DNA origami: how do you fold a genome? (360G-Wellcome-106130_Z_14_B)

Recent advances in DNA sequencing technology mean that it is now possible to identify genetic variants in patients with specific diseases which either cause or alter their risk of developing that disorder. However, linking these variants to the genes they regulate and the symptoms of the condition itself is time-consuming and challenging. The overarching aim of this project is to develop high-throughout methods to systematically investigate the impact of genetic variants associated with specific diseases on cell function and human health. This will be achieved via collaboration between several groups within the University of Oxford and multidisciplinary external groups, each bringing their own specific field of expertise relevant to the overall aims of the project. Over the past three years, we have developed and refined high-throughput techniques to link genetic variants to the genes they control, and analyse how and why these variants impact the activity of their target gene. Now that we have established these methodologies and associated computational analysis pipelines, we will apply these techniques to variants associated with various conditions during the next two years of the award. In the first instance, these will be disorders associated with red blood cells, multiple sclerosis, and type 2 diabetes. The final stage of the project is to optimize recently developed genome editing techniques to correct any variants that are found to have a functional impact on the condition in question. This will serve two purposes; first it will prove that the variants influence gene regulation and second it will provide the first steps to establishing proof-of principle for gene editing as a potential therapeutic opportunity. Of particular importance to the interpretation of this work will be ongoing basic research in modeling and visualization of how gene activity is regulated in the 3D space of the nucleus, which will aid our understanding of how these specific variants affect the activity of distant genes. Using state of the art methods to visualize and interact with the DNA molecule in three dimensions represents a unique opportunity to intuitively explain these complex but universally important concepts to the public.