While heredity mostly relies on DNA sequence, other molecular and cellular features are heritable across generations. This non-DNA based memory could be of importance for adaptation of organisms to varying environments. Here we test whether and how non-genetic inheritance systems are modulated by natural genetic variation using two experimental paradigms: the mortal germline phenotype and memory of RNA interference. The mortal germline (Mrt) phenotype is a progressive onset of sterility over multiple generations. Temperature-sensitive Mrt mutations are known to affect small RNA pathways, histone methylation and thereby multigenerational inheritance. We previously showed that some C. elegans natural isolates display a temperature-sensitive Mrt phenotype. Using recombinants between two isolates, we had identified a globally rare causal polymorphism in the
set-24 gene. To identify polymorphisms explaining a greater part of natural variation in the Mrt phenotype, we performed a genome-wide association study using 95 isolates. A strong association on chromosome III was found, and replicated across two labs. Introgressions of chromosome III from the Mrt isolate JU775 in non-Mrt genetic backgrounds confirmed the association. These results show that a genetic variant underlying the multigenerational phenotype is found at intermediate frequency at the species scale. The sterility phenotype is likely suppressed in nature, by variation in temperature or potentially other interactions. We indeed find that naturally associated bacteria or infection by microsporidia strongly suppress the Mrt phenotype. Thus, the Mrt phenotype is likely revealed by unnaturally homogenous standard laboratory conditions, thereby providing an experimental handle on natural variation in transgenerational inheritance pathways. Importantly, we also reveal a positive, condition-dependent effect of an intestinal "pathogen", affecting the C. elegans germline. In addition to the Mrt phenotype, we turned to directly assay the memory of RNA interference, using a
pie-1::GFP silencing paradigm. C. elegans isolates also differ greatly in the number of generations of silencing memory of an RNAi trigger provided only in the first generation; some isolates do not show any memory. Moreover, genetic variation on chromosome III also underlies the short RNAi memory of JU775 compared to N2. Overall, we show that multigenerational memory is widely modulated by natural genetic variation in C. elegans.