How genetic mutations affect development more complex than previously thought
A large-scale study, published in Wellcome Open Research and which passed peer review today, has shown that inactivating the same gene in mouse embryos that are virtually genetically identical can result in a wide range of different physical features or abnormalities. This suggests that the relationship between gene mutation and consequence is more complex than previously suspected.
The researchers, from the Deciphering the Mechanisms of Development Disorders (DMDD) consortium that is coordinated at the Francis Crick Institute, looked at 220 mouse embryos each missing one of 42 different genes. By scanning the entire embryo in minute detail, the researchers picked up on even the smallest differences in features – right down to the level of whether the structure of individual nerves, muscles and small blood vessels were abnormal.
The genes studied by DMDD are known as ‘embryonic lethal’, because they are so crucial to development that an embryo missing any one of them can’t survive to birth. Studying these genes can help us understand how embryos develop, why some miscarry, and why some mutations can lead to abnormalities at birth.
Clinicians commonly find that people with the same genetic disease can show different symptoms or be affected with differing severity. In part this is likely to be due to the fact that we all differ in our precise genetic makeup. However, this study in mice shows that even when individuals have virtually identical genomes, the same mutation can lead to a variety of different outcomes amongst affected embryos.
“This is a striking result, coming as it does from such a large study in which embryos have been studied in unprecedented detail. It shows us that even with an apparently simple and well-defined mutation, the precise outcome can be both complex and variable. We have a lot to learn about the roles of these lethal genes in embryonic development to understand why this happens.
“This is a surprising result, and more research into gene function is needed in order to make sense of the finding.”
Dr Tim Mohun Who led the study at Deciphering the Mechanisms of Developmental Disorders (DMDD)
“The fundamental processes driving how we develop have been conserved through evolution. This makes studying animal models enormously helpful in increasing our understanding of why some babies develop birth defects.
“This study throws new light on what we thought was a fairly straightforward relationship between what’s coded in our genes and how we develop. Researchers need to appreciate this added layer of complexity, as well as endeavouring to unpick the intricate processes of genetic control at play.”
Dr Andrew Chisholm Head of Cellular and Developmental Sciences at Wellcome, which funds the DMDD
“This study highlights the power of genetic analyses in mice and provides an unprecedented resource of data to inform clinical genetic studies in humans.”
Dr David Adams Group Leader at the Wellcome Trust Sanger Institute, who collaborated with the study
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About the DMDD programme
The DMDD programme aims to shed light on the genetic basis of human developmental disorders by studying the effects of ‘turning off’ individual genes in the mouse genome. All data from the programme has been made available to the scientific community at dmdd.org.uk with the goal of sparking new research in this area. The DMDD programme is funded by the Wellcome Trust, with support from the Francis Crick Institute.The DMDD programme aims to shed light on the genetic basis of human developmental disorders by studying the effects of ‘turning off’ individual genes in the mouse genome. All data from the programme has been made available to the scientific community at dmdd.org.uk with the goal of sparking new research in this area. The DMDD programme is funded by the Wellcome Trust, with support from the Francis Crick Institute.
About Wellcome
Wellcome exists to improve health for everyone by helping great ideas to thrive. We’re a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate.
About the Francis Crick Institute
The Francis Crick Institute is a new and distinctive biomedical research institute. Research groups are now moving into its purpose-built laboratory in the King’s Cross area of London. The institute’s work will help to understand why disease develops. We will find new ways to diagnose, prevent and treat a range of illnesses − such as cancer, heart disease and stroke, infections and neurodegenerative diseases. We will bring together outstanding scientists from all disciplines, carrying out research that will help improve the health and quality of people’s lives, and keeping the UK at the forefront of medical innovation. The Francis Crick Institute is a charity supported by the Medical Research Council, Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London.
About the Wellcome Trust Sanger Institute
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.
