 gene. Thus, unless novel genes have very different characteristics, it is reasonable to expect a similarly high level of success in their identification. Using these criteria a further 118 genes were identified.
What is likely to have been missed? First, there are gaps in the sequence of 21q. They are few (three) and small (<50 kb each), however, and therefore cannot harbor large numbers of genes. Second, genes that would not be identified would have to possess the following features: no similarity to any known protein; consistently very large introns (>30-60 kb), so that patterns of predicted exons would not be scored; and long intronless 3' untranslated regions (UTRs) or restricted and/or low expression levels, so that no spliced EST is present in dbEST. It is certainly possible that some number of genes with such characteristics exist; that they represent a significant proportion of chromosome 21 genes is unlikely, however. The distal one third of 21q is the most gene-rich (and GC-rich); but intergenic distances here are not large enough to accommodate additional genes with uniformly large introns. So, unless coding exons in these genes are for some reason not recognized, such genes would be scored on the basis of patterns of predicted exons. The proximal two thirds, in contrast, is uniformly AT-rich and does have large segments lacking gene features; indeed, there is one segment of approximately 7 Mb that harbors only seven genes. Here there is room for numerous genes that have large introns and restricted expression. One argument against this is a biological one: an individual who is monosomic for this region has only mild phenotypic abnormalities . A second argument is a general scarcity of any consistent exon prediction in the region, regardless of 'intron' size. If there are many coding exons within this region, they must also be largely unrecognized by prediction programs. Together, these data suggest that the total of 225 genes is likely to be reliable: false negatives should be few.
But what about the 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 do