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Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis
- Source :
- Nature Genetics, Nature Genetics, Nature Publishing Group, 2018, 50, pp.307-316. ⟨10.1038/s41588-017-0029-0⟩, Nature Genetics, 2018, 50, pp.307-316. ⟨10.1038/s41588-017-0029-0⟩
- Publication Year :
- 2018
- Publisher :
- Springer Nature, 2018.
-
Abstract
- International audience; To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 $Mycobacterium\ tuberculosis$ clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps ($drrA$ and $Rv2688c$) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.
- Subjects :
- DNA, Bacterial
0301 basic medicine
Candidate gene
Capreomycin
Extensively Drug-Resistant Tuberculosis
[SDV]Life Sciences [q-bio]
030106 microbiology
Antitubercular Agents
qw_125
Genome-wide association study
Microbial Sensitivity Tests
Drug resistance
medicine.disease_cause
Genome-wide association studies
Mycobacterium tuberculosis
03 medical and health sciences
Drug Resistance, Multiple, Bacterial
Tuberculosis, Multidrug-Resistant
Genetics
medicine
Humans
Tuberculosis
Phylogeny
Mutation
Geography
biology
Cycloserine
Genetic Variation
Sequence Analysis, DNA
biology.organism_classification
3. Good health
wf_360
Ethionamide
wf_200
Microbial genetics
Genome, Bacterial
Genome-Wide Association Study
medicine.drug
purl.org/pe-repo/ocde/ford#1.06.07 [https]
Subjects
Details
- Language :
- English
- ISSN :
- 10614036 and 15461718
- Database :
- OpenAIRE
- Journal :
- Nature Genetics, Nature Genetics, Nature Publishing Group, 2018, 50, pp.307-316. ⟨10.1038/s41588-017-0029-0⟩, Nature Genetics, 2018, 50, pp.307-316. ⟨10.1038/s41588-017-0029-0⟩
- Accession number :
- edsair.doi.dedup.....e582d147859ba8945b0591d02d3acf60