Novel insights into genetic cause of autoimmune diseases
A collaboration between researchers at the Babraham Institute and the University of Manchester has mapped the physical connections occurring in the genome to shed light on the parts of the genome involved in autoimmune diseases. Using a new technique, called Capture Hi-C, the team revealed novel insights into how changes in the genetic sequence have a biological effect and increase the risk of disease.
The human genome project provided the entire DNA code and large population studies have since identified which DNA sequence changes are associated with a range of diseases such as cancer, cardiovascular disease and immune system disease. Because many of these changes fall outside the parts of the genome that contain protein-coding genes, understanding the biological relevance of the genetic change was akin to the party game ‘pin the tail on the donkey’ when it came to identifying the genes that these regions associated with. Understanding these associations represents the key to uncovering the causal genetic factors of disease.
The new technique developed by researchers at the Babraham Institute identified a way to ‘freeze-frame’ the genome and capture its three dimensional conformation where the DNA folds to bring regions into close contact. This snapshot pinpoints where non-coding regulatory regions contact the genes that they control, often over large genomic distances. This technique gives the highest resolution view of the genome's interconnections available to date and allowed researchers to zoom in on and identify the genes affected by sequences changes in other parts of the genome.
Using this approach allowed disease geneticists from the University of Manchester to identify novel candidate genes relating to the risk of developing autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. Researcher Dr Stephen Eyre from the University of Manchester said “By looking at the genome’s interactions in two immune cell types of relevance to autoimmune diseases we identified examples of disease-associated DNA changes that do not interact with the nearest genes, normally implicated by association, but rather with gene regulatory elements some distances away. This implicates an entirely different set of gene targets and provides a completely new insight into autoimmune diseases and, potentially, how to treat them.”
Commenting on the use of the technique in this work, Dr Peter Fraser, Head of the Nuclear Dynamics research programme at the Babraham Institute, said “In order to be able to treat disease, we first need to fully understand what’s happening at a biological level. Using our Capture Hi-C technique has revealed new genes that may cause autoimmune disease and this new knowledge will be essential in designing new future treatments. We believe that our technique holds the key to transform our knowledge of the genetic basis of other diseases too. From this knowledge comes the hope of improved and preventative treatments.”
This work was published in the latest issue of Nature Communications and funded by Arthritis Research UK, the Wellcome Trust, the European Union’s 7th Framework Programme and the Biotechnology and Biosciences Research Council.
A three-dimensional portrait of a chromosome, created by compiling thousands of molecular measurements of chromosomes in single cells using the latest DNA sequencing technology and modelling techniques.
Associated researchers (in author order):
Stefan Schoenfelder, senior postdoc researcher (Fraser lab), Nuclear Dynamics Programme
Peter Fraser, Head of Nuclear Dynamics research programme
Martin, McGovern, Orozco et al. (2015) Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. Nature Communications