The origin of somatic gene rearrangement in the excision of a transposable element makes sense of an apparent paradox in the rearrangement of immune-system genes. This is that the RSSs are joined precisely in the excised DNA (see Section 5-5), which has no further function and whose fate is irrelevant to the cell, whereas the cut ends in the genomic DNA, which form part of the immunoglobulin or T-cell receptor gene, are joined by an error-prone process, which could be viewed as a disadvantage. However, when looked at from the transposon’s point of view, this makes sense, because the transposon preserves its integrity by this excision mechanism, whereas the fate of the DNA it leaves behind is of no significance to it. As it turned out, the error-prone joining in the primitive immunoglobulin gene generated useful diversity in antigen-recognition molecules and was strongly selected for. The RAG-based rearrangement system also provided something else that mutations could not—a means of rapidly modifying the size of the coding region, not just its diversity.
The next question is what sort of gene the transposon inserted into. Proteins containing Ig-like domains are ubiquitous throughout the plant, animal, and bacterial kingdoms, making this one of the most abundant protein super-families; in species whose genomes have been fully sequenced, the immunoglobulin superfamily is one of the largest families of protein domains in the genome. The functions of the members of this superfamily are very disparate, and they are a striking example of natural selection taking a useful structure— the basic Ig-domain fold—and adapting it to different purposes.
The immunoglobulin superfamily domains can be divided into four families on the basis of differences in structure and sequence of the immunoglobulin domain. These are V (resembling an immunoglobulin variable domain), C1 and C2 (resembling constant-region domains), and a type of immunoglobulin domain called an I domain (for intermediate). The target of the RSS-containing element is likely to have been a gene encoding a cell-surface receptor containing an Ig-like V domain, most probably a type similar to present-day VJ domains. These domains are found in some invariant receptor proteins and are so called because of the resemblance of one of the strands to a J segment. It is possible to imagine how transposon movement into such a gene could produce separate V and J gene segments (see Fig. 5.26). On the basis of phylogenetic analysis, agnathan paired receptors resembling Ag receptors, or APARs, which are encoded by a multigene family found in hagfish and lamprey, are currently the best candidates for being relatives of the ancestor of the antigen receptor. Their DNA sequences predict single-pass transmembrane proteins with a single extracellular VJ domain and a cytoplasmic region containing signaling modules. APARs are expressed in leukocytes.
5-20 Different species generate immunoglobulin diversity in different ways.
Most of the vertebrates we are familiar with generate a large part of their antigen receptor diversity in the same way as mice and humans, by putting together gene segments in different combinations. There are exceptions, however, even within the mammals. Some animals use gene rearrangement to always join together the same V and J gene segment initially, and then diversify this recombined V region. In birds, rabbits, cows, pigs, sheep, and horses, there is little or no germline diversity in the V, D, and J gene segments that are rearranged to form the genes for the initial B-cell receptors, and the rearranged V-region sequences are identical or similar in most immature B cells. These immature B cells migrate to specialized microenvironments—the bursa of Fabricius in the gut of chickens, and another intestinal lymphoid organ in rabbits. Here, B cells proliferate rapidly, and their rearranged immunoglobulin genes undergo further diversification.