A genetic desert on chromosome 21 may harbor a sinister oasis: a series of genes that might include one or more that lead to mental retardation in Down syndrome. The findings, reported in tomorrow's issue of the Proceedings of the National Academy of Sciences, suggest that disruption of a DNA-tagging system on this chromosome could be responsible for the syndrome.
Fa-Ten Kao, Jinjwei Yu, and their colleagues at the Eleanor Roosevelt Institute for Cancer Research in Denver homed in on a 20-million-base-pair stretch on the long arm of chromosome 21 called 21q11-21, which has a low percentage of cytidine and guanosine nucleotides--a telltale sign of low gene content, or "junk DNA." Exhaustive searches had previously turned up only five genes in the area. Kao's team cut DNA from chromosome 21 into stable fragments called "microclones," consisting of no more than a few hundred base pairs. When they sequenced 400 of these snippets and compared them to gene databases and to a library of genes expressed in the fetal brain, the researchers were able to identify 18 potential genes in 21q11-21, of which at least nine had been switched on.
The most striking phenomenon in the region, says Kao, is that 90% of the DNA is methylated--a chemical reaction in which DNA is tagged and deactivated with methyl groups (like making a computer disk read-only)--compared to only 60% to 70% in the whole genome. The presence of an extra copy of chromosome 21 in Down syndrome sufferers may disrupt this hyperactive methylation, leading to such developmental abnormalities as mental retardation, Kao suggests.
The study "tells us something that we may have been missing in the past," says Jan-Fang Cheng of the Human Genome Center at Lawrence Berkeley National Laboratory in California. But, he says, what researchers really need is the region's entire DNA sequence, which the Human Genome Project should produce in a couple of years. The team's method "is like looking through a keyhole and seeing whether you can see anything," says Cheng. "It's a quick sample."