D1 (superoxide dismutase), GART (a purine biosynthesis enzyme), CBS (cys-tathionine beta-synthetase), and those involved in RNA splicing and the ubiquitin pathway. A further set of 31 genes showed excellent informative matches but only over a domain or subregion of the human protein. Previously known homologs include MNB (minibrain) and SIM2 (single-minded). Perhaps most interesting in both sets are those genes for which there is little or no functional data. Table Table22 lists some of the known and novel chromosome 21 genes with partial and complete similarities in Drosophila. Among the novel genes, identities at the amino-acid level range as high as 64% (c21orf19) and over as many as 1,600 residues (c21orf5). Additional details remain to be resolved; for example, in several cases the lengths of the human and Drosophila proteins are significantly different. Correcting these differences, if it is necessary, may strengthen the similarity data. In addition, defining complete cDNAs may reveal new homologies not discernible with partial gene models. Determining the phenotypes of mutants in the Drosophila genes is likely to shed light on the function of the homologous human genes.
Regions of human chromosome 21 are conserved within segments of three mouse chromosomes. The centromere-proximal region of chromosome 21 through the MX genes is homologous with the telomeric region of mouse chromosome 16 (Figure (Figure1).1). The next approximately 2 Mb segment of chromosome 21 is homologous with the centromere-proximal region of mouse chromosome 17, and the telomeric 2 Mb of chromosome 21 is homologous with an internal segment of mouse chromosome 10. On the basis of current data, the order of chromosome 21 homologues in the mouse chromosome 16 and 10 segments appears to be completely conserved, although the boundaries of these regions are still approximate [28,29]. For example, the most centromere-proximal gene on chromosome 21 verified to map to mouse chromosome 16 is STCH. There are seven genes proximal to this that should be mapped in mouse. Similarly, although it is known that Mx maps to mouse chromosome 16 and Tff3, Cbs and Crya map to mouse chromosome 17, there are 11 genes between and among these that are of unknown map location in mouse. Lastly, PDXK is the most proximal chromosome 21 gene mapped to mouse chromosome 10 . Genes in this region are relatively small, however, and additional chromosome 21 genes may be located on mouse chromosome 10 between Pdxk and the adjacent region homologous with human chromosome 19. Defining the endpoints of these homologous regions is critical for evaluating gene-phenotype correlations within existing mouse models and for designing new ones.
Currently, the best mouse models of DS are the mouse chromosome 16 segmental trisomies, Ts65Dn and Ts1Cje. Ts65Dn is trisomic for the region spanning an undefined distance proximal to App through Mx to presumably the telomere of chromosome 16. The phenotype of Ts65Dn includes working memory impairment and long term memory deficits; delayed development and lower body weight; motor dysfunction; decreased responsiveness to pain; hyperactivity; and decreased ability to inhibit behavior (reviewed in [30,31]; see also [32,33]). Particularly interesting are observations of age-related loss of cholinergic neurons, decreased numbers of asymmetric synapses in the temporal cortex, abnormalities in neuron number in hippocampal regions, and deficiencies of beta-noradrenergic transmission within the hippocampus and cerebral cortex [34,35,36,37,38]. Some of these deficits have been observed in DS; others suggest new avenues of investigation. Knowing which genes cannot be responsible for the phenotype can be helpful. Table Table3a3a lists the 32 genes found centromeric to the Alzheimer's-associated gene APP on chromosome 21. On the basis of current comparative mapping data, most of these may be present in only two copies in Ts65Dn and therefore would not contribute to its phenotypic features. The Ts1Cje mouse is a more recent model, and is trisomic for the region of 