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Sci Rep. 2017 Jan 25;7:41120. doi: 10.1038/srep41120.

Potential molecular consequences of transgene integration: The R6/2 mouse example.

Author information

1
Centre for Brain Research, School of Biological Sciences, The University of Auckland 1010, New Zealand.
2
Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
3
Program in Medical and Population Genetics, Broad Institute of M.I.T and Harvard, Cambridge, Massachusetts 02143, USA.
4
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
5
Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115 USA.
6
Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, United Kingdom.
7
Department of Psychiatry, McGill University, Montreal, Quebec ON H4H 1R3, Canada.
8
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115 USA.
9
Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, 02114 USA.

Abstract

Integration of exogenous DNA into a host genome represents an important route to generate animal and cellular models for exploration into human disease and therapeutic development. In most models, little is known concerning structural integrity of the transgene, precise site of integration, or its impact on the host genome. We previously used whole-genome and targeted sequencing approaches to reconstruct transgene structure and integration sites in models of Huntington's disease, revealing complex structural rearrangements that can result from transgenesis. Here, we demonstrate in the R6/2 mouse, a widely used Huntington's disease model, that integration of a rearranged transgene with coincident deletion of 5,444 bp of host genome within the gene Gm12695 has striking molecular consequences. Gm12695, the function of which is unknown, is normally expressed at negligible levels in mouse brain, but transgene integration has resulted in cortical expression of a partial fragment (exons 8-11) 3' to the transgene integration site in R6/2. This transcript shows significant expression among the extensive network of differentially expressed genes associated with this model, including synaptic transmission, cell signalling and transcription. These data illustrate the value of sequence-level resolution of transgene insertions and transcription analysis to inform phenotypic characterization of transgenic models utilized in therapeutic research.

PMID:
28120936
PMCID:
PMC5264158
DOI:
10.1038/srep41120
[Indexed for MEDLINE]
Free PMC Article

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