Decoding the similarities and differences among mycobacterial species

Abstract

Mycobacteriaceae comprises pathogenic species such as Mycobacterium tuberculosis, M. leprae and M. abscessus, as well as non-pathogenic species, for example, M. smegmatis and M. thermoresistibile. Genome comparison and annotation studies provide insights into genome evolutionary relatedness, identify unique and pathogenicity-related genes in each species, and explore new targets that could be used for developing new diagnostics and therapeutics. Here, we present a comparative analysis of ten-mycobacterial genomes with the objective of identifying similarities and differences between pathogenic and non-pathogenic species. We identified 1080 core orthologous clusters that were enriched in proteins involved in amino acid and purine/pyrimidine biosynthetic pathways, DNA-related processes (replication, transcription, recombination and repair), RNA-methylation and modification, and cell-wall polysaccharide biosynthetic pathways. For their pathogenicity and survival in the host cell, pathogenic species have gained specific sets of genes involved in repair and protection of their genomic DNA. M. leprae is of special interest owing to its smallest genome (1600 genes and ~1300 psuedogenes), yet poor genome annotation. More than 75% of the pseudogenes were found to have a functional ortholog in the other mycobacterial genomes and belong to protein families such as transferases, oxidoreductases and hydrolases.

Spontaneous mutations conferring antibiotic resistance to antitubercular drugs at a range of concentrations in Mycobacterium smegmatis

“…Third, Msm features 90% genetic similarity with Mtb (Altaf, Miller, Bellows, & O'Toole, 2010;Hetherington, Watson, & Patrick, 1995;McGuire et al, 2012). A comparison of orthologs in nonpathogenic species of mycobacteria such as Msm versus pathogenic Mtb found at least a 70% similarity, thus justifying its use as a surrogate model for its pathogenic cousin Mtb (Malhotra, Vedithi, & Blundell, 2017). In this work, Msm mutants were isolated at a variety of concentrations, some of these have not been previously evaluated, and mutation rates were determined using the Po method (Rosche & Foster, 2000), and the estimates were then compared with the LC (Lea & Coulson, 1949) and ML methods (Sarkar et al, 1992) available on the FALCOR (Hall et al, 2009), and the three methods have not been previously tested simultaneously.…”

Structural Implications of Mutations Conferring Rifampin Resistance in Mycobacterium leprae

“…leprae ), which shares extensive similarity with Mycobacterium tuberculosis ( M . tuberculosis ) in proteomic and genomic composition 1 . The prevalence rate of the disease has gradually declined from 21.1 cases per 10,000 people in 1983 to 0.2 cases per 10,000 people in 2015, and this was achieved with the use of the World Health Organization (WHO) regimen of Multidrug Therapy (MDT) 2 .…”

The Many Lives of Nontuberculous Mycobacteria

“…High gene turnover rates have been observed in the evolutionary timeline of NTM (39), and the number of 1:1 orthologs between sequenced NTM genomes appears to be very low (38). Even though NTM species may share a similar number of genes, the presence of species-specific genes appears to be very high and diverse (40). The role of horizontal gene transfer in mycobacteria is debated, with some studies reporting a very low impact on mycobacterial evolution, evidenced by the low number of transposable elements present in mycobacterial genomes (38).…”

“…Importantly, mycobacterial genome comparisons have led to a novel model regarding the evolutionary divergence of NTM and obligate pathogenic mycobacteria: due to the relatively small genome sizes of the obligate pathogens M. leprae and M. tuberculosis, the evolution of human pathogenicity corresponded to a large loss of ancestral genes with a gain of several new genes more adapted to an obligate intracellular lifestyle (40,42). M. leprae and M. tuberculosis are remarkably distinct from one another in terms of evolution: whereas M. leprae evolved ϳ14 million years ago (43), the evolution of human-adapted M. tuberculosis was more recent, ϳ10 thousand to 70 thousand years ago (44), and it was possibly dispersed to New World populations via migratory seals and sea lions (45).…”

“…Based on their biologies, M. leprae and M. tuberculosis would therefore have less need for gene regulation and adaptive responses to the environment than NTM that are found in the environment. In addition to having smaller genome sizes, pathogenic mycobacteria also have genes enriched in DNA repair and recombination mechanisms, while opportunistic pathogens have an enrichment in membrane transport genes which aid in nutrient uptake and drug efflux (40). The genes responsible for energy metabolism appear to be more NTM species specific, owing to the fact that each NTM species must adapt to its own soil or aquatic environment (40).…”