BioWorld Today Correspondent

LONDON – The notion the 98.3 percent of the genome that does not code for proteins amounts to little more than junk is being superseded by increased understanding of the important regulatory roles of noncoding DNA.

Now, the impetus to find out more about how noncoding DNA exerts its effects is being increased by the unexpected findings of genomewide association studies (GWAS) that are searching for the genetic causes of particular diseases.

"What's shocking is that GWAS suggest that only 12 percent of disease-causing mutations are in the genes," said Alasdair Mackenzie, a researcher at the Institute of Medical Sciences at Aberdeen University in Scotland, who has devoted 10 years to research looking into what he calls the "dark matter" of the genome.

Although it contains no genes, noncoding DNA may turn out to be the main reservoir of disease-causing mutations in the genome, Mackenzie told the annual British Science Festival, held at Bradford University. "Multiple GWAS are finding all these polymorphisms associated with disease, and they are not in genes; we are trying to find out what are the mechanisms [of action]."

While as yet, very little is known about the noncoding part of the genome, Mackenzie told BioWorld Today that his research indicated the possibility it could become the basis of a whole new approach to drug discovery and development, with the opportunity to use subtle genomic variants to provide tailored treatments. He based that assertion on the fact that the noncoding genome actually contains a vast and largely unknown information source that is required to tell genes where, when and by how much, they should be turned on or off.

One of the clearest indications of the possible significance of that concerns the neuropeptide galanin, which among a number of other functions is produced in the hypothalamus to control appetite and food preferences. Overproduction makes mice prefer fatty food and choose alcohol over water.

Comparing the human genome with that of monkeys, cows, dogs, mice and hens led Mackenzie to an isolated piece of DNA, christened Gal 5.1, which occurred in each of those genomes. "We found it is a switch, which is highly conserved and that this controls galanin production in the hypothalamus," Mackenzie said.

Mackenzie went on to uncover mutations within Gal 5.1 that alter the level of activity of that switch, and he has also found that different human populations have different proportions of the weak and the strong switch.

As for the significance of the findings in terms of drug discovery, Mackenzie has shown that those switches can be manipulated with drugs. "It's at a very early stage, but this shows the possibility of using this to develop therapies – we are starting to get a handle on how to modulate them."

Mackenzie also has uncovered a switch controlling brain-derived neurotrophic factor (BDNF), a protein that is important for long-term memory and which has been implicated in depression and premature cognitive decline. The switch represses the BDNF gene, and there are polymorphisms within the switch that repress the gene to differing degrees.

In terms of commercialization, Mackenzie believes the work is both too preliminary and too far outside accepted concepts to be taken on by industry as yet. "We tried to patent a few [switches] and didn't get very far," he said. Similarly, approaches to companies have not met with any success. He is now trying to get more grant money to advance understanding of how to manipulate the switches with drugs.