ArticlePLoS genetics2013
Unlocking the bottleneck in forward genetics using whole-genome sequencing and identity by descent to isolate causative mutations.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Genetic determinants of blood pressure and heart rate identified through ENU-induced mutagenesis with automated meiotic mapping.Science advances · 2024Article
- Characterization of single nucleotide polymorphisms for a forward genetics approach using genetic crosses in C57BL/6 and BALB/c substrains of mice.Experimental animals · 2022Article
- Facilitating Complex Trait Analysis via Reduced Complexity Crosses.Trends in genetics : TIG · 2020Review
- Forward genetic analysis using OCT screening identifiesProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Screening for Antiviral Medaka Haploid Embryonic Stem Cells by Genome Wide Mutagenesis.Marine biotechnology (New York, N.Y.) · 2019Article
- Whole exome sequencing of ENU-induced thrombosis modifier mutations in the mouse.PLoS genetics · 2018Article
- Optimizing Genomic Methods for Mapping and Identification of Candidate Variants in ENU Mutagenesis Screens Using Inbred Mice.G3 (Bethesda, Md.) · 2018Article
- Sensitized mutagenesis screen in Factor V Leiden mice identifies thrombosis suppressor loci.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Mouse Genome Informatics (MGI) Resource: Genetic, Genomic, and Biological Knowledgebase for the Laboratory Mouse.ILAR journal · 2017Review
- Article
- Forward Genetics by Sequencing EMS Variation-Induced Inbred Lines.G3 (Bethesda, Md.) · 2017Article
- Frontline Science: Coincidental null mutation of Csf2rα in a colony of PI3Kγ-/- mice causes alveolar macrophage deficiency and fatal respiratory viral infection.Journal of leukocyte biology · 2017Article
- Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.Nature communications · 2016Article
- Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Variant mapping and mutation discovery in inbred mice using next-generation sequencing.BMC genomics · 2015Article
- Current strategies for mutation detection in phenotype-driven screens utilising next generation sequencing.Mammalian genome : official journal of the International Mammalian Genome Society · 2015Review
- Mouse Genome Informatics (MGI): reflecting on 25 years.Mammalian genome : official journal of the International Mammalian Genome Society · 2015Review
- Real-time resolution of point mutations that cause phenovariance in mice.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.Nucleic acids research · 2015Article
- Phenotypic instability between the near isogenic substrains BALB/cJ and BALB/cByJ.Mammalian genome : official journal of the International Mammalian Genome Society · 2014Article
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Authors and funding
17 authors.
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Abstract
Forward genetics screens with N-ethyl-N-nitrosourea (ENU) provide a powerful way to illuminate gene function and generate mouse models of human disease; however, the identification of causative mutations remains a limiting step. Current strategies depend on conventional mapping, so the propagation of affected mice requires non-lethal screens; accurate tracking of phenotypes through pedigrees is complex and uncertain; out-crossing can introduce unexpected modifiers; and Sanger sequencing of candidate genes is inefficient. Here we show how these problems can be efficiently overcome using whole-genome sequencing (WGS) to detect the ENU mutations and then identify regions that are identical by descent (IBD) in multiple affected mice. In this strategy, we use a modification of the Lander-Green algorithm to isolate causative recessive and dominant mutations, even at low coverage, on a pure strain background. Analysis of the IBD regions also allows us to calculate the ENU mutation rate (1.54 mutations per Mb) and to model future strategies for genetic screens in mice. The introduction of this approach will accelerate the discovery of causal variants, permit broader and more informative lethal screens to be used, reduce animal costs, and herald a new era for ENU mutagenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.