Natural allelic variation modifies acute ethanol response phenotypes in wild strains of C. elegans

• Published in: Alcohol, clinical & experimental research clinical & experimental research, 2023-08, Vol.47 (8), p.1505-1517
• Main Authors: Wijk, Marijke H., Davies, Andrew G., Sterken, Mark G., Mathies, Laura D., Quamme, Elizabeth C., Blackwell, GinaMari G., Riksen, Joost A. G., Kammenga, Jan E., Bettinger, Jill C.
• Format: Article
• Language: English
• Subjects: acute functional tolerance; alcohol sensitivity; behavior; Caenorhabditis elegans; natural variation
• ISSN: 2993-7175; 2993-7175
• DOI: 10.1111/acer.15139

Background Genetic variation contributes to the likelihood that an individual will develop an alcohol use disorder (AUD). Traditional laboratory studies in animal models have elucidated the molecular pharmacology of ethanol, but laboratory‐derived genetic manipulations rarely model the naturally occurring genetic variation observed in wild populations. Rather, these manipulations are biased toward identifying genes of central importance in the phenotypes. Because changes in such genes can confer selective disadvantages, they are not ideal candidates for carrying AUD risk alleles in humans. We sought to exploit Caenorhabditis elegans to identify allelic variation existing in the wild that modulates ethanol response behaviors. Methods We tested the acute ethanol responses of four strains recently isolated from the wild (JU1511, JU1926, JU1931, and JU1941) and 41 multiparental recombinant inbred lines (mpRILs) derived from them. We assessed locomotion at 10, 30, and 50 min on low and high ethanol concentrations. We performed principal component analyses (PCA) on the different phenotypes, tested for transgressive behavior, calculated heritability, and determined the correlations between behavioral responses. Results We observed a range of responses to ethanol across the strains. We detected a low‐concentration locomotor activation effect in some of the mpRILs not seen in the laboratory wild‐type strain. PCA showed different ethanol response behaviors to be independent. We observed transgressive behavior for many of the measured phenotypes and found that multiple behaviors were uncorrelated. The average broad‐sense heritability for all phenotypes was 23.2%. Conclusions Genetic variation significantly affects multiple acute ethanol response behaviors, many of which are independent of one another. This suggests that the genetic variation captured by these strains likely affects multiple biological mechanisms through which ethanol acts. Further study of these strains may allow these distinct mechanisms to be identified. Acute physiological reactions to ethanol are influenced by genetics and are risk indicators for developing alcohol use disorder. Classical animal knock‐out studies may not identify genes in which natural genetic variation affects these responses in wild populations. Due to conserved neurobiology and ethanol responses between mammals and invertebrates, we characterized ethanol response behaviors in genetically distinct wild and wild‐derived Caenorha