UShER-TB: scalable, comprehensive, accessible phylogenomic analysis of Mycobacterium tuberculosis

Background. Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, remains a leading cause of global infectious disease deaths. While genomic epidemiology is essential for understanding transmission dynamics and the rise of antibiotic resistance, significant computational limitations currently prevent comprehensive phylogenetic analysis of the vast number of publicly available M. tuberculosis genomes.Methods. We developed UShER-TB, a comprehensive collection of community resources, including a computational analysis pipeline designed for scalable phylogenomic analysis of M. tuberculosis. To demonstrate this system's utility, we processed 129,312 genomes to construct a global phylogeny. We evaluated the system's accuracy in transmission cluster reconstruction, its ability to identify novel genetic lineages and its performance in placing ancient DNA samples within the global tree.Results. The pipeline successfully constructed a global phylogeny capturing genomic diversity from over 129,000 samples. UShER-TB achieved high accuracy in reconstructing transmission clusters, reaching an adjusted Rand index of 0.95 when compared to conventional phylogenomic methods. This tool also facilitated the identification of putative novel lineages and sublineages. Furthermore, the platform enabled the successful phylogenetic placement of ancient samples. The system allows for real-time analysis of new genomes to reveal transmission dynamics and introduction patterns on a global scale.Conclusions. This approach overcomes longstanding computational barriers in genomic surveillance. UShER-TB provides researchers with efficient tools for tuberculosis monitoring, particularly for resource-limited settings where the disease burden is highest.Trial registration. Not applicable.