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The majority (but not all) of the BayGenomics ES cell lines were generated from 129P2/OlaHsd (formerly 129/Ola) ES cell lines, predominantly the E14Tg2A.4 parental subclone.

The Beta Cell Biology Consortium (BCBC) is a team science initiative that was established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2001. Currently, the BCBC consists of 29 extramural scientists and scientists from two intramural NIDDK laboratories.

Beutler Strains are from the MUTAGENETIX archive of phenotypes and mutations produced in Dr. Bruce Beutler’s Lab (Center for the Genetics of Host Defense, The University of Texas Southwestern Medical Center). The Beutler strains have been produced by random N-ethyl-N-nitrosourea (ENU)-induced germline mutagenesis.

In the Beutler lab, male C57BL/6J mice, termed first generation (G1) mice, are mutagenized with ENU and their exomes sequenced. The G1 mice are subsequently propagated to the second (G2) and third generations (G3), whereby ENU-induced mutations will be homozygous reference (wild-type), heterozygous, or homozygous variant. The G3 mice are actively screened for immunological phenotypes. However, many non-immunological phenotypes (e.g. changes in pigmentation, metabolism, behavior, development morphology, or lethality) are often incidentally identified, and some of them address major biological questions. Mutations are positionally cloned more rapidly than they can be investigated in depth, and in many cases, more rapidly than they can be published in conventional journals. Therefore, all mutations in each G1 mouse are described on the MUTAGENETIX website, as are the essential phenotypic characteristics, when available.

All information on chromosomal locations and critical region intervals are currently based on Ensembl Mouse annotation (release 71). Specific sequence information (gene sequences, positions of mutations, etc.) is based on the NCBI GRCm38 (mm10) mouse assembly. Individual strain records on the MUTAGENETIX website contain links to specific cDNA sequences and/or genomic DNA sequences in the NCBI database.

The Comparative Mouse Genomics Centers Consortium (CMGCC) was initiated by the National Institute of Environmental Health Sciences’ (NIEHS) Environmental Genome Project to develop transgenic and knockout mouse models based on human DNA sequence variants in environmentally responsive genes. These mouse models are useful tools to improve our understanding of the biological significance and functional relevance of these polymorphisms in human disease, particularly when validated with controlled exposures and environmental challenges. This program has resulted in the discovery of unique variants in environmentally responsive genes, the development of a number of resources, and capacity building in the environmental epidemiology communities in order to incorporate gene-environment hypotheses and tools into human population-based studies on a number of environmentally relevant diseases. This Consortium requires extensive collaboration and multidisciplinary research in molecular biology, biochemistry, structural biology, as well as expertise in mouse genetics and pathology, to achieve the following goals:

• Identify relevant and feasible mouse models for development by the Consortium;
• Identify mouse models that are relevant to human environmental health; and
• Validate developed mouse models that are relevant to environmentally induced human diseases.

The Collaborative Cross (CC) is a multiparent panel of recombinant inbred mouse strains derived from eight founder laboratory strains: 129S1/SvImJ, A/J, C57BL/6J, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ. These strains include three major Mus musculus subspecies (M. m. musculus, M. m. domesticus, and M. m. castaneus) and an extraordinarily high level of genetic diversity. Prior to their relocation to UNC, the CC project involved breeding at Oak Ridge National Laboratory in the United States, Geniad LLC in Australia, and Tel Aviv University in Israel.

This reproducible panel is uniquely suited for systems genetics and the study of complex traits. The CC panel is also a valuable source of novel laboratory models of human diseases. Additional information, including genotype and sequence data of CC strains, can be found in the related links section below.

The Collaborative Cross (CC) is a multiparent panel of recombinant inbred mouse strains derived from eight founder laboratory strains: 129S1/SvImJ, A/J, C57BL/6J, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ. These strains include three major Mus musculus subspecies (M. m. musculus, M. m. domesticus, and M. m. castaneus) and an extraordinarily high level of genetic diversity. Prior to their relocation to UNC, the CC project involved breeding at Oak Ridge National Laboratory in the United States, Geniad LLC in Australia, and Tel Aviv University in Israel.

This reproducible panel is uniquely suited for systems genetics and the study of complex traits. The CC panel is also a valuable source of novel laboratory models of human diseases. Additional information, including genotype and sequence data of CC strains, can be found in the related links section below.

