mains. Some zinc finger proteins have been shown to be transcription factors, so ZBF295 is classed as such. In general, genes are classified as broadly as possible. For example ITGB2, is classed only as a cell adhesion molecule, although because it has been studied essentially only in lymphocytes, it is regarded as an immune system gene . Future studies may well reveal functions other than those that have been observed, so it is as well to speculate about the functions of genes as broadly as possible.
Every biologist will bring their own expertise to bear in deciding which of the genes in Table Table11 are of greatest potential relevance to the DS phenotype. Transcription factors are attractive candidates because imbalance of one component of a transcription factor complex may alter the effectiveness of the activation or repression of transcription of target genes. Genes within the ubiquitin pathway may alter rates of target protein degradation. Cell adhesion was long ago postulated, with intriguing preliminary data , to play a role in altering rates and extents of cell migration during development. Overexpression of one potassium channel gene has been shown to disregulate expression of other channel genes, affecting neuronal network excitability . If mental retardation and cognitive deficits are the primary focus of study, almost any of the categories in Table Table11 could be relevant, such is the extent of our current understanding of the complex developmental processes leading to these conditions.
Only about half the 225 chromosome 21 genes have any functional association, and some of these are particularly weak - for example, the presence of a transmembrane domain is not very definitive. In some cases, the lack of protein or functional domain data may be due to the lack of complete coding sequence information. While awaiting the generation of complete cDNA sequences (which may be laborious to obtain), and even for further analysis of complete cDNAs lacking functional associations, expression patterns may help 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 SO