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© Research
Publication : Nature Communications

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Nature Communications - 18 Aug 2016

Paul K Potter, Michael R Bowl, Prashanthini Jeyarajan, Laura Wisby, Andrew Blease, Michelle E Goldsworthy, Michelle M Simon, Simon Greenaway, Vincent Michel, Alun Barnard, Carlos Aguilar, Thomas Agnew, Gareth Banks, Andrew Blake, Lauren Chessum, Joanne Dorning, Sara Falcone, Laurence Goosey, Shelley Harris, Andy Haynes, Ines Heise, Rosie Hillier, Tertius Hough, Angela Hoslin, Marie Hutchison, Ruairidh King, Saumya Kumar, Heena V Lad, Gemma Law, Robert E Maclaren, Susan Morse, Thomas Nicol, Andrew Parker, Karen Pickford, Siddharth Sethi, Becky Starbuck, Femke Stelma, Michael Cheeseman, Sally H Cross, Russell G Foster, Ian J Jackson, Stuart N Peirson, Rajesh V Thakker, Tonia Vincent, Cheryl Scudamore, Sara Wells, Aziz El-Amraoui, Christine Petit, Abraham Acevedo-Arozena, Patrick M Nolan, Roger Cox, Anne-Marie Mallon, Steve D M Brown

Link to Pubmed [PMID] – 27534441

Link to HAL – pasteur-03922337

Link to DOI – 10.1038/ncomms12444

Nature Communications, 2016, 7, pp.12444. ⟨10.1038/ncomms12444⟩

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.