Genes Essential to Life Discovered
Genes Essential to Life Discovered
Roughly a third of all genes in the mammalian genome are essential for life. A new article in Nature, from an international, multi-institutional research team including the Medical Research Council (MRC) Harwell, describes the large-scale discovery of those genes and how it will impact understanding of mammalian development and human disease.
MRC Harwell is a leading member of the International Mouse Phenotyping Consortium, which includes researchers representing over 30 institutions world-wide. The IMPC is generating and phenotyping (assessing the morphological and physiological characteristics of) knockout mutations for all of the protein-coding genes in the mouse genome. The Consortium aims to discover new functions for the roughly 20,000 genes shared with humans, and makes all of the mouse strains available to provide a platform for dissecting the mechanisms of human disease.
The Nature study reports the results of the first 1,751 genes characterized by the IMPC using these knock out mouse models, including the finding that nearly one third are essential for life. This includes 410 lines that are fully lethal where embryos did not survive, and an additional 198 for which fewer than half of the expected number of mutants were identified.
Using a new, standardized phenotyping platform and mouse lines on a single C57BL/6N genetic background, the researchers established both the time of embryonic death and the nature of the lethal phenotypes, discovering many novel characteristics that shed light on the function of these genes. The incorporation of high-resolution 3D imaging and automated, computational analysis of the images allowed the team to gather detailed information and make discoveries of new phenotypes on an unprecedented scale.
The group also showed that identification of essential genes in the mouse provides a window on human disease, including the discovery of a number of novel cases where these genes overlap with known human disease genes. In addition, in collaboration with the ExAC Consortium**, they showed that human orthologs of mouse essential genes are significantly depleted for loss-of-function mutations in humans, and that these genes are thus strong candidates for undiagnosed human genetic conditions.
Joint first author, Dr Lydia Teboul from MRC Harwell, says: “The MRC Harwell Institute is proud to have contributed to the international effort of the IMPC that has begun to dissect the function of many of the genes of the mouse genome. MRC Harwell has worked with our partners to design the testing pipeline and produce data. The collection of the data at the Data Coordination Centre at MRC Harwell has also been pivotal to the emerging findings from the study of the first 1700 genes analysed. Most excitingly, the consortium has identified a large number of essential genes in the mouse, many of which are associated with human disease. The work will contribute significantly to our understanding of the genetic bases for human diseases including spina bifida and cardiovascular defects amongst many others.”
Moreover, JAX Senior Research Scientist Dr Steve Murray, corresponding author of the study, notes “When looking across the seven or eight embryos generated for each knockout, we found variations in phenotype at a surprising frequency. We expect diversity when we look across different genetic backgrounds, but this is the first large-scale documentation of pervasive variable expressivity in a defined genetic background.”
The research collaboration included Dr Mary Dickinson at Baylor College of Medicine, Dr Ann Flenniken and Dr Michael Wong at the University of Toronto, and Dr Xiao Ji of the University of Pennsylvania. Groups from the Wellcome Trust Sanger Institute and the Francis Crick Institute were also involved. Dr David Adams, from the Wellcome Trust Sanger Institute, says: “This study heralds a landmark in our understanding of mammalian development with phenotypes described for over 600 genes important for embryonic development. The mouse lines produced are an invaluable resource for modelling human developmental diseases.”
All data and images generated by the project are available to the research community, disseminated via an open-source web portal in real time without embargo. The mouse models generated are also available to other researchers who may be investigating particular pathways or disease phenotypes.
“As current estimates indicate that only a small percentage of genes are studied by the broad research community,” the researchers note in the paper, “the systematic approach to phenotyping and unrestricted access to data and mouse models provided by the IMPC promises to fill this large gap in our understanding of mammalian gene function.”
Dr Lindsay Wilson, Programme Manager for Genetics and Genomics at the MRC, says: “The MRC, together with our international partners, recognises the value of building up a repository of high quality gene-function data that will shape the research of present-day and future scientists. This is especially true for underexplored genes, which might have roles we can’t imagine without seeing what happens when we remove them altogether. That is why we have made substantial investments over many years, through our world-class Harwell Institute, to secure the ambitions of the IMPC.”
Professor Steve Brown, Director at MRC Harwell and chair of the IMPC Steering Committee, says: "A worldwide consortium of labs, the International Mouse Phenotyping Consortium, is well on the way to generating a mutant for every gene in the mouse genome and characterising the effects of those mutations. This will provide a comprehensive catalogue of mammalian gene function and provide many new insights into the role of genes in disease. This report from the IMPC describes the phenotypes from the first 1700 genes analysed and indicates that at least a third of the genes are essential for life. In one of the most significant findings of the paper, the IMPC shows that many of these essential genes are associated with disease in humans throwing new light on the genetic bases for disease."