Associated Press Writer
2:30 PM EDT; May 8, 2000; (AP) -- In an achievement that could point the way to treatments for a host of illnesses, scientists have mapped Chromosome 21, the smallest human chromosome and the one associated with Down Syndrome, epilepsy, Lou Gehrig's Disease, and Alzheimer's Disease. It is the second human chromosome whose DNA has been fully deciphered. Chromosome 22 was mapped last Fall.
"Another volume has just been placed on the shelf. Now we really have to roll up our sleeves and assess what these genes are doing there, what role they play in causing disease,'" said Francis Collins, Director of the Human Genome Project at the National Institutes of Health in Bethesda, MD. The German- and Japanese-led team that mapped both chromosomes is part of the Human Genome Project, an international effort to decipher chemically the entire human genetic blueprint. Humans are normally born with 23 different pairs of chromosomes that are made up of genes.
Chromosome 21 contains relatively few genes, but they are laid out in a complex tangle. "When one stares at a sequence like this, it makes one realize how complex it really is,'' said Huntington F. Willard, Chairman of Genetics Department at Case Western Reserve University. (He was not involved in the research.) "It's not just a simple string of 225 genes. It's really a mess -- a hornet's nest, a hodgepodge of duplications, altered sequences, and arrangements that determine the health and welfare of our species." The findings will be published in Thursday's issue of the journal Nature. The researchers found that Chromosome 21 contains far fewer genes than the 545 in Chromosome 22, the second-smallest chromosome.
"The relative sparseness of genes in Chromosome 21 may mean the total number of genes in human DNA is under 40,000 -- not the 100,000 or more that had previously been thought!" said Andre Rosenthal, a Professor at the Institute for Molecular Biotechnology in Jena, Germany. That means "we are not so different from Drosophila [the fruit fly] or yeast," Rosenthal said. The map of Chromosome 21 is 99.7 percent complete; "technical limitations prevented a complete mapping," said Dr. David Patterson, an American scientist involved in the project.
Patterson said the map may allow researchers to home in on specific genes in the chromosome that cause mental retardation in people with Down's Syndrome and then perhaps develop drugs to treat such patients. "Once we can find the genes that are important for learning problems, what we hope is that we'll be able to understand what those genes do and somehow compensate for having an extra copy of the gene," said Patterson, president of the Eleanor Roosevelt Institute in Denver and Chairman of the Science Advisory Board of the National Down's Syndrome Society.
Down's Syndrome occurs when a person is born with an extra, third copy of Chromosome 21. Down's Syndrome, the most common form of genetically caused mental retardation, occurs in about 1:700 live births. Down's Syndrome can also cause congenital heart disease and Alzheimer's Disease by age 40. Dr. Rudolph Tanzi, a Professor of Neurology at Harvard Medical School, said "the chromosome map could eventually shed light on why people with Down's Syndrome have a very low rate of breast, lung, and gastrointestinal cancers. It could be that an extra copy of Chromosome 21 has tumor-suppressing qualities. One can argue that an extra dose of a gene will typically be a bad thing, but - once in awhile -- it can be a good thing; it can be protective."
The Human Genome Project expects to have a rough draft of the entire human genetic
blueprint completed by this Summer. The public project, which is expected finish its work by
2003, is competing against a private company, Celera Genomics Corp. of Rockville, MD, which
hopes to sell the information to pharmaceutical companies and others.
On the web:
Human Genome Project: http://www.ncbi.nlm.nih.gov/genome/seq
From the Editors of Nature
In the May 18th issue, an international group of scientists based mainly in Japan and Germany will report the DNA sequence of human Chromosome 21. The electronic version of this paper will be available at http://www.nature.com/genomics from May 8th prior to the print publication.
Chromosome 21 is the second human chromosome sequence to be documented, encompassing more than 33 million base pairs of DNA, and its publication therefore marks a major scientific milestone. A striking feature of the chromosome is that it contains less than 300 discernible genes. This implies that the entire Human Genome may contain no more than 40,000 genes, significantly fewer than previously thought.
The chromosome sequence reveals the organization of a number of genes linked to specific human disorders, and will speed the search for several more disease-linked genes. The availability of this sequence will also provide valuable tools for investigating the basis of Down's Syndrome, which is caused by the inheritance of three (rather than the normal two) copies of Chromosome 21.
M. HATTORI, A. FUJIYAMA, T. D. TAYLOR, H. WATANABE, T. YADA, H.-S.
PARK, A. TOYODA, K. ISHII, Y. TOTOKI, D.-K. CHOI, E. SOEDA, M. OHKI, T. TAKAGI,
Y. SAKAKI, S. TAUDIEN, K. BLECHSCHMIDT, A. POLLEY, U. MENZEL, J. DELABAR,
K. KUMPF, R. LEHMANN, D. PATTERSON, K. REICHWALD, A. RUMP, M.
SCHILLHABEL, A. SCHUDY, W. ZIMMERMANN, A. ROSENTHAL, J. KUDOH, K.
SHIBUYA, K. KAWASAKI, S. ASAKAWA, A. SHINTANI, T. SASAKI, K. NAGAMINE, S.
MITSUYAMA, S. E. ANTONARAKIS, S. MINOSHIMA, N. SHIMIZU, G. NORDSIEK, K.
HORNISCHER, P. BRANDT, M. SCHARFE, O. SCHON, A. DESARIO, J. REICHELT, G.
KAUER, H. BL™CKER, J. RAMSER, A. BECK, S. KLAGES, S. HENNIG, L.
RIESSELMANN, E. DAGAND, S. WEHRMEYER, K. BORZYM, K. GARDINER, D.
NIZETIC, F. FRANCIS, H. LEHRACH, R. REINHARDT, and M.-L. YASPO
"The DNA Sequence of Human Chromosome 21," Vol. 405, pp. 311-319, Nature (May 18, 2000).
Chromosome 21 is the smallest human autosome. An extra copy of chromosome 21 causes Down syndrome, the most frequent genetic cause of significant mental retardation, which affects up to 1:700 live births. Several anonymous loci for monogenic disorders and predispositions for common complex disorders have also been mapped to this chromosome, and loss of heterozygosity has been observed in regions associated with solid tumors. Here we report the sequence and gene catalogue of the long arm of Chromosome 21. We have sequenced 33,546,361 Base Pairs (BP) of DNA with very high accuracy, the largest contig being 25,491,867 BP. Only three small clone gaps and seven sequencing gaps remain, comprising about 100 KiloBases. Thus, we achieved 99.7 percent coverage of 21q. We also sequenced 281,116 BP from the short arm. The structural features identified include duplications that are probably involved in chromosomal abnormalities and repeat structures in the telomeric and pericentromeric regions. Analysis of the chromosome revealed 127 known genes, 98 predicted genes, and 59 pseudogenes.