Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis
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ArticleAuthors
Coll, Francesc
Phelan, Jody
Hill-Cawthorne, Grant A.

Nair, Mridul
Mallard, Kim
Ali, Shahjahan
Abdallah, Abdallah
Alghamdi, Saad
Alsomali, Mona

Ahmed, Abdallah O.
Portelli, Stephanie
Oppong, Yaa
Alves, Adriana
Bessa, Theolis Barbosa
Campino, Susana
Caws, Maxine
Chatterjee, Anirvan
Crampin, Amelia C.
Dheda, Keertan
Furnham, Nicholas
Glynn, Judith R.

Grandjean, Louis
Minh Ha, Dang
Hasan, Rumina
Hasan, Zahra

Hibberd, Martin L.

Joloba, Moses
Jones-López, Edward C.
Matsumoto, Tomoshige
Miranda, Anabela
Moore, David J.

Mocillo, Nora
Panaiotov, Stefan
Parkhill, Julian

Penha, Carlos
Perdigão, João

Portugal, Isabel
Rchiad, Zineb

Robledo, Jaime

Sheen, Patricia
Shesha, Nashwa Talaat
Sirgel, Frik A.
Sola, Christophe
Oliveira Sousa, Erivelton
Streicher, Elizabeth M.
Helden, Paul Van
Viveiros, Miguel

Warren, Robert M.
McNerney, Ruth

Pain, Arnab

Clark, Taane G.

KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Core Lab
Bioscience Program
Computational Bioscience Research Center (CBRC)
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
NGS, qPCR and Single Cell Genomics
Pathogen Genomics Laboratory
KAUST Grant Number
BAS/1/1020-01-01Date
2018-01-22Online Publication Date
2018-01-22Print Publication Date
2018-02Permanent link to this record
http://hdl.handle.net/10754/627255
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Show full item recordAbstract
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.Citation
Coll 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.Sponsors
The 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).Publisher
Springer NatureJournal
Nature GeneticsPubMed ID
29358649Additional Links
https://www.nature.com/articles/s41588-017-0029-0ae974a485f413a2113503eed53cd6c53
10.1038/s41588-017-0029-0
Scopus Count
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