Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project

Ayadi, Abdel; Birling, Marie‐Christine; Bottomley, Joanna; Bussell, James; Fuchs, Helmut; Fray, Martin; Gailus‐Durner, Valérie; Greenaway, Simon; Houghton, Richard; Karp, Natasha A.; Leblanc, Sophie; Lengger, Christoph; Maier, Holger R.; Mallon, Ann‐Marie; Marschall, Susan; Melvin, David; Morgan, Hugh W.; Pavlovic, Guillaume; Ryder, Edward; Skarnes, William C.; Selloum, Mohammed; Ramirez-Solis, Ramiro; Sorg, Tania; Teboul, Lydia; Vasseur, Laurent; Walling, Alison; Weaver, Tom; Wells, Sara; White, Jacqui; Bradley, Allan; Adams, David J.; Steel, Karen P.; Angelis, Martin Hrabé de; Brown, Steve; Hérault, Yann

doi:10.1007/s00335-012-9418-y

Cited by 139 publications

(109 citation statements)

References 29 publications

(32 reference statements)

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“…OWLTools was used to calculate the phenotypic similarity between each of the HPO-annotated OMIM disease records and all 28,176 MPO-annotated mutant lines from MGI and the Sanger Mouse Genetics Project (Ayadi et al 2012), resulting in a phenotypic relevance score for the corresponding mouse genes and their human orthologs. The pairwise comparisons were performed using OWL representations of the human and mouse phenotype annotations and a merged OWL file of the Phenotype and Trait Ontology (PATO), Uberon (Mungall et al 2012), MPO and HPO and their logical definitions, as previously described .…”

Section: Phenotypic Relevance Scorementioning

confidence: 99%

Improved exome prioritization of disease genes through cross-species phenotype comparison

et al. 2013

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Numerous new disease-gene associations have been identified by whole-exome sequencing studies in the last few years. However, many cases remain unsolved due to the sheer number of candidate variants remaining after common filtering strategies such as removing low quality and common variants and those deemed unlikely to be pathogenic. The observation that each of our genomes contains about 100 genuine loss-of-function variants makes identification of the causative mutation problematic when using these strategies alone. We propose using the wealth of genotype to phenotype data that already exists from model organism studies to assess the potential impact of these exome variants. Here, we introduce PHenotypic Interpretation of Variants in Exomes (PHIVE), an algorithm that integrates the calculation of phenotype similarity between human diseases and genetically modified mouse models with evaluation of the variants according to allele frequency, pathogenicity, and mode of inheritance approaches in our Exomiser tool. Large-scale validation of PHIVE analysis using 100,000 exomes containing known mutations demonstrated a substantial improvement (up to 54.1-fold) over purely variant-based (frequency and pathogenicity) methods with the correct gene recalled as the top hit in up to 83% of samples, corresponding to an area under the ROC curve of >95%. We conclude that incorporation of phenotype data can play a vital role in translational bioinformatics and propose that exome sequencing projects should systematically capture clinical phenotypes to take advantage of the strategy presented here.

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Section: Phenotypic Relevance Scorementioning

confidence: 99%

Improved exome prioritization of disease genes through cross-species phenotype comparison

et al. 2013

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“…From 100 pups, we did not identify any Dnm2 -/-mice, confirming that Dnm2 -/-is embryonically lethal. Dnm2 +/-pups were identified at expected Mendelian ratios and were further analyzed under the EUMODIC phenotyping program (32). Basic blood chemistry tests indicated no difference between WT and Dnm2 +/-mice for urea (indicating normal kidney function), calcium (implying osmotic homeostasis), and total cholesterol (suggesting absence of cardiovascular disease) levels (Supplemental Figure 2A).…”

Section: Characterization Of Dnm2 Heterozygous (Dnm2 +/-) Micementioning

confidence: 99%

Reducing dynamin 2 expression rescues X-linked centronuclear myopathy

Cowling¹,

Chevremont²,

Prokić³

et al. 2014

J. Clin. Invest.

118

147

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Centronuclear myopathies (CNM) are congenital disorders associated with muscle weakness and abnormally located nuclei in skeletal muscle. An autosomal dominant form of CNM results from mutations in the gene encoding dynamin 2 (DNM2), and loss-of-function mutations in the gene encoding myotubularin (MTM1) result in X-linked CNM (XLCNM, also called myotubular myopathy), which promotes severe neonatal hypotonia and early death. Currently, no effective treatments exist for XLCNM. Here, we found increased DNM2 levels in XLCNM patients and a mouse model of XLCNM (Mtm1 -/y ). Generation of Mtm1 -/y mice that were heterozygous for Dnm2 revealed that reduction of DNM2 in XLCNM mice restored life span, whole-body strength, and diaphragm function and increased muscle strength. Additionally, classic CNM-associated histological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructural analysis revealed improvement of sarcomere organization and triad structures. Skeletal muscle-specific decrease of Dnm2 during embryogenesis or in young mice after disease onset revealed that the rescue associated with downregulation of Dnm2 is cell autonomous and is able to stop and potentially revert XLCNM progression. These data indicate that MTM1 and DNM2 regulate muscle organization and force through a common pathway. Furthermore, despite DNM2 being a key mechanoenzyme, its reduction is beneficial for XLCNM and represents a potential therapeutic approach for patients.

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“…The efficient mutagenesis of essential genes can result in lethality in the F0 generation and therefore failure to transmit mutant alleles to subsequent generations. Genetic screens in mouse and zebrafish have estimated that as many as 30% of genes are embryonic lethal (Driever et al, 1996;Haffter et al, 1996;Ayadi et al, 2012). Therefore, improvements in current genetic tools and/ or manipulations to circumvent the lethality associated with mutation of essential genes would greatly accelerate progress in making mutant lines.…”

Section: Introductionmentioning

confidence: 99%

Leapfrogging: primordial germ cell transplantation permits recovery of CRISPR/Cas9-induced mutations in essential genes

2016

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CRISPR/Cas9 genome editing is revolutionizing genetic loss-offunction analysis but technical limitations remain that slow progress when creating mutant lines. First, in conventional genetic breeding schemes, mosaic founder animals carrying mutant alleles are outcrossed to produce F1 heterozygotes. Phenotypic analysis occurs in the F2 generation following F1 intercrosses. Thus, mutant analyses will require multi-generational studies. Second, when targeting essential genes, efficient mutagenesis of founders is often lethal, preventing the acquisition of mature animals. Reducing mutagenesis levels may improve founder survival, but results in lower, more variable rates of germline transmission. Therefore, an efficient approach to study lethal mutations would be useful. To overcome these shortfalls, we introduce 'leapfrogging', a method combining efficient CRISPR mutagenesis with transplantation of mutated primordial germ cells into a wild-type host. Tested using Xenopus tropicalis, we show that founders containing transplants transmit mutant alleles with high efficiency. F1 offspring from intercrosses between F0 animals that carry embryonic lethal alleles recapitulate loss-of-function phenotypes, circumventing an entire generation of breeding. We anticipate that leapfrogging will be transferable to other species.

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Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project

Cited by 139 publications

References 29 publications

Improved exome prioritization of disease genes through cross-species phenotype comparison

Improved exome prioritization of disease genes through cross-species phenotype comparison

Reducing dynamin 2 expression rescues X-linked centronuclear myopathy

Leapfrogging: primordial germ cell transplantation permits recovery of CRISPR/Cas9-induced mutations in essential genes

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