Immune System Genetics

The fundamental principle governing antibody generation is combinatorial diversity. A large number of genes are generated by choosing from among a smaller pool of differing gene segments and combining them in different ways. This process, known as somatic recombination, is similar in principle to constructing words. The alphabet's twenty-six letters can be combined to make 676 (26²) two-letter words and almost 12 million five-letter words.

To understand the molecular details of somatic recombination, let us focus on the creation of a kappa-type light chain. The process is similar for lambda light chains and only marginally more involved for a heavy chain.

We noted that the light chain has both a variable and a constant region. There are forty gene segments that can code for the variable (V) region and a single segment that codes for the constant (C) region. In addition, there are five possible coding segments for the J region, a short region that is also present on light chains. All of these genes and segments are located in sequence on chromosome 2. Each V and J segment is flanked by special noncoding sequences that facilitate the next stage, in which specific segments are joined.

Somatic recombination begins when special recombining proteins randomly bring together the downstream end of one V segment and the upstream end of one J segment. They do this by attaching to the flanking sequences and bending the intervening DNA into a loop. The loop is cut out and degraded, and the remaining DNA is spliced together. The product is the mature antibody gene.

Note in the diagram on the right that the resulting gene may still have some extra upstream V segments. An ingenious mechanism prevents such segments from being transcribed to make messenger RNA, however.

Each V segment contains a promoter, the region to which RNA polymerase binds to start transcription. The promoter is inactive, though, until it is brought close to an "enhancer" region between the J and C segments. Thus, transcription will begin at the V segment closest to the enhancer, and only this one V segment is transcribed—the others are too far from the enhancer. The gene may also have extra downstream J segments and intron sequences between J and C. These are transcribed, but they are removed by RNA processing.