Disease Ontology: improving and unifying disease annotations across species.

Model organisms are vital to uncovering the mechanisms of human disease and developing new therapeutic tools. Researchers collecting and integrating relevant model organism and/or human data often apply disparate terminologies (vocabularies and ontologies), making comparisons and inferences difficult. A unified disease ontology is required that connects data annotated using diverse disease terminologies, and in which the terminology relationships are continuously maintained. The Mouse Genome Database (MGD, http://www.informatics.jax.org), Rat Genome Database (RGD, http://rgd.mcw.edu) and Disease Ontology (DO, http://www.disease-ontology.org) projects are collaborating to augment DO, aligning and incorporating disease terms used by MGD and RGD, and improving DO as a tool for unifying disease annotations across species. Coordinated assessment of MGD's and RGD's disease term annotations identified new terms that enhance DO's representation of human diseases. Expansion of DO term content and cross-references to clinical vocabularies (e.g. OMIM, ORDO, MeSH) has enriched the DO's domain coverage and utility for annotating many types of data generated from experimental and clinical investigations. The extension of anatomy-based DO classification structure of disease improves accessibility of terms and facilitates application of DO for computational research. A consistent representation of disease associations across data types from cellular to whole organism, generated from clinical and model organism studies, will promote the integration, mining and comparative analysis of these data. The coordinated enrichment of the DO and adoption of DO by MGD and RGD demonstrates DO's usability across human data, MGD, RGD and the rest of the model organism database community.

Mouse Genome Informatics (MGI) Resource: Genetic, Genomic, and Biological Knowledgebase for the Laboratory Mouse.

The Mouse Genome Informatics (MGI) Resource supports basic, translational, and computational research by providing high-quality, integrated data on the genetics, genomics, and biology of the laboratory mouse. MGI serves a strategic role for the scientific community in facilitating biomedical, experimental, and computational studies investigating the genetics and processes of diseases and enabling the development and testing of new disease models and therapeutic interventions. This review describes the nexus of the body of growing genetic and biological data and the advances in computer technology in the late 1980s, including the World Wide Web, that together launched the beginnings of MGI. MGI develops and maintains a gold-standard resource that reflects the current state of knowledge, provides semantic and contextual data integration that fosters hypothesis testing, continually develops new and improved tools for searching and analysis, and partners with the scientific community to assure research data needs are met. Here we describe one slice of MGI relating to the development of community-wide large-scale mutagenesis and phenotyping projects and introduce ways to access and use these MGI data. References and links to additional MGI aspects are provided.

Mouse Genome Informatics (MGI): Resources for Mining Mouse Genetic, Genomic, and Biological Data in Support of Primary and Translational Research.

The Mouse Genome Informatics (MGI), resource ( www.informatics.jax.org ) has existed for over 25 years, and over this time its data content, informatics infrastructure, and user interfaces and tools have undergone dramatic changes (Eppig et al., Mamm Genome 26:272-284, 2015). Change has been driven by scientific methodological advances, rapid improvements in computational software, growth in computer hardware capacity, and the ongoing collaborative nature of the mouse genomics community in building resources and sharing data. Here we present an overview of the current data content of MGI, describe its general organization, and provide examples using simple and complex searches, and tools for mining and retrieving sets of data.

Mouse Genome Database (MGD)-2017: community knowledge resource for the laboratory mouse.

The Mouse Genome Database (MGD: http://www.informatics.jax.org) is the primary community data resource for the laboratory mouse. It provides a highly integrated and highly curated system offering a comprehensive view of current knowledge about mouse genes, genetic markers and genomic features as well as the associations of those features with sequence, phenotypes, functional and comparative information, and their relationships to human diseases. MGD continues to enhance access to these data, to extend the scope of data content and visualizations, and to provide infrastructure and user support that ensures effective and efficient use of MGD in the advancement of scientific knowledge. Here, we report on recent enhancements made to the resource and new features.

The mouse Gene Expression Database (GXD): 2017 update.

