DUAL ENIGMA OF SOMATIC HYPERMUTATION OF IMMUNOGLOBULIN VARIABLE GENES- TARGETING AND MECHANISM

The immunoglobulin loci are uniquely unstable regions of the genome wh ich undergo as much mutation and selection in a matter of days as a sp ecies can undergo in generations of evolution. We have studied the mut ational pattern and targeting of this unusual hypermutation process ov er the past 16 years. The pattern of somatic mutations in rearranged v ariable (V) genes differs from the pattern of meiotic mutations, indic ating that a different mechanism generates hypermutation than generate s spontaneous mutation. Hypermutations begin on the 5' end of rearrang ed V genes downstream of the transcription initiation site and continu e through the V exon and into the 3'-flanking region before tapering o ff. Mutations are located randomly throughout the DNA sequence and exh ibit strand bias. The targeting of mutations to the region in and arou nd the rearranged V gene appears to require interactions between the p romoter and downstream intronic DNA sequences. The same mechanism that initiates hypermutation around V genes may also produce double-strand breaks that catalyze homologous recombination between rearranged V ge nes on two chromosomal alleles. With this data we have built a model o f hypermutation which predicts that V-region DNA is destabilized at th e nuclear matrix during transcription and undergoes strand breaks.