The Mycobacterium tuberculosis complex pangenome is small and driven by sub-lineage-specific regions of difference

The Mycobacterium tuberculosis complex (MTBC) is a group of bacteria causing tuberculosis (TB) in humans and animals. Understanding MTBC genetic diversity is crucial for insights into its adaptation and traits related to survival, virulence, and antibiotic resistance. While it is known that within MTBC diversity is characterised by large lineage-specific deletions (regions of difference [RD]), a comprehensive pangenomic analysis incorporating both coding and non-coding regions remains unexplored. We utilised a curated dataset representing various MTBC genomes, including under-represented lineages to quantify the true diversity of the MTBC pangenome. The MTBC was found to have a small, closed pangenome with distinct genomic features and RDs both between lineages (as previously known) and between sub-lineages. The accessory genome was identified to be a product of genome reduction, showing both lineage-specific and independent deletions. This variation has implications for traits like virulence, drug resistance, and metabolism. The study provides a comprehensive understanding of the MTBC pangenome, highlighting the importance of genome reduction in its evolution and showing that within-lineage genome content diversity is present. The findings underline the significance of genomic variations in determining the pathogenic traits of different MTBC lineages.