Figure 24–28 The V–J joining process involved in making a human κ light chain. In the “germ-line” DNA (where the Ig gene segments are not rearranged and are therefore not being expressed), the cluster of five J gene segments is separated from the c-region coding sequence by a short intron and from the 35 or so functional V gene segments by thousands of nucleotide pairs. During the development of a B cell, a randomly chosen V gene segment (V3 in this case) is moved to lie precisely next to one of the J gene segments (J3 in this case). The “extra” J gene segments (J4 and J5) and the intron sequence are transcribed (along with the joined V3 and J3 gene segments and the c-region coding sequence) and then removed by rNA splicing to generate mrNA molecules with contiguous V3, J3, and C sequences, as shown. These mrNAs are then translated into κ light chains. A J gene segment encodes the 15 or so c-terminal amino acids of the  V region, and a short sequence containing the V–J segment junction encodes the third hypervariable region, which is the most variable part of the light-chain V region.
Figure 24–29 The human heavy-chain locus. There are 40 V segments, about 23 D segments, 6 J segments, and an ordered cluster of c-region coding sequences, each cluster encoding a different class of heavy chain. The D segment (and part of the J segment) encodes amino acids in the third hypervariable region, which is the most variable part of the heavy-chain V region. The genetic mechanisms involved in producing a heavy chain are the same as those shown in Figure 24–28 for light chains, except that two DNA rearrangement steps are required instead of one: first a D segment joins to a J segment, and then a V segment joins to the rearranged DJ segment. The rearrangements lead to the production of a VDJc mrNA that encodes a complete Ig heavy chain. The figure is not drawn to scale: the total length of the heavy-chain locus is over two megabases. Moreover, a number of details are omitted: for example, the exons encoding each c-region Ig domain and the hinge region (see Figure 24–27) and the different subclasses of cγ-coding segments are not shown.
the accumulation of point mutations in both heavy-chain and light-chain V-region coding sequences. The mutations occur long after the coding regions have been assembled. After B cells have been stimulated by antigen and helper T cells in a peripheral lymphoid organ, some of the activated B cells proliferate rapidly in the lymphoid follicles and form germinal centers (see Figure 24–20). Here, the B cells mutate at the rate of about one mutation per V-region coding sequence per cell generation. Because this is about a million times greater than the spontaneous mutation rate in other genes and occurs in somatic cells rather than germ cells, the process is called somatic hypermutation.
Very few of the altered Igs generated by hypermutation will have an increased affinity for the antigen. But, because the same Ig genes produce both BCRs and secreted antibodies, the antigen will stimulate preferentially those few B cells that do make BCRs with increased affinity for the antigen. Clones of these altered B cells will preferentially survive and proliferate, especially as the amount of antigen decreases to very low levels late in the response. Most other B cells in the germinal center will die by apoptosis. Thus, as a result of repeated cycles of somatic hyper-mutation followed by antigen-driven proliferation of selected clones of effector and memory B cells, antibodies of increasingly higher affinity become abundant during an adaptive immune response, providing progressively better protection against the pathogen (Movie 24.6).