The article presents the complete genome sequence of *Mycobacterium bovis* AF2122:97, a strain isolated from a diseased cow in Great Britain. The genome sequence is 4,345,492 bp long and is >99.95% identical to that of *Mycobacterium tuberculosis*. However, deletion of genetic information has led to a reduced genome size. Comparative analysis with *M. tuberculosis* and *Mycobacterium leprae* reveals common gene losses, suggesting the removal of functional redundancy. The cell wall components and secreted proteins show the greatest variation, indicating their potential role in host-bacillus interactions or immune evasion. No genes are unique to *M. bovis*, suggesting that differential gene expression may be key to the host tropisms of human and bovine bacilli. The genome sequence provides insights into the evolution, host preference, and pathobiology of *M. bovis*. The study also highlights the importance of regulatory genes and carbohydrate metabolism in the in vivo growth of *M. bovis*. The genome downsizing in *M. bovis* parallels that of *M. leprae*, with many deleted or pseudogenized genes involved in transport, cell surface structures, fatty acid metabolism, cofactor biosynthesis, detoxification, and intermediary metabolism. The findings support a new scenario for the evolution of the *M. tuberculosis* complex, placing *M. tuberculosis* closer to the common progenitor than *M. bovis*. The genome sequence will significantly impact our understanding of tuberculosis and contribute to the development of vaccines and diagnostics.The article presents the complete genome sequence of *Mycobacterium bovis* AF2122:97, a strain isolated from a diseased cow in Great Britain. The genome sequence is 4,345,492 bp long and is >99.95% identical to that of *Mycobacterium tuberculosis*. However, deletion of genetic information has led to a reduced genome size. Comparative analysis with *M. tuberculosis* and *Mycobacterium leprae* reveals common gene losses, suggesting the removal of functional redundancy. The cell wall components and secreted proteins show the greatest variation, indicating their potential role in host-bacillus interactions or immune evasion. No genes are unique to *M. bovis*, suggesting that differential gene expression may be key to the host tropisms of human and bovine bacilli. The genome sequence provides insights into the evolution, host preference, and pathobiology of *M. bovis*. The study also highlights the importance of regulatory genes and carbohydrate metabolism in the in vivo growth of *M. bovis*. The genome downsizing in *M. bovis* parallels that of *M. leprae*, with many deleted or pseudogenized genes involved in transport, cell surface structures, fatty acid metabolism, cofactor biosynthesis, detoxification, and intermediary metabolism. The findings support a new scenario for the evolution of the *M. tuberculosis* complex, placing *M. tuberculosis* closer to the common progenitor than *M. bovis*. The genome sequence will significantly impact our understanding of tuberculosis and contribute to the development of vaccines and diagnostics.