Singapore – Scientists at A*STAR’s Genome Institute of Singapore (GIS) have developed a new technique that simplifies the task of identifying the precise DNA mutations that cause disease, which lays the groundwork for the development of new drugs and new ways of diagnosing diseases.
It is generally extremely difficult to design new drugs for diseases such as diabetes or rheumatoid arthritis (for example), because we do not know which molecules in the body the drugs should target. This is where disease-causing DNA mutations come in. If we can pinpoint the genetic mutations that cause a particular disease, we can associate those mutations with specific proteins, and then design drugs to block or activate those proteins. We can also measure the activity of proteins identified in this manner to diagnose diseases more accurately, which is a major goal of precision medicine.
A team of scientists, led by Dr Shyam Prabhakar, Associate Director for Integrated Genomics at GIS, developed a new genetic analysis technique called the Genotype-independent Signal Correlation and Imbalance (G-SCI) test that senses specific chemical changes [1] within the genome and connects them to nearby genetic mutations. They then showed that mutations associated with the chemical changes were also likely to cause disease. The G-SCI test was validated in a study of 57 individuals and is reported in the scientific journal, Nature Methods.
When combined with the chemical profiling strategy used in this study, the G-SCI test is 10 times more sensitive than existing methods at identifying detrimental gene mutations. The study’s co-lead, Dr Ricardo del Rosario from GIS, said, "The G-SCI test is transformative – instead of examining gene expression correlations in 500 individuals, we can get away with histone acetylation analysis of a mere 50 to 60. This reduces the number of test subjects needed to conclude each study and gives us the ability to look into multiple diseases."
Dr Jeremie Poschmann from GIS, the other co-lead of the study, highlighted another benefit of the new approach: "Instead of using genome sequencing, we can use the histone acetylation sequencing data from our method to detect DNA mutations. This saves us a huge amount of time, effort and resources."
Prof Bing Ren of the Ludwig Institute of Cancer Research and the Department of Cellular and Molecular Medicine, University of California, San Diego (UCSD) said, "This is an exciting study that sets a new benchmark for genetic analysis of gene regulation. The method greatly enhances our ability to interpret the human genome and will benefit research into the genetic basis of diseases."
The scientists validated the efficiency of the new test and were able to identify links to certain genetic diseases. "We have found a strong association between mutations that perturbed the genome's chemical state and those that caused autoimmune diseases. That's when we knew we had hit the bulls-eye with the G-SCI test," said Dr Prabhakar.
“This work provides important new tools for linking genetic variation to variation in chromatin function, and provides compelling evidence for the central role of this type of genetic variation in human disease," commented Prof Jonathan Pritchard from Stanford University, who is also an Investigator at the Howard Hughes Medical Institute.
“I am thrilled by this new method with superior precision for identifying disease-causing mutations. The G-SCI method innovatively utilises epigenetic information to select regions of the human genome for disease association analysis. As we see bigger and more complex datasets, the community will face the forthcoming challenges of analysing big data. This method has expanded our arsenal of computational analytics capabilities at the Genome Institute of Singapore,” said Prof Huck-Hui Ng, Executive Director of GIS.
Notes to Editor:
The research findings described in the media release can be found in the Nature Methods journal, under the title, “Sensitive mapping of chromatin‐altering polymorphisms reveals molecular drivers of autoimmune disease” by Ricardo Cruz‐Herrera del Rosario1*, Jeremie Poschmann1*, Sigrid Laure Rouam1, Eileen Png2, Chiea Chuen Khor3,4, Martin Lloyd Hibberd2,5 and Shyam Prabhakar1#
1. Computational and Systems Biology, Genome Institute of Singapore, Singapore
2. Infectious Diseases, Genome Institute of Singapore, Singapore
3. Human Genetics, Genome Institute of Singapore, Singapore
4. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
5. Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, London UK
* Contributed equally
# Correspondence to Shyam Prabhakar
Tel: (65)6808-8046; email: [email protected]
For media queries and clarifications, please contact:
Ms Winnie Lim
Head, Office of Corporate Communications
Genome Institute of Singapore, A*STAR
Tel: +65 6808 8013
Email: [email protected]
About A*STAR’s Genome Institute of Singapore (GIS)
The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to achieve extraordinary improvements in human health and public prosperity. Established in 2000 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards academic, economic and societal impact.
The key research areas at the GIS include Human Genetics, Infectious Diseases, Cancer Therapeutics and Stratified Oncology, Stem Cell and Regenerative Biology, Cancer Stem Cell Biology, Computational and Systems Biology, and Translational Research.
The genomics infrastructure at the GIS is utilised to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.
For more information about GIS, please visit: www.gis.a-star.edu.sg
About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy.
In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore’s manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry.
A*STAR oversees 18 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis, as well as their vicinity. These two R&D hubs house a bustling and diverse community of local and international research scientists and engineers from A*STAR’s research entities as well as a growing number of corporate laboratories.
For more information about A*STAR, please visit: www.a-star.edu.sg
[1] The scientists used histone acetylation as the chemical change to identify specific gene mutations that cause certain diseases. Histone acetylation controls the activation of genes within cells of the human body.
