American researchers have revealed the first clues to the high failure rate of cloning and gene therapy - the concentration of genes at the core of the nucleus.The discovery, announced at the annual meeting of the American Association for the Advancement of Science in Washington, shows that DNA has an internal structure that scientists were previously unaware existed. It also provides clues to how active genes and 'junk DNA' might work together.
"Our genes are not uniformly distributed," said Dr Wendy Walter, head of the research team based at the Medical Research Council Human Genome Unit in US."They are aggregated together, and they are clustered on the chromosomes that are sequestrated in the central portion of the nucleus. We have a very active compartment in the centre of the cell nucleus, and a much more silent, passive compartment around the edges."The team's findings suggest that geneticists working on technologies such as cloning and gene therapy need to much more keenly target the genes at the core of the nucleus.Dolly the sheep may have been a success, but she was preceded by 274 stillborn, miscarried or dead sheep - a failure rate that has remained relatively steady since she was born in 1997. Gene therapy - inserting 'good' genes to replace defective ones - has also been dogged by a high failure rate. "It may not be sufficient to stuff genes into the nucleus and hope for the best," said Dr Walter. "We may need to think about targeting them to specific environments within the nucleus. We need to think of the genome not just as a linear DNA sequence but as a three-dimensional structure."The results may also have applications in the understanding of diseases. There are a growing number of human diseases that may be caused not just by genes, but where they appear on the genome."We call these 'position effects', which means we really don't yet understand them," Dr Walter said.
She gave the example of anirida, a hereditary condition in which individuals are born without an iris. Geneticists know it is caused by mutations within the PAX6 gene, and while there is nothing wrong with the gene itself, as soon as it is broken and rejoined or inverted - as soon as its spatial condition changes in the nucleus - the condition arises."For the first time, thisenables us allows us to think about how human genetic diseases can result not just by mutating gene sequences, but also by placing genes in the incorrect environment," she said.
It might also suggest why so much of the human genome is 'junk DNA'. DNA is made up of four bases that code for hereditary characteristics, known as genes. Humans have some three billion bases, but one of the surprises of the Human Genome Project is that humans were found to have between 30,000 and 50,000 genes. Scientists had expected closer to 100,000.
Some scientists have suggested that introns, or the remaining non-coding DNA, are not junk at all. In yeast and fruit flies, scientists have observed genes being shut down by being shuffled from the centre of the nucleus to the periphery. "You might 'turn off' a gene by taking from the centre to the edge," she said.
