ArticleOpen biology2012
Massively parallel sequencing of the mouse exome to accurately identify rare, induced mutations: an immediate source for thousands of new mouse models.
Article in Open biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 99 citations in OpenAlex.
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- DOCK2 Deficiency Causes Defects in Antiviral T-Cell Responses and Impaired Control of Herpes Simplex Virus Infection.The Journal of infectious diseases · 2024Article
- Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2021Article
- Saturation mutagenesis defines novel mouse models of severe spine deformity.Disease models & mechanisms · 2021Article
- A Point Mutation in IKAROS ZF1 Causes a B Cell Deficiency in Mice.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
- Article
- Machine Learning Techniques for Classifying the Mutagenic Origins of Point Mutations.Genetics · 2020Article
- Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb.Acta neuropathologica communications · 2020Article
- A divergent transcriptional landscape underpins the development and functional branching of MAIT cells.Science immunology · 2019Article
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- Gene editing of the multi-copy H2A.B gene and its importance for fertility.Genome biology · 2019Article
- Fishing forward and reverse: Advances in zebrafish phenomics.Mechanisms of development · 2018Review
- Whole exome sequencing of ENU-induced thrombosis modifier mutations in the mouse.PLoS genetics · 2018Article
- An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome.Scientific reports · 2018Article
- Whole exome sequencing reveals a functional mutation in the GAIN domain of the Bai2 receptor underlying a forward mutagenesis hyperactivity QTL.Mammalian genome : official journal of the International Mammalian Genome Society · 2017Article
- Katanin-like 2 (KATNAL2) functions in multiple aspects of haploid male germ cell development in the mouse.PLoS genetics · 2017Article
- Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease.Nature genetics · 2017Article
- Systems-guided forward genetic screen reveals a critical role of the replication stress response protein ETAA1 in T cell clonal expansion.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Genome-Wide Exome Analysis ofG3 (Bethesda, Md.) · 2017Article
- ASCT2 (SLC1A5)-Deficient Mice Have Normal B-Cell Development, Proliferation, and Antibody Production.Frontiers in immunology · 2017Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 3 institutions in 3 countries.
Funding
Abstract
Accurate identification of sparse heterozygous single-nucleotide variants (SNVs) is a critical challenge for identifying the causative mutations in mouse genetic screens, human genetic diseases and cancer. When seeking to identify causal DNA variants that occur at such low rates, they are overwhelmed by false-positive calls that arise from a range of technical and biological sources. We describe a strategy using whole-exome capture, massively parallel DNA sequencing and computational analysis, which identifies with a low false-positive rate the majority of heterozygous and homozygous SNVs arising de novo with a frequency of one nucleotide substitution per megabase in progeny of N-ethyl-N-nitrosourea (ENU)-mutated C57BL/6j mice. We found that by applying a strategy of filtering raw SNV calls against known and platform-specific variants we could call true SNVs with a false-positive rate of 19.4 per cent and an estimated false-negative rate of 21.3 per cent. These error rates are small enough to enable calling a causative mutation from both homozygous and heterozygous candidate mutation lists with little or no further experimental validation. The efficacy of this approach is demonstrated by identifying the causative mutation in the Ptprc gene in a lymphocyte-deficient strain and in 11 other strains with immune disorders or obesity, without the need for meiotic mapping. Exome sequencing of first-generation mutant mice revealed hundreds of unphenotyped protein-changing mutations, 52 per cent of which are predicted to be deleterious, which now become available for breeding and experimental analysis. We show that exome sequencing data alone are sufficient to identify induced mutations. This approach transforms genetic screens in mice, establishes a general strategy for analysing rare DNA variants and opens up a large new source for experimental models of human disease.
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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.