The Consortium for Functional Glycomics (CFG) is a large research initiative, funded by the National Institute of General Medical Sciences, and formed to define the paradigms by which protein-carbohydrate interactions mediate cell communication. The strategy to achieve this goal is to work with the scientific community to create unique resources and services that Participating Investigators can utilize in their own research. Data produced by the Scientific Cores, much of which is generated using samples provided by investigators, are uploaded into the CFG relational database, the primary vehicle for integrating data across platforms and for dissemination of data to investigators and to the scientific community. Specialty databases for glycan-binding proteins, glycan structures, and glycosyltransferases are available. The Mouse Core (G) targeted multiple associated genes to generate a collection of knockout and conditional knockout mutant models.

The participating research centers of the CvDC are using a variety of genome-wide approaches to build a higher-order cardiac development network model. Using forward genetic screening in mice will expand the number of mutant mouse lines that display phenotypes at the stages most relevant for human heart defects. Selected candidate molecules identified by the high-throughput techniques will be functionally validated by perturbation studies and subsequent characterization. Through interactions with its sister groups in the Bench to Bassinet program, the CvDC will identify and pursue those basic discoveries in cardiac regulatory networks with the greatest potential to translate to clinical applications for treatment and prevention.

These biallelic mutant mice from Dr. William T. Pu at Boston Children’s Hospital possess a FLAG/bio epitope tag downstream of the 3' UTR of the targeted gene and the Gt(ROSA)26Sor^{tm1(birA)Mejr} allele, which expresses HA (hemagglutinin) tagged bacterial birA, bifunctional protein (biotin ligase). In the double mutant mice, the targeted gene is biotinylated, allowing for its specific immunoprecipitation and any bound proteins.

On October 5, 2005, NIH announced that contracts had been signed with two companies, Deltagen, Inc. and Lexicon Genetics, Inc., to provide knockout mouse lines and extensive phenotyping data on them to NIH. This resource gives researchers unprecedented access to two private collections of knockout mice, providing valuable models for the study of human disease and laying the groundwork for a public, genome-wide library of knockout mice. The contracts also provide the opportunity for NIH to obtain up to 1500 additional mouse lines and phenotypic data over the next three years, pending available funds.

Deltagen targeted knockouts are constructed by homologous recombination and created in-house on consistent background strains. Most are on C57BL/6. Unlike random mutagenesis or gene trap approaches, the propriety methodology ensures a single targeted gene deletion or knockout event.

For each mouse line, Deltagen provided the mouse strain, but also detailed, objective data on the impact of the specific gene deletion on the mouse's phenotype, which includes appearance, health, fitness, behavior, ability to reproduce, and radiological and microscopic data. These detailed phenotypic data are available from the Mouse Genome Informatics (MGI) website, and a link to the data for each strain is provided in the MMRRC Strain Data Sheet. Such comprehensive information on such a large group of mice has never been available to public sector researchers and is expected to greatly accelerate efforts to explore gene functions in health and disease.

For each mouse line, frozen embryos, sperm, and embryonic stem (ES) cells were obtained under the contract. The materials were divided between the NIH-sponsored Mutant Mouse Regional Resource Centers (MMRRC) facility at the University of North Carolina and The Jackson Laboratory. The repositories expanded and archived these materials.

Collaboration between Genentech Inc. and Lexicon Pharmaceuticals Inc. created a mouse knockout library targeting genes encoding secreted and trans-membrane proteins. These efforts generated a collection of 472 mouse models specific to this project. “The knockout mice were subjected to a broad, unbiased phenotypic screen aimed at identifying potential defects in general metabolism, in bone metabolism, or in the function of the cardiovascular, the immune or the neural systems.” This collection of knockout mouse models, corresponding allele information and derived data was donated to the MMRRC for distribution to the scientific community. This valuable research resource includes several hundred unique lines that further enhance the goals of the KOMP Initiative.

The GENSAT project aims to map the expression of genes in the central nervous system of the mouse, using in situ hybridization and transgenic mouse techniques. The GENSAT project is sponsored through a contract with the National Institute of Neurological Disorders and Stroke (NINDS). The principal investigators of the study are Nathaniel Heintz, Ph.D., and Mary E. Hatten, Ph.D., Professors, Rockefeller University.

The GENSAT collection contains transgenic strains of mice in which each transgene is derived from bacterial artificial chromosomes (BACs) and expresses a reporter gene in the same environment as the native gene. In each of the BAC transgenic vectors, endogenous protein coding sequences have been replaced by sequences encoding the EGFP reporter gene. As in any gene replacement experiment, the stability of the reporter gene can vary somewhat from the endogenous gene. Thus these results measure the relative rates of transcription for each gene; they are not a direct measure of mRNA accumulation or of protein abundance for the endogenous gene products. Furthermore, the enhanced sensitivity of reporter gene assays, particularly in BAC lines carrying multiple copies of the BAC transgene may allow detection of sites of expression that are not evident in in situ hybridization experiments.

