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

被引：63

作者：

Potter, Paul K. ^{[1
]}

Bowl, Michael R. ^{[1
]}

Jeyarajan, Prashanthini ^{[1
]}

Wisby, Laura ^{[1
]}

Blease, Andrew ^{[1
]}

Goldsworthy, Michelle E. ^{[1
]}

Simon, Michelle M. ^{[1
]}

Greenaway, Simon ^{[1
]}

Michel, Vincent ^{[2
]}

Barnard, Alun ^{[3
,4
]}

Aguilar, Carlos ^{[1
]}

Agnew, Thomas ^{[1
]}

Banks, Gareth ^{[1
]}

Blake, Andrew ^{[1
]}

Chessum, Lauren ^{[1
]}

Dorning, Joanne ^{[1
]}

Falcone, Sara ^{[1
]}

Goosey, Laurence ^{[1
]}

Harris, Shelley ^{[1
]}

Haynes, Andy ^{[1
]}

Heise, Ines ^{[1
]}

Hillier, Rosie ^{[1
]}

Hough, Tertius ^{[1
]}

Hoslin, Angela ^{[1
]}

Hutchison, Marie ^{[1
]}

King, Ruairidh ^{[1
]}

Kumar, Saumya ^{[1
]}

Lad, Heena V. ^{[1
]}

Law, Gemma ^{[1
]}

MacLaren, Robert E. ^{[3
,4
]}

Morse, Susan ^{[1
]}

Nicol, Thomas ^{[1
]}

Parker, Andrew ^{[1
]}

Pickford, Karen ^{[1
]}

Sethi, Siddharth ^{[1
]}

Starbuck, Becky ^{[1
]}

Stelma, Femke ^{[1
]}

Cheeseman, Michael ^{[5
]}

Cross, Sally H. ^{[6
]}

Foster, Russell G. ^{[7
]}

Jackson, Ian J. ^{[5
,6
]}

Peirson, Stuart N. ^{[7
]}

Thakker, Rajesh V. ^{[8
]}

Vincent, Tonia ^{[9
]}

Scudamore, Cheryl ^{[1
]}

Wells, Sara ^{[1
]}

El-Amraoui, Aziz ^{[2
]}

Petit, Christine ^{[2
]}

Acevedo-Arozena, Abraham ^{[1
]}

Nolan, Patrick M. ^{[1
]}

机构：

[1] MRC Harwell Inst, Mammalian Genet Unit, Harwell Campus, Didcot OX11 0RD, Oxon, England

[2] Univ Paris 06, Sorbonne Univ, Coll France, INSERM,UMR S 1120,Inst Pasteur,Genet & Physiol Au, 25 Rue Dr Roux, F-75015 Paris, France

[3] Univ Oxford, Nuffield Lab Ophthalmol, Oxford OX3 9DU, England

[4] Univ Oxford, NIHR Oxford Biomed Res Ctr, Oxford OX3 9DU, England

[5] Univ Edinburgh, Sch Vet Studies, Roslin Inst & Royal Dick, Edinburgh EH25 9RG, Midlothian, Scotland

[6] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[7] Univ Oxford, John Radcliffe Hosp, Nuffield Lab Ophthalmol, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England

[8] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England

[9] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Nuffield Dept Orthopaed, Kennedy Inst Rheumatol, Oxford OX3 7FY, England

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会; 英国惠康基金;

关键词：

ENU-MUTAGENESIS; HEARING; MICE; IMPAIRMENT; MUTATIONS; VARIANTS;

D O I：

10.1038/ncomms12444

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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