Population genomics of ivermectin drug resistance in parasitic nematodes of livestock

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Resistance to the drugs used to control pests and pathogens is one of today's major global challenges. Anthelmintic drug resistance in GastroIntestinal Nematode (GIN) parasites of livestock is increasingly problematic and a significant threat to agricultural economics, animal welfare and food security in Canada and the rest of the world. The long-term objective of my overall research program is to develop a comprehensive understanding of how nematode parasites become resistant to anthelmintic drugs to improve diagnosis and sustainable control. Ivermectin is the by far the most important drug for livestock parasite control with its importance to animal and human health being recognized by the 2015 Nobel Prize for Medicine or Physiology. Ivermectin resistance is increasingly widespread in multiple livestock GIN species and, in spite of the continued global importance of this drug, the genetic basis of resistance remains an enigma. Most previous ivermectin resistance research has focused on candidate gene studies which have failed to identify the major genetic determinants. This NSERC Discovery proposal will build on our previous work and use the power of population genomics and evolutionary biology to elucidate the genetic basis of ivermectin resistance. In doing so, it will also address fundamental questions regarding the evolution of anthelmintic resistance in the field. The extent to which the genetic determinants of resistance are the result of convergent evolution in different nematode species, and in different geographical regions, will be explored and exploited to help identify causal resistance mutations. The project will investigate the origins and patterns of ivermectin resistance emergence and spread in the most important GIN parasites of sheep and cattle in Canada and several other regions of the world. The project will first focus on Haemonchus contortus, a small ruminant GIN parasite which has the best available tools for anthelmintic resistance research, and then undertake comparative analysis of closely related, economically important, GIN species of cattle. We will build on our discovery of a major QTL in laboratory-selected H. contortus strains by studying field populations. Objective 1: Application of population genomics to identify the major genetic loci underlying ivermectin resistance in H. contortus field populations. Objective 2: Investigation of the extent of convergent evolution of ivermectin resistance focusing on the most important GIN species of cattle. Objective 3: Investigation of the global patterns of ivermectin resistance emergence and spread in GIN parasites of sheep and cattle. As well as being of fundamental scientific interest, identifying the genetic determinants of resistance is necessary to develop much needed molecular diagnostic tests. Understanding patterns of resistance emergence and spread will provide the required evidence-base for mitigation strategies such as grazing and biosecurity management.