May 11, 2000 A basis for comprehensive understanding of trisomy 21 (Down syndrome), one of the most common genetic diseases
Chromosome 21 is one of the smallest among the 23 different human chromosomes. It is associated with Trisomy 21, one of the most common genetic diseases (also known as Down syndrome). An extra copy of chromosome 21 results in severely aberrant physical and mental development in children, leading to mental retardation. The disease affects up to 1 in 700 live births. An international collaborative group led by German and Japanese scientists will publish the sequence of chromosome 21 in the journal Nature (18th May 2,000). This work will be freely available on the Nature website from the 8th May. With these findings, the scientists deliver the key for a deeper understanding of the molecular mechanisms of trisomy 21 and other diseases involving chromosome 21, as well as for the design of novel diagnostic tools.
After the successful sequencing of chromosome 22 in December 1999 by a group of international scientists, chromosome 21 is now the second human chromosome which has been deciphered completely. Virtually all genes encoded by chromosome 21 have now been identified by computer-based analysis of the genomic sequence. This tremendous scientific effort was achieved by an international cooperation of scientists from 5 institutions: RIKEN genomic science center, Sagamihara (Japan), the Department of Molecular Biology of Keio University, Tokyo (Japan), the GBF-Gesellschaft fuer Biotechnologishe Forschung, Braunschweig (Germany), the Institut fuer Molekulare Biotechnologie (IMB), Jena (Germany), and the Max Planck Institute for Molecular Genetics, Berlin (Germany).
Historically, sequencing of chromosome 21 started in the early 90's. By 1995, the German-Japanese consortium was formed, with the aim of accomplishing the task of systematic sequencing of all of the 33.546.361 base pairs of chromosome 21. Altogether, a total of 170 people have worked on this international project. The German Ministry of Education and Science (BMBF) has financed the German groups with 23 million German marks over 5 years.
Based on the scientist’s results, we know today that chromosome 21 contains 225 genes: 127 of them are clearly characterized genes, whereas the remaining 98 have been discovered by computer gene predictions. Scientists use the fact that characteristic structural patterns are common to most human genes as the basis of these computer methods. Computer scanning of these hallmark features in the chromosome sequence allow the researchers to identify where the coding regions are located. The function of 103 out of the 127 characterized genes is known, meaning that the corresponding protein was previously identified or that at least its activity in a defined biochemical pathway is known. The next goal for the researchers is to characterize in detail the remaining novel genes and to find their function. Some of them are associated to a number of genetic diseases mapping to chromosome 21 but for which candidate genes are still unknown: several forms of deafness, solid tumors, a form of manic depressive psychosis for instance.
A focus of interest are the 14 known genes localized on chromosome 21 for which genetic modifications are associated with severe monogenic diseases. Among these are Alzheimer's disease, a particular form of epilepsy, auto-immune conditions, and also increased susceptibility for leukaemia. Also, the gene catalogue of chromosome 21 will provide the basis for identifying candidate genes responsible for genetic diseases mapping to chromosome 21 but for which the etiology is unknown. These include for instance, two loci for deafness, a form of manic psychosis and several forms of cancer. In the context of Down syndrome, the scientists are hoping that the sequence data will provide in the future a basis for research development towards the design of novel diagnostic tests. The future expectation is to provide alternative tests to alleviate the high risk associated with amniocentesis.
A completely different matter of long debate has been the estimate of the number of genes and proteins in mammals. With a total length of 3 to 4 milliards of base pairs, the human genome could in principle encode for more than 3 millions of proteins, a figure that is, however, far too big. It has been known for a long time that the part of the genome that encodes genes lies in particular regions, whereas the rest of it is devoid of coding information meaning "a lot of base pairs but little text". The current estimate of the total number of human genes is between 80.000 and 140.000. In light of the data examined here by the scientists, the number of genes would be far below any previous estimate. By extrapolation from the number of 225 genes encoded by chromosome 21 and from the 545 genes encoded by chromosome 22, and considering the size of the human genome, the total number of human genes may be as little as 40,000.
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