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

Francesc Coll; Jody Phelan; Grant Hill-Cawthorne; Mridul Nair; Kim Mallard; Shahjahan Ali; Abdallah Abdallah; Saad Alghamdi; Mona Alsomali; Abdallah Ahmed; Stephanie Portelli; Yaa Oppong; Adriana Alves; Theolis Barbosa Bessa; Susana Campino; Maxine Caws; Anirvan Chatterjee; Amelia Crampin; Keertan Dheda; Nicholas Furnham; Judith Glynn; Louis Grandjean; Dang Minh Ha; Rumina Hasan; Zahra Hasan; Martin Hibberd; Moses Joloba; Edward Jones-López; Tomoshige Matsumoto; Anabela Miranda; David Moore; Nora Mocillo; Stefan Panaiotov; Julian Parkhill; Carlos Penha; João Perdigão; Isabel Portugal; Zineb Rchiad; Jaime Robledo; Patricia Sheen; Nashwa Talaat Shesha; Frik Sirgel; Christophe Sola; Erivelton Oliveira Sousa; Elizabeth Streicher; Paul Van Helden; Miguel Viveiros; Robert Warren; Ruth Mcnerney; Arnab Pain; Taane Clark

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

Francesc Coll ¹ Jody Phelan ¹ Grant Hill-Cawthorne ^{2, 3} Mridul Nair ² Kim Mallard ¹ Shahjahan Ali Abdallah Abdallah ² Saad Alghamdi ⁴ Mona Alsomali ² Abdallah Ahmed ⁵ Stephanie Portelli ¹ Yaa Oppong ¹ Adriana Alves ⁵ Theolis Barbosa Bessa Susana Campino ¹ Maxine Caws Anirvan Chatterjee Amelia Crampin Keertan Dheda Nicholas Furnham ¹ Judith Glynn Louis Grandjean ⁶ Dang Minh Ha Rumina Hasan Zahra Hasan Martin Hibberd ^{7, 1} Moses Joloba ⁸ Edward Jones-López Tomoshige Matsumoto ⁹ Anabela Miranda David Moore ¹ Nora Mocillo Stefan Panaiotov ¹⁰ Julian Parkhill ¹¹ Carlos Penha João Perdigão Isabel Portugal ¹² Zineb Rchiad ¹³ Jaime Robledo ¹⁴ Patricia Sheen ¹⁵ Nashwa Talaat Shesha Frik Sirgel Christophe Sola Erivelton Oliveira Sousa Elizabeth Streicher Paul Van Helden Miguel Viveiros ¹⁶ Robert Warren Ruth Mcnerney ¹ Arnab Pain ² Taane Clark ¹

1 Faculty of Infectious and Tropical Diseases

2 KAUST - King Abdullah University of Science and Technology

3 SEIB - Sydney Emerging Infectious Diseases and Biosecurity Institute

4 King Abdullah Univ Sci & Technol, Phys Sci & Engn Div, Thuwal 23955, Makkah, Saudi Arabia

5 Umm Al-Qura University

6 LSHTM - London School of Hygiene and Tropical Medicine

7 GIS - Genome Institute of Singapore

8 Makerere University College of Health Sciences

9 Department of Clinical Research and Development, Osaka Prefectural Hospital Organization

10 National Center of Infectious and Parasitic Diseases

11 The Wellcome Trust Sanger Institute [Cambridge]

12 Faculdade de Farmácia da Universidade de Lisboa

13 KAUST - Division of Physical Sciences and Engineering (KAUST)

14 CIB - Corporacion para Investigaciones Biologicas

15 Universidad Peruana Cayetano Heredia, Lima, Peru

16 ULISBOA - Universidade de Lisboa

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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio]

Complete list of metadatas

https://hal-cea.archives-ouvertes.fr/cea-01882216
Contributor : Bruno Savelli <>
Submitted on : Wednesday, September 26, 2018 - 4:40:18 PM
Last modification on : Tuesday, August 13, 2019 - 12:02:05 PM

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

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

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