Down syndrome (DS) is caused by trisomy for human chromosome 21 (HSA21). This condition results in a constellation of phenotyping anomalies, a subset of which are observed in any given individual. The mechanisms by which trisomy 21 (Ts21) disrupts development are poorly characterized, but two major schools of thought have emerged. The first holds that dosage imbalance of specific individual genes from Chr21 can ultimately be linked to specific phenotypes observed among DS individuals. This one gene-one phenotype hypothesis draws support from analysis of a small percentage of DS in which a cytogenetic rearrangement results in duplication for a subset of the chromosome resulting from (""""""""translocation"""""""" DS). Determination of a shared minimally overlapping segment of HSA21 in patients who show the same specific DS phenotype has been used to map features to specific regions. This has led some investigators to posit that one or a few genes """"""""cause"""""""" DS. The same, limited patient database has been interpreted differently by others. At the opposite extreme from the one gene-one phenotype hypothesis, some have suggested that Ds phenotypes result from a disruption of homeostasis which is the product of an evolutionary-achieved balance of genetic programs regulating development. This """"""""quantitative"""""""" hypothesis suggests that dosage imbalance for large numbers of genes will disrupt multiple genetic pathways, overcoming canalization and resulting in developmental anomalies. Its proponents stress the increased features of these two schools of thought are first, they are not mutually exclusive; second, both rely on examination of different select subsets of patients and other available data; and third, neither can be proved or disproved by studies in human beings. Whole genome approaches using animal models are required to advance investigation in this area. The Ts65Dn mouse is at dosage imbalance for most of the same genes triplicated in DS. We have characterized specific, completely penetrant phenotypic changes that are highly similar in Ts21 and in Ts65Dn, and that map to a DS """"""""critical region"""""""" on HSA21. Chromosome engineering in mouse will produce defined dosage imbalance for the same genes that are in the HSA21 critical region. If the hypothesis that genes in this region are responsible is correct, these phenotypes will occur in these mice. The proposed experiments provide a genomic approach for a direct test of the hypothesis that one or a few genes in a ca.4.5 MB region of Chr21 are responsible for many DS phenotypes. Mutagenesis and gene expression strategies are described which will characterize expression and functions of genes in this segment and so identify those genes that contribute to developmental anomalies in DS.
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