Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12444
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Funding
- Medical Research Council, UK [MC U142684172, MC U142661184, MC U142684173, MC U142684175, MC_PC_U127561112]
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis [20205]
- BBSRC
- EC-TREATRUSH [Health-F2-2010-242013]
- ERC advanced grant 'Hair bundle' [ERC-2011-AdG 294570]
- Wellcome Trust [098461/Z/12/Z, 090532/Z/09/Z]
- MRC [G0900747 91070]
- Biotechnology and Biological Sciences Research Council [BB/I021086/1] Funding Source: researchfish
- Medical Research Council [MC_U142684173, 1774724, MC_UP_1502/1, MC_U142684175, MC_U142684172, MC_PC_U127561112, 1330931, G0901338, MC_U142661184, MC_U142684171, MC_UP_A390_1106, 1191860] Funding Source: researchfish
- RNID [G65] Funding Source: researchfish
- BBSRC [BB/I021086/1] Funding Source: UKRI
- MRC [MC_UP_1502/1, MC_U142684172, G0901338, MC_U142684175, MC_U142684171, MC_PC_U127561112, MC_U142661184, MC_U142684173, MC_UP_A390_1106] Funding Source: UKRI
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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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