September 15, 2001

Article at New Scientist

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NEWS | Rip up life's blueprint

It’s time to rethink the way we look at the human genome.

Wilson da Silva, Glasgow

WE STORE our most important genes in the centre of the nuclei of our cells, a geneticist told the British Association meeting in Glasgow last week. This discovery that our nuclei have an internal architecture may explain why cloning and gene therapy so often fail. It could also force scientists to rethink the way they look at the human genome, she says.

“Our genes are not uniformly distributed,” says Wendy Bickmore of the Medical Research Council’s Human Genetics Unit in Edinburgh. “They are clustered together. We have a very active compartment in the centre of the cell nucleus, and a much more silent, passive compartment around the edges.”

This may mean that gene engineers will only get new genes to work if they insert nuclei with the correct architecture into stripped-down cells, or target genes at the core of the nucleus rather than taking a “shotgun” approach. Dolly the sheep, cloned in 1997, was preceded by 277 stillborn, miscarried or dead lambs--and research teams today still don’t do much better. 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,” Bickmore told New Scientist. “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.”

Bickmore’s team tagged genes on particular human chromosomes with jellyfish fluorescence proteins that glow green under ultraviolet light. Time-lapse photography revealed that our most important genetic material is organised into discrete territories and structural landmarks.

Although this has recently been noted in the DNA of fruit flies and yeast, Bickmore’s group is the first to identify it in the human genome. And it could have startling applications in treating disease.

We know that a growing number of human diseases are caused not just by gene mutations, but also by moving genes to new locations in the human genome. “We call these ‘position effects’, which means we really don’t understand them,” says Bickmore.

One example is anirida, a hereditary condition associated with the PAX6 gene, in which babies are born with no iris in their eyes. In some families there is nothing wrong with the gene itself; it has just been moved to a new position on the chromosome.

Scientists have already discovered that some genes in yeasts and fruit flies can be shut down by shuffling them from the centre of the nucleus to the periphery. The same thing might happen in people, says Bickmore. “This 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.”