Last month, a multinational consortium reported the completion of the sequencing of chromosome 21, the smallest human chromosome. A description of the sequence soon followed. Chromosome 21 represents approximately 1 to 1.5% of the total human genome. It was expected to be relatively gene-poor based on the fact that trisomy 21 is one of the only viable human trisomies. Surprisingly, researchers found that it contained even fewer genes than they had expected; only 225 genes were identified, compared with the 545 found on chromosome 22. The total length of the sequence is 33.8 million base pairs (or megabases, Mb).
Chromosome 21 has been of particular interest since it was discovered in 1959 that Down's syndrome occurs when there are three copies of the chromosome. The complete sequence analysis is expected to have profound implications for research in this area in terms of bringing about both improved understanding of the pathogenesis of diseases and speeding up the development of new therapeutic approaches. Individuals with Down's syndrome exhibit several phenotypes other than mental retardation, including congenital heart disease and early-onset Alzheimer's disease, all of which are, ultimately, the product of the three copies of genes on chromosome 21 instead of two. It is believed that only a subset of genes on chromosome 21 may be involved in the Down's syndrome phenotype and that these gene products may be more sensitive than others to gene dosage imbalance. The gene catalogue now allows the hypothesis-driven selection of different sets of candidates, which can then be used to study the molecular pathophysiology of the gene dosage effects.
Mutations in 14 known genes on chromosome 21 have been identified as the causes of several monogenetic disorders, although the loci for several other monogenetic disorders have not yet been cloned. The gene catalogue and mapping coordinates will help in the identification of these loci, and the mutation analysis of candidate genes in patients will lead to the cloning of the responsible genes. The challenge now is to unravel the function of all the genes on chromosome 21.
- Hatori et al. Nature 2000. 405:311-319.
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