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

Paul K Potter (1) , Michael R Bowl (1) , Prashanthini Jeyarajan (1) , Laura Wisby (1) , Andrew Blease (1) , Michelle E Goldsworthy (1) , Michelle M Simon (1) , Simon Greenaway (1) , Vincent Michel (2) , Alun Barnard (3) , Carlos Aguilar (1) , Thomas Agnew (1) , Gareth Banks (1) , Andrew Blake (1) , Lauren Chessum (1) , Joanne Dorning (1) , Sara Falcone (1) , Laurence Goosey (1) , Shelley Harris (1) , Andy Haynes (1) , Ines Heise (1) , Rosie Hillier (1) , Tertius Hough (1) , Angela Hoslin (1) , Marie Hutchison (1) , Ruairidh King (1) , Saumya Kumar (1) , Heena V Lad (1) , Gemma Law (1) , Robert E Maclaren (3) , Susan Morse (1) , Thomas Nicol (1) , Andrew Parker (1) , Karen Pickford (1) , Siddharth Sethi (1) , Becky Starbuck (1) , Femke Stelma (1) , Michael Cheeseman (4) , Sally H Cross (4) , Russell G Foster (3) , Ian J Jackson (4) , Stuart N Peirson (3) , Rajesh V Thakker (3) , Tonia Vincent (3) , Cheryl Scudamore (1) , Sara Wells (1) , Aziz El-Amraoui (2) , Christine Petit (2, 5) , Abraham Acevedo-Arozena (1) , Patrick M Nolan (1) , Roger Cox (1) , Anne-Marie Mallon (1) , Steve D M Brown (1)

1 MRC Harwell Institute [UK]
2 Génétique et Physiologie de l'Audition
3 University of Oxford
4 University of Edinburgh
5 Collège de France - Chaire Génétique et physiologie cellulaire

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.

Domains: Life Sciences [q-bio]

Paul K Potter, Michael R Bowl, Prashanthini Jeyarajan, Laura Wisby, Andrew Blease, et al.. Novel gene function revealed by mouse mutagenesis screens for models of age-related disease. Nature Communications, 2016, 7, pp.12444. ⟨10.1038/ncomms12444⟩. ⟨pasteur-03922337⟩