Abstract
BackgroundThe sequence of the pathogen Mycobacterium tuberculosis (Mtb) strain H37Rv has been available for over a decade, but the biology of the pathogen remains poorly understood. Genome sequences from other Mtb strains and closely related bacteria present an opportunity to apply the power of comparative genomics to understand the evolution of Mtb pathogenesis. We conducted a comparative analysis using 31 genomes from the Tuberculosis Database (TBDB.org), including 8 strains of Mtb and M. bovis, 11 additional Mycobacteria, 4 Corynebacteria, 2 Streptomyces, Rhodococcus jostii RHA1, Nocardia farcinia, Acidothermus cellulolyticus, Rhodobacter sphaeroides, Propionibacterium acnes, and Bifidobacterium longum.ResultsOur results highlight the functional importance of lipid metabolism and its regulation, and reveal variation between the evolutionary profiles of genes implicated in saturated and unsaturated fatty acid metabolism. It also suggests that DNA repair and molybdopterin cofactors are important in pathogenic Mycobacteria. By analyzing sequence conservation and gene expression data, we identify nearly 400 conserved noncoding regions. These include 37 predicted promoter regulatory motifs, of which 14 correspond to previously validated motifs, as well as 50 potential noncoding RNAs, of which we experimentally confirm the expression of four.ConclusionsOur analysis of protein evolution highlights gene families that are associated with the adaptation of environmental Mycobacteria to obligate pathogenesis. These families include fatty acid metabolism, DNA repair, and molybdopterin biosynthesis. Our analysis reinforces recent findings suggesting that small noncoding RNAs are more common in Mycobacteria than previously expected. Our data provide a foundation for understanding the genome and biology of Mtb in a comparative context, and are available online and through TBDB.org.
Highlights
The sequence of the pathogen Mycobacterium tuberculosis (Mtb) strain H37Rv has been available for over a decade, but the biology of the pathogen remains poorly understood
Our analysis suggests that DNA repair and molybdopterin cofactors are expanded in pathogenic Mycobacteria and Mtb
The single most significant trend in our analysis of protein family evolution is that genes related to lipid metabolism are greatly expanded across all Mycobacteria and related organisms, consistent with previous observations [2,31] (Table 5). Our analysis extends these previous observations by identifying the emergence of this expansion in lipid metabolism genes as occurring at the root node of the Mycobacteria and Rhodococcus (Figure 3)
Summary
The sequence of the pathogen Mycobacterium tuberculosis (Mtb) strain H37Rv has been available for over a decade, but the biology of the pathogen remains poorly understood. We conducted a comparative analysis using 31 genomes from the Tuberculosis Database (TBDB.org), including 8 strains of Mtb and M. bovis, 11 additional Mycobacteria, 4 Corynebacteria, 2 Streptomyces, Rhodococcus jostii RHA1, Nocardia farcinia, Acidothermus cellulolyticus, Rhodobacter sphaeroides, Propionibacterium acnes, and Bifidobacterium longum. We report here the results of a comparative analysis of 31 publicly available genomes (http://www.tbdb.org, Figure 1, Table 1). These include eight closely related members of the Mtb complex that can cause tuberculosis disease, (two M. bovis strains and six Mtb strains). Another 11 additional Mycobacteria range from obligate parasites to free-living soil bacteria: M. leprae and M. avium subsp. The Mycobacteria included in our dataset span an ecological range from host-dependent pathogens to soil bacteria, allowing us to study multiple evolutionary transitions
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