The Gene Expression Database (GXD; www.informatics.jax.org/expression.shtml) is an extensive and well-curated community resource of mouse developmental expression information. Through curation of the scientific literature and by collaborations with large-scale expression projects, GXD collects and integrates data from RNA in situ hybridization, immunohistochemistry, RT-PCR, northern blot and western blot experiments. Expression data from both wild-type and mutant mice are included. The expression data are combined with genetic and phenotypic data in Mouse Genome Informatics (MGI) and made readily accessible to many types of database searches. At present, GXD includes over 1.5 million expression results and more than 300 000 images, all annotated with detailed and standardized metadata. Since our last report in 2014, we have added a large amount of data, we have enhanced data and database infrastructure, and we have implemented many new search and display features. Interface enhancements include: a new Mouse Developmental Anatomy Browser; interactive tissue-by-developmental stage and tissue-by-gene matrix views; capabilities to filter and sort expression data summaries; a batch search utility; gene-based expression overviews; and links to expression data from other species.

Mouse genome database 2016.

The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the primary community model organism database for the laboratory mouse and serves as the source for key biological reference data related to mouse genes, gene functions, phenotypes and disease models with a strong emphasis on the relationship of these data to human biology and disease. As the cost of genome-scale sequencing continues to decrease and new technologies for genome editing become widely adopted, the laboratory mouse is more important than ever as a model system for understanding the biological significance of human genetic variation and for advancing the basic research needed to support the emergence of genome-guided precision medicine. Recent enhancements to MGD include new graphical summaries of biological annotations for mouse genes, support for mobile access to the database, tools to support the annotation and analysis of sets of genes, and expanded support for comparative biology through the expansion of homology data.

The International Mouse Strain Resource (IMSR): cataloging worldwide mouse and ES cell line resources.

The availability of and access to quality genetically defined, health-status known mouse resources is critical for biomedical research. By ensuring that mice used in research experiments are biologically, genetically, and health-status equivalent, we enable knowledge transfer, hypothesis building based on multiple data streams, and experimental reproducibility based on common mouse resources (reagents). Major repositories for mouse resources have developed over time and each has significant unique resources to offer. Here we (a) describe The International Mouse Strain Resource that offers users a combined catalog of worldwide mouse resources (live, cryopreserved, embryonic stem cells), with direct access to repository sites holding resources of interest and (b) discuss the commitment to nomenclature standards among resources that remain a challenge in unifying mouse resource catalogs.

Finding mouse models of human lymphomas and leukemia's using the Jackson laboratory mouse tumor biology database.

Many mouse models have been created to study hematopoietic cancer types. There are over thirty hematopoietic tumor types and subtypes, both human and mouse, with various origins, characteristics and clinical prognoses. Determining the specific type of hematopoietic lesion produced in a mouse model and identifying mouse models that correspond to the human subtypes of these lesions has been a continuing challenge for the scientific community. The Mouse Tumor Biology Database (MTB; http://tumor.informatics.jax.org) is designed to facilitate use of mouse models of human cancer by providing detailed histopathologic and molecular information on lymphoma subtypes, including expertly annotated, on line, whole slide scans, and providing a repository for storing information on and querying these data for specific lymphoma models.

Mouse Genome Informatics (MGI): reflecting on 25 years.

From its inception in 1989, the mission of the Mouse Genome Informatics (MGI) resource remains to integrate genetic, genomic, and biological data about the laboratory mouse to facilitate the study of human health and disease. This mission is ever more feasible as the revolution in genetics knowledge, the ability to sequence genomes, and the ability to specifically manipulate mammalian genomes are now at our fingertips. Through major paradigm shifts in biological research and computer technologies, MGI has adapted and evolved to become an integral part of the larger global bioinformatics infrastructure and honed its ability to provide authoritative reference datasets used and incorporated by many other established bioinformatics resources. Here, we review some of the major changes in research approaches over that last quarter century, how these changes are reflected in the MGI resource you use today, and what may be around the next corner.

Orthology for comparative genomics in the mouse genome database.

The mouse genome database (MGD) is the model organism database component of the mouse genome informatics system at The Jackson Laboratory. MGD is the international data resource for the laboratory mouse and facilitates the use of mice in the study of human health and disease. Since its beginnings, MGD has included comparative genomics data with a particular focus on human-mouse orthology, an essential component of the use of mouse as a model organism. Over the past 25 years, novel algorithms and addition of orthologs from other model organisms have enriched comparative genomics in MGD data, extending the use of orthology data to support the laboratory mouse as a model of human biology. Here, we describe current comparative data in MGD and review the history and refinement of orthology representation in this resource.

