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The vertebrate immune system can respond to an ever-changing spectrum of pathogens, and V(D)J recombination plays a central role in achieving this stunning versatility. V(D)J recombination first appeared in vertebrates about 450 million years ago and seemingly emerged without antecedent in evolution, an observation suggesting that the essentials of the recombination machinery were acquired through horizontal transfer and subsequent exaptation. This chapter examines the idea that the very apparatus is derived from part of a DNA transposon by comparing the biochemistry of transposases and the RAG recombinase. We hypothesize that the recombinase not only functions in lymphocytes but has since its acquisition also acted on germ cell genomic sequence, thereby influencing the structure and organization of immunoglobulin and T cell receptor loci. Lastly, we consider the nature of the immune system in the ancestral vertebrate, prior to the development of V(D)J recombination, and review current thinking on how V(D)J recombination fits into the evolution of adaptive immunity as a whole.

Publisher Summary This chapter attempts an interdisciplinary perspective to consider that that both molecular biologists and immunologists have learned about the V (D) J recombination process, as instructed by cross-species (and cross-locus) comparisons. Immune recognition in vertebrates is based on the antigen receptors manufactured by B and T cells. The antigen-binding polypeptides within these multiunit conglomerates are encoded at the immunoglobulin (Ig) and T cell receptor (TCR) loci. Through the process called “V (D) J joining,” antigen receptor genes are constructed from multiply reiterated DNA segments in B and T cells. By this means, an enormous number of binding specificities can be generated in lymphoid cells from a relatively minimal amount of germline information. V (D) J rearrangement can culminate in the production of alternative or “nonstandard” junction products. Demonstrated nonstandard products can account for all theoretically possible signal end-to-coding end assortments. A picture emerges of V (D) J joining as an orderly process that is the sum of disorderly parts. Variability comes into play at a number of levels—namely, variable crossover sites, variable joining signals, variable strand exchange, variable degrees of reciprocity, and so forth. It is argued that the main tactic employed by other site-directed recombination systems is not in evidence for V (D) J joining.