Somatic versus germline mutation processes at minisatellite CEB1 (D2S90) in humans and transgenic mice

The most variable human minisatellites show extreme germline instability do minated by complex intra-allelic rearrangements plus a lower frequency of i nter-allelic transfers of repeat units. In contrast, little is known about somatic instability at such loci. We have therefore used single-molecule PC R to analyze mutation at minisatellite CEB1 (D2S90) in human blood DNA, Som atic mutants were rare and involved only relatively simple intra-allelic ev ents, with no bias toward expansions, in sharp contrast to the complex gain -biased rearrangements seen in sperm. Somatic and germline mutation process es were further analyzed in mice transgenic for a cosmid insert containing CEB1. Mutant molecules in transgenic sperm and blood were detected but only at the low frequencies seen in human blood and arose mainly by simple dupl ications and deletions as seen for somatic mutations in human. These data s uggest distinct pathways for germline and somatic CEB1 mutations with germl ine instability involving recombination-based repair of meiotic double-stra nd breaks and somatic mutation arising by replication slippage or mitotic r ecombination. The problem of transferring germline-specific features of min isatellite instability from human to mouse suggests, with other recent obse rvations, that long-range chromatin conformation may be required for the re combination-based mode of germline instability at human minisatellites. (C) 2000 Academic Press.