The Mouse Genome Database (MGD): integration nexus for the laboratory mouse

The Mouse Genome Database (MGD) is the community database resource for the laboratory mouse, a key model organism for interpreting the human genome and for understanding human biology and disease (http://www.informatics.jax.org). MGD provides standard nomenclature and consensus map positions for mouse genes and genetic markers; it provides a curated set of mammalian homology records, user-defined chromosomal maps, experimental data sets and the definitive mouse 'gene to sequence' reference set for the research community. The integration and standardization of these data sets facilitates the transition between mouse DNA sequence, gene and phenotype annotations. A recent focus on allele and phenotype representations enhances the ability of MGD to organize and present data for exploring the relationship between genotype and phenotype. This link between the genome and the biology of the mouse is especially important as phenotype information grows from large mutagenesis projects and genotype information grows from large-scale sequencing projects.     

Laboratory mouse models for the human genome-wide associations

The agnostic screening performed by genome-wide association studies (GWAS) has uncovered associations for previously unsuspected genes. Knowledge about the functional role of these genes is crucial and laboratory mouse models can provide such information. Here, we describe a systematic juxtaposition of human GWAS-discovered loci versus mouse models in order to appreciate the availability of mouse models data, to gain biological insights for the role of these genes and to explore the extent of concordance between these two lines of evidence. We perused publicly available data (NHGRI database for human associations and Mouse Genome Informatics database for mouse models) and employed two alternative approaches for cross-species comparisons, phenotype- and gene-centric. A total of 293 single gene-phenotype human associations (262 unique genes and 69 unique phenotypes) were evaluated. In the phenotype-centric approach, we identified all mouse models and related ortholog genes for the 51 human phenotypes with a comparable phenotype in mice. A total of 27 ortholog genes were found to be associated with the same phenotype in humans and mice, a concordance that was significantly larger than expected by chance (p<0.001). In the gene-centric approach, we were able to locate at least 1 knockout model for 60% of the 262 genes. The knockouts for 35% of these orthologs displayed pre- or post-natal lethality. For the remaining non-lethal orthologs, the same organ system was involved in mice and humans in 71% of the cases (p<0.001). Our project highlights the wealth of available information from mouse models for human GWAS, catalogues extensive information on plausible physiologic implications for many genes, provides hypothesis-generating findings for additional GWAS analyses and documents that the concordance between human and mouse genetic association is larger than expected by chance and can be informative.     

MGD: the Mouse Genome Database

The Mouse Genome Database (MGD) (http://www.informatics.jax.org) one component of a community database resource for the laboratory mouse, a key model organism for interpreting the human genome and for understanding human biology. MGD strives to provide an extensively integrated information resource with experimental details annotated from both literature and on-line genomic data sources. MGD curates and presents the consensus representation of genotype (sequence) to phenotype information including highly detailed information about genes and gene products. Primary foci of integration are through representations of relationships between genes, sequences and phenotypes. MGD collaborates with other bioinformatics groups to curate a definitive set of information about the laboratory mouse. Recent developments include a general implementation of database structures for controlled vocabularies and the integration of a phenotype classification system.     

The Mouse Phenome Project

The laboratory mouse is the organism of choice for many studies in biology and medicine. Reliable phenotypic data are essential for the full utility of genotypic information emerging from efforts to sequence human and mouse genomes. The Mouse Phenome Project has been organized to help accomplish this task by establishing a collection of baseline phenotypic data on commonly used and genetically diverse inbred mouse strains and making this information publicly available through a web-accessible database. The Mouse Phenome Database (MPD) is being developed to manage these data and to provide researchers with tools for exploring both raw phenotypic data and comparative summary analyses. The MPD serves as a repository for detailed protocols and raw data. This resource enables investigators to identify appropriate strains for (1) physiological testing, (2) drug discovery, (3) toxicology studies, (4) mutagenesis, (5) modeling human diseases, (6) QTL analyses and identification of new genes and (7) unraveling the influence of environment on genotype.     

Comparative systems biology of human and mouse as a tool to guide the modeling of human placental pathology

Placental abnormalities are associated with two of the most common and serious complications of human pregnancy, maternal preeclampsia (PE) and fetal intrauterine growth restriction (IUGR), each disorder affecting ～5% of all pregnancies. An important question for the use of the mouse as a model for studying human disease is the degree of functional conservation of genetic control pathways from human to mouse. The human and mouse placenta show structural similarities, but there have been no systematic attempts to assess their molecular similarities or differences. We collected protein and mRNA expression data through shot‐gun proteomics and microarray expression analysis of the highly vascular exchange region, microdissected from the human and mouse near‐term placenta. Over 7000 ortholog genes were detected with 70% co‐expressed in both species. Close to 90% agreement was found between our human proteomic results and 1649 genes assayed by immunohistochemistry for expression in the human placenta in the Human Protein Atlas. Interestingly, over 80% of genes known to cause placental phenotypes in mouse are co‐expressed in human. Several of these phenotype‐associated proteins form a tight protein–protein interaction network involving 15 known and 34 novel candidate proteins also likely important in placental structure and/or function. The entire data are available as a web‐accessible database to guide the informed development of mouse models to study human disease.     

