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 L 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 UPCH - Universidad Peruana Cayetano Heredia
16 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.

Domains: Life Sciences [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⟩