Mouse Genome Database: From sequence to phenotypes and disease models.

The Mouse Genome Database (MGD, www.informatics.jax.org) is the international scientific database for genetic, genomic, and biological data on the laboratory mouse to support the research requirements of the biomedical community. To accomplish this goal, MGD provides broad data coverage, serves as the authoritative standard for mouse nomenclature for genes, mutants, and strains, and curates and integrates many types of data from literature and electronic sources. Among the key data sets MGD supports are: the complete catalog of mouse genes and genome features, comparative homology data for mouse and vertebrate genes, the authoritative set of Gene Ontology (GO) annotations for mouse gene functions, a comprehensive catalog of mouse mutations and their phenotypes, and a curated compendium of mouse models of human diseases. Here, we describe the data acquisition process, specifics about MGD's key data areas, methods to access and query MGD data, and outreach and user help facilities.

Allele, phenotype and disease data at Mouse Genome Informatics: improving access and analysis.

A core part of the Mouse Genome Informatics (MGI) resource is the collection of mouse mutations and the annotation phenotypes and diseases displayed by mice carrying these mutations. These data are integrated with the rest of data in MGI and exported to numerous other resources. The use of mouse phenotype data to drive translational research into human disease has expanded rapidly with the improvements in sequencing technology. MGI has implemented many improvements in allele and phenotype data annotation, search, and display to facilitate access to these data through multiple avenues. For example, the description of alleles has been modified to include more detailed categories of allele attributes. This allows improved discrimination between mutation types. Further, connections have been created between mutations involving multiple genes and each of the genes overlapping the mutation. This allows users to readily find all mutations affecting a gene and see all genes affected by a mutation. In a similar manner, the genes expressed by transgenic or knock-in alleles are now connected to these alleles. The advanced search forms and public reports have been updated to take advantage of these improvements. These search forms and reports are used by an expanding number of researchers to identify novel human disease genes and mouse models of human disease.

The mouse gene expression database: New features and how to use them effectively.

The Gene Expression Database (GXD) is an extensive and freely available community resource of mouse developmental expression data. GXD curates and integrates expression data from the literature, via electronic data submissions, and by collaborations with large-scale projects. As an integral component of the Mouse Genome Informatics Resource, GXD combines expression data with genetic, functional, phenotypic, and disease-related data, and provides tools for the research community to search for and analyze expression data in this larger context. Recent enhancements include: an interactive browser to navigate the mouse developmental anatomy and find expression data for specific anatomical structures; the capability to search for expression data of genes located in specific genomic regions, supporting the identification of disease candidate genes; a summary displaying all the expression images that meet specified search criteria; interactive matrix views that provide overviews of spatio-temporal expression patterns (Tissue × Stage Matrix) and enable the comparison of expression patterns between genes (Tissue × Gene Matrix); data zoom and filter utilities to iteratively refine summary displays and data sets; and gene-based links to expression data from other model organisms, such as chicken, Xenopus, and zebrafish, fostering comparative expression analysis for species that are highly relevant for developmental research.

GXD: a community resource of mouse Gene Expression Data.

The Gene Expression Database (GXD) is an extensive, easily searchable, and freely available database of mouse gene expression information (www.informatics.jax.org/expression.shtml). GXD was developed to foster progress toward understanding the molecular basis of human development and disease. GXD contains information about when and where genes are expressed in different tissues in the mouse, especially during the embryonic period. GXD collects different types of expression data from wild-type and mutant mice, including RNA in situ hybridization, immunohistochemistry, RT-PCR, and northern and western blot results. The GXD curators read the scientific literature and enter the expression data from those papers into the database. GXD also acquires expression data directly from researchers, including groups doing large-scale expression studies. GXD currently contains nearly 1.5 million expression results for over 13,900 genes. In addition, it has over 265,000 images of expression data, allowing users to retrieve the primary data and interpret it themselves. By being an integral part of the larger Mouse Genome Informatics (MGI) resource, GXD's expression data are combined with other genetic, functional, phenotypic, and disease-oriented data. This allows GXD to provide tools for researchers to evaluate expression data in the larger context, search by a wide variety of biologically and biomedically relevant parameters, and discover new data connections to help in the design of new experiments. Thus, GXD can provide researchers with critical insights into the functions of genes and the molecular mechanisms of development, differentiation, and disease.

