UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Coll, F; Phelan, J; Hill-Cawthorne, GA; Nair, MB; Mallard, K; Ali, S; Abdallah, AM; ... Clark, TG; + view all (2018) Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis. Nature Genetics , 50 (2) pp. 307-316. 10.1038/s41588-017-0029-0. Green open access

[thumbnail of Accepted Manuscript]
Preview
Text (Accepted Manuscript)
Coll_Phelan_et_al_NG_2018_manuscript.pdf - Accepted Version

Download (2MB) | Preview
[thumbnail of Supplementary Material]
Preview
Text (Supplementary Material)
Coll_Phelan_et_all_NG_2018_Supplementary_tables.pdf - Accepted Version

Download (187kB) | Preview
[thumbnail of Supplementary Material]
Preview
Text (Supplementary Material)
Coll_Phelan_et_al_NG_2018_Supplementary_figures.pdf - Accepted Version

Download (882kB) | Preview

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.

Type: Article
Title: Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41588-017-0029-0
Publisher version: https://doi.org/10.1038/s41588-017-0029-0
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Genome-wide association studies, Microbial genetics, Tuberculosis
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10100785
Downloads since deposit
93Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item