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

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  • 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
  • Russell G Foster
  • 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

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    Rights statement: © The Author(s) 2016 This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
Article number12444
JournalNature Communications
Early online date18 Aug 2016
Publication statusE-pub ahead of print - 18 Aug 2016


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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