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The recent completion of the DNA sequence of human chromosome 21 has provided the first look at the 225 genes that are candidates for involvement in Down syndrome (trisomy 21). A broad functional classification of these genes, their expression data and evolutionary conservation, and comparison with the gene content of the major mouse models of Down syndrome, suggest how the chromosome sequence may help in understanding the complex Down syndrome phenotype.
Down syndrome (DS), affecting one in 700 live births, is the most common genetic cause of mental retardation . The phenotype of DS is complex and variable in severity among individuals; it includes mental retardation and cognitive deficits, heart defects, hypotonia, motor dysfunction, immune system deficiencies, an increased risk of leukemia, and development of the pathology of Alzheimer's disease . Most commonly, DS is due to the presence of an extra copy of a complete chromosome 21 and it is assumed that the DS phenotypic features are a direct consequence of the overexpression of some number of genes contained within 21q (21p is largely made up of ribosomal RNA genes and other repeat sequences). Recently, the essentially complete sequence of 21q - 33.5 Mb - was finished, and 225 genes were identified by the application of a variety of experimental and computer-based approaches . The availability of this massive amount of new data has immediate importance to DS research. This review discusses the following issues: the reliability of gene identification; what is known or can be inferred about the biological function of the 225 identified genes; expression patterns of the novel genes; evolutionary conservation of, in particular, those genes lacking functional associations; inferences about the gene content of the major mouse models of DS and therefore the causes of the phenotypic differences among them; and reasonable next steps towards the goal of understanding the gene-phenotype relationships in DS. Throughout the following discussions, references to numbers and kinds of genes and additional analyses of 21q gene content are based on the data presented in .
Two hundred and twenty-five is a surprisingly small number for the complete gene content of approximately 1% of the human genome. It is significantly less than 1% of the 50,000-100,000 genes previously estimated in total for the human genome (see also ) and it is significantly less than the 545 genes identified on chromosome 22 in approximately the same amount of DNA . Previous data from the mapping of expressed sequence tags (ESTs) and genes, and efforts at cDNA selection, have consistently suggested that chromosome 21 was relatively gene-poor overall, and extremely so in some regions [6,7]. It could also be predicted that chromosome 21 would have fewer genes than chromosome 22. Approximately half of chromosome 21 is a large dark band when stained with Giemsa, and such bands are known to be gene-poor, while chromosome 22 is almost entirely comprised of gene-rich R bands [8,9]. In addition, trisomy 21 is compatible with life, while trisomy 22 is not . Chromosome 21, therefore, was expected to be relatively gene-poor. Its extreme paucity of genes, however, justifies further consideration. In particular, are there consistent errors or weaknesses in gene-finding techniques that could have missed a significant proportion of genes? To see where errors may have accumulated, it is worth reviewing the gene identification methods.
Genes were identified on the basis of the following types of data: identities or similarities to known proteins; identities to spliced ESTs; and patterns of consistent coding-exon prediction. First, protein matches identified genes that were identical or similar to known genes, and also found pseudogenes. With some minor corrections, all 107 genes associated with complete cDNAs that had been mapped previously to chromosome 21 (listed by Swiss-PROT  in March 2000) were found. In addition, within 21q, 52 protein matches were classed as pseudog