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

Abstract

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.

Keywords: database; genetics; genomics; human disease model; informatics; model organism; mouse; phenotypes.

Figure 1

The number of protein-coding genes identified in mice over time. The earliest genes discovered in mouse were in genetic segregation studies of morphological and physiological characters. A significant uptick can be seen when biochemical and molecular measurements became widespread in the 1980s, followed by the advent of molecular markers (e.g., cloned genes/gene fragments, RFLPs, SSLPs) in the 1990s, and finally the sequencing of the mouse genome, which was published by the Mouse Genome Sequencing Consortium in 2002. The number of protein-coding genes for mouse has consistently maintained at 20,000 to 25,000 for the last several years. The functional noncoding RNAs and myriad expanding identification of regulatory elements will continue to greatly expand the functional map of the mouse for the foreseeable future.

Figure 2

The Mammalian Phenotype Ontology (MP) Browser example. At the left, the MP browser is shown displaying the detail for the term “abnormal craniofacial bone morphology.” At the top are the term name, common synonyms, the MP ID, and the definition. Below are two term paths shown as hierarchical trees, with paths listed as multiple sequential hierarchies. The “abnormal craniofacial bone morphology” term is followed by a link to MGI genotypes and annotations associated with that term. On the right is a graphical representation (as a DAG) for the abnormal craniofacial bone morphology term. The MP Browser is accessed using the pull-down “Search” menu from the MGI homepage and either following the Phenotypes submenu or the Vocabularies submenu to select the Mammalian Phenotype (MP) Browser (http://www.informatics.jax.org/searches/MP_form.shtml) (Mouse Genome Informatics (MGI) 2016b).

Figure 3

MGI homepage (www.informatics.jax.org) (Mouse Genome Informatics (MGI) 2016l) The MGI Homepage is the gateway to data, tools, news, and release notes. The major sections of the Homepage allow users to (1) do a “Quick Search” to broadly sweep their area of interest, (2) jump to topic area pages, (3) visit the tutorial and introduction areas, (4) use the navy blue navigation bar to find specific search forms or tools, and (5) read news about MGI and follow informational links for MGI statistics, publications, about pages, help documents, and FAQs.

Figure 4

Quick Search results page example. The Quick Search tool is found at the top left of the MGI homepage and on other MGI pages in the upper right corner. In this example, leukemia was entered as the search term, resulting in 1295 results in the Genome Features section and 68 results in the Vocabulary Terms section. From the Quick Search Results page, the symbols in the Genome Features section link to the relevant MGI Gene Detail page or Mutant Allele Detail page. In the Vocabulary Terms section, the term links to the relevant term page: for phenotype terms, to the Mammalian Phenotype Ontology Browser; for disease terms, to the MGI Human Disease and Mouse Model Detail Page; and for a protein family term to the MGI Protein Superfamily Detail page. The Associated Data column links to the underlying annotations and brings the user to the relevant annotation detail page.

Figure 5

Genes and markers query form and results example. Panels A and B show two methods for accessing the Genes and Markers Query Form and illustrate the general principle for accessing other Query Forms within MGI. Beginning on the MGI homepage (www.informatics.jax.org) (Mouse Genome Informatics (MGI) 2016l), use either the pull-down “Search” (panel A) navigating to the Genes submenu and the Genes & Marker Query (circled) or click on the “Genes” topical area button that leads to the Genes, Genome Features & Maps subpage (panel B), where the Genes & Markers Query (circled) also can be selected. On the Genes and Markers Query Form (Mouse Genome Informatics (MGI) 2016j), panel C users may specify as one or more search parameters as desired. In this case, the following parameters were chosen: Feature type = protein coding gene AND Genome location = Chromosome 2 AND Mouse phenotype term = “dilated cardiomyopathy” (enclosed in parentheses for an exact match against the two-word term). The Results page is shown in panel D, where six genes satisfied the query. Note the “You searched for…” feature at the top, which tells the user what parameters were used, and the “Export” utilities for downloading or forwarding the results for additional analysis.

Figure 6.1 and 6.2

Phenotypes, alleles, and disease models search form and results example. For navigation to the Search Form, see the Genes and Markers access method illustrated in Figure 5, panels A and B. The same overall method utilizing the Search pull-down menu or the topical area buttons on the MGI homepage are used throughout the MGI system. Figure 6.1 shows the phenotypes, alleles, and disease model search form (panel A) where, in this example, only a single search parameter was entered into the gene/marker, or allele field. The entry, Smoc*, uses a wildcard and will return all alleles beginning with Smoc…, as well as any synonyms or allele names containing a term beginning Smoc… Additional parameters may be specified in the search, including phenotype and disease terms, genome location, allele generation methods, allele attributes, and/or alleles that were created as part of large projects. There also is an option to exclude alleles if they only exist in cell lines. Panel B show the results of this search, with 4 of the 16 alleles returned shown here (see upper right of the screen for the allele count). For each allele, its symbol, name, synonyms, chromosome assignment, category of mutant generation, and attributes, systems showing abnormal phenotypes and human disease models are provided. Links are provided from the allele symbol (circled) to the Allele Detail Page (Figure 6.2) and from the human disease to the Disease Ontology browser.

