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.