In conjunction with these strains, several cre transgenic strains have been created where BAC engineering was used to insert an intron containing cre or creERT2 cassettes, followed by a polyadenylation sequence to terminate transcription of the fusion transcript immediately after the recombinase gene, into the BAC vector at the initiating ATG codon in the first coding exon of the gene.

The GENSAT database contains histological data from given BAC transgenic mouse lines at three developmental stages – embryonic day 15.5 (E15.5), postnatal day 7 (P7) and adult; in all cases the data represent results of multiple transgenic lines. A link to the data for each strain is provided in the MMRRC Strain Data Sheet. EGFP is visualized by staining with an anti-EGFP antibody using the DAB method, or by confocal microscopy of unstained tissue sections. Protocols for the modification of BACs, BAC transgenesis production, and histology are available at the GENSAT website; a complete description of the procedure can be found in "A gene expression atlas of the central nervous system based on bacterial artificial chromosomes", Nature. 2003 Oct 30;425(6961):917-25.

The recommended citation for the resource is:
The Gene Expression Nervous System Atlas (GENSAT) Project, NINDS Contract # N01NS02331 to The Rockefeller University (New York, NY).

The Noncoding RNA project was developed by the Michael McManus Lab in collaboration with colleagues at UCSF and the Gladstone Institute.
Using genome-scale RNA interference (RNAi) screening and other high-throughput methodologies to uncover the functions of noncoding RNAs in the mammalian system, the McManus Lab has generated and characterized many small (micro) RNA conditional knockout mice. These mouse models could shed light on a wide range of human diseases such as diabetes, many types of cancers, and even neurological diseases such as depression.
Each miRKO targeting vector is designed to insert an FRT site followed by a lacZ gene, a loxP site, a neomycin cassette, an FRT site and a loxP site (FRT-lacZ-loxP-Neo-FRT-loxP) upstream of the stem loop, with one loxP site placed immediately downstream of the Mir (microRNA) stem loop. When a Mir strain is combined with a Flp recombinase-expressing strain, the lacZ and neomycin genes are removed leaving an FRT site and the loxP-flanked Mir stem loop. A further cross to a Cre-recombinase-expressing strain generates the null allele. When combined with a Cre-recombinase-expressing strain, the neomycin cassette and Mir stem loop are removed leaving a lacZ tagged null allele (FRT-lacZ-loxP). These miRKO models provide a tool for understanding how noncoding RNAs contribute to the specification of cell fate and function, and how deregulation of these RNAs may contribute to human disease.

The Knockout Mouse Project (KOMP & KOMP2) is a trans-NIH initiative that aims to generate a comprehensive and public resource comprised of mouse embryonic stem (ES) cells containing a null mutation in every gene in the mouse genome. The NIH KOMP initiative aims to:

Towards those ends, NIH awarded five-year cooperative agreements totaling up to $47.2 million to two groups for the creation of the knockout mice lines. Recipients of those awards are Velocigene, a division of Regeneron Pharmaceuticals, Inc., in Tarrytown, N.Y., and a collaborative team from Children's Hospital Oakland Research Institute (CHORI) in Oakland, Calif., the School of Veterinary Medicine, University of California, Davis (UC Davis); and the Wellcome Trust Sanger Institute in Hinxton, England. Under its cooperative agreement, the team led by Pieter deJong, Ph.D., CHORI, along with K. C. Kent Lloyd, D.V.M., Ph.D., UC Davis; and Allan Bradley, Ph.D. FRS, and William Skarnes, Ph.D., at the Wellcome Trust Sanger Institute, plans to systematically create mouse ES cell lines in which 5,000 genes have been knocked out by gene targeting. The VelociGene division of Regeneron, led by David Valenzuela, Ph.D. and George D. Yancopoulos, M.D., Ph.D., will take aim at a different set of 3,500 genes. Both groups will utilize information from the finished mouse genome sequence to design targeting vectors, which will be built by large-scale, automated technologies. The combined collection of mouse ES cells with knockouts in 8,500 genes will be useful for producing knockout mice.

In addition, NIH awarded another five-year cooperative agreement totaling $2.5 million to Mouse Genome Informatics (MGI) to set up a Data Coordination Center for the Knockout Mouse Project. The center will collect information that will allow the research community to track the scheduling and progress of knockout production. The NIH also awarded cooperative agreements to the University of Pennsylvania in Philadelphia and to the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto to improve the efficiency of methods for creating knockout lines.

