Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus

Stephen R. Doyle, Christopher J. R. Illingworth, Roz Laing, David J. Bartley, Elizabeth Redman, Axel Martinelli, Nancy Holroyd, Alison A. Morrison, Andrew Rezansoff, Alan Tracey, Eileen Devaney, Matthew Berriman, Neil Sargison, James A. Cotton, John S. Gilleard

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52 Scopus citations


Background Infections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved. Results Here, we present a genome-wide analysis of two genetic crosses between ivermectin resistant and sensitive isolates of the parasitic nematode Haemonchus contortus, an economically important gastrointestinal parasite of small ruminants and a model for anthelmintic research. Whole genome sequencing of parental populations, and key stages throughout the crosses, identified extensive genomic diversity that differentiates populations, but after backcrossing and selection, a single genomic quantitative trait locus (QTL) localised on chromosome V was revealed to be associated with ivermectin resistance. This QTL was common between the two geographically and genetically divergent resistant populations and did not include any leading candidate genes, suggestive of a previously uncharacterised mechanism and/or driver of resistance. Despite limited resolution due to low recombination in this region, population genetic analyses and novel evolutionary models supported strong selection at this QTL, driven by at least partial dominance of the resistant allele, and that large resistance-associated haplotype blocks were enriched in response to selection. Conclusions We have described the genetic architecture and mode of ivermectin selection, revealing a major genomic locus associated with ivermectin resistance, the most conclusive evidence to date in any parasitic nematode. This study highlights a novel genome-wide approach to the analysis of a genetic cross in non-model organisms with extreme genetic diversity, and the importance of a high-quality reference genome in interpreting the signals of selection so identified.
Original languageEnglish (US)
JournalBMC Genomics
Issue number1
StatePublished - Mar 15 2019

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: Acknowledgements: We thank Pathogen Informatics and DNA Pipelines (WSI) for their support and expertise, and Guillaume Sallé and the Parasite Genomics team at WSI for constructive feedback on the manuscript. We are grateful to the Bioservices Division, Moredun Research Institute, for expert care and assistance with animals. Funding: Work at the Wellcome Sanger Institute was funded by Wellcome (grants 098051 and 206194) and by the Biotechnology and Biological Sciences Research Council (BB/M003949). Work at the Moredun Research Institute was funded by The Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS) and at the University of Glasgow by Wellcome Trust (grant 094751), the Scottish Government under the Scottish Partnership for Animal Science Excellence and BBSRC (BB?M))3949). CJRI was supported by a Sir Henry Dale Fellowship, jointly funded by Wellcome and the Royal Society (grant 101239/Z/13/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


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