Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis
Hill-Cawthorne, Grant A.
Ahmed, Abdallah O.
Bessa, Theolis Barbosa
Crampin, Amelia C.
Glynn, Judith R.
Minh Ha, Dang
Hibberd, Martin L.
Jones-López, Edward C.
Moore, David J.
Shesha, Nashwa Talaat
Sirgel, Frik A.
Oliveira Sousa, Erivelton
Streicher, Elizabeth M.
Helden, Paul Van
Warren, Robert M.
Clark, Taane G.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Bioscience Core Lab
Pathogen Genomics Laboratory
KAUST Grant NumberBAS/1/1020-01-01
MetadataShow full item record
AbstractTo 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.
CitationColl F, Phelan J, Hill-Cawthorne GA, Nair MB, Mallard K, et al. (2018) Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis. Nature Genetics 50: 307–316. Available: http://dx.doi.org/10.1038/s41588-017-0029-0.
SponsorsThe project was supported by the KAUST faculty baseline research fund (BAS/1/1020-01-01) to A.P. The authors wish to thank members of the KAUST Bioscience Core laboratory who sequenced samples. We thank the Wellcome Trust Sanger Institute core and pathogen sequencing and informatics teams who were involved in the Malawi and Uganda studies. The work was funded in part by the Wellcome Trust (grant numbers WT096249/Z/11/B, WT088559MA, WT081814/Z/06/Z and WT098051) and the Wellcome Trust–Burroughs Wellcome Fund Infectious Diseases Initiative grant (number 063410/ABC/00/Z). F.C. was the recipient of a Bloomsbury College PhD Studentship and was supported by the Wellcome Trust (201344/Z/16/Z); J. Perdigão received a Fundação para a Ciência e a Tecnologia (Portugal) postdoctoral fellowship fund (SFRH/BPD/95406/2013). The Calouste Gulbenkian Foundation, the Institute Gulbenkian in Lisbon and the European Society of Clinical Microbiology and Infectious Diseases supported the research of C.P., J. Perdigão, I.P. and M.V. J. Phelan is funded by a BBSRC PhD studentship. T.G.C. is funded by the Medical Research Council UK (grant numbers MR/K000551/1, MR/M01360X/1, MR/N010469/1 and MC_PC_15103). N.F. is funded by the Medical Research Council UK (grant number MR/K020420/1). T.M. is supported by the Ministry of Health, Labor and Welfare of Japan (H21-Shinkou-Ippan-008 and H24-Shinkou-Ippan-010). We thank N. Mistry (Foundation for Medical Research, Mumbai) for contributing Mtb archived strains and drug sensitivity testing data. We wish to thank G. Moniz at the Laboratorio Central de Saúde Pública for supporting the collection of samples in Brazil and the South African National Health Laboratory Service for their contribution providing access to clinical Mtb isolates. The MRC eMedLab computing resource was used for bioinformatics and statistical analysis. The authors declare no conflicts of interest. The work has been performed as part of the TB Global Drug Resistance Collaboration (see URLs).
- RNA expression analysis of efflux pump genes in clinical isolates of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis in South Korea.
- Authors: Oh TS, Kim YJ, Kang HY, Kim CK, Cho SY, Lee HJ
- Issue date: 2017 Apr
- Increased expression of efflux pump genes in extensively drug-resistant isolates of Mycobacterium tuberculosis.
- Authors: Kanji A, Hasan R, Zhang Y, Shi W, Imtiaz K, Iqbal K, Shafiq S, Hasan Z
- Issue date: 2016 Dec
- Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal.
- Authors: Cohen KA, Abeel T, Manson McGuire A, Desjardins CA, Munsamy V, Shea TP, Walker BJ, Bantubani N, Almeida DV, Alvarado L, Chapman SB, Mvelase NR, Duffy EY, Fitzgerald MG, Govender P, Gujja S, Hamilton S, Howarth C, Larimer JD, Maharaj K, Pearson MD, Priest ME, Zeng Q, Padayatchi N, Grosset J, Young SK, Wortman J, Mlisana KP, O'Donnell MR, Birren BW, Bishai WR, Pym AS, Earl AM
- Issue date: 2015 Sep
- [The rates of resistance to second-line drugs in multidrug resistant Mycobacterium tuberculosis strains].
- Authors: Kayali R, Cöplü N, Ceyhan I, Ocak F, Citil BE, Esen B
- Issue date: 2006 Jan-Apr
- Anti tuberculosis drug resistance in west of iran.
- Authors: Mohajeri P, Norozi B, Atashi S, Farahani A
- Issue date: 2014 Jul