The second human chromosome sequence to be mapped, chromosome 21, was published in the science journal Nature May 18, and is available free on the Internet.
Chromosome 21 is best known for being the only chromosome that sometimes occurs in three copies rather than the usual pair, resulting in Down's syndrome, the commonest cause of intellectual disability, affecting one in 700 live births. A consortium of scientists from Japan, Germany, Switzerland, France, the United States and Britain read the 33 million base pairs of DNA that make up the chromosome.
Chromosome 21 is the smallest human chromosome of the 23 pairs, and was expected to contain few genes. Even so, the sequence revealed fewer than expected: fewer than 300 genes. Estimates of the total number of genes in the human genome were between 80,000 and 100,000, but extrapolating from the number found on chromosome 21 puts the number at around 40,000, far fewer than predicted.
Each of the 300 genes codes for a protein enzyme with some role in the biochemical factories of our cells. Identifying the genes on chromosome 21 that cause various disorders, including two forms of deafness and Usher's and Knobloch's syndromes, will be much easier now that the sequence is mapped and freely available. Research into genes linked to diseases such as Alzheimer's and certain forms of cancer will also get a boost.
The research that will be most advanced by the publishing of the sequence, however, will be that into the condition for which the chromosome is best known: Down's syndrome.
No other chromosome is ever present in three copies. Most other chromosome defects cause death in early childhood or before birth, but children with three copies of chromosome 21 live a healthy life for many years. This, says Roger Reeves in Nature, is probably because there are so few genes on chromosome 21. The imbalance in gene numbers caused by having an extra copy of the chromosome in each cell leads to over 80 physical and mental disorders. How genes and gene products interact to cause these disorders can now be studied in detail.
If there are 33 million base pairs on chromosome 21 making up about 300 genes, does this mean that each gene is 11,000 base pairs long? No. Much of the genome, and chromosome 21 is no exception, is made up of base pairs that code for nothing: so-called junk DNA. Genes contain the information for proteins, but all the information that is needed could fit in far less space than it does. It's as if the recipe for a sponge cake was written out on ticker tape, but every few words of the recipe were interspersed with hundreds of meaningless words. In the genome the meaningful words of the recipe are called exons, and the meaningless junk parts are called introns.
From even the current incomplete sequencing of the human genome it is clear that most of it does not code for anything. Ninety-seven percent of the genome is junk -- with respect to humans, that is. Introns contain codes for recipes that are not used by us, but are used by the introns themselves. Introns contain the instruction "copy me" in the DNA alphabet. They are genetic parasites that get a free ride down the generations in our genomes.
Although there are relatively few "proper" genes on chromosome 21, and the usual stretches of junk DNA, children born with an extra copy of this chromosome experience changes in the development of the body and the brain. The extra copy usually derives from the mother, and the condition is more likely with older mothers.
Researchers in the U.S. have identified a possible mechanism for the extra chromosome 21 in individuals with Down's syndrome. In the American Journal of Human Genetics, they show how an error can occur during sexual cell division to form eggs or sperm.
Normally the chromosome pairs line up and are dragged by protein cables into new cells. Sometimes, however, two protein cables may attach to the same chromosome, leading to a kind of tug-of-war. If the "winning" cell already has a cable attached to the other pair of the chromosome, then it will receive two copies. The losing cell receives no copy of the chromosome and dies.
At fertilization, an embryo is formed by the fusion of an egg and a sperm each carrying 23 chromosomes. If one of the sex cells (usually it's the egg) has gained an extra chromosome 21 from a "tug-of-war error," then the resultant embryo will have trisomy: three copies of chromosome 21.
Now the sequence is known, the genes producing the Down's syndrome symptoms can be identified and cloned. Transgenic mice with genes from the Down's syndrome region will be created to provide a test system for treatment. Gene therapy may one day be used to target and inactivate the extra genes.
Dr. Eiichi Momotani, general secretary of the Japan Down's Syndrome Network, is hopeful about the prospects for research.
"I hope the sequencing of chromosome 21 will make our children's lives and our society better," Momotani says.