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Complete genomes reveal the full extent of Mycobacterium tuberculosis complex diversity across evolutionary scales

Garcia-Marin, A. M.; Torres-Puente, M.; Martinez-Priego, L.; De Marco, G.; Moreno-Molina, M.; Hunt, M.; Iqbal, Z.; Gil-Brusola, A.; Valencia Region TB Working Group, ; Lopez, M. G.; Gonzalez-Candelas, F.; Alonso-del-Real, J.; Comas, I.

2025-08-05 genomics
10.1101/2025.08.05.667821 bioRxiv
Show abstract

Advances in short-read sequencing have enhanced our understanding of Mycobacterium tuberculosis complex (MTBC), but fail to capture its complete genomic diversity. We applied long-read sequencing to 216 isolates from the Valencia Region (Spain) and generated high-quality, complete genomes, revealing detailed insights into MTBC evolution across timescales. Complete genome comparisons increased the estimated evolutionary rate by 1.5-fold, resulting in a median of 312 (-1 to 792) additional SNPs per pairwise comparison. Multiple diversity hotspots were identified, mostly in the pe/ppe genes and driven by gene conversion. However, most PE/PPE epitopes were hyperconserved, with notable exceptions involving vaccine candidates. Incorporating previously undetected SNPs and indels improved resolution in transmission analyses. Furthermore, patient-specific reference mapping validates only 5-10% of within-host diversity detected by standard pipelines, indicating substantial overestimation in previous studies. These findings expand our view of MTBC diversity and have important implications for understanding host-pathogen interactions, epidemiology, and transmission dynamics.

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