The Happy Hopping of Transposons: The Origins of V(D)J Recombination in Adaptive Immunity

Abstract

Nearly 50% of the human genome is derived from transposable elements (TEs). Though dysregulated transposons are deleterious to humans and can lead to diseases, co-opted transposons play an important role in generating alternative or new DNA sequence combinations to perform novel cellular functions. The appearance of an adaptive immune system in jawed vertebrates, wherein the somatic rearrangement of T and B cells generates a repertoire of antibodies and receptors, is underpinned by Class II TEs. This review follows the evolution of recombination activation genes (RAGs), components of adaptive immunity, from TEs, focusing on the structural and mechanistic similarities between RAG recombinases and DNA transposases. As evolution occurred from a transposon precursor, DNA transposases developed a more targeted and constrained mechanism of mobilization. As DNA repair is integral to transposition and recombination, we note key similarities and differences in the choice of DNA repair pathways following these processes. Understanding the regulation of V(D)J recombination from its evolutionary origins may help future research to specifically target RAG proteins to rectify diseases associated with immune dysregulation.