Finally, in June 2007, NIH announced it will provide $4.8 million to establish and support a repository for its Knockout Mouse Project. This award is the final component of a more than $50 million trans-NIH initiative to increase the availability of genetically altered mice and related materials. The University of California, Davis (UC Davis) and Children's Hospital Oakland Research Institute (CHORI) in Oakland, Calif., will collaborate to preserve, protect, and make available about 8,500 types of knockout mice and related products available to the research community.

On October 5, 2005, NIH announced that contracts had been signed with two companies, Deltagen, Inc. and Lexicon Genetics, Inc. (now Lexicon Pharmaceuticals), to provide knockout mouse lines and extensive phenotyping data on them to NIH. This resource gives researchers unprecedented access to two private collections of knockout mice, providing valuable models for the study of human disease and laying the groundwork for a public, genome-wide library of knockout mice. The contracts also provide the opportunity for NIH to obtain up to 1500 additional mouse lines and phenotypic data over the next three years, pending available funds.

The Lexicon efforts are focused on gene families that are pharmaceutically important, such as transporters, G-protein coupled receptors (GPCRs), ion channels, kinases and other key enzymes, membrane proteins (e.g., receptors), and secreted proteins.

For each mouse line, Lexicon provided not only the mouse strain itself, but also detailed, objective data on the impact of the specific gene deletion on the mouse's phenotype, which includes appearance, health, fitness, behavior, ability to reproduce, and radiological and microscopic data. These detailed phenotypic data are available from the Mouse Genome Informatics (MGI) website, and a link to the data for each strain is provided in the MMRRC Strain Data Sheet. Such comprehensive information on such a large group of mice has never been available to public sector researchers, and is expected to greatly accelerate efforts to explore gene functions in health and disease.

For each mouse line, frozen embryos, sperm, and embryonic stem (ES) cells were obtained under the contract. The materials were divided between the NIH-sponsored Mutant Mouse Regional Resource Centers (MMRRC) facilities at UC Davis and the University of North Carolina.

This collection, assembled and maintained by Dr. Lynn Lamoreux while at Texas A&M University, contains pigment mutant mouse strains, virtually all as congenic strains on a C57BL/6 background. These numerous pigmentary mutations, individually and in appropriate combinations, enable the rigorous evaluation of mutations at the organism, organ and tissue levels, and the assessment of genic interactions. The collection was created to help investigators achieve a complete understanding of the genetic control of development and function of the mammalian pigmentation system and its diseases, including interacting functions that affect other biological systems by pleiotropic effects.

Pigmentation and the pigment cell form an ideal system for genetic analysis of a developmental system, since pigmentary mutations are readily detected and most often are not lethal. Rich genetic resources exist for study of mouse pigmentation: germline mutations mapped now to over 120 loci, around 50 of which have been cloned. These mutations are also relevant to melanoma and to numerous associated birth defects of organs including the ear, eye, brain, reproductive, digestive and respiratory tracts, hemophilia, and cellular defects in protein transport, organelle biogenesis and apoptosis.

Cell lines from many of these mutants have been made and can be obtained from the Wellcome Trust Functional Genomics Cell Bank. These melanocyte and melanoblast lines, carrying diverse pigmentary mutations, are used to study gene functions at the cellular, biochemical and molecular levels.

The goal of the ENU Mutagenesis project is to determine the function of genes on mouse Chromosome 11 by saturating the chromosome with recessive mutations. The distal 40 cM of mouse Chromosome 11 exhibits linkage conservation with human Chromosome 17. The chemical N-ethyl-N-nitrosourea (ENU) was used to saturate wild type chromosomes with point mutations. By determining the function of genes on a mouse chromosome, extrapolation leads to predicting function on a human chromosome. Many of the new mutants are expected to represent models of human diseases such as birth defects, patterning defects, growth and endocrine defects, neurological anomalies, and blood defects. Because many of the mutations expected to be isolated may be lethal or detrimental to the mice, a unique approach to isolate mutations is used. This approach uses a balancer chromosome that is homozygous lethal and carries a dominant coat color marker to suppress recombination over a reasonable interval.

The Nagy ES cell collection is a panel of basic ES cells that can be used for gene targeting. Two of the lines are from inbred C57BL/6 and the others are either 129 x 129 or 129 x B6 F1 hybrids. Several carry fluorescent reporter transgenes that enable one to follow the cell lines in chimeras.

The NIH Neuroscience Blueprint has established three centers in the USA for the generation of genetically modified mice expressing Cre recombinases in the nervous system on the C57BL/6 genetic background. The mouse lines are being generated at the Baylor College of Medicine, Cold Spring Harbor Lab, and Scripps Research Institute. Mice are being made available via the Mutant Mouse Regional Resource Centers facility at the University of Missouri and The Jackson Laboratory Cre Repository.

