Immunoglobulin differentiation is dictated by repeated recombination sequences within the V region prototype gene: a hypothesis.

Analysis of the available DNA sequences of immunoglobulin light chain genes reveals a unique structural pattern. A stretch of about 15 nucleotides repeats five times within the variable (V) region gene, with few base changes. Identification of these homologous sequences is apparent in the embryonic V(lambda) gene and might also be recognized in V(kappa) genes isolated from a myeloma. Although different from each other, the V(lambda) and V(kappa) hyperhomologous sequences display a remarkable resemblance to different prokaryote sequences associated with recombinational events. The homologous sequences appear at all three sites where hypervariable regions of the mature peptide are encoded. In addition, they are located at the site where V/constant (C) recombination is supposed to take place. Consequently, a general model is proposed for immunoglobulin differentiation. The hyperhomologous loci are postulated to be comprised of recombination sequences which makes them available for a mechanism of single-stranded DNA exposure. B cell maturation begins with V/C recombination, a step that is rate limiting. The fidelity of the process is ensured by extensive DNA homology between the two embryonic subgenes of V and C. Next, an error-prone repair system is activated and thereby introduces changes into the content of the immunoglobulin gene at the exposed loci. The process ends when mutations make the recombination sequence unrecognizable as such. The model is consistent with large amounts of data and is compatible with the view that immunoglobulin diversity is being generated somatically.