Publications by authors named "Molly Bogue"

39 Publications

Integration of evidence across human and model organism studies: A meeting report.

Genes Brain Behav 2021 Apr 23:e12738. Epub 2021 Apr 23.

Department of Psychiatry, Yale University School of Medicine, West Haven, Connecticut, USA.

The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration-particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.
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http://dx.doi.org/10.1111/gbb.12738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365690PMC
April 2021

17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex.

Aging Cell 2021 05 31;20(5):e13328. Epub 2021 Mar 31.

Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.

In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the "non-feminizing" estrogen, 17-α-estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log-rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang-Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex-specific aspects of aging.
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http://dx.doi.org/10.1111/acel.13328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135004PMC
May 2021

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.

Aging Cell 2020 11 4;19(11):e13269. Epub 2020 Nov 4.

The Jackson Laboratory, Bar Harbor, ME, USA.

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex.
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http://dx.doi.org/10.1111/acel.13269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681050PMC
November 2020

Canagliflozin extends life span in genetically heterogeneous male but not female mice.

JCI Insight 2020 11 5;5(21). Epub 2020 Nov 5.

Sam and Ann Barshop Institute for Longevity and Aging Studies and Departments of Physiology and Molecular Medicine, UT Health San Antonio, San Antonio, Texas, USA; South Texas Veterans Healthcare System, San Antonio, Texas, USA.

Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.
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http://dx.doi.org/10.1172/jci.insight.140019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710304PMC
November 2020

A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes.

Mamm Genome 2020 02 14;31(1-2):30-48. Epub 2020 Feb 14.

Department of Neurology, Friedrich-Baur-Institute, Klinikum Der Ludwig-Maximilians-Universität München, Ziemssenstr. 1a, 80336, Munich, Germany.

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads.
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http://dx.doi.org/10.1007/s00335-020-09827-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060152PMC
February 2020

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis.

Genes Brain Behav 2020 03 11;19(3):e12645. Epub 2020 Feb 11.

Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine.

Despite substantial evidence for sex differences in addiction epidemiology, addiction-relevant behaviors and associated neurobiological phenomena, the mechanisms and implications of these differences remain unknown. Genetic analysis in model organism is a potentially powerful and effective means of discovering the mechanisms that underlie sex differences in addiction. Human genetic studies are beginning to show precise risk variants that influence the mechanisms of addiction but typically lack sufficient power or neurobiological mechanistic access, particularly for the discovery of the mechanisms that underlie sex differences. Our thesis in this review is that genetic variation in model organisms are a promising approach that can complement these investigations to show the biological mechanisms that underlie sex differences in addiction.
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http://dx.doi.org/10.1111/gbb.12645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060801PMC
March 2020

Mouse Phenome Database: a data repository and analysis suite for curated primary mouse phenotype data.

Nucleic Acids Res 2020 01;48(D1):D716-D723

The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA.

The Mouse Phenome Database (MPD; https://phenome.jax.org) is a widely accessed and highly functional data repository housing primary phenotype data for the laboratory mouse accessible via APIs and providing tools to analyze and visualize those data. Data come from investigators around the world and represent a broad scope of phenotyping endpoints and disease-related traits in naïve mice and those exposed to drugs, environmental agents or other treatments. MPD houses rigorously curated per-animal data with detailed protocols. Public ontologies and controlled vocabularies are used for annotation. In addition to phenotype tools, genetic analysis tools enable users to integrate and interpret genome-phenome relations across the database. Strain types and populations include inbred, recombinant inbred, F1 hybrid, transgenic, targeted mutants, chromosome substitution, Collaborative Cross, Diversity Outbred and other mapping populations. Our new analysis tools allow users to apply selected data in an integrated fashion to address problems in trait associations, reproducibility, polygenic syndrome model selection and multi-trait modeling. As we refine these tools and approaches, we will continue to provide users a means to identify consistent, quality studies that have high translational relevance.
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http://dx.doi.org/10.1093/nar/gkz1032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145612PMC
January 2020

Glycine supplementation extends lifespan of male and female mice.

Aging Cell 2019 06 27;18(3):e12953. Epub 2019 Mar 27.

Department of Pharmacology, Barshop Institute for Longevity and Aging Studies, Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%-6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males (p = 0.002) and females (p < 0.001). Pooling across sex, glycine increased lifespan at each of the three independent sites, with significance at p = 0.01, 0.053, and 0.03, respectively. Glycine-supplemented females were lighter than controls, but there was no effect on weight in males. End-of-life necropsies suggested that glycine-treated mice were less likely than controls to die of pulmonary adenocarcinoma (p = 0.03). Of the 40 varieties of incidental pathology evaluated in these mice, none were increased to a significant degree by the glycine-supplemented diet. In parallel analyses of the same cohort, we found no benefits from TM5441 (an inhibitor of PAI-1, the primary inhibitor of tissue and urokinase plasminogen activators), inulin (a source of soluble fiber), or aspirin at either of two doses. Our glycine results strengthen the idea that modulation of dietary amino acid levels can increase healthy lifespan in mice, and provide a foundation for further investigation of dietary effects on aging and late-life diseases.
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http://dx.doi.org/10.1111/acel.12953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516426PMC
June 2019

Mouse Phenome Database: an integrative database and analysis suite for curated empirical phenotype data from laboratory mice.