Models and assumptions underlying genetic risk assessment

Various methods employed for estimating the genetic risks of radiation are reviewed. With the doubling-dose method, genetic damage is expressed as an increase in cases of known genetic disease. The actual doubling dose is based on figures obtained with the mouse. There have been no recent data on induced mutation frequencies. Recent results suggest that the prevalence figure for multifactorial disease may be at least one order of magnitude higher than before. Various assumptions underlying the doubling-dose concept are discussed in the light of recent findings on: (1) spontaneous mutations resulting from insertion elements, and (2) the comparability between spontaneous and induced mutations. The so-called direct method makes use of figures for induction of dominant mutations affecting the skeleton and the lens of the eye in the mouse, and of translocation induction in monkeys. Induction rates are converted to overall rates of induced dominant effects in man by applying certain assumptions. The proportionality between dose and effect is the basis for all genetic risk assessments. The possible significance of data on human lymphocytes indicating a threshold below 4 rad and the induction of repair enzymes by low radiation doses is discussed. The parallelogram approach is based on the principle that estimates can be obtained on the amount of genetic damage that cannot always be assessed directly. Thus mutations in mouse germ cells can be predicted by using mutation frequencies in cultured mammalian cells and O6-ethylguanine adducts. Measurement of haemoglobin mutations in human and mouse erythrocytes, and of HPRT-deficient mutations in lymphocytes of man and mouse should make more precise estimates of mutation frequencies in human germ cells possible. The development of a database on mutations in somatic cells of the mouse, their induction frequencies and molecular nature are considered an important priority. Used in combination with mouse germ-cell mutation frequencies, they should enable more precise risk estimates on the basis of mutations in somatic cells of man.     

Deconstructing Mus gemischus: advances in understanding ancestry, structure, and variation in the genome of the laboratory mouse

The laboratory mouse is an artificial construct with a complex relationship to its natural ancestors. In 2002, the mouse became the first mammalian model organism with a reference genome. Importantly, the mouse genome sequence was assembled from data on a single inbred laboratory strain, C57BL/6. Several large-scale genetic variant discovery efforts have been conducted, resulting in a catalog of tens of millions of SNPs and structural variants. High-density genotyping arrays covering a subset of those variants have been used to produce hundreds of millions of genotypes in laboratory stocks and a small number of wild mice. These landmark resources now enable us to determine relationships among laboratory mice, assign local ancestry at fine scale, resolve important controversies, and identify a new set of challenges—most importantly, the troubling scarcity of genetic data on the very natural populations from which the laboratory mouse was derived. Our aim with this review is to provide the reader with an historical context for the mouse as a model organism and to explain how practical decisions made in the past have influenced both the architecture of the laboratory mouse genome and the design and execution of current large-scale resources. We also provide examples on how the accomplishments of the past decade can be used by researchers to streamline the use of mice in their experiments and correctly interpret results. Finally, we propose future steps that will enable the mouse community to extend its successes in the decade to come.     

MitoP2: An Integrative Tool for the Analysis of the Mitochondrial Proteome

Mitochondria are crucial for normal cell metabolism and maintenance. Mitochondrial dysfunction has been implicated in a spectrum of human diseases, ranging from rare monogenic to common multifactorial disorders. Important for the understanding of organelle function is the assignment of its constituents, and although over 1,500 proteins are predicted to be involved in mammalian mitochondrial function, so far only about 900 are assigned to mitochondria with reasonable certainty. Continuing efforts are being taken to obtain a complete inventory of the mitochondrial proteome by single protein studies and high-throughput approaches. To be of best value for the scientific community this data needs to be structured, explored, and customized. For this purpose, the MitoP2 database () was established and is maintained in order to incorporate such data. The central database contains manually evaluated yeast, mouse, and human reference proteins, which show convincing evidence of a mitochondrial location. In addition, entries from genome-wide approaches that suggest protein localization are integrated and serve to compile a combined score for each candidate, which provides a best estimate of mitochondrial localization. Furthermore, it integrates information on the orthology between species, including Saccharomyces cerevisiae, mouse, human, Arabidopsis thaliana, and Neurospora crassa, thus mutually enhancing evidence across species. In contrast to other known databases, MitoP2 takes into account the reliability by which the protein is estimated as being mitochondrially located, as described herein. Multiple search functions, as well as information on disease causing genes and available mouse models, makes MitoP2 a valuable tool for the genetic investigation of human mitochondrial pathology.     

