Abstract
Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.
Highlights
Down syndrome is the most common genetic cause of intellectual disability, accounting for,1 in 750 births, and is caused by trisomy of chromosome 21 [1]
Parallel array Comparative Genomic Hybridisation of the HT1080 cell line demonstrated that Tc1
The copy number imbalances detected by our microarray analysis were confirmed by mapping of sequence reads to the Hsa21 reference genome (NCBI37) using MAQ (Fig. 1)
Summary
Down syndrome is the most common genetic cause of intellectual disability, accounting for ,1 in 750 births, and is caused by trisomy of chromosome 21 [1]. To help model and understand the molecular genetics of DS, the first transchromosomic mouse, the Tc1 model (Tc(Hsa21)1TybEmcf) was created, which carries a freely segregating copy of human chromosome 21 [3]. This model was generated by irradiation microcell-mediated chromosome transfer (XMMCT); briefly Hsa was isolated in microcells from a human cell-line (HT1080) ([4]) and c-irradiated before transfer into a 129S2 mouse embryonic stem (ES) cell line. Resulting chimeric animals were bred and a single germ-line transmission of an irradiated Hsa led to the establishment of the Tc1 mouse strain
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
