Search

The latest Cre drivers are integral to mouse genetic studies, and Perry et al. review the CrePortal resource which provides expression and activity data for recombinase alleles. Data and data resources Genomic and genetic datasets from mammalian model organisms are increasingly comprehensive and complex, often encompassing high-dimensional data. The International Mouse Phenotyping Consortium (IMPC) has been in the vanguard of producing a comprehensive catalogue of mammalian gene function through generation and characterisation of a mutant mouse null resource for all mouse-human orthologues. [Extracted from the article]

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome. [ABSTRACT FROM AUTHOR]

Mutagenesis-based screens in mice are a powerful discovery platform to identify novel genes or gene functions associated with disease phenotypes. An N-ethyl- N-nitrosourea (ENU) mutagenesis screen induces single nucleotide variants randomly in the mouse genome. Subsequent phenotyping of mutant and wildtype mice enables the identification of mutated pathways resulting in phenotypes associated with a particular ENU lesion. This unbiased approach to gene discovery conducts the phenotyping with no prior knowledge of the functional mutations. Before the advent of affordable next generation sequencing (NGS), ENU variant identification was a limiting step in gene characterization, akin to 'finding a needle in a haystack'. The emergence of a reliable reference genome alongside advances in NGS has propelled ENU mutation discovery from an arduous, time-consuming exercise to an effective and rapid form of mutation discovery. This has permitted large mouse facilities worldwide to use ENU for novel mutation discovery in a high-throughput manner, helping to accelerate basic science at the mechanistic level. Here, we describe three different strategies used to identify ENU variants from NGS data and some of the subsequent steps for mutation characterisation. [ABSTRACT FROM AUTHOR]

We have applied the Neuro Behavior Ontology (NBO), an ontology for the annotation of behavioral gene functions and behavioral phenotypes, to the annotation of more than 1,000 genes in the mouse that are known to play a role in behavior. These annotations can be explored by researchers interested in genes involved in particular behaviors and used computationally to provide insights into the behavioral phenotypes resulting from differences in gene expression. We developed the OntoFUNC tool and have applied it to enrichment analyses over the NBO to provide high-level behavioral interpretations of gene expression datasets. The resulting increase in the number of gene annotations facilitates the identification of behavioral or neurologic processes by assisting the formulation of hypotheses about the relationships between gene, processes, and phenotypic manifestations resulting from behavioral observations. [ABSTRACT FROM AUTHOR]

The International Mouse Phenotyping Consortium (IMPC) () will reveal the pleiotropic functions of every gene in the mouse genome and uncover the wider role of genetic loci within diverse biological systems. Comprehensive informatics solutions are vital to ensuring that this vast array of data is captured in a standardised manner and made accessible to the scientific community for interrogation and analysis. Here we review the existing EuroPhenome and WTSI phenotype informatics systems and the IKMC portal, and present plans for extending these systems and lessons learned to the development of a robust IMPC informatics infrastructure. [ABSTRACT FROM AUTHOR]

Phenotype-driven approaches in mice are powerful strategies for the discovery of genes and gene functions and for unravelling complex biological mechanisms. Traditional methods for mutation discovery are reliable and robust, but they can also be laborious and time consuming. Recently, high-throughput sequencing (HTS) technologies have revolutionised the process of forward genetics in mice by paving the way to rapid mutation discovery. However, successful application of HTS for mutation discovery relies heavily on the sequencing approach employed and strategies for data analysis. Here we review current HTS applications and resources for mutation discovery and provide an overview of the practical considerations for HTS implementation and data analysis. [ABSTRACT FROM AUTHOR]

