p in prioritizing genes for further study. Of the novel genes with incomplete cDNAs, thirty-eight are represented by ESTs from Soares or CGAP cDNA libraries . Of these, only seven would be classed as ubiquitous in expression - that is, present in dbEST with more than 30 entries from numerous tissues. Twenty-six ESTs are each associated with fewer than five dbEST entries. Five of these ESTs are seen only in testes/prostate and three are seen only in fetal sources. While there are features of dbEST construction that can produce artifactual pictures of expression patterns, these data suggest that the novel genes within 21q may be largely of limited expression. In some cases at least, this is consistent with the failure to identify these genes previously.
For relevance to mental retardation and cognitive deficits, genes with brain-specific expression, such as PCP4 , are of interest. Equally interesting are examples of brain-specific alternative processing, as is seen with Intersectin and DSCAM [22,23]. In an analysis of a number of novel gene models, alternative processing, some of it brain-specific, was observed in the majority of cases . It is unlikely that even most known genes have been examined thoroughly for instances of multiple transcripts. Because these may alter protein sequences and therefore function, their role in DS may be relevant.
Model organisms will provide the basis for functional studies of the known and novel chromosome 21 genes. The genomes of Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila [25,26,27] have been completely sequenced, and thus the complete set of proteins of each of these organisms is known. Annotation of the Drosophila genome identified approximately 13,500 genes. Comparison of the translations of all annotated chromosome 21 genes with the Drosophila set identified 23 chromosome 21 gene products with similarity to a Drosophila protein over the complete length. Many of these similarities involve basic biochemical/biological functions and include such proteins as SOD1 (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 shou