Exposure to environmental chemicals is a potent health risk in which we need to understand the levels of toxin that affect our health. 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 predict detrimental health effects better. It is difficult to identify these factors because human genome-wide association studies often lack the statistical power and controlled toxin exposures to make variant identification possible. 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 define effective toxin doses across diverse individuals using low-cost, high-throughput, and high-accuracy offspring production and growth rate assays. Then, we will map toxin response differences to candidate genes using two mapping panels: (1) CeNDR - the C. elegans Natural Diversity Resource and (2) CeMEE - the C. elegans Multiparental Experimental Evolution panel. In Aim 2, we will define causal relationships between toxin response differences and genetic variants. Then, define the variability in conserved genetic networks using gene expression analyses. These steps will ensure that we discover conserved genes and/or pathways that can vary to cause differences in toxin responses across populations. To increase our likelihood of identifying conserved attributes of toxin response, we will combine mapping results from species that are as genetically different as mice and humans along with comparing to population-wide differences in toxin response across Drosophila, mice, and humans. 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. Decades of research in C. elegans have identified countless examples of widely conserved molecular mechanisms underlying signaling, gene regulation, and metabolism, suggesting that toxin-response mechanisms discovered here will extend to humans despite overt differences in life history and anatomy.
|Effective start/end date||2/1/19 → 1/31/24|
- National Institute of Environmental Health Sciences (5R01ES029930-03)