Population genomics of anthelmintic resistance in parasitic nematodes of livestock : Haemonchus contortus as a model system

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The emergence of drug resistance to pests and pathogens is one of the major challenges of the 21st century. Parasitic nematodes are metazoan parasites that are of huge economic importance to the global and Canadian livestock industries and in which drug resistance is a major problem. Thelong term objective of my research program is to develop a comprehensive understanding of how livestock parasites become resistant to drugs (anthelmintics) and to apply this knowledge to improve surveillance and sustainable control. In this discovery grant project, I will apply population genomic approaches to investigate the genetic basis of anthelmintic drug resistance and the evolutionary processes leading to its emergence and spread using the small ruminant parasite Haemonchus contortus. This is an excellent study model since this parasite has widespread resistance to the major anthelmintic drug classes, has a high quality reference genome, has excellent population genetic tools and is one of the most experimentally tractable animal parasitic nematodes. It is also an important emerging disease problem for the Canadian sheep industry. This NSERC Discovery Grant renewal directly builds on my previous work and has the following specific objectives. Objective 1 will investigate the origin and spread of anthelmintic resistance. Deep sequencing approaches will be used to provide an unprecedented view of resistant and susceptible haplotype diversity at known, and candidate, drug resistance loci for the major broad spectrum anthelmintic drugs. The aim is to provide the first clear picture of the number of independent origins of resistance in different parts of the world and also to test the leading candidate resistance loci for evidence of selection and therefore relevance in the field. Objective 2 will undertake genome-wide scans to investigate signatures of selection in H. contortus field populations. The aim is to identify novel  drug resistance loci (as well as confirm or refute the importance of previously implicated candidate loci). This is an important aim since there is ample evidence that many important anthelmintic resistance loci remain to be discovered. Objective 3 will investigate whether interspecies hybridization leads to introgression of drug resistance loci between H. contortus and the closely related cattle parasite Haemonchus placei. The aim is to provide a proof-of-concept that drug resistance can be transferred between different parasitic nematode species in the field. This objective will also provide an additional novel approach to identify new drug resistance loci (based on the identification of "super invasive" introgressed loci). This program of research will provide an excellent opportunity to apply state-of-the-art population genomic approaches to an important practical problem that is of major significance to global food production.**