Sequences of the joining region genes for immunoglobulin heavy chains and their role in generation of antibody diversity.

Abstract

The contribution to Ig heavy chain diversity made by recombination between variable region (VH) genes and joining region (JH) genes was assessed to the sequence of .apprx. 2000 nucleotides spanning the rearranged JH gene cluster associated with the VH gene expressed in plasmacytoma HPC76. The active VH76 gene has recombined with the 2nd germ-line JH gene. The region contains 2 other JH genes, designated JH3 and JH4. No other JH gene was found within the region 1000 nucleotides downstream from JH4. Between JH3 and JH4 there is a pseudo-JH sequence with substantial homology to the authentic JH genes. The 4 JH genes whose sequences now are known can account for all known JH amino acid sequences. The JH genes are more divergent than the J.kappa. genes and vary in length, encoding either 15 or 17 amino acid residues. Because JH regions comprise part of the 3rd hypervariable region (HV3), combinatorial VH-JH joining substantially augments VH diversity. A VH gene can recombine with each JH gene at several positions, and either 1 or 2 germ-line JH codons can be excised. This JH truncation markedly reduces the length of HV3 and hence must alter antigen-binding specificity. The sequence of the JH4 region in 2 different .gamma.2a mRNA was determined. Each suffered a point mutation (aspartate to asparagine) which would alter the charge of the antigen-binding site.