Nucleic Acids Res 2018 01;46(D1):D843-D850

The Jackson Laboratory, Bar Harbor, Maine 04609, USA.

The Mouse Phenome Database (MPD; https://phenome.jax.org) is a widely used resource that provides access to primary experimental trait data, genotypic variation, protocols and analysis tools for mouse genetic studies. Data are contributed by investigators worldwide and represent a broad scope of phenotyping endpoints and disease-related traits in naïve mice and those exposed to drugs, environmental agents or other treatments. MPD houses individual animal data with detailed, searchable protocols, and makes these data available to other resources via API. MPD provides rigorous curation of experimental data and supporting documentation using relevant ontologies and controlled vocabularies. Most data in MPD are from inbreds and other reproducible strains such that the data are cumulative over time and across laboratories. The resource has been expanded to include the QTL Archive and other primary phenotype data from mapping crosses as well as advanced high-diversity mouse populations including the Collaborative Cross and Diversity Outbred mice. Furthermore, MPD provides a means of assessing replicability and reproducibility across experimental conditions and protocols, benchmarking assays in users' own laboratories, identifying sensitized backgrounds for making new mouse models with genome editing technologies, analyzing trait co-inheritance, finding the common genetic basis for multiple traits and assessing sex differences and sex-by-genotype interactions.
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http://dx.doi.org/10.1093/nar/gkx1082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753241PMC
January 2018

Ovariectomy results in inbred strain-specific increases in anxiety-like behavior in mice.

Physiol Behav 2016 12 29;167:404-412. Epub 2016 Sep 29.

Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, United States; Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC, United States; Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, United States. Electronic address:

Women are at an increased risk for developing affective disorders during times of hormonal flux, including menopause when the ovaries cease production of estrogen. However, while all women undergo menopause, not all develop an affective disorder. Increased vulnerability can result from genetic predisposition, environmental factors and gene by environment interactions. In order to investigate interactions between genetic background and estrogen depletion, we performed bilateral ovariectomy, a surgical procedure that results in estrogen depletion and is thought to model the post-menopausal state, in a genetically defined panel of 37 inbred mouse strains. Seventeen days post-ovariectomy, we assessed behavior in two standard rodent assays of anxiety- and depressive-like behavior, the open field and forced swim tests. We detected a significant interaction between ovariectomy and genetic background on anxiety-like behavior in the open field. No strain specific effects of ovariectomy were observed in the forced swim assay. However, we did observe significant strain effects for all behaviors in both the open field and forced swim tests. This study is the largest to date to look at the effects of ovariectomy on behavior and provides evidence that ovariectomy interacts with genetic background to alter anxiety-like behavior in an animal model of menopause.
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http://dx.doi.org/10.1016/j.physbeh.2016.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289389PMC
December 2016

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer.

Aging Cell 2016 10 16;15(5):872-84. Epub 2016 Jun 16.

The Jackson Laboratory, Bar Harbor, ME, 04609, USA.

The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin - the latter with and without rapamycin, and two drugs previously examined: 17-α-estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17-α-estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male-specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α-glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.
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http://dx.doi.org/10.1111/acel.12496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013015PMC
October 2016

Collaborative Cross and Diversity Outbred data resources in the Mouse Phenome Database.

Mamm Genome 2015 Oct 19;26(9-10):511-20. Epub 2015 Aug 19.

The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.

The Mouse Phenome Database was originally conceived as a platform for the integration of phenotype data collected on a defined collection of 40 inbred mouse strains--the "phenome panel." This model provided an impetus for community data sharing, and integration was readily achieved through the reproducible genotypes of the phenome panel strains. Advances in the development of mouse populations lead to an expanded role of the Mouse Phenome Database to encompass new strain panels and inbred strain crosses. The recent introduction of the Collaborative Cross and Diversity Outbred mice, which share an extensive pool of genetic variation from eight founder inbred strains, presents new opportunities and challenges for community data resources. A wide variety of molecular and clinical phenotypes are being collected across genotypes, tissues, ages, environmental exposures, interventions, and treatments. The Mouse Phenome Database provides a framework for retrieval, integration, analysis, and display of these data, enabling them to be evaluated in the context of existing data from standard inbred strains. Primary data in the Mouse Phenome Database are supported by extensive metadata on protocols and procedures. These are centrally curated to ensure accuracy and reproducibility and to provide data in consistent formats. The Mouse Phenome Database represents an established and growing community data resource for mouse phenotype data and encourages submissions from new mouse resources, enabling investigators to integrate existing data into their studies of the phenotypic consequences of genetic variation.
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http://dx.doi.org/10.1007/s00335-015-9595-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602074PMC
October 2015

Accessing Data Resources in the Mouse Phenome Database for Genetic Analysis of Murine Life Span and Health Span.

