Cross-species analysis provides new insights into the hereditary transmission of type 2 diabetes
Error in DNA regulation increases risk of developing diabetes
A number of different institutions were involved in the study, including Technische Universität München (TUM) and Helmholtz Zentrum München, Harvard Medical School in Boston, USA, the University of Bergen, Norway, Genomatix Software GmbH, Germany, and the Weill Cornell Medical College in Qatar.
Scientists around the globe are investigating the human DNA code to discover how it influences diseases with a view to developing new therapies. However, the genes that contain the blueprint for all proteins comprise just one percent of DNA. Ninety-nine percent of DNA does not encode protein sequences and is therefore known as non-coding DNA.
“We know that diseases are often associated with non-coding regions of DNA,” explains Dr. Melina Claussnitzer from the Else Kröner-Fresenius Center for Nutritional Science at TUM. “It seems that these sequences control whether a protein is coded and how much of the protein is created. Diseases can therefore be caused by an error in DNA regulation here.”
Health risk increases with the number of free fatty acids
For the first time, the scientists have identified a DNA regulation “error” that can trigger type 2 diabetes. “A gene must be activated before it can be selected and translated into a protein,” explains Prof. Hans Hauner, head of both the working group at TUM and the clinical collaboration team exploring the interaction between nutrition and genetics in type 2 diabetes in collaboration with Helmholtz Zentrum München. “The process is initiated by proteins known as transcription factors, which bind to certain non-coding DNA regions.”
The newly discovered type 2 diabetes variant interferes with the bonding process between a DNA binding site and the transcription factors. “This means that insufficient amounts of glycerol 3-phosphate are produced, a molecule that plays a central role in the metabolism of fat cells. Fewer glycerol 3-phosphate molecules result in a higher concentration of free fatty acids, which are regarded as a risk factor in the development of insulin resistance, a precursor of type 2 diabetes,” reports Claussnitzer.
New process uncovers biological importance of DNA sequences
For their investigations into non-coding DNA regions, the scientists developed a new computer-based process that compares the DNA binding sites of different vertebrate species. The researchers were particularly interested in recurring patterns in these sites.
The process builds on the fact that important DNA sequences have persisted throughout evolution across different species. The greater the similarities between sequences, the greater their biological significance. The scientists used this fact to track down important DNA binding sites and their variants.
Known as phylogenetic module complexity analysis (PCMA), the process is not restricted to type 2 diabetes but can also be applied to a range of other diseases including osteoporosis, Alzheimer’s and cancer. As such, the researchers’ work opens up new ways of using non-coding DNA to identify risks of disease.
Leveraging Cross-Species Transcription Factor Binding Site Patterns: From Diabetes Risk Loci to Disease Mechanisms; Melina Claussnitzer, Simon N. Dankel, Bernward Klocke, Harald Grallert, Viktoria Glunk, Tea Berulava, Heekyoung Lee, Nikolay Oskolkov, Joao Fadista, Kerstin Ehlers, Simone Wahl, Christoph Hoffmann, Kun Qian, Tina Ronn, Helene Riess, Martina Müller-Nurasyid, Nancy Bretschneider, Timm Schroeder, Thomas Skurk, Bernhard Horsthemke, DIAGRAM+Consortium, Derek Spieler, Martin Klingenspor, Martin Seifert, Michael J. Kern, Niklas Mejhert, Ingrid Dahlman, Ola Hansson, Stefanie M. Hauck, Matthias Blüher, Peter Arner, Leif Groop, Thomas Illig, Karsten Suhre, Yi-Hsiang Hsu, Gunnar Mellgren, Hans Hauner, and Helmut Laumen, Cell (2014), DOI: 10.1016/j.cell.2013.10.058
Technische Universität München
Else Kröner-Fresenius-Zentrum für Ernährungsmedizin
Dr. Melina Claussnitzer (currently at Harvard Medical School, Boston, USA)
Tel.: +001 617 852-1948
Prof. Dr. Hans Hauner
Tel.: +49 8161 71-2000
Dr. Helmut Laumen
Tel.: +49 8161 71-2006