Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes

Abstract

Over evolutionary time, many genes undergo duplication and one copy accumulates mutations that render it non-functional. These 'pseudogenes' are generally thought to be rather uninteresting, dead-end pieces of the genome. Yet there now appears to be more to it than that. Two groups report in this issue on pseudogenes that can in fact influence gene expression. The mechanism involves pairing of RNA antisense transcripts from pseudogenes with the mRNAs of protein-coding genes, forming a duplex RNA that is processed into endogenous siRNAs. Over evolutionary time genes can undergo duplication, and may accumulate mutations that render them non-functional pseudogenes, which are thought to be uninteresting. This study (and that of the group of Sasaki) shows that pseudogenes can in fact influence gene expression. Pseudogenes populate the mammalian genome as remnants of artefactual incorporation of coding messenger RNAs into transposon pathways1. Here we show that a subset of pseudogenes generates endogenous small interfering RNAs (endo-siRNAs) in mouse oocytes. These endo-siRNAs are often processed from double-stranded RNAs formed by hybridization of spliced transcripts from protein-coding genes to antisense transcripts from homologous pseudogenes. An inverted repeat pseudogene can also generate abundant small RNAs directly. A second class of endo-siRNAs may enforce repression of mobile genetic elements, acting together with Piwi-interacting RNAs. Loss of Dicer, a protein integral to small RNA production, increases expression of endo-siRNA targets, demonstrating their regulatory activity. Our findings indicate a function for pseudogenes in regulating gene expression by means of the RNA interference pathway and may, in part, explain the evolutionary pressure to conserve argonaute-mediated catalysis in mammals.