Transcript Level Alterations Reflect Gene Dosage Effects Across Multiple Tissues in a Mouse Model of Down Syndrome

Abstract

Human trisomy 21, which results in Down syndrome (DS), is one of the most complicated congenital genetic anomalies compatible with life, yet little is known about the molecular basis of DS. It is generally accepted that chromosome 21 (Chr21) transcripts are overexpressed by about 50% in cells with an extra copy of this chromosome. However, this assumption is difficult to test in humans due to limited access to tissues, and direct support for this idea is available for only a few Chr21 genes or in a limited number of tissues. The Ts65Dn mouse is widely used as a model for studies of DS because it is at dosage imbalance for the orthologs of about half of the 284 Chr21 genes. Ts65Dn mice have several features that directly parallel developmental anomalies of DS. Here we compared the expression of 136 mouse orthologs of Chr21 genes in nine tissues of the trisomic and euploid mice. Nearly all of the 77 genes which are at dosage imbalance in Ts65Dn showed increased transcript levels in the tested tissues, providing direct support for a simple model of increased transcription proportional to the gene copy number. However, several genes escaped this rule, suggesting that they may be controlled by additional tissue-specific regulatory mechanisms revealed in the trisomic situation

Aneuploidy: Cells Losing Their Balance

“…Transcript levels of genes encoded on chromosome 21 parallel the increase in gene copy number in patients with Down's syndrome (Mao et al 2003). Similar results were obtained in mice with a partial trisomy for chromosome 16 or 17 (Kahlem et al 2004;Lyle et al 2004;Vacik et al 2005). In addition, changes in gene expression appear to correlate with changes in gene copy number in aneuploid cancer cells (Pollack et al 2002;Tsafrir et al 2006).…”

Age‐specific hormonal decline is accompanied by transcriptional changes in human sebocytes in vitro

“…Data normalization was carried out as described by Kahlem et al (2004) and, in order to verify whether a given gene was significantly expressed, we compared its signal to a signal distribution derived from negative controls (Adjaye, 2005). In our array design, we distributed 3362 empty spot positions on the array.…”

Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

“…There have been several general approaches to this problem: (i) mapping of partial trisomy 21 cases in human, 3 -8 (ii) the construction of partial trisomy mouse models with different orthologous regions of HSA21 9 -11 and (iii) the analysis of gene expression in cells and tissues of DS individuals or mouse models of DS, both of the transcriptome 12 -15 and genes from the aneuploid chromosome. 16,17 Expression studies, while showing dysregulation of gene expression, have been inconclusive in identifying genes, or small HSA21 regions, for specific DS phenotypes.…”