Dose-response and quantitative genetic analyses reveal a complex genetic basis underlying susceptibility to diverse toxicants in C. elegans
Authors: Samuel Widmayer 1; Timothy Crombie 1; Janneke Wit 1; James Collins 1; Sophia Gibson 1; Joy Nyaanga 1; Emily Koury 1; Robyn Tanny 1; Erik Andersen 1,2
Affiliations: 1) Department of Molecular Biosciences, Northwestern University, Evanston, IL; 2) Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
Keywords: Complex traits
Toxic exposure is a known risk factor in the onset of many human diseases, but the contributions and abundance of specific genetic variants to xenobiotic-induced disease risk at the population level are unknown. Because of the limited power and scale of toxicological assessments across genetically diverse human subjects, a tractable model system is required to characterize hazard levels of xenobiotic compounds and identify genes linked to susceptibility. Toxicological assessments using C. elegans have revealed previously unknown and translational features of xenobiotic metabolism, but investigations of natural variation in these responses are extremely limited. We measured the susceptibility of eight genetically diverse C. elegans wild strains to an array of toxicants, including several heavy metals, mitochondrial poisons, organophosphate insecticides, fungicides, herbicides, and one flame retardant using dose-response assessments. We measured phenotypic responses to each compound by adapting a high-throughput fitness assay using the Molecular Devices ImageXpress Nano automated imaging microscope and developed open-source software to extract and analyze animal morphology measurements from images. Wild strains varied significantly in susceptibility to most compounds and exhibited variable lowest observed adverse response levels, motivating us to search for quantitative trait loci (QTL) associated with differential responses. To accomplish this search, we measured phenotypic responses to a single dose of each compound across a panel of 200 C. elegans strains and performed genome-wide association mappings. These analyses revealed dozens of xenobiotic response loci with measurable effects on population-wide toxicant susceptibility and genetically correlated responses to compounds with similar modes of action. We conclude that differential xenobiotic susceptibility among C. elegans strains is highly heritable and controlled largely by toxicant-specific genetic architectures. Future work will validate the effects of these QTL in complementary recombinant populations in order to characterize their modes of action and determine any conserved functions in diverse human populations.