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

TitlePotential molecular consequences of transgene integration: The R6/2 mouse example.
Publication TypeJournal Article
Year of Publication2017
AuthorsJacobsen JC, Erdin S, Chiang C, Hanscom C, Handley RR, Barker DD, Stortchevoi A, Blumenthal I, Reid SJ, Snell RG, MacDonald ME, A Morton J, Ernst C, Gusella JF, Talkowski ME
JournalSci Rep
Volume7
Pagination41120
Date Published2017 Jan 25
ISSN2045-2322
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.

DOI10.1038/srep41120
Alternate JournalSci Rep
PubMed ID28120936
PubMed Central IDPMC5264158
Grant ListR00 MH095867 / MH / NIMH NIH HHS / United States
K99 MH095867 / MH / NIMH NIH HHS / United States
R01 NS091161 / NS / NINDS NIH HHS / United States
P01 GM061354 / GM / NIGMS NIH HHS / United States
R21 HD065286 / HD / NICHD NIH HHS / United States