title: Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.
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.
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Potter
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bowl
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Prashanthini
authors.initials: P
authors.lastname: Jeyarajan
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Wisby
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Blease
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Goldsworthy
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Simon
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Greenaway
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Michel
authors.affiliation: The Nuffield Laboratory of Ophthalmology &NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Alun
authors.initials: A
authors.lastname: Barnard
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Aguilar
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Agnew
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Banks
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Blake
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Chessum
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Dorning
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Falcone
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Laurence
authors.initials: L
authors.lastname: Goosey
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Shelley
authors.initials: S
authors.lastname: Harris
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Andy
authors.initials: A
authors.lastname: Haynes
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Ines
authors.initials: I
authors.lastname: Heise
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Rosie
authors.initials: R
authors.lastname: Hillier
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Tertius
authors.initials: T
authors.lastname: Hough
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Hoslin
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Hutchison
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Ruairidh
authors.initials: R
authors.lastname: King
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Saumya
authors.initials: S
authors.lastname: Kumar
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Heena V
authors.initials: HV
authors.lastname: Lad
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Gemma
authors.initials: G
authors.lastname: Law
authors.affiliation: The Nuffield Laboratory of Ophthalmology &NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacLaren
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Morse
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nicol
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Parker
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Pickford
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sethi
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Becky
authors.initials: B
authors.lastname: Starbuck
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Femke
authors.initials: F
authors.lastname: Stelma
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Cheeseman
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Sally H
authors.initials: SH
authors.lastname: Cross
authors.affiliation: Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Foster
authors.affiliation: 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.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.affiliation: Nuffield Department of Clinical Neurosciences (Nuffield Laboratory of Ophthalmology), John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Peirson
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, UK.
authors.forename: Tonia
authors.initials: T
authors.lastname: Vincent
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Scudamore
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.affiliation: 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.
authors.forename: Aziz
authors.initials: A
authors.lastname: El-Amraoui
authors.affiliation: 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Abraham
authors.initials: A
authors.lastname: Acevedo-Arozena
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Nolan
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Cox
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mallon
authors.affiliation: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX11 0RD, UK.
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D003051:Cochlea / Q000378:metabolism; D004195:Disease Models, Animal; D004848:Epithelium / Q000648:ultrastructure; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005260:Female; D005820:Genetic Testing; D006309:Hearing / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype