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Nat Commun. 2016 Aug 18;7:12444. doi: 10.1038/ncomms12444.

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

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MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
Génétique et Physiologie de l'Audition, Institut Pasteur, INSERM UMR-S 1120, Sorbonne Universités, UPMC Univ Paris 06, Collège de France, 25 rue Dr Roux, Paris 75015, France.
The Nuffield Laboratory of Ophthalmology &NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 9DU, UK.
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, UK.


Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.

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