Two large-scale phenotyping efforts, the European Mouse Disease Clinic (EUMODIC) and the Wellcome Trust Sanger Institute Mouse Genetics Project (SANGER-MGP), started during the late 2000s with the aim to deliver a comprehensive assessment of phenotypes or to screen for robust indicators of diseases in mouse mutants. They both took advantage of available mouse mutant lines but predominantly of the embryonic stem (ES) cells resources derived from the European Conditional Mouse Mutagenesis programme (EUCOMM) and the Knockout Mouse Project (KOMP) to produce and study 799 mouse models that were systematically analysed with a comprehensive set of physiological and behavioural paradigms. They captured more than 400 variables and an additional panel of metadata describing the conditions of the tests. All the data are now available through EuroPhenome database () and the WTSI mouse portal (), and the corresponding mouse lines are available through the European Mouse Mutant Archive (EMMA), the International Knockout Mouse Consortium (IKMC), or the Knockout Mouse Project (KOMP) Repository. Overall conclusions from both studies converged, with at least one phenotype scored in at least 80 % of the mutant lines. In addition, 57 % of the lines were viable, 13 % subviable, 30 % embryonic lethal, and 7 % displayed fertility impairments. These efforts provide an important underpinning for a future global programme that will undertake the complete functional annotation of the mammalian genome in the mouse model. [ABSTRACT FROM AUTHOR]

Now that the laboratory mouse genome is sequenced and the annotation of its gene content is improving, the next major challenge is the annotation of the phenotypic associations of mouse genes. This requires the development of systematic phenotyping pipelines that use standardized phenotyping procedures which allow comparison across laboratories. It also requires the development of a sophisticated informatics infrastructure for the description and interchange of phenotype data. Here we focus on the current state of the art in the description of data produced by systematic phenotyping approaches using ontologies, in particular, the EQ (Entity-Quality) approach, and what developments are required to facilitate the linking of phenotypic descriptions of mutant mice to human diseases. [ABSTRACT FROM AUTHOR]

The whirler mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs). BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein called whirlin. The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31. In the mouse cochlea, whirlin is expressed in the sensory IHC and OHC stereocilia. Our findings suggest that this novel PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia. [ABSTRACT FROM AUTHOR]

X-linked dominant disorders that are exclusively lethal prenatally in hemizygous males have been described in human and mouse. None of the genes responsible has been isolated in either species. The bare patches (Bpa) and striated (Str) mouse mutations were originally identified in female offspring of X-irradiated males. Subsequently, additional independent alleles were described. We have previously mapped these X-linked dominant, male-lethal mutations to an overlapping region of 600 kb that is homologous to human Xq28 (ref. 4) and identified several candidate genes in this interval. Here we report mutations in one of these genes, Nsdhl, encoding an NAD(P)H steroid dehydrogenase-like protein, in two independent Bpa and three independent Str alleles. Quantitative analysis of sterols from tissues of affected Bpa mice support a role for Nsdhl in cholesterol biosynthesis. Our results demonstrate that Bpa and Str are allelic mutations and identify the first mammalian locus associated with an X-linked dominant, male-lethal phenotype. They also expand the spectrum of phenotypes associated with abnormalities of cholesterol metabolism. [ABSTRACT FROM AUTHOR]

The article presents a study related to comparative visualization of genotype-phenotype relationships, conducted by researchers Ron S. Kenett and Galit Shmueli. Topics discussed include objectives of the International Mouse Phenotyping Consortium (IMPC), the web-based tool Phenoview developed by IMPC that allows users viewing genotype-phenotype relationships by plrovbiding data on single access point to researchers.

A correction to the article "Comparative visualization of genotype-phenotype relationships" that was published in the July 30, 2015 issue is presented.

An introduction is presented in which the editor discusses various reports within the issue on topics including annotation of the mouse reference genome, role of CRISPR-Cas9 protein in mutation detection and genome editing, and big data generation in mouse genetics.

An introduction to the journal is presented in which the editor discusses various articles within the issue on topics including use of mouse phenotype data into human disease research, association of mouse gene catalog with orthologous human genes and the Mouse Genome Informatics (MGI) resource.

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease., (© 2022. The Author(s).)