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 MAK - Makerere University [Kampala, Ouganda]
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 = Université de Lisbonne
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 MAK - Makerere University [Kampala, Ouganda]
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 = Université de Lisbonne
Anirvan Chatterjee
- Fonction : Auteur
Amelia Crampin
- Fonction : Auteur
Keertan Dheda
- Fonction : Auteur
Judith Glynn
- Fonction : Auteur
Dang Minh Ha
- Fonction : Auteur
Rumina Hasan
- Fonction : Auteur
Zahra Hasan
- Fonction : Auteur
Edward Jones-López
- Fonction : Auteur
Anabela Miranda
- Fonction : Auteur
Nora Mocillo
- Fonction : Auteur
Carlos Penha
- Fonction : Auteur
João Perdigão
- Fonction : Auteur
Nashwa Talaat Shesha
- Fonction : Auteur
Frik Sirgel
- Fonction : Auteur
Christophe Sola
- Fonction : Auteur
Erivelton Oliveira Sousa
- Fonction : Auteur
Elizabeth Streicher
- Fonction : Auteur
Paul Van Helden
- Fonction : Auteur
Robert Warren
- Fonction : Auteur
Arnab Pain
- Fonction : Auteur
- PersonId : 777756
- ORCID : 0000-0002-1755-2819
Résumé
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]| Origine | Publication financée par une institution |
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