Pan and Core Genome Analysis of 183 Mycobacterium tuberculosis Strains Revealed a High Inter-Species Diversity among the Human Adapted Strains.

Tuberculosis (TB) is an airborne communicable disease with high morbidity and mortality rates, especially in developing countries. The causal agents of TB belong to the complex Mycobacterium tuberculosis (MTBc), which is composed of different human and animal TB associated species. Some animal associated species have zoonotic potential and add to the burden of TB management. The BCG ("Bacillus Calmette-Guérin") vaccine is widely used for the prevention against TB, but its use is limited in immunocompromised patients and animals due to the adverse effects and disseminated life-threatening complications. In this study, we aimed to carry out a comparative genome analysis between the human adapted species including BCG vaccine strains to identify and pinpoint the conserved genes related to the virulence across all the species, which could add a new value for vaccine development. For this purpose, the sequences of 183 Mycobacterium tuberculosis (MTB) strains were retrieved from the freely available WGS dataset at NCBI. The species included: 168 sensu stricto MTB species with other human MTB complex associated strains: M. tuberculosis var. africanum (3), M. tuberculosis var. bovis (2 draft genomes) and 10 BCG species, which enabled the analysis of core genome which contains the conserved genes and some virulence factor determinants. Further, a phylogenetic tree was constructed including the genomes of human (183); animals MTB adapted strains (6) and the environmental Mycobacterium strain "M. canettii". Our results showed that the core genome consists of 1166 conserved genes among these species, which represents a small portion of the pangenome (7036 genes). The remaining genes in the pangenome (5870) are accessory genes, adding a high inter-species diversity. Further, the core genome includes several virulence-associated genes and this could explain the rare infectiousness potential of some attenuated vaccine strains in some patients. This study reveals that low number of conserved genes in human adapted MTBc species and high inter-species diversity of the pan-genome could be considered for vaccine candidate development.