Project summary:
Exposure to environmental chemicals is a major health risk. Unfortunately, the detrimental impacts of toxin
exposure vary among individuals in a population because of unknown genetic differences. With a better
understanding of how our genetics influence toxin response, we can more accurately predict detrimental
health effects. It is difficult to identify these factors because human genome-wide association studies often
lack the necessary statistical power and controlled toxin exposures. For this reason, we will use defined
population-wide variation in the roundworm Caenorhabditis elegans to enable precise measurements of toxin
responses 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 in
response to 30 diverse toxins, including metals/metalloids, mitochondrial toxins, pesticides, and flame
retardants. 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 in
response to these 30 toxins and use these data to map toxin-response differences to genes using two
mapping panels: (1) CeNDR - the C. elegans Natural Diversity Resource, a set of 500 strains representing
nearly all known genetic variation for the species, and (2) CeMEE - the C. elegans Multiparental Experimental
Evolution 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 will
define causal relationships between toxin response differences and genetic variants using state-of-the-art
breeding 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 elucidate
conserved mechanisms of toxin-response variation by mapping toxin responses in two other Caenorhabditis
species that are as genetically different from each other as mice and humans. An innovative comparative
quantitative trait locus analysis will ensure identification of sources of toxin-response variation that arise
convergently (and therefore predictably) in multiple evolutionary lineages. We will extend this approach by
further comparing our mapping results to those from Drosophila, rodents, and humans, identifying conserved
pathways responsible for toxin-response variation. Our Caenorhabditis genetic resources have levels of
variation, allele frequencies, and phenotypic effects similar to humans, providing a framework to discover the
characteristics of genes and variants that underlie differences in human toxin responses. Indeed, decades of
research in C. elegans have identified countless examples of widely conserved molecular mechanisms
underlying signaling, gene regulation, and metabolism, suggesting that the toxin-response mechanisms
discovered here will extend to humans despite overt differences in life history and anatomy.
