H Chains Are Assembled by Two Sequential Recombination Events

KEY CONCEPTS
- The units for H chain recombination are a V_H gene, a D segment, and a J_H -C_H gene segment.
- The first recombination joins D to J_H -C_H . The second recombination joins V_H to D_HJ_H -C_H to yield V_H -D_HJ_H -C_H .
- The C_H segment consists of four exons.
The IgH locus includes an additional set of gene segments, the D segments. Thus, the assembly of a complete H chain entails recombination of V_H , D, and J_H genes. The D segment (for diversity) was discovered by the presence in the H chain peptide sequences of an extra 2 to 13 amino acids between the sequences coded by the V_H and the J_H segments. An array of D segments lies on the chromosome between the cluster of V_H segments and that of J_H segments.
V_H DJ_H joining takes place in two stages (FIGURE 1). First, one of the D segments recombines with a J_H segment; second, a V_H segment recombines with the already recombined DJ_Hsegment. The resulting V_H DJ_H DNA sequence is then expressed with the nearest downstream C_H gene, which consists of a cluster of four exons (the use of different C_H genes is discussed in the section in this chapter titled Class Switch DNA Recombination). The D segments are organized in a tandem array. The human locus comprises about 30 D segments, followed by a cluster of 6 J_H gene segments. The same D segment is involved in the DJ_H recombination and related V_H DJ_H recombination.

FIGURE 1. Heavy genes are assembled by sequential recombination events. First a D_H segment is recombined with a J_H segment, and then a V_H gene segment is recombined with the D_H segment.
The structure of recombined V(D)J segments is similar in organization in the H chain and λ and κ chain loci. The first exon codes for the signal sequence, which is involved in membrane attachment, and the second exon codes for the major part of the variable region itself, which is about 100 codons long. The remainder of the variable region is provided by the D segment (in the H chain locus only) and by a J segment (in all three loci).

The structure of the C region differs in different H and L chains. In both κ and λ chains, the C region is encoded by a single exon, which becomes the third exon of the recombined V_κ J_κ -C_κ or V_λ J_λ - C_λ gene. In H chains, the C region is encoded by multiple and discrete exons, separately coding for four regions: C_H1; C_H hinge; C_H 2 and C_H 3 (IgG, IgA, and IgD); or C_H 1, C_H 2, C_H 3, and C_H 4 (IgM and IgE). Each C_H exon consists of about 100 codons, with the  hinge exon being shorter; the intronic sequences are about 300 bp each.