Repair of a double-strand break (DSB) in yeast can induce very frequent expansions and contractions in a tandem array of 375-bp repeats. These results strongly suggest that DSB repair can be a major source of amplification of tandemly repeated sequences. Most of the DSB repair events are not associated with crossover. Rearrangements appear in 50% of these repaired recipient molecules. In contrast, the donor template nearly always remains unchanged. Among the rare crossover events, similar rearrangements are found. These results cannot readily be explained by the gap repair model of Szostak et al. (J. W. Szostak, T. L. Orr-Weaver, R. J. Rothstein, and F. W. Stahl, Cell 33:25-35, 1983) but can be explained by synthesis-dependent strand annealing (SDSA) models that allow for crossover. Support for SDSA models is provided by a demonstration that a single DSB repair event can use two donor templates located on two different chromosomes.Tandem repeat instability is implicated in several human genetic diseases. The best-documented examples of deleterious rearrangements in tandem repeats are the massive amplifications of microsatellite DNA, known to be responsible for a dozen diseases, including fragile X syndrome and Huntington's disease (for reviews, see references 62 and 74). Rearrangements affecting minisatellites (repeats of 10 to 50 nucleotides) can be harmful, too (4). For example, expansions of a minisatellite are associated with epilepsy (30,31,73). During meiosis, minisatellites can display a very high rate of modification, including intra-allele duplications and deletions, and nonreciprocal interallelic transfer of information (2, 24). Recently, a human minisatellite was also found to display massive amplification (78). Rearrangements in tandem repeats are not specific to micro-and minisatellites. Expansions and contractions of larger tandem repeats have been observed in Drosophila melanogaster and yeast (48,49,69,75,76).While replication slippage can easily account for small changes in microsatellite copy number (63), the origin of massive amplifications remains a mystery. Since the predominant rearrangement events observed in minisatellites are nonreciprocal interallelic transfers of information, the meiotic instability affecting those sequences is thought to result from gene conversions rather than replication (24). Tandem repeat rearrangements observed in Drosophila are linked to P-M dysgenesis and have also been supposed to be the consequence of genetic recombination, because P-element excision is known to induce gene conversion (9,29,48,49,69).Gene conversions are most often explained by the doublestrand break (DSB) repair model, proposed by Resnick and Martin (54) and Szostak et al. (68) to account for recombination events in yeast and other fungi. Many of the features of this model, or of its revised version (67), have been experimentally verified in Saccharomyces cerevisiae. The initial observation that a DSB in the DNA double helix induced a gene conversion in mitotic cells (45) was corroborated by...