The sequence of human chromosome 21 and implications for research into Down syndrome

Down syndrome (DS), affecting one in 700 live births, is the most common genetic cause of mental retardation [1]. 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 [2]. 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 [3]. 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 [3].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 [4]) and it is significantly less than the 545 gene