Natural genetic variation in the pheromone production of C. elegans.

From bacterial quorum sensing to human language, communication is essential for social interactions. Nematodes produce and sense pheromones to communicate among individuals and respond to environmental changes. These signals are encoded by different types and mixtures of ascarosides, whose modular structures further enhance the diversity of this nematode pheromone language. Interspecific and intraspecific differences in this ascaroside pheromone language have been described previously, but the genetic basis and molecular mechanisms underlying the variation remain largely unknown. Here, we analyzed natural variation in the production of 44 ascarosides across 95 wild Caenorhabditis elegans strains using high-performance liquid chromatography coupled to high-resolution mass spectrometry. We discovered wild strains defective in the production of specific subsets of ascarosides (e.g., the aggregation pheromone icas#9) or short- and medium-chain ascarosides, as well as inversely correlated patterns between the production of two major classes of ascarosides. We investigated genetic variants that are significantly associated with the natural differences in the composition of the pheromone bouquet, including rare genetic variants in key enzymes participating in ascaroside biosynthesis, such as the peroxisomal 3-ketoacyl-CoA thiolase, daf-22, and the carboxylesterase cest-3. Genome-wide association mappings revealed genomic loci harboring common variants that affect ascaroside profiles. Our study yields a valuable dataset for investigating the genetic mechanisms underlying the evolution of chemical communication.

Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism.

We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).