Journal
HUMAN MOLECULAR GENETICS
Volume 20, Issue 3, Pages 580-588Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddq501
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Funding
- University of Rochester Paul D. Wellstone Muscular Dystrophy Cooperative Research Center with National Institute of Health [NIH/NS048843, AR049077, AR48143]
- Muscular Dystrophy Association
- Saunders Family Research Fund
- Cell Science Research Foundation
- Uehara Memorial Foundation
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More than 12 neurogenetic disorders are caused by unstable expansions of (CTG)center dot(CAG) repeats. The expanded repeats are unstable in germline and somatic cells, with potential consequences for disease severity. Previous studies have shown that contractions of (CAG)(95) are more frequent when the repeat tract is transcribed. Here we determined whether transcription can promote repeat expansion, using (CTG)center dot(CAG) repeat tracts in the size range that is typical for myotonic dystrophy type 1. We derived normal human fibroblasts having single-copy genomic integrations of 800 CTG repeats. The repeat tract showed modest instability when it was not transcribed, yielding an estimated mutation rate of 0.28% per generation. Instability was enhanced several-fold by transcription in the forward or reverse transcription, and 30-fold by bidirectional transcription, yielding many expansions and contractions of more than 200 repeats. These results suggest that convergent bidirectional transcription, which has been reported at several disease loci, could contribute to somatic instability of highly expanded (CTG)center dot(CAG) repeats.
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