Gene expression variation in 'Down syndrome' mice allows prioritization of candidate genes

Background : Down syndrome ( DS) or trisomy 21 is a complex developmental disorder showing many clinical signs that vary in occurrence and severity among patients. The molecular mechanisms responsible for DS have so far remained elusive. We argue here that normal variation of gene expression in the population contributes to the heterogeneous DS clinical picture, and we estimated the amplitude of this variation for 50 mouse orthologs of chromosome 21 genes in brain regions of Ts65Dn, a mouse model of DS. We analysed the RNAs of eight Ts65Dn and eight euploid mice by real-time PCR. Results : On pooled RNAs, we confirmed that trisomic: euploid gene expression ratios were close to 1.5. However, we observed that inter-individual gene expression levels spanned a broad range of values. We identified three categories of genes: genes with expression levels consistently higher in Ts65Dn than in euploids ( 9, 17 and 7 genes in the cerebellum, cortex and midbrain, respectively; of these, App, Cbr1 and Mrps6, which showed tight regulation in the three tissues, are attractive candidates); genes whose expression levels partially overlap between the two groups ( 10, 9, and 14 genes, respectively); and genes with intermingled expression, which cannot be used to differentiate trisomics from euploids ( 12, 5 and 9 genes, respectively). Conclusions : This is the first analysis addressing inter-individual gene expression levels as a function of trisomy. We propose a strategy allowing discrimination between candidates for the constant features of DS and those genes that may contribute to the partially penetrant signs of DS.