小家鼠和实验小鼠遗传特性的比较研究

本文用同工酶电泳法、微量细胞毒法和免疫双向扩散法对我国4个动物地理区的6个采集点的156个小家鼠(Mus musculus)进行了遗传特性的调查。结果发现:在全部被测的13个位点中,小家鼠在7个位点上存在着多种实验小鼠中罕见的基因组成;而不同动物地理区和亚区的小家鼠的遗传特性又各不相同。从而指出将小家鼠的特有基因导入实验小鼠,培育新品系的重大意义。     

The use of different test systems with yeasts for the evaluation of chemically induced gene conversions and gene mutations

The wide variety of genetic alterations that can be induced in human populations when exposed to chemical genotoxic substances present in our environment may be predictable using laboratory organisms such as yeasts.In the present paper methodologies are described for analysing the genetic effects induced by a well known chemical mutagen, ethyl methanesulfonate (EMS). Haploid or diploid yeast cells have been treated in vitro, in buffer or in the presence of mouse liver microsomes, and in vivo, in the peritoneum of the mouse (host-mediated assay).With these different methods of assaying the genetic activity of a compound, its metabolic activation occuring in the mammalian body is taken into account: this might lead to a more reliable extrapolation of data from laboratory experiments to man.The relationships between doses and frequencies of the induced genetic effects are described by equations obtained after regression analysis of the data, thus allowing a quantitative comparison among different methodologies and different genetic systems.One genetic system analyzed is represented by forward-mutations scored phenotypically on a non selective medium. Mutations induced in five loci with different sensitivity and average data of mutation-induction per locus have been derived. The second genetic system was provided by scoring on a selective medium mitotic gene-conversions induced in two loci with different kinetics.Haploid cells of Schizosaccharomyces pombe and diploid cells of Saccharomyces cerevisiae were submitted to analysis for the evaluation of gene-mutations and gene-conversions respectively.     

Unique genetic variation revealed by a microsatellite polymorphism survey in ten wild-derived inbred strains

Here we report on a genome polymorphism survey using 254 microsatellite markers in ten recently wild-derived inbred strains. Allele size analysis showed that the rate of polymorphism of these wild-derived mouse strains when compared with any of the common laboratory strains is on average 79.8%. We found 632 wild-derived alleles that were not present in the common laboratory strains, representing a 61% increase over the genetic variation observed in the laboratory strains. We also found that on average 14.5% of the microsatellite alleles of any given wild-derived inbred strain were unique. Our results indicate that the recently wild-derived mouse strains represent repositories of unique naturally occurring genetic variability and may prove invaluable for the study of complex phenotypes and in the construction of new mouse models of human disease.     

Integrating mouse anatomy and pathology ontologies into a phenotyping database: Tools for data capture and training

The Mouse Disease Information System (MoDIS) is a data capture system for pathology data from laboratory mice designed to support phenotyping studies. The system integrates the mouse anatomy (MA) and mouse pathology (MPATH) ontologies into a Microsoft Access database facilitating the coding of organ, tissue, and disease process to recognized semantic standards. Grading of disease severity provides scores for all lesions that can then be used for quantitative trait locus (QTL) analyses and haplotype association gene mapping. Direct linkage to the Pathbase online database provides reference definitions for disease terms and access to photomicrographic images of similar diagnoses in other mutant mice. MoDIS is an open source and freely available program (). This provides a valuable tool for setting up a mouse pathology phenotyping program.     

The mouse ascending: perspectives for human-disease models

The laboratory mouse is widely considered the model organism of choice for studying the diseases of humans, with whom they share 99% of their genes. A distinguished history of mouse genetic experimentation has been further advanced by the development of powerful new tools to manipulate the mouse genome. The recent launch of several international initiatives to analyse the function of all mouse genes through mutagenesis, molecular analysis and phenotyping underscores the utility of the mouse for translating the information stored in the human genome into increasingly accurate models of human disease.     

Current problems of estimation of genetic risk of human exposure to radiation

The methodology of assessing the genetic risk of radiation exposure is based on the concept of "hitting the target" in development of which N.V. Timofeeff-Ressovsky has played and important role. To predict genetic risk posed by irradiation, the UN Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) has worked out direct and indirect methods of assessment, extrapolational, integral and populational criteria of risk analysis that together permit calculating the risk from human exposure on the basis of data obtained for mice. Laboratory mice are the main objects in studying radiation mutagenesis due to the fact that the data on the frequency of radiation-induced human mutations are rather scarce. The method of doubling dose based on the determination of a dose doubling the level of natural mutational process in humans is the main one used to predict the genetic risk. The evolution of views about the genetics risk of human exposure to radiation for last 40 years is considered. Till 1972 the main model for assessing the genetic risk was the "human/mouse" model (the use of data on the spontaneous human variability and data on the frequency of induced mutations in mice). In the period form 1972 till 1994 the "mouse/mouse" model was intensively elaborated in many laboratories. This model was also used in this period by UNSCEAR experts to analyze the genetic risk from human irradiation. Recent achievements associated with the study of the molecular nature of many hereditary human diseases as well as the criticism of number fundamental principles of the "mouse/mouse" model for estimating the genetic risk on a new basis. The estimates of risk for the different classes of genetic diseases have been obtained using the doubling-dose method. The estimate of doubling dose used in the calculations is 1 Gy for low dose/chronic low-LET radiation conditions.     

