Genetic basis of Down syndrome: Physical, comparative, and molecular analysis of chromosome 21

Down syndrome is the most prevalent live born autosomal aneuploidy. It results from the presence of a third copy of chromosome 21 and is associated with a spectrum of phenotypes affecting almost every tissue type. Regions of the mouse genome, chromosomes 10 and 16 in this study, that contain conserved synteny with human chromosome 21 were examined for the purpose of better understanding the gene content of these related regions in both mouse and human, evaluate how accurately the Down syndrome genomic insult has been replicated in currently existing mouse models, as well as generate the information and substrates necessary for the construction of new mouse models. P1 and Bacterial Artificial Chromosomes (PACs and BACs) covering 6.6 Mb of chromosome 21-related sequence in mouse were assembled into contigs. These physical maps revealed no difference in gene content across the entire mouse chromosome 10/human chromosome 21 conserved synteny region but a mouse gene, Itgb2l, lacking a human ortholog was mapped to the region of mouse chromosome 16 that is present in three copies in the mouse models Ts65Dn and Ts1Cje. Such differences in gene content will have to be accounted for when attempts are made to correlate phenotypes in the mouse model to the human condition. Additionally, these PAC maps are being used to generate genomic sequence for further analysis.; The Ts65Dn mouse model displays many phenotypes that are commonly observed in Down syndrome including a reduction in cerebellar size and decrease in granule cell density in the cerebellum. To determine how this change in morphology affects the normal functioning of an adult cerebellum, RNA populations from Ts65Dn and euploid mice were compared on multiple microarray formats. Little difference was found in the expression pattern of the two samples, indicating that if behavioral deficits result from the malformed cerebellum, they are due to structural abnormalities of the cells or tissue as a whole and not functional failing in gene transcription by individual cells. A complete picture, knowing all those genes involved in the initiation of Down syndrome due to their placement on chromosome 21 and what transcripts are eventually misregulated to the point that they result in an abnormal phenotype, will be necessary for a true understanding of the molecular mechanisms of Down syndrome. These studies take steps in developing both sides of that picture.