Uncovering the hidden mutations in developmental disorders

Mouse models are teaching us a lot about developmental disorders, but some mutations remain hidden because of their very nature. Tim Mohun explains how a major new genetics project is going to uncover them.

What are the functions of all the genes in our genome and which of them cause inherited disease? Answering these questions is an ambitious challenge, but one which is now becoming feasible. Already, there is a coordinated international effort making progress along this path, using the laboratory mouse as a model. The goal is to knock out each of the 20,000 genes in the mouse genome one by one and test their effect on growth, development, health and behaviour of the mouse. Production of the mutant mouse lines is underway, based in the UK at the Wellcome Trust Sanger Institute and the MRC Mary Lyon Centre at Harwell. Adults from each line are comprehensively tested to identify any effects of the mutation on health of the mouse, using a range of standardised tests to study their physiology, metabolism and structure.

Exciting as this is, there is one serious problem: over a third of the mutations produced can’t be studied properly because they result in death of the mutant mouse while it is still an embryo. But looked at another way, these same mouse mutants are a potential treasure trove for developmental biologists because they are identifying genes that are important for embryo development. By studying them we can learn a great deal about how an embryo develops. By the same token, these lethal mutations could be just as important for clinicians, identifying genes in which mutations contribute to congenital disorders. These are debilitating diseases and abnormalities that are frequently evident in the newborn and which can have devastating effects on subsequent health and lifespan of the child.

That’s why the Wellcome Trust has now funded a major new programme of research dedicated to studying these “embryonic lethal” mouse mutations. Deciphering the Mechanisms of Developmental Disorders (DMDD) is a consortium of scientists that brings together developmental biologists and clinicians from across the UK in a common effort to identify these genes and to begin to study why their mutation has such a profound effects on embryo development and survival. To achieve this, DMDD will study each embryonic lethal mutation produced at the Sanger Institute over the next five years (about 50 each year) combining state-of-the art imaging with the DNA sequencing methods to identify changes in gene expression. We already know that a proportion of these mutations will be lethal for the embryo because they affect not the embryo itself, but rather the placenta, which supports embryo growth in the womb. By imaging the structure of the placenta, DMDD will be able to identify this group of mutants.

However, we also know from previous studies that around two thirds of all the embryonic lethal mutations have a direct impact on the developing embryo, causing major abnormalities in the arrangement of tissues or the structure of the developing organs. By using the latest 3D imaging techniques, DMDD will screen the external and internal structure of mutant embryos, cataloguing the range and severity of the abnormalities that are detected. In some cases, embryos appear completely normal in structure but still die around the time of normal birth. In these cases we suspect that this results from defects affecting neural tissue (such as regions of the brain) that are more difficult to detect, but nevertheless prevent the newborn mouse from surviving. DMDD will use specialised imaging to study the arrangement, distribution and connections of nerves in these mutants to better understand why the mutants are lethal.

For each mouse line studied, DMDD plans to use the formidable resources for DNA sequencing available at the Sanger Institute, each mutant being studied to identify its pattern of gene expression and the differences it shows when compared with normal embryos. Combining this with the imaging data and the catalogue of abnormalities will provide a systematic first analysis of embryonic lethal mutations. At the heart of the DMDD programme is the commitment to make all this wealth of data freely and readily available to the biomedical community via a dedicated website. This will go hand in hand with efforts to engage the developmental biology and clinical research communities, bringing them together to exploit a unique opportunity to better understand normal development and developmental disease.

Tim Mohun

Dr Tim Mohun is a developmental biologist at the MRC National Institute for Medical Research.

DMDD is funded by the Wellcome Trust.

Image credit: Wellcome Library, London