Management, presentation and interpretation of genome scans using GSCANDB

MOTIVATION: Advances in high-throughput genotyping have made it possible to carry out genome-wide association studies using very high densities of genetic markers. This has led to the problem of the storage, management, quality control, presentation and interpretation of results. In order to achieve a successful outcome, it may be necessary to analyse the data in different ways and compare the results with genome annotations and other genome scans. RESULTS: We created GSCANDB, a database for genome scan data, using a MySQL backend and Perl-CGI web interface. It displays genome scans of multiple phenotypes analysed in different ways and projected onto genome annotations derived from EnsMart. The current version is optimized for analysis of mouse data, but is customizable to other species. AVAILABILITY: Source code and example data are available under the GPL, in versions tailored to either human or mouse association studies, from http://gscan.well.ox.ac.uk/software.     

A gene map of the rat derived from linkage analysis and related regions in the mouse and human genomes

We report the localization by linkage analysis in the rat genome of 148 new markers derived from 128 distinct known gene sequences, ESTs, and anonymous sequences selected in GenBank database on the basis of the presence of a repeated element. The composite linkage map of the rat contributed by our group integrates mapping information on a total of 370 different known genes, ESTs, and anonymous mouse or human sequences, and provides a valuable tool for comparative genome analysis. 206 and 254 homologous loci were identified in the mouse and human genomes respectively. Our linkage map, which combines both anonymous markers and gene markers, should facilitate the advancement of genetic studies for a wide variety of rat models characterized for complete phenotypes. The comparative genome mapping should define genetic regions in human likely to be homologous to susceptibility loci identified in rat and provide useful information for the identification of new potential candidates for genetic disorders. Received: 2 January 1999 / Accepted: 7 March 1999     

Rat–Mouse and Rat–Human Comparative Maps Based on Gene Homology and High-Resolution Zoo-FISH

The laboratory rat, Rattus norvegicus, and the laboratory mouse, Mus musculus, are key animal models in biomedical research. A deeper understanding of the genetic interrelationsships between Homo sapiens and these two rodent species is desirable for extending the usefulness of the animal models. We present comprehensive rat-human and rat-mouse comparative maps, based on 1090 gene homology assignments available for rat genes. Radiation hybrid, FISH, and zoo-FISH mapping data have been integrated to produce comparative maps that are estimated to comprise 83-100% of the conserved regions between rat and mouse and 66-82% of the conserved regions between rat and human. The rat-mouse zoo-FISH analysis, supported by data for individual genes, revealed nine previously undetected conserved regions compared to earlier reports. Since there is almost complete genome coverage in the rat-mouse comparative map, we conclude that it is feasible to make accurate predictions of gene positions in the rat based on gene locations in the mouse.     

The BioGRID database: A comprehensive biomedical resource of curated protein,genetic, and chemical interactions

The BioGRID (Biological General Repository for Interaction Datasets, thebiogrid.org ) is an open‐access database resource that houses manually curated protein and genetic interactions from multiple species including yeast, worm, fly, mouse, and human. The ~1.93 million curated interactions in BioGRID can be used to build complex networks to facilitate biomedical discoveries, particularly as related to human health and disease. All BioGRID content is curated from primary experimental evidence in the biomedical literature, and includes both focused low‐throughput studies and large high‐throughput datasets. BioGRID also captures protein post‐translational modifications and protein or gene interactions with bioactive small molecules including many known drugs. A built‐in network visualization tool combines all annotations and allows users to generate network graphs of protein, genetic and chemical interactions. In addition to general curation across species, BioGRID undertakes themed curation projects in specific aspects of cellular regulation, for example the ubiquitin‐proteasome system, as well as specific disease areas, such as for the SARS‐CoV‐2 virus that causes COVID‐19 severe acute respiratory syndrome. A recent extension of BioGRID, named the Open Repository of CRISPR Screens (ORCS, orcs.thebiogrid.org ), captures single mutant phenotypes and genetic interactions from published high throughput genome‐wide CRISPR/Cas9‐based genetic screens. BioGRID‐ORCS contains datasets for over 1,042 CRISPR screens carried out to date in human, mouse and fly cell lines. The biomedical research community can freely access all BioGRID data through the web interface, standardized file downloads, or via model organism databases and partner meta‐databases.