Show simple item record

dc.contributor.authorJacobsen, JCen
dc.contributor.authorErdin, Sen
dc.contributor.authorChiang, Cen
dc.contributor.authorHanscom, Cen
dc.contributor.authorHandley, RRen
dc.contributor.authorBarker, DDen
dc.contributor.authorStortchevoi, Aen
dc.contributor.authorBlumenthal, Ien
dc.contributor.authorReid, SJen
dc.contributor.authorSnell, RGen
dc.contributor.authorMacDonald, MEen
dc.contributor.authorMorton, Jenniferen
dc.contributor.authorErnst, Cen
dc.contributor.authorGusella, JFen
dc.contributor.authorTalkowski, MEen
dc.date.accessioned2017-02-28T12:45:07Z
dc.date.available2017-02-28T12:45:07Z
dc.date.issued2017-01-25en
dc.identifier.issn2045-2322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/262805
dc.description.abstractIntegration 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.
dc.description.sponsorshipThis 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).
dc.languageengen
dc.language.isoenen
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titlePotential molecular consequences of transgene integration: The R6/2 mouse exampleen
dc.typeArticle
prism.number41120en
prism.publicationDate2017en
prism.publicationNameScientific Reportsen
prism.volume7en
dc.identifier.doi10.17863/CAM.8091
dcterms.dateAccepted2016-11-11en
rioxxterms.versionofrecord10.1038/srep41120en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-01-25en
dc.contributor.orcidMorton, Jennifer [0000-0003-0181-6346]
dc.identifier.eissn2045-2322
rioxxterms.typeJournal Article/Reviewen
cam.issuedOnline2017-01-25en
cam.orpheus.successThu Jan 30 12:57:10 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International