Characterizing the mouse genome reveals new gene functions and their role in human disease

The first results from a functional genetic catalogue of the laboratory mouse has been shared with the biomedical research community, revealing new insights into a range of rare diseases and the possibility of accelerating development of new treatments and precision medicine.

The research, which generated over 20 million pieces of data, has found 360 new disease models and provides 28,406 new descriptions of the genes' effects on mouse biology and disease. The new disease models are being made available to the biomedical community to aid their research.

The International Mouse Phenotyping Consortium (IMPC)* is aiming to produce a complete catalogue of mammalian gene function across all genes. Their initial results, now published in Nature Genetics, is based on an analysis of the first 3,328 genes (15 per cent of the mouse genome coding for proteins).

Lead author Dr Damian Smedley from Queen Mary University of London (QMUL) and a Monarch Initiative** Principal Investigator, said: "Although next generation sequencing has revolutionised the identification of new disease genes, there is still a lack of understanding of how these genes actually cause disease.

"These 360 new disease models that we've identified in mice represent the first steps of a hugely important international project. We hope researchers will be able to use this knowledge to develop new therapies for patients, which is ultimately what we're all striving to achieve."

With its similarity to human biology and ease of genetic modification, the laboratory mouse is arguably the preferred model organism for studying human genetic disease. However, the vast majority of the mouse genome remains poorly understood, as scientists tend to focus their research on a few specific areas of the genome linked to the most common inherited diseases.

Development of therapies for rare disease lags far behind, with over half of diagnosed rare diseases still having no known causative gene. This is why the IMPC is aiming to build a complete database that systematically details the functions of all areas of the mouse genome, including neurological, metabolic, cardiovascular, respiratory and immunological systems.

Terry Meehan, IMPC Project Coordinator at European Bioinformatics Institute (EMBL-EBI) said: "Mouse models allow us to speed up patient diagnosis and develop new therapies. But before that can work, we need to understand exactly what each gene does, and what diseases it is associated with. This is a significant effort in data collection and curation that goes well beyond the capabilities of individual labs. IMPC is creating a data resource that will benefit the entire biomedical community."

The project involves going through the mouse genome systematically and knocking out a particular gene, one by one, in different mice. By looking at the mouse's resulting characteristics in a variety of standardised tests, the team then see if and how the gene knockout manifests itself as a disease, and link their findings to what is already known about the human version of the disease. The 'one by one' knockout approach lends itself to rare gene discovery, as often these diseases are caused by variants of a single gene.

More than half of the 3,328 genes characterised have never been investigated in a mouse before, and for 1,092 genes, no molecular function or biological process were previously known from direct experimental evidence. These include genes that have now been found to be involved in the formation of blood components (potentially involved in a type of anaemia), cell proliferation and stem cell maintenance.

For the first time, human disease traits were seen in mouse models for forms of Bernard-Soulier syndrome (a blood clotting disorder), Bardet-Biedl syndrome (causing vision loss, obesity and extra fingers or toes) and Gordon Holmes syndrome (a neurodegenerative disorder with delayed puberty and lack of secondary sex characteristics).

The team also identified new candidate genes for diseases with an unknown molecular mechanism, including an inherited heart disease called 'Arrhythmogenic Right Ventricular Dysplasia' that affects the heart muscle, and Charcot-Marie-Tooth disease, which is characterised by nerve damage leading to muscle weakness and an awkward way of walking.

Dr Smedley added: "In addition to a better understanding of the disease mechanism and new treatments for rare disease patients, many of the lessons we learn here will also be of value to precision medicine, where the goal is to improve treatment through the customisation of healthcare based on a patient's genomic information."

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The study was a collaboration between the European Bioinformatics Institute, Medical Research Council Harwell, the Monarch Initiative and QMUL, and funded by the National Institutes of Health.

For more information, please contact:

Joel Winston, Public Relations Manager

Queen Mary University of London
j.winston@qmul.ac.uk
Tel: +44 (0) 207 882 7943 / +44 (0) 7970 096 188

* The International Mouse Phenotyping Consortium consists of Medical Research Council Harwell, Wellcome Trust Sanger Institute, Helmholtz-Zentrum Muenchen, Toronto Centre for Phenogenomics, PHENOMIN, Australian Phenomics Network, RIKEN BioResource Center, CNR Monterotondo, MARC Nanjing University, The Jackson Laboratory, The Davis, Toronto, Charles River and CHORI Consortium (DTCC), Korea Mouse Phenotype Consortium, Bayor College of Medicine, National Laboratory Animal Center (National Applied Research Laboratories - NARLabs, Taiwan), EBI, Czech centre for Phenogenomics (IMG) and Universitat Autònoma de Barcelona.

** The Monarch Initiative consists of QMUL, Oregon Health & Science University, The Jackson Laboratory, Lawrence Berkeley National Laboratory, the Garvan Institute in Australia, and the Charité - Universitätsmedizin Berlin.

Research paper: 'Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium' by Meehan et al., Nature Genetics. DOI: 10.1038/ng.3901

Paper is available here after the embargo lifts: http://dx.doi.org/10.1038/ng.3901

Queen Mary University of London (QMUL) is one of the UK's leading universities, and one of the largest institutions in the University of London, with 23,120 students from more than 155 countries.

A member of the Russell Group, we work across the humanities and social sciences, medicine and dentistry, and science and engineering, with inspirational teaching directly informed by our research. In the most recent national assessment of the quality of research, we were placed ninth in the UK (REF 2014).

As well as our main site at Mile End - which is home to one of the largest self-contained residential campuses in London - we have campuses at Whitechapel, Charterhouse Square, and West Smithfield dedicated to the study of medicine, and a base for legal studies at Lincoln's Inn Fields.

We have a rich history in London with roots in Europe's first public hospital, St Barts; England's first medical school, The London; one of the first colleges to provide higher education to women, Westfield College; and the Victorian philanthropic project, the People's Palace at Mile End.

Today, as well as retaining these close connections to our local community, we are known for our international collaborations in both teaching and research.

QMUL has an annual turnover of £350m, a research income worth £125m (2014/15), and generates employment and output worth £700m to the UK economy each year.

The European Bioinformatics Institute (EMBL-EBI) is a global leader in the storage, analysis and dissemination of large biological datasets. EMBL-EBI helps scientists realise the potential of 'big data' by enhancing their ability to exploit complex information to make discoveries that benefit humankind.

EMBL-EBI is at the forefront of computational biology research, with work spanning sequence analysis methods, multi-dimensional statistical analysis and data-driven biological discovery, from plant biology to mammalian development and disease.

We are part of the European Molecular Biology Laboratory (EMBL), an international, innovative and interdisciplinary research organisation funded by 22 member states and two associate member states, and are located on the Wellcome Genome Campus, one of the world's largest concentrations of scientific and technical expertise in genomics.

Website: http://www.ebi.ac.uk

The Monarch Initiative is an international, NIH Office of Director funded consortium that integrates genotype and phenotype data from a diverse array of human and model and non-model organism data sources using semantic technologies. The Monarch Initiative develops the Human Phenotype Ontology, which provisions interoperability with models such as the mouse. Sophisticated semantic algorithms developed by Monarch and used in this study, have been shown to aid non-exact phenotyping matching against known human diseases and assist in the interrogation of model organism data for rare disease diagnosis. A portal containing the extensive human and model organism genotype-phenotype data, including the IMPC data, is available at http://www.monarchinitiative.org.