Bi-directional Transcription, Double-Stranded RNA and the Implications on Genome Evolution

Double-stranded RNA (dsRNA) within cells indicates viral infection and triggers a robust innate immune response. Counterintuitively, cells also produce endogenous dsRNA from repetitive sequences and antisense transcription in the nucleus as well as bi-directional transcription of the mitochondrial genome. Under physiological conditions, dsRNA is prevented from entering the cytoplasm, though in situations of disease or stress these barriers may be breached. In the cytoplasm, dsRNA binds to various sensor proteins that recognise features such as unmodified 5′ ends and long perfect dsRNA helices. Upon binding to the sugar-phosphate backbone, the sensors oligomerize and trigger various downstream pathways that promote immune signalling or apoptosis. The overwhelming majority of dsRNA derives from repetitive regions of the genome, inverted Alu repeats in particular, but also from long interspersed repeats and endogenous retroviruses. The interplay between these elements and the dsRNA sensors with specific binding preferences helps to shape innate immunity. Natural antisense transcripts have the potential to form dsRNA with co-expressed sense transcripts. Such RNA hybrids may contribute to breaching protective mechanisms and causing immune diseases. In specialized tissues such as testis or early embryos, sense-antisense RNA hybrids may play key roles in the timing of gene expression during development. Alternatively, the dsRNA may be an essential intermediate of a molecular mechanism to scan the male germ cell genome for deleterious mutations.