Cause of rare genetic disorder found in 'dark matter' of DNA

A genetic mutation linked to a rare disorder that results in babies being born without a pancreas has been uncovered in the 'dark matter' of DNA, the part of the human genome that does not contain genes.

The discovery was possible because of advances in technology that enables scientists to analyse the entire genetic material, or genome, not just the parts that encode genes.

In a breakthrough for genetic research, an international collaboration led by the University of Exeter Medical School and Imperial College London found that the condition is most commonly caused by mutations in a in a remote part of the genome that controls gene expression, which can now be explored thanks to advances in genetic sequencing.

Professor Andrew Hattersley, a Wellcome Trust Senior Investigator who led the Exeter team, said: "This finding gives a deeper understanding to families affected by this disorder, and it also tells us more about how the pancreas develops. In the longer term, this insight could have implications for regenerative stem cell treatments for type 1 diabetes."

The pancreas plays an essential part in regulating levels of sugar (glucose) in the blood. It does this by releasing the hormone insulin, which is generated and released by cells known as pancreatic beta cells. It also produces enzymes to help digest and absorb food.

Pancreatic agenesis results in babies being born without a pancreas, leaving them with a lifetime of diabetes and problems digesting food, which prevents weight gain. The disease is rare, but studying it also helps scientists gain a better understanding of how the pancreas works, which helps shed light on research into diabetes.

The team discovered that the condition is caused by mutations in genomic 'dark matter', the vast stretches of DNA that do not contain genes and account for 99 per cent of the human genome. Instead, these parts of the genome are responsible for making sure that genes are 'switched on' at the right time and in the right part of the body. The effects of this region on human development are only beginning to be understood, thanks to technologies that allow scientists to analyse the whole genome – all 3 billion letters of DNA.

Six different mutations were uncovered in a newly discovered PTF1A regulatory region of DNA in 11 people affected by pancreatic agenesis from across the world.

Dr Mike Weedon, lead researcher and Senior Lecturer at the University of Exeter Medical School, said: "This breakthrough delves into the 'dark matter' of the genome, which, until recently, was very difficult to systematically study. Now, advances in DNA sequencing technology mean we have the tools to explore these non-protein coding regions far more thoroughly, and we are finding it has a significant impact on development and disease."

The findings are published online today in the journal 'Nature Genetics'.