Induced Mutations and Antibody Diversity
We have seen that lymphocytes use reasonably small numbers of V, J, and D segments to generate a large number of different genes coding for antibody polypeptide chains. This, plus the fact that antigenic specificity is generated by the combination of two unrelated antibody chains, permits an animal to synthesize millions of different antibodies. As mentioned earlier, however, survivability of a species dictates that antibody specificities be randomly determined. Furthermore, it is likely that within the population of animals of one species, the genes involved with antibody diversity should themselves be considerably more vari-able than other genes. Such variability at a genetic locus is known as a genetic polymorphism and indeed is observed in the antibody genes.
The evidence for variability beyond that introduced at the ends of D segments and the variable crossover points in the splicing of J segments is direct. In one study involving a special line of mice, myelomas whose IgG products bound phosphocholine were examined. In contrast to most similar situations, the light chain variable region RNAs from these myelomas was found to hybridize to only one genomic V region. Thus, only one V region gene encoded all the different V region RNAs. Some of the V regions cloned from mouse myelomas were found to possess exactly the same V region sequence as the homologous V region cloned from embryonic mouse DNA. Others, however, differed from the em-bryonic sequence in one or more locations. Since all the V region genes originated from the same germ line V region and the corresponding sequence in nonlymphocyte cells is unaltered, the slight sequence dif-ferences represent mutations that were selectively introduced into the gene. Some of the differences encoded different amino acids, whereas others were neutral. Furthermore, the changes were localized to within about 2 Kb of the V region gene. These results mean that the mechanism responsible for generating the mutations makes mutations randomly but confines the changes to the immediate vicinity of the V region gene.
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