Coupling Transcriptional State to Large-Scale Repeat Expansions in Yeast

Abstract

Summary: Expansions of simple DNA repeats cause numerous hereditary disorders in humans. Replication, repair, and transcription are implicated in the expansion process, but their relative contributions are yet to be distinguished. To separate the roles of replication and transcription in the expansion of Friedreich’s ataxia (GAA)n repeats, we designed two yeast genetic systems that utilize a galactose-inducible GAL1 promoter but contain these repeats in either the transcribed or nontranscribed region of a selectable cassette. We found that large-scale repeat expansions can occur in the lack of transcription. Induction of transcription strongly elevated the rate of expansions in both systems, indicating that active transcriptional state rather than transcription through the repeat per se affects this process. Furthermore, replication defects increased the rate of repeat expansions irrespective of transcriptional state. We present a model in which transcriptional state, linked to the nucleosomal density of a region, acts as a modulator of large-scale repeat expansions. : The molecular pathways of replication and transcription are implicated in the expansion of simple DNA repeats, but it has been difficult to distinguish their relative contributions. Shah et al. design and utilize genetic systems to investigate repeat instability in the absence of transcription, showing that transcriptional state rather than transcription through the repeat per se affects this process. The authors present a model linking transcriptional state to the density of nucleosomes in the repeat-containing region, which inherently acts as a modulator of large-scale expansions.