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Expanded trinucleotide repeats cause many human diseases, including Huntington's disease (HD). Recent studies indicate that somatic instability of these repeats contributes to pathogenesis in several expansion disorders. We find that lowering huntingtin protein (HTT) levels reduces somatic instability of both the Htt and Atxn2 CAG tracts in knockin mouse models, and the HTT CAG tract in human iPSC-derived neurons, revealing an unexpected role for HTT in regulating somatic instability. ### Competing Interest Statement Research Funding: JBC has received research support from CHDI Foundation, Ionis Pharmaceuticals, Wave Life Sciences, and Triplet Therapeutics. Besides the authors of this paper who are employed by Ionis Pharmaceuticals (CFB, HK), no staff of these companies had any role in the design or interpretations of these experiments. SJT, HG and JH were funded by CHDI Foundation and DRI UK. MF was funded by DRI UK and Health Education England (HEE). JBC was funded by CHDI foundation and the Huntington Society of Canada. GA was funded by the DFG. RMP was the recipient of the Berman/Topper Family HD Career Development Fellowship from the Huntington's Disease Society of America. SOZ was funded by the CHDI Foundation and by NIH NS090914. VCW was supported by the National Institutes of Health [NS049206] and by the CHDI Foundation. Employment: CFB and HBK are employees of Ionis Pharmaceuticals. JBC is a member of the scientific advisory board of Triplet Therapeutics. Personal financial interest: JBC is a member of the scientific advisory board of Triplet Therapeutics and has received consulting fees from Skyhawk Therapeutics. In the past 2 years, SJT has undertaken consultancy services, including membership of scientific advisory boards, with Alnylam Pharmaceuticals Inc., Annexon Inc., LoQus therapeutics (DDF Discovery Ltd), F. Hoffmann-La Roche Ltd, Genentech, PTC Bio, Novartis Pharma, Takeda Pharmaceuticals Ltd, Triplet Therapeutics, UCB Pharma S.A., University College Irvine and Vertex Pharmaceuticals Incorporated. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. None of these companies had any role in the design or interpretations of these experiments. Other authors report no conflicts. VCW is a scientific advisory board member of Triplet Therapeutics, a company developing new therapeutic approaches to address triplet repeat disorders such Huntington's disease and Myotonic Dystrophy, and of LoQus23 Therapeutics and has provided paid consulting services to Alnylam. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.

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