INFLUENCES OF ARRAY SIZE AND HOMOGENEITY ON MINISATELLITE MUTATION

Unstable minisatellites display high frequencies of spontaneous gain a nd loss of repeats in the human germline. Most length changes arise th rough complex recombination events including intra-allelic duplication s/deletions and inter-allelic transfers of repeats. Definition of the factors modulating instability requires bath measurement of mutation r ate and detailed analysis of mutant structures at the level of individ ual alleles, We have measured mutation rates in sperm for a wide range of aIleles of the highly unstable human minisatellite CEB1. Instabili ty varies by three orders of magnitude between alleles and increases s teadily with the size of the tandem array. Structural analysis of muta nt molecules derived from six alleles revealed that it is the rate of intra-allelic rearrangements which increases with array size and that intra-allelic duplication events tend to cluster within homogeneous se gments of alleles; both phenomena resemble features of trinucleotide r epeat instability. In contrast, inter-allelic transfers occur at a fai rly constant rate, irrespective of array length, and show a mild polar ity towards one end of the minisatellite, suggesting the possible infl uence of flanking DNA on these conversion-like events.