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 iden...

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Vydáno v:	Nature communications Ročník 7; číslo 1; s. 12444 - 13
Hlavní autoři:	Potter, Paul K., Bowl, Michael R., Jeyarajan, Prashanthini, Wisby, 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, MacLaren, Robert E., Morse, Susan, Nicol, Thomas, Parker, Andrew, Pickford, Karen, Sethi, Siddharth, Starbuck, Becky, Stelma, Femke, Cheeseman, Michael, Cross, Sally H., Foster, Russell G., Jackson, Ian J., Peirson, Stuart N., Thakker, Rajesh V., Vincent, Tonia, Scudamore, Cheryl, Wells, Sara, El-Amraoui, Aziz, Petit, Christine, Acevedo-Arozena, Abraham, Nolan, Patrick M., Cox, Roger, Mallon, Anne-Marie, Brown, Steve D. M.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 18.08.2016 Nature Publishing Group Nature Portfolio
Témata:	631/1647/334/1874/345 631/208/191/1908 64 64/60 692/699 Age Aging Aging - genetics Animals Cochlea - metabolism Diabetes Disease Disease Models, Animal Epithelium - ultrastructure Evoked Potentials, Auditory, Brain Stem - physiology Female Females Genes Genetic Testing Genetics Genomes Genotype & phenotype Hearing - genetics Hearing loss Hospitals Humanities and Social Sciences Life Sciences Male Males Mice, Inbred C57BL multidisciplinary Mutagenesis Mutagenesis - genetics Mutation Mutation - genetics Ophthalmology Pedigree Phenotype Physiology Rheumatology Science Science (multidisciplinary) United Kingdom > UK France
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. Random mutagenesis can uncover novel genes involved in phenotypic traits. Here the authors perform a large-scale phenotypic screen on over 100 mouse strains generated by ENU mutagenesis to identify mice with age-related diseases, which they attribute to specific mutations revealed by whole-genome sequencing.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC4992138 These authors contributed equally to this work
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms12444