- KOMP2 UM1 Administrative Supplement Request to support HaploEssential Early Stage Knockout Mouse Embryonic Phenotyping Essential genes, genes whose function is necessary for the basic function of life, are enriched for variants causing human developmental disorders. Mice with recessive null mutations of essential genes supports this hypothesis, with human variant candidate genes identified by rare disease genetic consortia being enriched for orthologous null mouse alleles that are lethal or subviable. In companion supplemental proposals, our KOMP- funded partners propose to extend the mouse phenotyping pipeline to the study of null alleles with dominant lethality (haploinsufficiency) by characterising pre-implantation embryos of up to 600 potential essential genes where one allele has been made non-functional using CRISPR-based methods. These embryos will be analysed preimplantation using time-lapse video technology with surviving embryos implanted and analysed via the current embryo phenotyping pipeline. This project will be of high value to clinical geneticists studying developmental disorders as it will help identify potential disease associated genes in days rather than months, which will aid speedy diagnosis. The project will also identify genetic features that characterise haplo-essential genes leading to better predictive tools and deepening our understanding of how early embryonic developmental processes manifest in disease. To support our KOMP partners and ensure the results from pre-implantation and early stage embryo phenotyping of haplo-essential genes are widely disseminated, we will perform the following activities: Develop and implement bioinformatic approaches to identify candidate haploinsufficient genes using integrated analysis of human intolerance to loss of function scores, human de novo mutations associated with rare disease, cellular gene essentiality studies, and model organism data. Coordinate activity across the KOMP partners by extending our production tracking database to capture milestones in pre-implantation studies and disseminate updates in real time. Standardize the methods used in pre-implantation embryo phenotyping to by collaborating with the KOMP partners to develop new SOPs and define the necessary QC methods to ensure the data is of high quality. Extend existing data flow pipelines to capture image and video data produced by the KOMP partners as well as post-implantation studies on different genetic backgrounds. Freely disseminate early stage embryo phenotyping data and essential gene lists via a dedicated component of the mousephenotype.org that will allow specialised search and host dedicated visualisation tools. Host a Data Analysis Workshop to review results, organise writing for a consortium publication and develop an outreach strategy to maximize the impact of the project.

Public Health Relevance

? KOMP2 UM1 Administrative Supplement Request to support HaploEssential Early Stage Knockout Mouse Embryonic Phenotyping Studies from human population genetic studies and cellular based screens suggest certain genes are essential to the basic functioning of life, with mutations in only one of two copies of the gene having an increased chance of leading to human developmental disorders. We will provide the informatics infrastructure needed by our KOMP-funded partners to develop a high-throughput pipeline to identify putative essential genes and study the impact of mutating one gene copy upon the earliest stages of embryogenesis. This project will impact human health by delivering high-quality translatable results to fertility specialists and clinical geneticists who are trying to identify genes harboring variants that are responsible for developmental disorders. 1

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project with Complex Structure Cooperative Agreement (UM1)
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Special Emphasis Panel (ZHG1)
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Fletcher, Colin F
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European Molecular Biology Laboratory
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