Natural Genetic Variation in a Multigenerational Phenotype in <i>C. Elegans</i>

Abstract

While heredity mostly relies on the transmission of DNA sequence, additional molecular and cellular features are heritable across several generations. In the nematode Caenorhabditis elegans, insights into such unconventional inheritance result from two lines of work. First, the mortal germ line (Mrt) phenotype was defined as a multigenerational phenotype whereby a selfing lineage becomes sterile after several generations, implying multigenerational memory. Second, certain RNA interference (RNAi) effects are heritable over several generations in the absence of the initial trigger. Both lines of work converged when the subset of Mrt mutants that are heat-sensitive were found to closely correspond to mutants defective in the RNAi-inheritance machinery, including histone modifiers [6-9]. Here we report the surprising finding that several C. elegans wild isolates display a heat-sensitive mortal germline phenotype in laboratory conditions: upon chronic exposure to higher temperatures such as 25°C, lines reproducibly become sterile after several generations. This phenomenon is reversible as it can be suppressed by temperature alternations at each generation, suggesting a non-genetic basis for the sterility. We tested whether natural variation in the temperature-induced Mrt phenotype was of genetic nature by building recombinant inbred lines between the isolates MY10 (Mrt) and JU1395 (non-Mrt). Using bulk segregant analysis, we detected two quantitative trait loci. After further recombinant mapping and genome editing, we identified the major causal locus as a polymorphism in the set-24 gene, encoding a SET- and SPK-domain protein. We conclude that C. elegans natural populations harbor natural genetic variation in epigenetic inheritance phenomena.