Abstract
Parasitic nematodes impose a debilitating health and economic burden across much of the world1. Nematode resistance to anthelmintic drugs threatens parasite control efforts in both human2, 3and veterinary4 medicine. Despite this threat, the genetic landscape of potential resistance mechanisms to these critical drugs remains largely unexplored. Here, we exploit natural variation in the model nematode Caenorhabditis elegans to discover quantitative trait loci (QTL) that control benzimidazole sensitivity and show that piwi-interacting RNAs (piRNAs) are capable of regulating benzimidazole resistance. We narrowed a major-effect albendazole QTL to a small piRNA-enriched region of the C. elegans genome and demonstrate that the albendazole-resistance phenotype results from strain-specific piRNA variation that is dependent on the function of the piRNA-associated argonaute prg-1. We identified candidate piRNAs causal to the resistance phenotype and putative genes targeted for silencing by downstream 22G RNAs. We further show that piRNAs may regulate benzimidazole susceptibility in the related model nematode C. briggsae. Our results indicate that small RNAs require consideration in drug resistance mechanisms in nematodes, because the piRNA pathway and related small RNA pathways are conserved in many medically and agriculturally important parasitic nematodes. This finding has significant implications for parasite control and the management of drug resistance in other phyla and systems.
Footnotes
↵* erik.andersen{at}northwestern.edu