Genomic landscape of drug response reveals novel mediators of anthelmintic resistance

Stephen R. Doyle; Roz Laing; David J. Bartley; Alison A. Morrison; Nancy E. Holroyd; Kirsty Maitland; Alistair Antonopoulos; Umer Naveed Chaudhry; Ilona Flis; Sue Howell; Jennifer McIntyre; John S. Gilleard; Andy Tait; Barbara K. Mable; Ray M. Kaplan; Neil  Donald Sargison; Collette Britton; Matthew Berriman; Eileen Devaney; James Anthony Cotton

doi:10.1101/2021.11.12.465712

GenomicsbioRxivNov 12, 2021

Preprint

Genomic landscape of drug response reveals novel mediators of anthelmintic resistance

Stephen R. Doyle iD, Roz Laing iD, David J. Bartley iD, Alison A. Morrison iD, Nancy E. Holroyd iD, Kirsty Maitland iD, Alistair Antonopoulos iD, Umer Naveed Chaudhry iD, Ilona Flis iD, Sue Howell iD, Jennifer McIntyre iD, John S. Gilleard iD, Andy Tait, Barbara K. Mable iD, Ray M. Kaplan iD, Neil Donald Sargison iD, Collette Britton iD, Matthew Berriman iD, Eileen Devaney iD, James Anthony Cotton iD

Abstract

Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to improving the efficacy and sustainability of parasite control. Here, we use a genetic cross in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies novel 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; functional validation using knockout experiments supports a role for cky-1 overexpression in ivermectin resistance. 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. One-Sentence SummaryGenetic mapping of known and novel anthelmintic resistance-associated alleles in a multi-drug resistant parasitic nematode

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