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

Author

Listed:
  • Paul K. Potter

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Michael R. Bowl

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Prashanthini Jeyarajan

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Laura Wisby

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Andrew Blease

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Michelle E. Goldsworthy

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Michelle M. Simon

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Simon Greenaway

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Vincent Michel

    (Génétique et Physiologie de l'Audition, Institut Pasteur, INSERM UMR-S 1120, Sorbonne Universités, UPMC Univ Paris 06, Collège de France)

  • Alun Barnard

    (The Nuffield Laboratory of Ophthalmology & NIHR Oxford Biomedical Research Centre, University of Oxford)

  • Carlos Aguilar

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Thomas Agnew

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Gareth Banks

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Andrew Blake

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Lauren Chessum

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Joanne Dorning

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Sara Falcone

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Laurence Goosey

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Shelley Harris

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Andy Haynes

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Ines Heise

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Rosie Hillier

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Tertius Hough

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Angela Hoslin

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Marie Hutchison

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Ruairidh King

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Saumya Kumar

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Heena V. Lad

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Gemma Law

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Robert E. MacLaren

    (The Nuffield Laboratory of Ophthalmology & NIHR Oxford Biomedical Research Centre, University of Oxford)

  • Susan Morse

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Thomas Nicol

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Andrew Parker

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Karen Pickford

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Siddharth Sethi

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Becky Starbuck

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Femke Stelma

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Michael Cheeseman

    (The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh)

  • Sally H. Cross

    (MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital)

  • Russell G. Foster

    (John Radcliffe Hospital, University of Oxford)

  • Ian J. Jackson

    (The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh
    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital)

  • Stuart N. Peirson

    (John Radcliffe Hospital, University of Oxford)

  • Rajesh V. Thakker

    (Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital)

  • Tonia Vincent

    (Kennedy Institute of Rheumatology, Rheumatology and Musculoskeletal Sciences, University of Oxford)

  • Cheryl Scudamore

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Sara Wells

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Aziz El-Amraoui

    (Génétique et Physiologie de l'Audition, Institut Pasteur, INSERM UMR-S 1120, Sorbonne Universités, UPMC Univ Paris 06, Collège de France)

  • Christine Petit

    (Génétique et Physiologie de l'Audition, Institut Pasteur, INSERM UMR-S 1120, Sorbonne Universités, UPMC Univ Paris 06, Collège de France)

  • Abraham Acevedo-Arozena

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Patrick M. Nolan

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Roger Cox

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Anne-Marie Mallon

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

  • Steve D. M. Brown

    (MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus)

Abstract

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.

Suggested Citation

  • 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, 2016. "Novel gene function revealed by mouse mutagenesis screens for models of age-related disease," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12444
    DOI: 10.1038/ncomms12444
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