£22 million investment launches MRC National Mouse Genetics Network

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The MRC National Mouse Genetics Network marks a major new £22 million investment in mouse genetics for modelling human disease that will capitalise on the UK’s international excellence in the biomedical sciences.

The Network is comprised of 7 challenge-led research clusters, bringing together members from across the UK.

The partnerships established by the Network will enable integration of basic science research with clinical findings in order to accelerate our understanding of human disease and translation to patient benefit.

Congenital Anomalies

Approximately one in 20 babies are born with birth defects, also known as congenital anomalies. Of the 8 million newborns affected each year, 300,000 die within their first four weeks of life. With recent advances in sequencing technology, identification of possibly disease-causing changes in the genetic code of these infants has been accelerated. However, it still remains a major challenge to prove which of these genetic variants cause these malformations as well as to establish the cellular mechanisms by which these changes disrupt normal development.

Dr Pleasantine Mill will co-lead a team within the Congenital Anomalies cluster which is spearheaded by Professor Karen Liu (King’s College London) to tackle this challenge. The cluster is receiving around £3.7 million of MRC investment which aims to generate and characterise new mouse models of human congenital disorders in collaboration with the Mary Lyon Centre. The cluster will bring together diverse expertise from across the country to understand disease mechanisms and use these mice as pre-clinical models to identify potential therapies.

Digging deep into syndromic congenital anomalies across developmental windows, Pleasantine’s cluster is looking to build stronger ties with human clinical genetics teams across the UK to prioritize which clinically relevant models should be generated and taken for deep phenotyping, with the goal of developing preclinical models for therapeutics.

The cluster will also develop national community-led programmes to better align mouse genetics and developmental biology with human congenital anomalies, including improving the symmetry of human and mouse pathology in order to maximize the clinical relevance of mice as models of human disease. With this programme of work, this cluster ultimately hopes to provide improved diagnoses and prognoses for patients with congenital anomalies.

Our cluster aims to make precisely engineered mouse models of gene variants identified in patients in order to understand how they lead to disease, often through effects on multiple organ systems. Many of these disease genes play many roles in different tissues across development. They control complex interactions between different cell and tissue types - these are difficult to study in humans or even stem cell ‘disease-in-a dish’ models. Mouse models are really important to help us understand how these genetic changes lead to malformations and syndromic disorders at birth.

Dr Pleasantine Mill

Degron Tagging 

Degron tags are already widely and successfully used in cultured cells and invertebrates. However, research on their use in mouse models is at an early stage and the complex environment of mammalian tissues poses several challenges.

Currently, methods to disrupt protein function in mice involve targeting DNA or RNA which works slowly and doesn’t accurately reflect how many drugs work.

Degron tagging enables proteins to be directly targeted for destruction by small drug-like molecules, which should greatly improve our ability to understand the basis of many human diseases, and to determine whether promising drug targets are likely to work in the clinic.  

The Degron Tagging cluster aims to translate degron technologies into mouse models of human disease and to share protocols with the community.

The team brings together expertise in genome editing, protein engineering, protein turnover, medicinal chemistry and pharmacology.

Dr Andrew Wood will lead the cluster which will use a £1 million award to develop methods to rapidly change the dose of proteins within mouse tissues. He is joined by co-investigators Dr Joe Marsh, Professor Asier Unciti-Broceta (Edinburgh Cancer Research Centre) and researchers from the University of Dundee.  

Degron-tagging has already revolutionised how we study the function of proteins using cells grown in the laboratory, and this cluster investment will bring this powerful technology to bear on mouse models of human disease and therapy. Our cluster brings together skills in the engineering of genomes, proteins and small molecules, which is made possible by the diverse range of expertise within the Institute of Genetics and Cancer and in the broader Scottish biomedical research community.

Dr Andrew Wood

The seven cluster themes are:

• Cancer, led by Prof Karen Blyth at the CRUK Beatson Institute/University of Glasgow and Prof Louis Chesler at the Institute of Cancer Research
• Congenital Anomalies, led by Prof Karen Liu at King’s College London
• Degron Tagging, led by Dr Andrew Wood at the MRC Human Genetics Unit at the University of Edinburgh
• Haem, led by Dr David Kent at the University of York
• Microbiome, led by Prof Fiona Powrie at the University of Oxford
• Mitochondria, led by Dr Robert Pitceathly at the UCL Queen Square Institute of Neurology
• MURIDAE (Modalities for Understanding, Recording and Integrating Data Across Early life) led by Prof Anthony Isles at the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University

Links

• Andrew Wood Research Group
• Joe Marsh Research Group
• Pleasantine Mill Research Group
• MRC National Mouse Genetics Network website