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
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.
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Submitted on : Wednesday, September 26, 2018 - 4:40:18 PM
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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, Nature Publishing Group, 2018, 50, pp.307 - 316. ⟨10.1038/s41588-017-0029-0⟩. ⟨cea-01882216⟩

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