How mice teach us about disease
Open-access resource reveals new genes and pathways linked to human disease
Researchers have created a large new resource of more than 900 genes switched off one-at-a-time in mice to discover which genes are important for a wide range of biological functions such as fertility or hearing.
This resource, known as the Mouse Genetics Project, screens for characteristics and early signs of disease, revealing many new functions for well-known genes, as well as for genes with no previously-known role in disease. Many of these variations in body function are likely to underlie human diseases.
The human genome has more than 20,000 identified genes, but our understanding of what they do and how disease results from their malfunction is quite limited. Studies using mice are central to understanding how genes function and how variation to genes causes disease. Mice share the vast majority of their genes with humans and researchers can use mice that have a specific gene switched off to start to unravel human disease.
The Mouse Genetics Project provides researchers and clinicians with a wealth of freely available clinical and biological information that will help find new treatment strategies and options for a wide range of diseases. Furthermore, research groups worldwide can use these new mouse lines to continue the work of investigating the fundamental mechanisms of disease, as the mouse lines are openly available to researchers.
“Our project has revealed many completely unexpected associations between genes and traits like body weight, emphasising how difficult it is to predict the importance of a gene in disease until there is a model like the mouse to give us clues. There are many paths to developing a disease that aren’t immediately obvious. This resource provides an efficient way to uncover these paths.
“This resource is the largest collection of mouse lines available to researchers where all other genes are virtually identical except the gene switched off. Together with the careful optimisation of their environment and the systematic analysis of a wide range of characteristics in each line, we are able to detect features that otherwise would be missed.”
Professor Karen Steel Lead author from King’s College London and Honorary Faculty at the Wellcome Trust Sanger Institute
So far the team have individually switched off more than 900 genes in mice to understand how they function and how they relate to disease. Rather than tunnelling in on one or two potential effects, the team are systematically studying a large number of potential outcomes to build an entire catalogue of gene functions and effects. The new report published today describes the detailed analysis of the first 250 lines to undergo this systematic health screen.
The researchers discovered that newly identified and unknown genes are just as likely to underlie disease features as known genes. This finding emphasises the value of a broad approach to studying diseases rather than the current tendency of researchers to focus on well-known genes. The availability of mouse models and publicly-available information about their characteristics should encourage a broader understanding of the full extent of gene function and how genetic changes can result in disease.
The team revealed that a gene, Kptn, previously thought to be linked to deafness could actually be associated with obesity. They found that when the gene is switched off in mice fed with a high-fat diet, the mice gain weight faster than those that have working copies of the gene. This is one of the many examples of genes identified by the team to have a surprising new role in disease.
Among the genes reported in detail are 26 brand new mouse models for human diseases, allowing detailed investigation of the underlying biology of these diseases. For example, variations to the gene SMS can cause a rare, inherited condition associated with both mental and physical difficulties, called Snyder-Robinson syndrome. The team switched off the same gene in mice and the results reproduced those seen in the human disease. They also detected male infertility, suggesting a new feature of the disease that may not have been recognised in humans with SMS mutations.
“Not only is the biological information openly available to the wider scientific and clinical community, but so are our mouse models. Already 447 research teams in 25 different countries across the world are using our mouse lines and taking this research to new levels. Our hope is that other research teams will take our research forward to better understand disease and develop new and effective therapies against these diseases.”
Dr Jacqui White First author from the Wellcome Trust Sanger Institute
“This resource is revealing a wealth of information about human disease that has great potential for improved diagnosis and treatment options. This is just the start of a long journey, but I’m excited by the research that this resource will allow us to do.”
Professor Philip Beales Professor of Medical Genetics at the Institute of Child Health, University College London, and a consultant clinical geneticist at Guy’s Hospital and Great Ormond Street Hospital
The Mouse Genetics Projects has been awarded three Wellcome Trust strategic awards to investigate developmental biology, infection susceptibility and bone disease traits. It is extremely difficult to predict which genes are involved in disease. These programmes will look at different aspects of disease traits more closely and link both common and rare human diseases to malfunctioning genes.
This work was supported by the Wellcome Trust, Medical Research Council NIH, European Commission, Research to Prevent Blindness Australian Research Council, and Cancer Research UK.
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK
- Omics Laboratory, University of Iowa, Iowa City, IA 52242, USA
- Harkness Eye Institute, Columbia University, New York, NY 10032, USA
- Monash University, Melbourne, Victoria 3800, Australia
- Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, UK
- Wolfson Centre for Age-Related Diseases, King’s College London, Guy’s Campus, London SE1 1UL, UK
King’s College London is one of the top 30 universities in the world (2011/12 QS World University Rankings), and the fourth oldest in England. A research-led university based in the heart of London, King’s has more than 25,000 students (of whom more than 10,000 are graduate students) from nearly 140 countries, and some 6,500 employees. King’s is in the second phase of a £1 billion redevelopment programme which is transforming its estate.
King’s has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £450 million.
King’s has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar. It is the largest centre for the education of healthcare professionals in Europe.
King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts
King’s College London and Guy’s and St Thomas’, King’s College Hospital and South London and Maudsley NHS Foundation Trusts are part of King’s Health Partners. King’s Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world’s leading research-led universities and three of London’s most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services.
The Wellcome Trust Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.
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