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 (2) , Abdallah Abdallah (2) , Saad Alghamdi (4) , Mona Alsomali (2) , Abdallah Ahmed (5) , Stephanie Portelli (1) , Yaa Oppong (1) , Adriana Alves (5) , Theolis Barbosa Bessa (6) , Susana Campino (1) , Maxine Caws (7) , Anirvan Chatterjee , Amelia Crampin , Keertan Dheda , Nicholas Furnham (1) , Judith Glynn , Louis Grandjean (8) , Dang Minh Ha , Rumina Hasan , Zahra Hasan , Martin L Hibberd (9, 1) , Moses Joloba (10) , Edward Jones-López , Tomoshige Matsumoto (11) , Anabela Miranda , David Moore (1) , Nora Mocillo , Stefan Panaiotov (12) , Julian Parkhill (13) , Carlos Penha , João Perdigão , Isabel Portugal (14) , Zineb Rchiad (15) , Jaime Robledo (16) , Patricia Sheen (17) , Nashwa Talaat Shesha , Frik Sirgel , Christophe Sola , Erivelton Oliveira Sousa , Elizabeth Streicher , Paul Van Helden , Miguel Viveiros (18) , 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 [Saudi Arabia]
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 FIOCRUZ - Fundação Oswaldo Cruz / Oswaldo Cruz Foundation
7 LSTM - Liverpool School of Tropical Medicine
8 LSHTM - London School of Hygiene and Tropical Medicine
9 GIS - Genome Institute of Singapore
10 Makerere University College of Health Sciences
11 Department of Clinical Research and Development, Osaka Prefectural Hospital Organization
12 National Center of Infectious and Parasitic Diseases
13 The Wellcome Trust Sanger Institute [Cambridge]
14 Faculdade de Farmácia da Universidade de Lisboa
15 KAUST - Division of Physical Sciences and Engineering (KAUST)
16 CIB - Corporacion para Investigaciones Biologicas
17 UPCH - Universidad Peruana Cayetano Heredia
18 ULISBOA - Universidade de Lisboa = University of Lisbon

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.

Domaines: Sciences du Vivant [q-bio]

Francesc Coll, Jody Phelan, Grant Hill-Cawthorne, Mridul Nair, Kim Mallard, et al.. Genome-wide analysis of multi- and extensively drug-resistant $Mycobacterium\ tuberculosis$. Nature Genetics, 2018, 50, pp.307 - 316. ⟨10.1038/s41588-017-0029-0⟩. ⟨cea-01882216⟩