Blood cell analysis identifies 1000s of disease-related genes. Using a pioneering technique developed at the Babraham Institute, results are beginning to make biological sense of the mountains of genetic data linking very small changes in our DNA sequence to our risk of disease. Discovering these missing links will inform the design of new drugs and future treatments for a range of diseases.
Comparing the genome sequences of 100s of 1000s of patients and healthy volunteers has revealed single-letter changes found more frequently in the DNA sequences of individuals with specific diseases. In most cases, the disease-linked changes occur in the large swaths of DNA located between genes, ie junk DNA. Promoter Capture Hi-C technique is being used to fill in the missing pieces by charting interactions between genes and sequences far away on the DNA thread.
The Promoter Capture Hi-C technique works by identifying parts of the genome that physically contact and regulate genes. The long thread of DNA is highly folded inside cells, allowing regions very far apart on the thread to contact each other directly. Dr Peter Fraser explained: “By identifying which parts of the genome connect with which genes we have discovered hundreds of thousands of regions that are necessary to switch genes on and off. Small changes to the DNA sequence of these distal regulatory regions can interfere with the normal control of genes, leading to a greater chance of developing a specific disease. The power of this approach is that it allows us to make biological sense of very tiny changes in the genome that have big impacts on health.”
By mapping the regions of the genome that interact with genes in 17 different blood cell types the researchers were able to create an “atlas” of contacts between genes and the remote regions that regulate them in each cell type. They then matched this information to known changes in DNA at these regions that are linked to specific diseases. This allowed them to uncover which genes are affected by these DNA changes, pointing to their roles in disease.
These results are a giant leap in understanding the inherited and cellular origins of common diseases and in how the human genome works. The team found thousands of new genes linked to specific diseases, including autoimmune diseases such as RA, type 1 diabetes and Crohn’s disease. This knowledge could enable new drugs to be designed targeting those genes, or repurposing of already existing drugs to treat these conditions.
Dr Mikhail Spivakov said: “Mapping the genome’s regulatory interactions establishes the missing link between a genetic change at one part of the genome with the gene it ultimately affects. While the results currently look promising, it will take many more years of work and rigorous testing before new treatments become available as a result of this fundamental research.” http://www.babraham.ac.uk/news/2016/11/researchers-identify-missing-links-that-connect-human-dna-variation-with-disease
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