Toxicol Sci. 2026 Feb 18:kfag019. doi: 10.1093/toxsci/kfag019.
Natural variation suggests candidate genes underlying Caenorhabditis elegans susceptibility to diverse toxicants
Timothy A Crombie1, Ryan Mckeown2,3, Samuel J Widmayer2, Amanda O Shaver4, Nicolas D Moya4,5, J B Collins4, Janneke Wit2, Robyn E Tanny4, Christian Braendle6, Lewis Stevens7, Lisa Van Sluijs8, Matthew V Rockman9, Mark G Sterken8, Marie-Anne Félix10, Erik C Andersen4
Affiliations
1Department of Biomedical Engineering and Science, Florida Institute of Technology, Melbourne, FL, 32901, United States.
2Molecular Biosciences, Northwestern University, Evanston, IL, 60208, United States.
3Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL, 60208, United States.
4Department of Biology, Johns Hopkins University, Baltimore, MD, 21218, United States.
5Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, Baltimore, MD, 21218, United States.
6Université Côte d’Azur, CNRS, Inserm, IBV, Nice, 06100, France.
7Wellcome Sanger Institute, Tree of Life, Wellcome Genome Campus, Cambridge, CB10 1SA, United Kingdom.
8Laboratory of Nematology, Wageningen University & Research, Wageningen, the Netherlands.
9Department of Biology and Center for Genomics & Systems Biology, New York University, New York, NY, 10003, United States.
10Institut de Biologie de l’École Normale Supérieure, CNRS, Paris, France.
Abstract
Genetic differences among individuals shape how they respond to environmental toxicants, but the identification and validation of the genes responsible for this variation is difficult, particularly in humans. Consequently, our limited knowledge of the genes that influence susceptibility constrains our ability to accurately predict the risks posed by environmental toxicants. To identify genes underlying natural differences in toxicant susceptibilities, we measured the effects of 23 environmental toxicants on larval development across 195 genetically diverse Caenorhabditis elegans strains using a high-throughput imaging platform. We then combined these response data with whole-genome sequences to perform genome-wide association mappings, identifying 40 genomic regions where genetic variants are correlated with susceptibility differences. Many of these regions are enriched for genes involved in biological processes previously linked with toxicant responses, supporting the potential contributions of these genes to natural variation in susceptibility. Using biologically informed heuristics based on genomic context and functional annotation, we prioritized genes for follow-up experimentation and identified 94 candidate susceptibility genes, offering feasible targets for experimental validation that could ultimately inform toxicant risk prediction and regulatory assessment by linking genetic variation to differences in susceptibility. Analysis of natural genetic variation among 195 wild C. elegans strains identified 94 candidate genes putatively linked to differences in susceptibility to 23 environmental toxicants. These findings can inform the discovery of conserved susceptibility genes and the development of biomarkers that improve chemical risk assessment by accounting for genetic differences among humans.