These mice were created and deposited by The Pleiades Promoter Project (Centre for Molecular Medicine and Therapeutics, University of British Columbia); their goal is to generate 160 fully characterized, human DNA promoters of less than 4 kb (MiniPromoters) to drive gene expression in defined brain regions of therapeutic interest for studying disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis (Lou Gehrig's disease), Multiple Sclerosis, Spinocerebellar Ataxia, Depression, Autism, and Cancer.

  With the advent of CRISPR/Cas9 genome editing technology, the ability to manipulate the genomes of animals to enhance their relevance to human biology and disease has dramatically expanded.  Recognizing the potential for advancing translational research using this new methodology, over the last few years the NIH has launched new programs and awarded administrative supplements to existing grants to enable the production and phenotyping of animal models that recapitulate human coding sequences associated with and/or directly causative of disease. For example, in 2018 the NIH/Office of the Director funded an administrative supplement to the MMRRC at UC Davis to create and study ~20 mouse models of specific genetic variants to determine their relationship to disease phenotypes in patients. More recently, the NIH funded projects to produce and phenotype mouse models of SARS-CoV-2 infection and COVID-19, especially post-acute sequelae of COVID, or PASC, that express human-specific coding sequences in orthologous mouse genes directly involved in disease pathogenesis (e.g., ACE2, TMPRSS2, etc).  These and other projects have generated human disease-relevant mouse models for pre-clinical and co-clinical biomedical research. To ensure their availability and accessibility, the MMRRC has established this “Precision Genetically-Humanized Models” produced by NIH-funded researchers.

MicroRNAs (miRNA) are gaining recognition as important post-transcriptional regulators of gene expression. While more than 500 miRNAs have been identified in the mammalian genome, studies addressing their physiological roles are at an early stage and miRNA functions are only now being elucidated. Toward this end, the Sanger Institute is generating a continually expanding collection of MicroRNA Knockout ES cell lines for use by the scientific community through the MMRRC. Additionally, Sanger has created a searchable data portal through which investigators can access additional information such as vector design, PCR results, and gene details. Schematic of MirKO targeting vector and alleles

The Sanger Institute Gene Trap Resource (SIGTR) mouse ES cell line collection was developed to provide a powerful and cost effective approach using gene trapping to create large numbers of insertional mutations that are immediately accessible to molecular characterization. This resource is based on a new generation of gene trap vector designs that are equipped with site-specific recombination sites for post-insertional modification of the trapped locus to create other desired alleles.

Users of SIGTR ES cell lines are advised to follow the protocols available on the SIGTR website. In addition to individual protocols, all the procedures and protocols can be downloaded from the General Information section of SIGTR's website. Detailed information contained there includes:

• Molecular confirmation of gene trap insertions
• Cell culture media and reagent preparation
• Thawing and growing feeder-independent ES cell lines
• X-gal staining of ES cells
• Sub-cloning gene trap cell lines

To identify growth factor regulated genes, gene traps are used in embryonic stem (ES) cells. In this approach, a promoterless reporter gene (for instance encoding beta galactosidase, or beta geo) is introduced into ES cells. Selection for expression of the gene requires transcription from a cellular promoter, and consequently a mutation in a cellular gene, and the activity of the tagged gene can be followed by staining for beta galactosidase activity. Detailed description of methods used for gene trap mutagenesis may be found in Friedrich, G., and Soriano, P. (1993) and Chen, W.V., and Soriano, P. (2003). Large scale sequencing of ES cell clones was conducted and sequence tags have been deposited to NCBI's dbGSS. Sequence searches for genes that have been trapped can be performed by running a BLAST search of the dbGSS database.

The recommended citations for the resource are:
Friedrich, G., and Soriano, P., Methods Enzymol. 1993;225:681-701 (PMID:8231879)
Chen, W.V., and Soriano, P., Methods Enzymol. 2003;365:367-86 (PMID:14696359)

The mission of the UC Davis/NIH NeuroMab Facility is to provide a unique neuroscience-based approach to generating mouse monoclonal antibodies optimized for use in the mammalian brain. The UC Davis/NIH NeuroMab Facility serves as a resource to the entire neuroscience community through its generation of a collection of highly validated antibodies that serve as critical links between information emerging from genomic efforts and future proteomic approaches to brain function.

Hybridoma cell lines are immortal, monoclonal, antibody-producing cells that can be grown in tissue culture at any scale to produce monoclonal antibodies. Each of the 473 cell lines in the MMRRC were use to produce monoclonal antibodies that have been validated for specificity and efficacy in brain research applications at the UC Davis/NIH NeuroMab Facility.