mtb pangenome, with most variation in accessory genes and HVRs. The PGRR provides a foundation for improved drug/vaccine target discovery and highlights the need to move beyond the commonly used H37Rv strain to study Mtb genetic and phenotypic diversity.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 04 Nov 2025.
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