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


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.

DOI: 10.1038/ncomms12444

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@inproceedings{Potter2016NovelGF, title={Novel gene function revealed by mouse mutagenesis screens for models of age-related disease}, author={Paul Keith Potter and Michael R. Bowl and Prashanthini Jeyarajan and Laura Wisby and Andrew Blease and Michelle E. Goldsworthy and Michelle Simon and Simon Greenaway and Vincent Michel and Alun R Barnard and Carlos J Aguilar and Thomas A. Agnew and Gareth T. Banks and Andrew Blake and Lauren Chessum and Joanne Dorning and Sara Falcone and Laurence Goosey and Shelley A Harris and Andy Haynes and Ines Heise and Rosie Hillier and Tertius A. Hough and Angela Hoslin and Marie Hutchison and Ruairidh King and Saumya Kumar and Heena V. Lad and Gemma Law and Robert E Maclaren and Susan A Morse and Thomas Nicol and Andrew D M Parker and Karen Pickford and Siddharth Kumar Sethi and Becky Starbuck and Femke Stelma and Michael T. Cheeseman and Sally H. Cross and Russell G . Foster and Ian J Jackson and Stuart N Peirson and Rajesh V Thakker and T. L. Vincent and Cheryl L. Scudamore and Sara Wells and Aziz El-Amraoui and Christine Petit and Abraham Acevedo-Arozena and Patrick M. Nolan and Roger D . Cox and Anne-Marie Mallon and Steve D. M. Brown}, booktitle={Nature communications}, year={2016} }