Caruana, GeorginaFarlie, Peter GHart, Adam HBagheri-Fam, StefanWallace, Megan JDobbie, Michael SGordon, Christopher TMiller, Kerry AWhittle, BelindaAbud, Helen EArkell, RuthCole, TimothyHarley, Vincent RSmyth, Ian MBertram, John F2015-11-262015-11-261932-6203http://hdl.handle.net/1885/16827BACKGROUND Mice harbouring gene mutations that cause phenotypic abnormalities during organogenesis are invaluable tools for linking gene function to normal development and human disorders. To generate mouse models harbouring novel alleles that are involved in organogenesis we conducted a phenotype-driven, genome-wide mutagenesis screen in mice using the mutagen N-ethyl-N-nitrosourea (ENU). METHODOLOGY/PRINCIPAL FINDINGS ENU was injected into male C57BL/6 mice and the mutations transmitted through the germ-line. ENU-induced mutations were bred to homozygosity and G3 embryos screened at embryonic day (E) 13.5 and E18.5 for abnormalities in limb and craniofacial structures, skin, blood, vasculature, lungs, gut, kidneys, ureters and gonads. From 52 pedigrees screened 15 were detected with anomalies in one or more of the structures/organs screened. Using single nucleotide polymorphism (SNP)-based linkage analysis in conjunction with candidate gene or next-generation sequencing (NGS) we identified novel recessive alleles for Fras1, Ift140 and Lig1. CONCLUSIONS/SIGNIFICANCE In this study we have generated mouse models in which the anomalies closely mimic those seen in human disorders. The association between novel mutant alleles and phenotypes will lead to a better understanding of gene function in normal development and establish how their dysfunction causes human anomalies and disease.This work was enabled by the Australian Phenomics Network and partly supported by funding from the Australian Government’s National Collaborative Research Infrastructure Strategy, a Strategic Grant from the Faculty of Medicine, Nursing and Health Sciences at Monash University, and the Victorian Government’s Operational Infrastructure Support Program. IS acknowledges support through the NH&MRC R. Douglas Wright and ARC Future Fellowship schemes. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.© 2013 Caruana et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.allelesanimalscongenital abnormalitiesdna ligasesethylnitrosoureaexomeextracellular matrix proteinsfemalegenome-wide association studygenotypegerm-line mutationhigh-throughput nucleotide sequencinghomozygoteleft-right determination factorsmalemicemice, inbred c57blmutagenesismutagensphenotypedisease models, animalpolymorphism, single nucleotide2013-03-0110.1371/journal.pone.00554292015-12-11