Potential molecular consequences of transgene integration: The R6/2 mouse example
Authors
Jacobsen, JC
Erdin, S
Chiang, C
Hanscom, C
Handley, RR
Barker, DD
Stortchevoi, A
Blumenthal, I
Reid, SJ
Snell, RG
MacDonald, ME
Ernst, C
Gusella, JF
Talkowski, ME
Publication Date
2017-01-25Journal Title
Scientific Reports
ISSN
2045-2322
Publisher
Nature Publishing Group
Volume
7
Number
41120
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Jacobsen, J., Erdin, S., Chiang, C., Hanscom, C., Handley, R., Barker, D., Stortchevoi, A., et al. (2017). Potential molecular consequences of transgene integration: The R6/2 mouse example. Scientific Reports, 7 (41120)https://doi.org/10.1038/srep41120
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 G$\textit{m}$12695 has striking molecular consequences. G$\textit{m}$12695, 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.
Sponsorship
This work was supported by the National Institutes of Health HD065286 (JFG), MH095867 (MET), GM061354 (MET, JFG), CHDI Inc. (JFG, AJM), NARSAD (MET), the Canada Research Chairs program and a grant from the Natural Science and Engineering Research Council of Canada (CE), and the Neurological Foundation of New Zealand (JJ).
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/srep41120
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262805
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International