Horizontal Gene Transfer and Drug Resistance Involving Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) acquires drug resistance at a rate comparable to that of bacterial pathogens that replicate much faster and have a higher mutation rate. One explanation for this rapid acquisition of drug resistance in Mtb is that drug resistance may evolve in other fast-replicating mycobacteria and then be transferred to Mtb through horizontal gene transfer (HGT). This paper aims to address three questions. First, does HGT occur between Mtb and other mycobacterial species? Second, what genes after HGT tend to survive in the recipient genome? Third, does HGT contribute to antibiotic resistance in Mtb? I present a conceptual framework for detecting HGT and analyze 39 ribosomal protein genes, 23S and 16S ribosomal RNA genes, as well as several genes targeted by antibiotics against Mtb, from 43 genomes representing all major groups within Mycobacterium. I also included mgtC and the insertion sequence IS6110 that were previously reported to be involved in HGT. The insertion sequence IS6110 shows clearly that the Mtb complex participates in HGT. However, the horizontal transferability of genes depends on gene function, as was previously hypothesized. HGT is not observed in functionally important genes such as ribosomal protein genes, rRNA genes, and other genes chosen as drug targets. This pattern can be explained by differential selection against functionally important and unimportant genes after HGT. Functionally unimportant genes such as IS6110 are not strongly selected against, so HGT events involving such genes are visible. For functionally important genes, a horizontally transferred diverged homologue from a different species may not work as well as the native counterpart, so the HGT event involving such genes is strongly selected against and eliminated, rendering them invisible to us. In short, while HGT involving the Mtb complex occurs, antibiotic resistance in the Mtb complex arose from mutations in those drug-targeted genes within the Mtb complex and was not gained through HGT.

Differential Selection for Translation Efficiency Shapes Translation Machineries in Bacterial Species

“…Second, the bacterial species we use are highly divergent. Even the two most closely related species, M. tuberculosis and M. leprae, have an evolutionary distance of more than 0.3 even for conserved ribosomal protein genes [160], so phylogenetic inertia might not affect the quantified relationships, i.e., the data points might be considered to be roughly independent.…”

Pangenome-wide association study reveals selective absence of CRISPR genes (Rv2816c-19c) in drug-resistantMycobacterium tuberculosis

“…Unlike in other bacteria, Horizontal Gene Transfer (HGT) of the drug resistance-conferring plasmids do not contribute to the development of drug resistance in Mtb (6)(7)(8). However, Mtb is susceptible to infection by Mycobacteriophages and can also undergo natural intra-genome recombination events (9,10).…”

“…Drug resistance in Mtb is primarily associated with the acquisition of Single Nucleotide Polymorphisms (SNPs) in the drug target genes, prodrug-activating genes, their promoter regions, and other genes that are involved in the mechanism of action of respective drugs. Unlike in other bacteria, Horizontal Gene Transfer (HGT) of the drug resistance-conferring plasmids do not contribute to the development of drug resistance in Mtb (6–8). However, Mtb is susceptible to infection by Mycobacteriophages and can also undergo natural intra-genome recombination events (9,10).…”