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Hum Mol Genet. 2016 Apr 15;25(8):1619-36. doi: 10.1093/hmg/ddw040. Epub 2016 Feb 14.

Allelic series of Huntington's disease knock-in mice reveals expression discorrelates.

Author information

1
Department of Cell, Developmental and Integrative Biology.
2
Department of Biochemistry and Molecular Genetics.
3
VAAAHS GRECC, Ann Arbor, MI, USA and Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
4
Department of Genetics, and.
5
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
6
Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL, USA.
7
Department of Biochemistry and Molecular Genetics, detloff@uab.edu.

Abstract

Identifying molecular drivers of pathology provides potential therapeutic targets. Differentiating between drivers and coincidental molecular alterations presents a major challenge. Variation unrelated to pathology further complicates transcriptomic, proteomic and metabolomic studies which measure large numbers of individual molecules. To overcome these challenges towards the goal of determining drivers of Huntington's disease (HD), we generated an allelic series of HD knock-in mice with graded levels of phenotypic severity for comparison with molecular alterations. RNA-sequencing analysis of this series reveals high numbers of transcripts with level alterations that do not correlate with phenotypic severity. These discorrelated molecular changes are unlikely to be drivers of pathology allowing an exclusion-based strategy to provide a short list of driver candidates. Further analysis of the data shows that a majority of transcript level changes in HD knock-in mice involve alteration of the rate of mRNA processing and/or degradation rather than solely being due to alteration of transcription rate. The overall strategy described can be applied to assess the influence of any molecular change on pathology for diseases where different mutations cause graded phenotypic severity.

PMID:
26908599
PMCID:
PMC4805312
DOI:
10.1093/hmg/ddw040
[Indexed for MEDLINE]
Free PMC Article
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