Abstract
Expansions of trinucleotide GAA•TTC tracts are associated with the human disease Friedreich's ataxia, and long GAA•TTC tracts elevate genome instability in yeast. We show that tracts of (GAA)230•(TTC)230 stimulate mitotic crossovers in yeast about 10,000-fold relative to a “normal” DNA sequence; (GAA)n•(TTC)n tracts, however, do not significantly elevate meiotic recombination. Most of the mitotic crossovers are associated with a region of non-reciprocal transfer of information (gene conversion). The major class of recombination events stimulated by (GAA)n•(TTC)n tracts is a tract-associated double-strand break (DSB) that occurs in unreplicated chromosomes, likely in G1 of the cell cycle. These findings indicate that (GAA)n•(TTC)n tracts can be a potent source of loss of heterozygosity in yeast.
Highlights
Several inherited human diseases are a consequence of the expansion of trinucleotide tracts [1,2]
We show that a 690 base pair region consisting of 230 copies of the (GAA)nN(TTC)n trinucleotide repeat stimulates mitotic crossovers in yeast 10,000-fold more strongly than an ‘‘average’’ yeast sequence
Our findings may be relevant to understanding the expansions of the (GAA)nN(TTC)n trinucleotide repeat tracts that are associated with the human disease Friedreich’s ataxia
Summary
Several inherited human diseases are a consequence of the expansion of trinucleotide tracts [1,2]. Friedreich’s ataxia is caused by expansion of tracts of the trinucleotide GAANTTC, a sequence that is associated with triplex formation [3]. In the yeast Saccharomyces cerevisiae, (GAA)nN(TTC)n tracts greater than 40 repeats in length result in an orientation-dependent stall of the replication fork [4,5]. The stall of the replication fork is observed when the (GAA)n sequence is located on the lagging strand template. (GAA)230 tracts stimulate ectopic recombination between lys heteroalles 200-fold more than (TTC)230 tracts [5]. In contrast to the strong orientationdependence observed in studies of replication fork stalling, DSB formation, and ectopic recombination, the frequency of large-scale expansions of the long (GAA)nN(TTC)n tracts is affected only slightly by tract orientation [6]
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