From RNA interference to chromatin silencing, diverse genome defense pathways silence selfish genetic elements to safeguard genome integrity. Despite their diversity, different defense pathways share a modular organization, where numerous specificity factors identify diverse targets and common effectors silence them. In the PIWI-interacting RNA (piRNA) pathway, target RNAs are first identified by complementary base pairing with piRNAs and then silenced by PIWI-clade nucleases. Such a binary architecture allows the defense systems to be readily adaptable, where new targets can be captured via innovation of specificity factors. Thus, our current understanding of genome defense against lineage-specific selfish genes has been largely limited to specificity factor innovations, while it remains poorly understood whether other types of innovations are required. Here, we describe a new type of innovation, which escalates the genome defense capacity to control a recently expanded selfish gene in Drosophila melanogaster. Through a targeted RNAi screen for repressors of Stellate-a recently evolved meiotic driver-we identified a defense factor, Trailblazer. Trailblazer is a transcription factor that promotes the expression of two PIWI-clade nucleases, Aub and AGO3, to match Stellate in abundance. Recent innovation in the DNA-binding domain of Trailblazer enabled it to elevate Aub and AGO3 expression, thereby escalating the silencing capacity of piRNA pathway to tame expanded Stellate and safeguard fertility. As copy-number expansion is a recurrent feature of diverse selfish genes across the tree of life, we envision that augmenting the defense capacity to quantitatively match selfish genes is a repeatedly employed defense strategy in evolution.
Keywords: Stellate; genetic innovation; intragenomic conflict; piRNA; zinc finger protein.