FISH of tri.21
Image: TOKYO MEDICAL UNIVERSITY

DOWN SYNDROME, a condition in which an individual inherits an extra copy of chromosome 21, is also known as trisomy 21. The fluorescent in situ hybridization (FISH) image above clearly shows all three copies of 21. With the chromosome responsible for the disorder now fully sequenced, scientists should be able to get a better handle on understanding it.

The journal Nature set an important precedent for the Web world recently, publishing a paper on-line 10 days in advance of its scheduled May 18 print debut. Their decision, of course, hinged on the importance of the paper. In it, an international consortium of scientists reveals the complete sequence of chromosome 21, the smallest of all 24 human chromosomes. And what they found--an unexpected paucity of genes on 21--hints that the total number of human genes has very likely been overestimated.

Chromosome 21, which represents about 1 percent of the entire genome, was expected to be gene-poor, but not as impoverished as it now seems. Indeed, the Unigene project guessed that 21 would bear only 80 percent of the number of genes one might expect for a chromosome of its size. So if the total number of expected human genes is around 100,000, the prediction was that 21 would contain 800 to 1,000 genes, or 80 percent of 1 percent of the genome.

But in fact, the chromosome 21 consortium--which included researchers from Japan, Germany, France, Switzerland, England and the U.S.--found only 225 genes. This is a small number not only in terms of what was predicted, but also in comparison to the other completely sequenced chromosome to date, 22, which contains 545 genes and is similar in size. Chromosome 22 is considered "gene-rich," but the new information is still making researchers revise their predictions about the genome itself.

"These two chromosomes together," the paper's authors write, "represent about 2 percent of the human genome and collectively contain 770 genes. Assuming that both chromosomes combined reflect an average gene content of the genome, we estimate that the total number of human genes may be close to 40,000."

Despite the small number of genes on chromosome 21, it was not an easy ball of DNA to untangle, and in doing so, the consortium made several technical advancements. All chromosomes look like X's, having short and long arms of DNA, comprised of millions of base pairs. The group reports a sequence covering 99.7 percent of chromosome 21's long arm, or 33.55 million base pairs. And within that sequence is an uninterrupted stretch of 28.5 million base pairs--the longest continuous DNA sequence known so far.

The paper also describes a sequence of 281,000 base pairs on chromosome 21's short arm, which was difficult to map and clone because it contains a number of highly repetitive sequences (see illustration at left). The length of this short arm varies greatly among individuals, and so this sequence marks the first example of a large part of the genome that can drastically expand or contract.

Figuring out in more detail what the genes on chromosome 21 do could be a boon to medical researchers. Mutations in 14 known genes on chromosome 21 play roles in one form of Alzheimer's disease, amytrophic lateral sclerosis and progressive myoclonus epilepsy, among other diseases. Also on chromosome 21 are genes that are as yet unidentified, but known to be responsible for five so-called monogenic disorders, including two forms of deafness and Usher and Knobloch's syndromes.

Perhaps most significant, having a third copy of chromosome 21, or trisomy 21, results in Down syndrome, which affects up to one in 700 births and is the most common cause of mental retardation. It is probable because chromosome 21 has so few genes that trisomy 21, unlike many other chromosomal disorders, is not fatal before birth, or even at a young age. Even so, Down syndrome is associated with more than 80 physical and mental problems, including congenital heart disease, an increased risk for certain leukemias, and immunological deficiencies.

The paper bears good news for scientists hoping to pinpoint the genes on chromosome 21 that lie behind Down syndrome's varied complications: regions of human chromosome 21 share a lot in common with several regions of mouse chromosomes 10, 16 an 17--regions that are called conserved syntenies across species. This high degree of conservation means that scientists can begin to use the mouse maps for guidance. Better ways of managing Down syndrome may not emerge right away, but it is a start.