REGULATION 3: Programmed DNA Rearrangements

The mammalian immune system is capable of synthesizing many millions of different versions of various proteins involved in what we call the immune response, which kicks into high gear whenever we get infected with a new bacterium, virus, or parasite. The way we do this goes beyond the aspects of regulation of gene expression that we have considered during the previous two classes. In the case of the immune response, actual changes to the DNA itself are involved, as described in the sub-section titled "Antibody and T-Cell Receptor Variability" on pages 485-488 of your textbook. The specific question we will explore today is "How is it possible for a person to be able to make over a hundred million different antibody proteins?"


1. What is the general structure of an immunoglobulin (antibody protein)?

Antibody proteins, as shown in Figure 11.35, consist of two identical "light chains" and two identical "heavy chains". Both light chain and heavy chain have regions that are called "variable" and regions that are called "constant". The genetic loci of light chain and heavy chain are similar, and so are the mechanisms involved in the synthesis of the proteins.


2. How does "combinatorial joining" allow about 1,000 different light chains and about 10,000 different heavy chains to be made by a single person?

In the human genome, there is one very complicated locus for the "light chain", as shown in Figure 11.36. Various "parts" of the gene are present as multiple coding sequences. Some of these multiple coding sequences are eliminated in the DNA of the B cells that produce antibody. Note that this is something we have not seen before; actual programmed removal of DNA from the genome in some specialized differentiated cells. After transcription, some more of the remaining multiple coding sequences are eliminated from the primary transcripts. In any one B cell, this results in an mRNA containing only one coding sequence for each "part". Because both the DNA splicing and the RNA splicing occur differently (randomly) in different B cells, the overall result is that the mammalian body is capable of producing about a thousand different light chain protein sequences from this single genetic locus in the germ-line DNA. The "heavy chain" locus produces even more variety (about 10,000 different sequences), because it has an additional region, D, with multiple parts. So, the level of antibody variability created by combinatorial joining is about 1,000 x 10,000 = 10 million different antibody proteins (difference in amino acid sequence somewhere in either light and/or heavy chain).


3. What additional processes give rise to even greater variability?

For both light chain and heavy chain, even more variability arises from the two processes described on page 488 in your textbook. Overall, taking all the processes into account, the total number of different antibodies that can be made by your body is over a hundred million.


4. Why is it important to be able to make so many different antibodies?

When you get infected with a virus (or bacteria) that your body has never seen before, any B cells in you that just happen to be producing an antibody that can bind specifically to the virus surface are stimulated to start dividing and producing lots more of this antibody. This starts the process of clearing the infectious agent from the body.



Problem S-10: "Synthesis of antibody light chain V5J2C".

Draw an equivalent of Figure 11.36 that shows how light chain V5J2C gets synthesized by a B cell in which the appropriate DNA rearrangement has occurred.