EXPANSIONS OF CAG REPEAT TRACTS ARE FREQUENT IN A YEAST MUTANT DEFECTIVE IN OKAZAKI FRAGMENT MATURATION

To understand the causes of CAG repeat tract changes that occur in the passage of human disease alleles, we are studying the effect of repli cation and repair mutations on CAG repeat tracts embedded in a yeast c hromosome, In this report, we examine the effect of a mutation in the RTH1/RAD27 gene encoding a deoxyribonuclease needed for removal of exc ess nucleotides at the 5'-end of Okazaki fragments, Deletion of the RT H1/RAD27 gene has two effects on CAG tracts, First, the rfh1/rad27 mut ation destabilizes CAG tracts, Second, although most tract length chan ges in wild-type yeast cells are tract contractions, approximately hal f 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 hyp othesis that tract expansions that occur during passage of human disea se alleles bearing expanded CAG tracts result from excess DNA synthesi s on the lagging strand of replication.