Figure 6.2

In panel C the Smoc1^{tm1a(EUCOMM)Wtsi} allele detail page is shown, containing data on the nomenclature and location of the mutant allele, cell lines that contain this mutation, if it has been germline transmitted, its strain of origin, and the project collection that created it. This is followed by a brief description of the mutation itself and its molecular specificity, as known. Images (with additional links to more images and image captions and references) are provided for phenotypic images as well as mutation/vector images, if available. The Phenotypes section of this page shows various genotypes that have been studied with this allele, in this case there are both homozygous and heterozygous genotypes on a C57BL/6N genetic background. The full genotype is always presented, given that genetic background can have significant effect on the phenotypic presentation of mutant genes. A table specifying the anatomical systems in which phenotype was detected is presented, along with the source project, and sex-specific phenotypes, if applicable. It should be noted for each anatomical system, a toggle opens to reveal finer phenotypic detail. Towards the bottom of this detail page are the disease models section showing disease association for this allele, the Find Mice (IMSR) section showing mice available from repositories for the specific mutation being viewed or for all mutations in this gene and linking the user directly to IMSR for information and further access to holding repositories, and finally, a link to all references describing this mutation. Panel D illustrates one of the many links from this Allele Detail Page. Here the link is shown from the genotype “hm1” (homozygous Smoc1^{tm1a(EUCOMM)Wtsi} allele on C57BL/6N) to the finer detail of the phenotypes observed in this genotype. Within panel D, links can be seen from the Mammalian Phenotype Ontology term (e.g., neonatal lethality, complete penetrance) to the Mammalian Phenotype Ontology page (see Figure 2) and to the reference from which this phenotypic data came (e.g., J:174198).

Figure 7

MGI batch query and results example. The Batch Query (Mouse Genome Informatics (MGI) 2016d) is a quick way to translate IDs between databases and to pull selected data from MGI for further analysis. For navigation to the Batch Query Form, follow the method shown in Figure 5, panels A and B, and use the Search pull-down menu or the topical area buttons on the MGI homepage. In this Batch Query example, a list of gene symbols was entered into the Input box at the upper left: Atp7b, Fbn, Oca2, Pax8, Slc26a2. Note that various IDs can be entered (IDs from MGI, Ensembl, GenBank, UniProt, etc.), or a file of gene symbols or IDs, as well. In the Output box at the upper right, Nomenclature, Genome Location and Human Disease (OMIM) were selected. The results returned are a tabular display of all data matching the request and can be downloaded as text or Excel files or forwarded to MouseMine (Motenko et al. 2015) for further analysis. Links in the Nomenclature Symbol column take the user to the Gene Detail page for that gene; and links in the Disease (OMIM) Term column take the user to the MGI Human Disease and Mouse Model Detail page.

Figure 8

Human-Mouse Disease Connection (www.diseasemodel.org) (Human-Mouse: Disease Connection (HMDC) 2016) example. For navigation to the Human-Mouse Disease Connection page, follow the method shown in Figure 5, panels A and B, and use the Search pull-down menu or the topical area buttons on the MGI Homepage. In this figure, the top panel shows the HMDC homepage with its facile search form. Users select what they wish to search by from a pull-down list that includes: Gene symbol or ID; Gene name; Phenotype or Disease ID; Phenotype or Disease term; Genome location; or Gene File upload. Once a category and value are entered, the user may choose to add additional search parameters. In this example, the Phenotype/Disease term Osteogenesis Imperfecta Congenita; OIC was selected and an additional search for Gene symbols was selected and entered as: Col1a1, col1a2. Finally the selection was made to “or” these fields together. The lower panel shows the resulting grid display where human and mouse orthologs are shown in rows and phenotypes and disease shown in columns. Blue indicates mouse data; orange indicates human data. The highlighted Osteogenesis Imperfecta column shows both human COL1A1 and COL1A2 and mouse Col1a1 and Col1a2 are associated to the disease. In addition, mice mutant for Smpd3 have been used to model Osteogenesis Imperfecta, suggesting that the human orthologous gene might be a candidate gene for a patient without COL1A1 or COL1A2 mutations. Note also, that in the column for Caffey Disease that there is an association to human COL1A1, but no mouse model has shown this association. In this case, a researcher might want to look at (or engineer) a Col1a1 mutation to create a potential model for Caffey Disease.

Figure 9

International Mouse Strain Resource (www.findmice.org) (International Mouse Strain Resource (IMSR) 2016) example. The link to the IMSR search is found on the navy blue navigation bar appearing near the top of all MGI pages. Here, the results page for an IMSR search for Fgfr2 is shown. The results of this search show 41 strains returned, with each strain row providing links from the strain name to the repository’s strain page, links to email the repository or go to its ordering page, and links to information in MGI about the mutant allele carried and to the gene page. Note that new searches can be initiated from this same page by replacing this gene symbol with other gene symbols or strain designations. A new search including additional options (e.g., strain state (ES cell, embryo, live, etc.), strain type (coisogenic strain, congenic strain, etc.), specific repository of choice, or specific mutations type of choice) can be accessed from the IMSR homepage or by choosing “show options” next to the search box.