AID/APOBEC-like cytidine deaminases are important mediators of VLR-based adaptive immunity in lampreys

Jawless vertebrates offer critical insights into the evolutionary origins of adaptive immunity due to their unique phylogenetic position among chordates. However, the convergent evolution of adaptive immunity between jawless and jawed vertebrates remains incompletely understood. In this study, we characterized cytidine deaminases (CDAs), ancestral members of the AID/APOBEC deaminase family, in the lamprey Lethenteron reissneri. Functional analyses demonstrated that Lr-CDA1 exhibits in vivo activity comparable to activation-induced cytidine deaminase (AID) in jawed vertebrates. Loss of Lr-CDA1 disrupted the assembly of the three types of variable lymphocyte receptors (VLRs), with the strongest effect observed for VLRB. Within the germline VLR (gVLR) loci of Lethenteron reissneri, we identified CDA-associated regulatory regions that are required for proper VLR assembly and diversification. These regions were specifically bound by Lr-CDAs, and their repression resulted in a marked downregulation of VLRB expression. Collectively, our findings indicate that lampreys possess a CDA-mediated VLR rearrangement mechanism that acts on germline VLRs to regulate their assembly, maturation, and diversification. Moreover, the association of Lr-CDAs with tumorigenesis- and chromosomal translocation-related genes highlights an ancient molecular link between immune diversification and genome instability.