 possibility of false positives? Genes with complete protein or cDNA sequences identical or highly similar to known genes (these are the class 1 and class 2 genes in ) are unambiguous. Gene models (classes 3 and 4), however, are still open to further investigation and interpretation. For example, some investigators will choose to disregard a specific match to a protein domain if the similarity is weak. How many exons to include in a model, and whether an EST should be included will also sometimes be debatable. Thus, details in the gene catalog of 21q should be considered provisional. Investigators should review the basis for specific gene predictions of interest (available at ).
DS can be considered as a contiguous gene syndrome, with almost the entirety of 21q the relevant region. The segment of 21q22.2 that is referred to as the Down syndrome chromosomal region (DSCR) was defined to contain genes relevant to aspects of the DS phenotype on the basis of the phenotypes of several cases of partial trisomy 21 [14,15]. Data using a larger number of partial trisomy cases showed that only the most centromeric region of 21q could be excluded from containing relevant genes, in particular for mental retardation . It is assumed that overexpression of chromosome 21 genes, as a result of their presence in an extra copy, causes the DS phenotype. Are all chromosome 21 genes overexpressed? Can overexpression of some genes be tolerated with no phenotypic effect? How many genes are overexpressed and relevant? Currently, there are no answers to these questions. It is, however, worth considering what is known about the function of chromosome 21 genes.
Table Table11 lists the 122 genes for which some functional association can be inferred. Functional inferences are based on partial or complete similarities of the chromosome 21 genes or gene models to proteins or protein domains for which experimental data has demonstrated a specific function. For example, ZNF295 is a gene model with an open reading frame that contains zinc finger domains. 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 hel