Expanding the mammalian phenotype ontology to support automated exchange of high throughput mouse phenotyping data generated by large-scale mouse knockout screens.

BACKGROUND: A vast array of data is about to emerge from the large scale high-throughput mouse knockout phenotyping projects worldwide. It is critical that this information is captured in a standardized manner, made accessible, and is fully integrated with other phenotype data sets for comprehensive querying and analysis across all phenotype data types. The volume of data generated by the high-throughput phenotyping screens is expected to grow exponentially, thus, automated methods and standards to exchange phenotype data are required. RESULTS: The IMPC (International Mouse Phenotyping Consortium) is using the Mammalian Phenotype (MP) ontology in the automated annotation of phenodeviant data from high throughput phenotyping screens. 287 new term additions with additional hierarchy revisions were made in multiple branches of the MP ontology to accurately describe the results generated by these high throughput screens. CONCLUSIONS: Because these large scale phenotyping data sets will be reported using the MP as the common data standard for annotation and data exchange, automated importation of these data to MGI (Mouse Genome Informatics) and other resources is possible without curatorial effort. Maximum biomedical value of these mutant mice will come from integrating primary high-throughput phenotyping data with secondary, comprehensive phenotypic analyses combined with published phenotype details on these and related mutants at MGI and other resources.

Global genetic analysis in mice unveils central role for cilia in congenital heart disease.

Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births; the incidence of CHD is up to tenfold higher in human fetuses. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.

Mouse Tumor Biology (MTB): a database of mouse models for human cancer.

The Mouse Tumor Biology (MTB; http://tumor.informatics.jax.org) database is a unique online compendium of mouse models for human cancer. MTB provides online access to expertly curated information on diverse mouse models for human cancer and interfaces for searching and visualizing data associated with these models. The information in MTB is designed to facilitate the selection of strains for cancer research and is a platform for mining data on tumor development and patterns of metastases. MTB curators acquire data through manual curation of peer-reviewed scientific literature and from direct submissions by researchers. Data in MTB are also obtained from other bioinformatics resources including PathBase, the Gene Expression Omnibus and ArrayExpress. Recent enhancements to MTB improve the association between mouse models and human genes commonly mutated in a variety of cancers as identified in large-scale cancer genomics studies, provide new interfaces for exploring regions of the mouse genome associated with cancer phenotypes and incorporate data and information related to Patient-Derived Xenograft models of human cancers.

The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community.

Identifying mouse models for skin cancer using the Mouse Tumor Biology Database.

In recent years, the scientific community has generated an ever-increasing amount of data from a growing number of animal models of human cancers. Much of these data come from genetically engineered mouse models. Identifying appropriate models for skin cancer and related relevant genetic data sets from an expanding pool of widely disseminated data can be a daunting task. The Mouse Tumor Biology Database (MTB) provides an electronic archive, search and analysis system that can be used to identify dermatological mouse models of cancer, retrieve model-specific data and analyse these data. In this report, we detail MTB's contents and capabilities, together with instructions on how to use MTB to search for skin-related tumor models and associated data.

The mouse Gene Expression Database (GXD): 2014 update.

The Gene Expression Database (GXD; http://www.informatics.jax.org/expression.shtml) is an extensive and well-curated community resource of mouse developmental expression information. GXD collects different types of expression data from studies of wild-type and mutant mice, covering all developmental stages and including data from RNA in situ hybridization, immunohistochemistry, RT-PCR, northern blot and western blot experiments. The data are acquired from the scientific literature and from researchers, including groups doing large-scale expression studies. Integration with the other data in Mouse Genome Informatics (MGI) and interconnections with other databases places GXD's gene expression information in the larger biological and biomedical context. Since the last report, the utility of GXD has been greatly enhanced by the addition of new data and by the implementation of more powerful and versatile search and display features. Web interface enhancements include the capability to search for expression data for genes associated with specific phenotypes and/or human diseases; new, more interactive data summaries; easy downloading of data; direct searches of expression images via associated metadata; and new displays that combine image data and their associated annotations. At present, GXD includes >1.4 million expression results and 250,000 images that are accessible to our search tools.