Discovery of conserved molecular mechanisms underlying population-wide variation in toxin responses

Project summary:Exposure to environmental chemicals is a major health risk. Unfortunately, the detrimental impacts of toxinexposure vary among individuals in a population because of unknown genetic differences. With a betterunderstanding of how our genetics influence toxin response, we can more accurately predict detrimentalhealth effects. It is difficult to identify these factors because human genome-wide association studies oftenlack the necessary statistical power and controlled toxin exposures. For this reason, we will use definedpopulation-wide variation in the roundworm Caenorhabditis elegans to enable precise measurements of toxinresponses at the scale and statistical power of single-cell organisms but with conserved molecular, cellular,and developmental properties of a metazoan. In Aim 1, we will identify genetic loci underlying variation inresponse to 30 diverse toxins, including metals/metalloids, mitochondrial toxins, pesticides, and flameretardants. We will define effective toxin doses across diverse individuals using low-cost, high-throughput,and high-accuracy assays of growth and fertility. Then, we will define the population-wide variation inresponse to these 30 toxins and use these data to map toxin-response differences to genes using twomapping panels: (1) CeNDR - the C. elegans Natural Diversity Resource, a set of 500 strains representingnearly all known genetic variation for the species, and (2) CeMEE - the C. elegans Multiparental ExperimentalEvolution panel, a set of 1000 recombinant inbred lines that enable mapping to the resolution of single genes.In Aim 2, we will identify specific genetic variants and pathways affecting toxin-response variation. We willdefine causal relationships between toxin response differences and genetic variants using state-of-the-artbreeding and genome-editing techniques. Then, we will use gene expression analyses and hypothesis-directed experiments to determine the molecular basis of toxin-response variation. In Aim 3, we will elucidateconserved mechanisms of toxin-response variation by mapping toxin responses in two other Caenorhabditisspecies that are as genetically different from each other as mice and humans. An innovative comparativequantitative trait locus analysis will ensure identification of sources of toxin-response variation that ariseconvergently (and therefore predictably) in multiple evolutionary lineages. We will extend this approach byfurther comparing our mapping results to those from Drosophila, rodents, and humans, identifying conservedpathways responsible for toxin-response variation. Our Caenorhabditis genetic resources have levels ofvariation, allele frequencies, and phenotypic effects similar to humans, providing a framework to discover thecharacteristics of genes and variants that underlie differences in human toxin responses. Indeed, decades ofresearch in C. elegans have identified countless examples of widely conserved molecular mechanismsunderlying signaling, gene regulation, and metabolism, suggesting that the toxin-response mechanismsdiscovered here will extend to humans despite overt differences in life history and anatomy.