@article{ae38bc3ad71e4121ae13ab6e50e685b0,
title = "Genomic landscape of drug response reveals novel mediators of anthelmintic resistance",
abstract = "Like other pathogens, parasitic helminths can rapidly evolve resistance to drug treatment. Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to tracking its spread and improving the efficacy and sustainability of parasite control. Here, we use an in vivo genetic cross between drug-susceptible and multi-drug-resistant strains of Haemonchus contortus in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies new alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor cky-1 in ivermectin resistance. This gene is within a locus under selection in ivermectin-resistant populations worldwide; expression analyses and functional validation using knockdown experiments support that cky-1 is associated with ivermectin survival. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode and identifies variants for the development of molecular diagnostics to combat drug resistance in the field.",
keywords = "Anthelmintics/pharmacology, Benzimidazoles, Drug Resistance/genetics, Genomics, Ivermectin/pharmacology, Levamisole, Transcription Factors",
author = "S.R. Doyle and R Laing and David Bartley and A. Morrison and N. Holroyd and K. Maitland and A. Antonopoulos and C. Britton and Umer Chaudhry and I. Flis and S. Howell and J. McIntyre and J.S. Gilleard and A. Tait and B. Mable and R. Kaplan and Neil Sargison and C. Britton and M. Berriman and E Devaney and J. Cotton",
note = "Funding Information: This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) [BB/M003949], the Scottish Government's Rural and Environment Science and Analytical Services (RESAS) division, a University of Glasgow James Herriot Scholarship, the Wellcome Trust (208390/Z/17/Z, 206194, and 216614/Z/19/Z), and UKRI (MR/T020733/1). We would like to acknowledge members of the BUG Consortium and Parasite Genomics group at the Wellcome Sanger Institute for insightful discussions throughout this project. We also thank Pathogen Informatics and DNA Pipelines (WSI) for their support and expertise and the Biosciences Division at the Moredun Research Institute for expert care and animal assistance. For the purpose of Open Access, the authors have applied a CC BY public copyright License to any Author Accepted Manuscript version arising from this submission. Conceptualization: R.L. A.T. E.D. and J.A.C. Investigation: S.R.D. R.L. D.B. A.M. K.M. A.A. C.B. U.C. I.F. and J.M. Formal analysis: S.R.D. and R.L. Software: S.R.D. Resources: D.B. A.M. R.K. and N.S. Supervision: C.B. J.S.G. N.S. M.B. E.D. and J.A.C. Project administration: N.H. and E.D. Writing - Original Draft: S.R.D. J.A.C. R.L. and E.D. Writing - Review & Editing: All authors. Funding acquisition: R.L. A.T. M.B. E.D. J.A.C. N.S. B.M. D.B. C.B. and S.R.D. The authors declare no competing interests. Funding Information: This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) [ BB/M003949 ], the Scottish Government{\textquoteright}s Rural and Environment Science and Analytical Services ( RESAS ) division, a University of Glasgow James Herriot Scholarship, the Wellcome Trust ( 208390/Z/17/Z , 206194 , and 216614/Z/19/Z ), and UKRI ( MR/T020733/1 ). We would like to acknowledge members of the BUG Consortium and Parasite Genomics group at the Wellcome Sanger Institute for insightful discussions throughout this project. We also thank Pathogen Informatics and DNA Pipelines (WSI) for their support and expertise and the Biosciences Division at the Moredun Research Institute for expert care and animal assistance. For the purpose of Open Access, the authors have applied a CC BY public copyright License to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = oct,
day = "18",
doi = "10.1016/j.celrep.2022.111522",
language = "English",
volume = "41",
pages = "1--24",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}