Rare genetic variation in C. elegans underlies differences in resistance to the environmental toxicant chlorfenapyr.

I luman responses to environmental toxicants vary due to genetic differences among individuals. which makes risk assessment challenging. To overcome this obstacle, knowledge of the specific genetic variants that drive disparities in environmental toxicant responses is required. The nematode Caenorhabditis elegans is a useful model for addressing this challenge because it has levels of natural variation that are similar to humans, is easy to screen for· toxicant responses, and has the conserved molecular. cellular. and developmental properties of a metazoan. Here we use high-throughput C elegans toxicant response assays and genetic mapping approaches to find genetic variants that influence responses to chlorfenapyr, a widely used commercial insecticide. We found that among a sample of 192 genetically distinct wild nematode strains, most of the variation in chlorfenapyr response was driven by a single, highly resistant strain. ECA36. Most strains exposed to 0.6uM chlorfenapyr develop 50% slower than normal. but the development of ECA36 is unaffected. To map the genetic differences underlying ECA36 chlorfenapyr resistance, we built a panel of 192 recombinant inbred lines (RILs). sequenced their genoines, and measured their chlorfenapyr responses. We then used a linkage mapping approach to correlate genotype with phenotype across more than 10,000 markers. We found that 88% of the variation in chlorfenapyr resistance among the RILs is explained by a 164 kb genomic region on chromosome V. This region contains 49 distinct genes, including 10 cytochrome P450 genes. Future work will use CRISPR-Cas9 genome editing techniques to measure the effect of specific variants within these genes on chlorfenapyr resistance. [ABSTRACT FROM AUTHOR]

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