All this provoked speculation that the origin of RAG-dependent adaptive immunity was the invasion of a DNA transposon into a gene similar to an immunoglobulin or a T-cell receptor V-region gene, an event that would have occurred in some ancestor of the jawed vertebrates (Fig. 5.26). DNA transposons carry inverted repeated sequences at either end, which are bound by the transposase for transposition to occur. These terminal repeats are considered to be the ancestors of the RSSs in present-day antigen-receptor genes (see Section 5-4), while the RAG-1 protein is believed to have evolved from a transposase. Subsequent duplication, reduplication, and recombination of the immune-receptor gene and its inserted RSSs eventually led to the separation of the RAG genes from the rest of the relic transposon and to the multisegmented immunoglobulin and T-cell receptor loci of present-day vertebrates.
The ultimate origins of the RSSs and the RAG-1 catalytic core are now thought to lie in the Transib superfamily of DNA transposons, and genome sequencing has led to the discovery of sequences related to RAG1 in animals as distantly related to vertebrates as the sea anemone Nematostella. The origin of RAG2 is
Top panel: a DNA transposon in an ancestor of the deuterostomes (the large group of phyla to which the chordates belong) is thought to have had genes related to RAG1 and RAG2—prototype RAG1 (purple) and RAG2 (blue), which acted as its transposase. DNA transposons are bounded by terminal inverted repeat (TR) sequences. Second panel: to excise a transposon from DNA, the transposase proteins (purple and blue) bind the TRs, bringing them together, and the transposase enzymatic activity cuts the transposon out of the DNA, leaving a footprint in the host DNA that resembles the TRs. After excision from one site, the transposon reinserts elsewhere in the genome, in this case into a V-type immunoglobulin receptor (green). The enzymatic activity of the transposase enables the transposon to insert into DNA in a reaction that is the reverse of the excision reaction. Third panel: the integration of the RAG1/2-like transposon into the middle of the gene for a V-type immunoglobulin receptor splits the V exon into two parts. Fourth and fifth panels: in the evolution of the immunoglobulin and T-cell receptor genes, the initial integration event has been followed by DNA rearrangements that separate the transposase genes (now known as the RAG1 and RAG2 genes) from the transposon TRs, which we now term the recombination signal sequences (RSSs). The purple sea urchin (an invertebrate deuterostome) has a RAG1/2-like gene cluster (not shown) and expresses proteins similar to RAG-1 and RAG-2 proteins, but does not have immunoglobulins, T-cell receptors, or adaptive immunity. The RAG-like proteins presumably retain some other cellular function (so far unknown) in this animal.
more obscure, but a RAG1–RAG2-related gene cluster was recently discovered in sea urchins, invertebrate relatives of the chordates. Sea urchins themselves show no evidence of immunoglobulins, T-cell receptors, or adaptive immunity, but the proteins expressed by the sea-urchin RAG genes form a complex with each other and with RAG proteins from the bull shark (Carcharhinus leucas), a primitive jawed vertebrate, but not with those from mammals. This suggests that these proteins could indeed be related to the vertebrate RAGs, and that RAG-1 and RAG-2 were already present in a common ancestor of chordates and echinoderms (the group to which sea urchins belong), presumably fulfilling some other cellular function.