Is Mycobacterium tuberculosis a closer relative to Gram-positive or Gram-negative bacterial pathogens?

The phylogenetic position of Mycobacterium tuberculosis relative to other bacteria is controversial. Its cell wall has characteristics of both Gram-positive and Gram-negative bacteria. In the standard reference of bacterial phylogeny based on 16S ribosomal RNA sequence comparison, M. tuberculosis belongs to the high G+C Gram-positive bacteria that form a monophyletic group with the low G+C Gram-positive bacteria such as Bacillus subtilis. Some analyses indicate no particular relationship between these two groups. The availability of the complete genome sequence of M. tuberculosis allows us to reexamine this issue from genomic perspectives, as genome-based phylogenies may be more representative of the evolutionary history of whole organisms than molecular trees. In the genome tree constructed based on conserved gene content, M. tuberculosis is more related to Gram-negative than to Gram-positive bacteria as reflected by the evolutionary distance between nearest ancestral units. This conclusion may be supported by another analysis showing that M. tuberculosis shares relatively more orthologous genes for energy production and conversion with Gram-negative bacteria, in particular, Escherichia coli and Pseudomonas aeruginosa, than with Gram-positive bacteria.