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    Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis

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    Name:
    Coll_Phelan_et_al_NG_2018_manuscript.pdf
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    Accepted manuscript
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    Type
    Article
    Authors
    Coll, Francesc cc
    Phelan, Jody
    Hill-Cawthorne, Grant A. cc
    Nair, Mridul
    Mallard, Kim
    Ali, Shahjahan
    Abdallah, Abdallah
    Alghamdi, Saad
    Alsomali, Mona cc
    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. cc
    Grandjean, Louis
    Minh Ha, Dang
    Hasan, Rumina
    Hasan, Zahra cc
    Hibberd, Martin L. cc
    Joloba, Moses
    Jones-López, Edward C.
    Matsumoto, Tomoshige
    Miranda, Anabela
    Moore, David J. cc
    Mocillo, Nora
    Panaiotov, Stefan
    Parkhill, Julian cc
    Penha, Carlos
    Perdigão, João cc
    Portugal, Isabel
    Rchiad, ‍Zineb cc
    Robledo, Jaime cc
    Sheen, Patricia
    Shesha, Nashwa Talaat
    Sirgel, Frik A.
    Sola, Christophe
    Oliveira Sousa, Erivelton
    Streicher, Elizabeth M.
    Helden, Paul Van
    Viveiros, Miguel cc
    Warren, Robert M.
    McNerney, Ruth cc
    Pain, Arnab cc
    Clark, Taane G. cc
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience 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/1/1020-01-01
    Date
    2018-01-22
    Online Publication Date
    2018-01-22
    Print Publication Date
    2018-02
    Permanent link to this record
    http://hdl.handle.net/10754/627255
    
    Metadata
    Show full item record
    Abstract
    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 Nature
    Journal
    Nature Genetics
    DOI
    10.1038/s41588-017-0029-0
    PubMed ID
    29358649
    Additional Links
    https://www.nature.com/articles/s41588-017-0029-0
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41588-017-0029-0
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program; Computational Bioscience Research Center (CBRC); Bioscience Core Lab; Computer, Electrical and Mathematical Science and Engineering (CEMSE) Division

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