To understand the causes of CAG repeat tract changes that occur in the passage of human disease alleles, we are studying the effect of replication and repair mutations on CAG repeat tracts embedded in a yeast chromosome. In this report, we examine the effect of a mutation in the RTH1/RAD27 gene encoding a deoxyribonuclease needed for removal of excess nucleotides at the 5'-end of Okazaki fragments. Deletion of the RTH1/RAD27 gene has two effects on CAG tracts. First, the rth1/rad27 mutation destabilizes CAG tracts. Second, although most tract length changes in wild-type yeast cells are tract contractions, approximately half of the changes that occur as a result of the rth1/rad27 mutation are expansions of one or more repeat units. These results support the hypothesis that tract expansions that occur during passage of human disease alleles bearing expanded CAG tracts result from excess DNA synthesis on the lagging strand of replication.
Bibliographical noteFunding Information:
We thank Harry Orr for his encouragement and for his comments on the manuscript. This work was supported by grant P01NS33718 from the National Institutes of Health.