INSERTIONS AND DELETIONS IN HYPERVARIABLE LOOPS OF ANTIBODY HEAVY-CHAINS CONTRIBUTE TO MOLECULAR DIVERSITY

Antibody diversity, a molecular feature which allows these proteins to specifically interact with a diverse set of targets, is created at th e genetic level by a variety of means. These include germline gene seg ment recombination, junctional diversity and single basepair (bp) subs titution. We here demonstrate that a human high affinity antibody spec ific for an exogenous protein antigen carry three amino acid residues immediately adjacent to the first hypervariable loop of the heavy chai n. These additional residues are shown not to be encoded by the germli ne repertoire. We also describe the characteristics of insertions and deletions, not found in any known germline sequence, within the first and second hypervariable loops of other previously described antibody- encoding genes. These findings demonstrate that insertions or deletion s of entire codons provide yet another approach by which the human ant ibody repertoire is diversified in vivo. Since these major genetic mod ifications occur within or immediately adjacent to loops contributing to the antigen-binding site, they are likely to affect the binding pro perties of the mutated antibodies. (C) 1998 Elsevier Science Ltd. All rights reserved.