Co-evolution of mutagenic genome editors and vertebrate adaptive immunity

Abstract

The adaptive immune systems of all vertebrates rely on self-DNA mutating enzymes to assemble their antigen receptors in lymphocytes of their two principal lineages. In jawed vertebrates, the RAG1/2 recombinase directs V(D)J recombination of B cell and T cell receptor genes, whereas the activation-induced cytidine deaminase AID engages in their secondary modification. The recombination activating genes (RAG) 1 and 2 evolved from an ancient transposon-encoded genome modifier into a self-DNA mutator serving adaptive immunity; this was possible as a result of domestication, involving several changes in RAG1 and RAG2 proteins suppressing transposition and instead facilitating-coupled cleavage and recombination. By contrast, recent evidence supports the notion that the antigen receptors of T-like and B-like cells of jawless vertebrates, designated variable lymphocyte receptors (VLRs), are somatically assembled through a process akin to gene conversion that is believed to be dependent on the activities of distant relatives of AID, the cytidine deaminases CDA1 and CDA2, respectively. It appears, therefore, that the precursors of AID and CDAs underwent a domestication process that changed their target range from foreign nucleic acids to self-DNA; this multi-step evolutionary process ensured that the threat to host genome integrity was minimized. Here, we review recent findings illuminating the evolutionary steps associated with the domestication of the two groups of genome editors, RAG1/2 and cytidine deaminases, indicating how they became the driving forces underlying the emergence of vertebrate adaptive immune systems.

Figure 1

Evolutionary trajectory of vertebrates and their adaptive immune systems. (a) Cladogram depicting the evolutionary split between and within jawless and jawed vertebrates. About 500 million years ago, the hypothetical common vertebrate ancestor gave rise to both jawless and jawed vertebrate ancestors, and subsequently to their diversified descendants. In jawless vertebrates, extant species are restricted to the clades of hagfishes and lampreys, whereas jawed vertebrates comprise a more diverse group, here exemplified by cartilaginous fishes and mammals. (b) Cladogram representing the emergence of B-like and T-like cells during vertebrate evolution. Following the evolutionary timeline of (a), the two arms of the adaptive immune system originated from the hypothetical pan-lymphocyte, a primordial lymphoid cell type present in the common vertebrate ancestor. B-like and T-like cell lineages were specified at a later stage, however most likely before the emergence of the distinct ancestors of jawless and jawed vertebrates. This evolutionary scenario explains why both jawless and jawed vertebrates possess B-like and T-like cell types.

Figure 2

Evolution of key components of vertebrate adaptive immune systems. (a) Evolution of key genetic features that characterize the vertebrate adaptive immune systems. Four sets of immune-related genes were initially present in the common vertebrate ancestor: the split antigen receptor (split AgR) gene and its companion, proto-RAG (a vertebrate-specific descendant of the ProtoRAG present in amphioxus); the proto-variable lymphocyte receptor (proto-VLR) and its self-DNA targeting AID/APOBEC deaminase (AAD) companion(s). The genes evolving from each of the four sets are indicated in the same colored box as the one of origin (red, purple, yellow and green). The indicated genetic building blocks of adaptive immunity evolved along different evolutionary trajectories in jawless and jawed vertebrates. It appears likely that the genomes of jawless and jawed vertebrate ancestors retained only parts of the original gene sets. Jawless vertebrates lost the split AgR gene and proto-RAG (represented by faded boxes); by contrast, a proto-VLR gene(s) was retained alongside a proto-CDA2 gene that emerged from a self DNA-targeting AAD. The dashed box around proto-CDA2 and proto-VLR indicate that these were subsequently exapted to underpin the adaptive immune systems of jawless fishes, comprising hagfishes and lampreys (upper brown boxes). In lampreys, it has now been demonstrated that CDA2 is required for VLRB receptor gene assembly [20^••]; likewise, it is assumed but not yet proven that CDA1 assembles VLRA/C receptor genes. In hagfishes, the VLR/CDA system might operate in a similar fashion; however, since the repertoire of AAD genes in this group of animals remains uncharacterized, their potential roles in the assembly of VLRA/C are unknown. The proto-RAG gene originates from the transposon of the Transib family that later gave rise to the domesticated RAG1/2 variants in the jawed vertebrate ancestor. Concomitantly, the insertion (and subsequent excision) of the transposon into a gene encoding a primordial cell surface receptor established the prototype of a split AgR in the common vertebrate ancestor. The common jawed vertebrate ancestor lost the proto-VLR gene, here represented by the faded box, possessing instead three of the four sets of genes, the split AgR, RAG1/2 and proto-AID, the latter derived from a self DNA-targeting AAD. These genes (outlined by a dashed box) were later exapted to support the adaptive immune systems of jawed vertebrates, here exemplified by cartilaginous fishes and mammals (lower brown boxes). The process of V(D)J recombination, the antigen receptor (BCR and TCR) genes, and the domesticated forms of the recombinase (RAG1/2) are shared by both groups; the same is true for AID, derived from proto-AID, which is involved in the affinity maturation of the BCR. Note, however, that in cartilaginous fishes, recent evidence points to an additional (perhaps ancestral) role of AID in the somatic hypermutation of the TCR, a function that seems to have been lost in other jawed vertebrates.