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Identification of gene fusion events in Mycobacterium tuberculosis that encode chimeric proteins.

ABSTRACT: Mycobacterium tuberculosis is a facultative intracellular pathogen responsible for causing tuberculosis. The harsh environment in which M. tuberculosis survives requires this pathogen to continuously adapt in order to maintain an evolutionary advantage. However, the apparent absence of horizontal gene transfer in M. tuberculosis imposes restrictions in the ways by which evolution can occur. Large-scale changes in the genome can be introduced through genome reduction, recombination events and structural variation. Here, we identify a functional chimeric protein in the ppe38-71 locus, the absence of which is known to have an impact on protein secretion and virulence. To examine whether this approach was used more often by this pathogen, we further develop software that detects potential gene fusion events from multigene deletions using whole genome sequencing data. With this software we could identify a number of other putative gene fusion events within the genomes of M. tuberculosis isolates. We were able to demonstrate the expression of one of these gene fusions at the protein level using mass spectrometry. Therefore, gene fusions may provide an additional means of evolution for M. tuberculosis in its natural environment whereby novel chimeric proteins and functions can arise.

SUBMITTER: Gallant J

PROVIDER: S-EPMC7671302 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Identification of gene fusion events in Mycobacterium tuberculosis that encode chimeric proteins.

Gallant James J Mouton Jomien J Ummels Roy R Ten Hagen-Jongman Corinne C Kriel Nastassja N Pain Arnab A Warren Robin M RM Bitter Wilbert W Heunis Tiaan T Sampson Samantha L SL

NAR genomics and bioinformatics 20200518 2

Mycobacterium tuberculosis is a facultative intracellular pathogen responsible for causing tuberculosis. The harsh environment in which M. tuberculosis survives requires this pathogen to continuously adapt in order to maintain an evolutionary advantage. However, the apparent absence of horizontal gene transfer in M. tuberculosis imposes restrictions in the ways by which evolution can occur. Large-scale changes in the genome can be introduced through genome reduction, recombi ...[more]

PMID: 33575588

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Project description:BackgroundMycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects approximately 2 billion people worldwide and is the leading cause of mortality due to infectious disease. Current TB therapy involves a regimen of four antibiotics taken over a six month period. Patient compliance, cost of drugs and increasing incidence of drug resistant M. tuberculosis strains have added urgency to the development of novel TB therapies. Eradication of TB is affected by the ability of the bacterium to survive up to decades in a dormant state primarily in hypoxic granulomas in the lung and to cause recurrent infections.MethodsThe availability of M. tuberculosis genome-wide DNA microarrays has lead to the publication of several gene expression studies under simulated dormancy conditions. However, no single model best replicates the conditions of human pathogenicity. In order to identify novel TB drug targets, we performed a meta-analysis of multiple published datasets from gene expression DNA microarray experiments that modeled infection leading to and including the dormant state, along with data from genome-wide insertional mutagenesis that examined gene essentiality.ResultsBased on the analysis of these data sets following normalization, several genome wide trends were identified and used to guide the selection of targets for therapeutic development. The trends included the significant up-regulation of genes controlled by devR, down-regulation of protein and ATP synthesis, and the adaptation of two-carbon metabolism to the hypoxic and nutrient limited environment of the granuloma. Promising targets for drug discovery were several regulatory elements (devR/devS, relA, mprAB), enzymes involved in redox balance and respiration, sulfur transport and fixation, pantothenate, isoprene, and NAD biosynthesis. The advantages and liabilities of each target are discussed in the context of enzymology, bacterial pathways, target tractability, and drug development.ConclusionBased on our bioinformatics analysis and additional discussion of in-depth biological rationale, several novel anti-TB targets have been proposed as potential opportunities to improve present therapeutic treatments for this disease.

Dataset Information

Identification of gene fusion events in Mycobacterium tuberculosis that encode chimeric proteins.

Publications

Identification of gene fusion events in <i>Mycobacterium tuberculosis</i> that encode chimeric proteins.

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