2004 West Coast Worm Meeting abstract 113
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Gallo Center, UCSF, Emeryville, CA, 94608
We have been working to unravel the molecular basis of variation in ethanol sensitivity in C. elegans. Natural variation in ethanol sensitivity in humans is strongly correlated with the propensity to abuse alcohol; people with relatively higher innate tolerance are relatively more likely to become alcoholic (Schuckit, 2002). Ethanol is intoxicating to worms and humans at similar tissue concentrations. Drunk worms become progressively more uncoordinated, slow and Egl as ethanol concentration increases (Davies et al., 2003). This response is not static; over time worms undergo an acute adaptation (acute tolerance) to the presence of ethanol that does not reflect a decrease in internal ethanol concentration. We noted that there is substantial natural variation in ethanol response, particularly in the rate of development of acute tolerance, between the wild strains N2 and CB4856. This difference is due to the previously described allelic variation at the npr-1 locus (de Bono and Bargmann, 1998; Davies et al., 2004). Genetic analysis indicates that NPR-1 activity antagonizes the development of acute tolerance.
We have performed a genetic screen for molecules involved in the development of acute tolerance by screening for suppressors of the npr-1(ky13) rapid development of acute tolerance phenotype. We have screened approximately 4000 haploid genomes and have isolated 10 suppressors, identifying at least 6 complementation groups. Only a small subset of these mutations (two) suppresses npr-1-mediated clumping. Thus, most of our mutants presumably identify components that are more specific to the acute ethanol tolerance pathway, rather than general suppressors of npr-1. None of the mutations has an obvious phenotype in the absence of ethanol.
We are pursuing molecular characterization of two of these suppressors, eg613 and eg614. Both are completely recessive, and neither has a detectable ethanol-sensitivity phenotype in the absence of the npr-1 mutation.