Complex biological processes evolve by co-opting bits and pieces of preexisting cellular machinery and using them for new purposes. On page 1207 of this issue, Cascalho et al.(1) provide a new example of this strategy in the case of somatic mutation of antibody variable (V) genes. The mutation of V genes is the key mechanism by which the body develops and modifies the antibody repertoire, the huge diversity of antibodies that allows us to keep pace with emerging and antigenically altered pathogens. V gene mutation differs from spontaneous mutation in two ways: The rate is extremely high (six to seven orders of magnitude higher), and luckily, this hypermutation is confined to a region in and around expressed V genes. Cascalho et al. have discovered that a protein ordinarily involved in correcting mutations is involved in causing V gene hypermutation.

Somatic hypermutation is not the first immunological process to co-opt ubiquitous proteins. The other key immunological process for generating diversity, V (D) J recombination, also evolved by using this strategy (2). Rearrangement of variable (V), diversity (D), and joining (J) gene segments to produce functional antibody and T cell receptors requires the lymphocyte-specific RAG-1 and RAG-2 (the products of recombination activation genes). In and of themselves, though, the RAG proteins cannot complete the process of gene recombination; instead, the RAGs primarily recognize specific sequences and nick the DNA. Ubiquitous factors then take over to complete the recombination process. Many of these co-opted factors have been identified by educated guesswork and experiments with mouse strains impaired in V (D) J recombination. For example, the scidmutation renders mice both radiation-sensitive and recombination-deficient (3). The connection between these two phenotypes became obvious when the scid mutation was shown to affect DNA-dependent protein kinase, part of the machinery for repairing breaks in double-stranded DNA (4). Thus, to accomplish V (D) J recombination, the immune system co-opted DNA repair machinery.