Abstract
Gene silencing is a significant obstacle to genome engineering and has been proposed to be a non-self response against foreign DNA1,2,3,4. Yet, some foreign genes remain expressed for many generations1,3,4 and some native genes remain silenced for many generations1,5,6. How organisms determine whether a sequence is expressed or silenced is unclear. Here we show that a stably expressed foreign DNA sequence in C. elegans is converted into a stably silenced sequence when males with the foreign DNA mate with wild-type hermaphrodites. This conversion does not occur when the hermaphrodite also has exonic sequences from the foreign DNA. Once initiated, silencing persists for many generations independent of mating and is associated with a DNA-independent signal that can silence other homologous loci in every generation. This mating-induced silencing resembles piRNAmediated silencing because it requires the Argonaute PRG-1 (ref. 7) for initiation and the Argonaute HRDE-1 (ref. 1,5) for maintenance. Loss of HRDE-1 can revive gene expression even after 150 generations. Thus, our results reveal the existence of a mechanism that maintains gene silencing initiated upon ancestral mating. By allowing retention of potentially detrimental sequences acquired through mating, this mechanism could create a reservoir of sequences that contribute to novelty when activated during evolution.