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Researchers identify missing links that connect human DNA variation with disease

Copyright: Dr. Muthugapatti Kandasamy, University of Georgia

News from: The Babraham Institute

A team of Cambridge researchers led by scientists at the Babraham Institute have discovered the hidden connections in our genomes that contribute to common diseases. Using a pioneering technique developed at the Babraham Institute, the 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, including rheumatoid arthritis and other types of autoimmune disease.

Comparing the genome sequences of hundreds of thousands 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, often referred to as junk DNA. The fact that the changes are not in or near genes has made it challenging to understand how they could cause disease. Now, as reported in the leading journal Cell, the 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.

Copyright: The Babraham Institute 2016
Image shows a cut-away cell nucleus (top left) with one chromosome highlighted and enlarged on the right. Each chromosome contains hundreds of genes. Enlarged section of the chromosome (bottom left) shows how chromosome folds to allow distal control regions of the DNA thread (yellow) to directly interact with a gene (blue). These distal control regions switch genes on and off. Small changes in the DNA sequence of the control regions may interfere with normal gene expression and lead to disease susceptibility. Image: Dr C. Varnai and Dr P. Fraser, Copyright: The Babraham Institute 2016.

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, Head of the BBSRC-funded Nuclear Dynamics research programme at the Babraham Institute which coordinated the study and a senior author on the paper, 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.

The different blood cell types were obtained from blood samples donated by healthy volunteers of the NIHR Cambridge BioResource or by culture of blood stem cells in the laboratory of Dr Mattia Frontini, leader of the blood cell epigenome team at the University of Cambridge’s Department of Haematology.

Professor John Todd, Director of the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory and founder and former principal investigator of the Cambridge BioResource said: “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 rheumatoid arthritis, type 1 diabetes and Crohn’s disease that are currently incurable and notoriously difficult to treat or prevent. 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, group leader in the Nuclear Dynamics research programme at the Babraham Institute and a senior author on the paper, 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”.

As a large multi-partner study, this research was collaboratively undertaken by the Babraham Institute, the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory in the Cambridge Institute for Medical Research and the Departments of Medicine and Haematology at the University of Cambridge, the EMBL-European Bioinformatics Institute, the NHS Blood and Transplant organisation and the MRC Biostatistics Unit. The research was funded by a grant from the Medical Research Council whereas the researchers and organisations involved are supported by several funders including the UK’s Biotechnology and Biological Sciences Research Council, the British Heart Foundation, the Juvenile Diabetes Research Foundation (JDRF) and the Wellcome Trust in addition to funding from the European Commission (multiple sources).


Notes for editors

Publication reference: Javierre, Burren, Wilder, Kreuzhuber, Hill et al. (2016) Lineage specific genome architecture links disease variants to target genes, Cell.

About the Babraham Institute

The Babraham Institute, which receives strategic funding (a total of £21.2M in 2015-16) from the Biotechnology and Biological Sciences Research Council (BBSRC), undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute’s research provides greater understanding of the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing.


The European Bioinformatics Institute helps scientists realise the potential of ‘big data’ in biology, exploiting complex information to make discoveries that benefit humankind. We make the world’s public biological data freely available to the scientific community via a range of services and tools, perform basic research and provide professional training in bioinformatics. We are part of the European Molecular Biology Laboratory (EMBL), an international, innovative and interdisciplinary research organisation funded by 22 member states and two associate member states. We are situated on the Wellcome Genome Campus in Hinxton, Cambridge, UK, one of the world’s largest concentrations of scientific and technical expertise in genomics.

About NHS Blood and Transplant

NHS Blood and Transplant (NHSBT) is a joint England and Wales Special Health Authority. Its remit includes the provision of a reliable, efficient supply of blood, platelets, plasma and associated services to the NHS in England. It is also the organ donor organisation for the UK and is responsible for matching and allocating donated organs.

For more information about NHS Blood and Transplant see:, or on Twitter @NHSBT_RD

About the MRC Biostatistics Unit

The Medical Research Council has had a statistical unit since its inception in 1913. One hundred years on, the Biostatistics Unit (BSU) is one of the largest groups of biostatisticians in Europe. It is a major centre for research, training and knowledge transfer, with a mission 'to advance biomedical science and human health through the development, application and dissemination of statistical methods'.

BSU’s critical mass of methodological, applied and computational expertise provides a unique and stimulating environment of cutting edge biostatistics, striking a balance between statistical innovation, dissemination of methodology and engagement with biomedical and public health priorities.

Pioneering work on fundamental aspects of medical statistics, clinical trials and public health has been developed throughout the BSU’s rich history. Our recent research has delivered innovative methodology in important biostatistics research areas, such as statistical genomics, longitudinal analysis, complex evidence synthesis, and clinical trial design. Alongside this methodological focus, the Unit is involved in major collaborations on dementia and aging, rheumatology, auto-immune diseases, blood disorders, oncology, HIV, HCV and influenza. The BSU places a strong emphasis on anticipating needs for statistical expertise in the health domain and on tackling contemporary challenges arising in clinical sciences and public health posed by new types of data and new scientific questions.

About the University of Cambridge

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 96 affiliates of the University have won the Nobel Prize.

Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions.

Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.

The University sits at the heart of one of the world’s largest technology clusters. The ‘Cambridge Phenomenon’ has created 1,500 hi-tech companies, 14 of them valued at over US$1Bn and two at over US$10Bn. Cambridge promotes the interface between academia and business, and has a global reputation for innovation.


BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by government, BBSRC invested £473 million in world-class bioscience, people and research infrastructure in 2015-16. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

More information about BBSRC, our science and our impact.
More information about BBSRC strategically funded institutes.

Header image copyright: Dr. Muthugapatti Kandasamy, Director of the Biomedical Microscopy Core. University of Georgia on Flickr by CC 2.0. A super resolution image of a human cell stained for actin (green), mitochondria (red) and DNA (blue).


UK Research and Innovation Media Office

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