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

作者：Potter Paul K; Bowl Michael R; Jeyarajan Prashanthini; Wi**y Laura; Blease Andrew; Goldsworthy Michelle E; Simon Michelle M; Greenaway Simon; Michel Vincent; Barnard Alun; Aguilar Carlos; Agnew Thomas; Banks Gareth; Blake Andrew; Chessum Lauren; Dorning Joanne; Falcone Sara; Goosey Laurence; Harris Shelley; Haynes Andy; Heise Ines; Hillier Rosie; Hough Tertius; Hoslin Angela; Hutchison Marie; King Ruairidh; Kumar Saumya; Lad Heena V; Law Gemma

来源：Nature Communications, 2016, 7(1): 12444.

DOI：10.1038/ncomms12444

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.

• 出版日期2016-8