The variation in immunoglobulin heavy chain constant regions in evolution

The sequences of immunoglobulin (Ig) heavy chain constant (C) region genes do not appear to be well conserved in evolution. The nature of C region change was examined by comparing VH and CH segment variability in the shark, which has numerous C mu as well as VH genes. The sequence diversity among VH was found to be similar to that among C mu 1, suggesting that one Ig segment does not change faster than the other. Although the frequencies of nucleotide substitution were similar, changes in the form of insertions or deletions in loop segments occurred more often in C; the resulting loss of sequence continuity in C exons would make it more difficult to recover C region sequences by crosshybridization. Thus the C regions would seem to be less well conserved than they are. The C region sequences isolated from different animals are described, and sequence and structure are discussed with respect to functions found in mammalian Ig. It is suggested that, although fish, amphibians and reptiles have fewer Ig classes than mammals, heterogeneous gene products are in fact produced and may mediate different effector functions. A theory based on C region selection is presented to explain antibody maturation in animals with a multicluster Ig gene organization.