The DNA code

Monday 3 February 2014 11:56am

Professor Vicky Cameron and her team at the Christchurch Heart Institute are looking at the role of non-coding DNA – or "junk DNA" – as a risk factor for heart disease.

Professor Vicky Cameron's first laboratory was the vast expanse of Antarctica where, as an undergraduate, she studied parasites in fish and was the first
woman to live at Scott Base.

Three decades later Cameron is still at the forefront of science, but instead of exploring the "white continent", Cameron now works in Christchurch uncovering the importance of so-called genetic "dark matter" and its possible role in heart disease.

"People are familiar with chromosomes and that our DNA codes for genes from which we inherit characteristics and, sometimes, susceptibility to disease from our parents. What scientists are increasingly realising is that non-coding DNA, also known as the 'dark matter of the genome' or 'junk DNA' may actually play a critical role in conditions such as cancer and cardiovascular disease,'' Cameron says.

"DNA is a store of genetic code which essentially tells each cell what to do, but although we are familiar with DNA coding for protein, this only accounts for about two per cent of the DNA in our genome.'' For a long time it has been a mystery what function the remaining 98 per cent served.

"New technology now allows scientists to compare large groups of people with, and without, diseases to detect genetic variations associated with disease. One of the most startling things uncovered by these studies is that fewer than 10 per cent of the genetic variations significantly associated with disease – or the 'top hits' – are in protein-coding genes. This suggests non-protein coding DNA is far more important than previously thought.

"It has also recently been found that the more complex the organism, the higher the proportion of non-coding DNA to coding DNA. For example, while about 98 per cent of the human genome is non-coding DNA, in the genomes of bacteria this figure is reversed.''

Cameron is a member of the University of Otago's Christchurch Heart Institute (CHI), a multidisciplinary team of researchers and clinicians whose aim is to develop improved diagnostic tests for heart disease, and to discover and trial new treatments.

"We suspect this is how this 9p21 non-coding gene has its effect – by affecting other coding genes and speeding up production of plaque in the arteries."

She is also a member of the Centre for Translational Health Research, that looks to link common issues in conditions including cancer and cardiovascular disease. Cameron's laboratory is focusing its attention on the impact of variations in both coding and non-coding DNA on our ability to predict risk of developing heart disease.

Over the past 25 years the CHI (formerly the Christchurch Cardioendocrine Research Group) has run large studies involving many heart disease patients and healthy volunteers, and collected DNA from these heart disease and control groups. Molecular biologist Dr Anna Pilbrow is studying human heart tissue provided by the Cleveland Clinic where many heart transplant operations are done, as well as collaborating with a Swedish research group who have access to samples of human artery tissue.

This means Cameron and her team are well equipped to zone in on certain DNA regions they suspect to be important in susceptibility to heart disease, by looking at the effects on the heart and blood vessels.

"There is an area on chromosome 9 most strongly associated with heart disease, but it is not located in a protein-coding gene, but rather in one of these non-coding regions that gets transcribed into RNA but never made into protein.

"As this region is so strongly associated with increased susceptibility to heart disease we wanted to see if it had an impact on patient outcomes. We found those with the risk form of this 9p21 region get heart disease earlier, but don't die earlier from it.

"We then looked at how inheriting the 9p21 risk genotype affected levels of activity of all our 20,000 genes and found that activity of many protein-coding genes, both close to the 9p21 region and elsewhere in the genome, was altered in association with the genetic risk variant.

"Furthermore, several of these protein-coding genes acted within a cell-signalling pathway that has been implicated with the speed at which cells divide. We suspect this is how this 9p21 non-coding gene has its effect – by affecting other coding genes and speeding up production of plaque in the arteries.''

Cameron says this work will form the basis of further investigations with the aim of gaining a better understanding of how variations in "dark matter" make certain people more susceptible to an often deadly disease.