J Gerontol A Biol Sci Med Sci 2016 Feb 22;71(2):170-7. Epub 2014 Dec 22.

The Jackson Laboratory Nathan Shock Center of Excellence in the Basic Biology of Aging, The Jackson Laboratory, Bar Harbor, Maine.

Understanding the source of genetic variation in aging and using this variation to define the molecular mechanisms of healthy aging require deep and broad quantification of a host of physiological, morphological, and behavioral endpoints. The murine model is a powerful system in which to understand the relations across age-related phenotypes and to identify research models with variation in life span and health span. The Jackson Laboratory Nathan Shock Center of Excellence in the Basic Biology of Aging has performed broad characterization of aging in genetically diverse laboratory mice and has placed these data, along with data from several other major aging initiatives, into the interactive Mouse Phenome Database. The data may be accessed and analyzed by researchers interested in finding mouse models for specific aging processes, age-related health and disease states, and for genetic analysis of aging variation and trait covariation. We expect that by placing these data in the hands of the aging community that there will be (a) accelerated genetic analyses of aging processes, (b) discovery of genetic loci regulating life span, (c) identification of compelling correlations between life span and susceptibility for age-related disorders, and (d) discovery of concordant genomic loci influencing life span and aging phenotypes between mouse and humans.
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http://dx.doi.org/10.1093/gerona/glu223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707687PMC
February 2016

The antipsychotic olanzapine interacts with the gut microbiome to cause weight gain in mouse.

PLoS One 2014 15;9(12):e115225. Epub 2014 Dec 15.

Departments of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

The second-generation antipsychotic olanzapine is effective in reducing psychotic symptoms but can cause extreme weight gain in human patients. We investigated the role of the gut microbiota in this adverse drug effect using a mouse model. First, we used germ-free C57BL/6J mice to demonstrate that gut bacteria are necessary and sufficient for weight gain caused by oral delivery of olanzapine. Second, we surveyed fecal microbiota before, during, and after treatment and found that olanzapine potentiated a shift towards an "obesogenic" bacterial profile. Finally, we demonstrated that olanzapine has antimicrobial activity in vitro against resident enteric bacterial strains. These results collectively provide strong evidence for a mechanism underlying olanzapine-induced weight gain in mouse and a hypothesis for clinical translation in human patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115225PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266663PMC
May 2016

Variation and genetic control of gene expression in primary immunocytes across inbred mouse strains.

J Immunol 2014 Nov 29;193(9):4485-96. Epub 2014 Sep 29.

Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; and

To determine the breadth and underpinning of changes in immunocyte gene expression due to genetic variation in mice, we performed, as part of the Immunological Genome Project, gene expression profiling for CD4(+) T cells and neutrophils purified from 39 inbred strains of the Mouse Phenome Database. Considering both cell types, a large number of transcripts showed significant variation across the inbred strains, with 22% of the transcriptome varying by 2-fold or more. These included 119 loci with apparent complete loss of function, where the corresponding transcript was not expressed in some of the strains, representing a useful resource of "natural knockouts." We identified 1222 cis-expression quantitative trait loci (cis-eQTL) that control some of this variation. Most (60%) cis-eQTLs were shared between T cells and neutrophils, but a significant portion uniquely impacted one of the cell types, suggesting cell type-specific regulatory mechanisms. Using a conditional regression algorithm, we predicted regulatory interactions between transcription factors and potential targets, and we demonstrated that these predictions overlap with regulatory interactions inferred from transcriptional changes during immunocyte differentiation. Finally, comparison of these and parallel data from CD4(+) T cells of healthy humans demonstrated intriguing similarities in variability of a gene's expression: the most variable genes tended to be the same in both species, and there was an overlap in genes subject to strong cis-acting genetic variants. We speculate that this "conservation of variation" reflects a differential constraint on intraspecies variation in expression levels of different genes, either through lower pressure for some genes, or by favoring variability for others.
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http://dx.doi.org/10.4049/jimmunol.1401280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201955PMC
November 2014

Mouse phenome database.

Nucleic Acids Res 2014 Jan 15;42(Database issue):D825-34. Epub 2013 Nov 15.

The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609 USA.

The Mouse Phenome Database (MPD; phenome.jax.org) was launched in 2001 as the data coordination center for the international Mouse Phenome Project. MPD integrates quantitative phenotype, gene expression and genotype data into a common annotated framework to facilitate query and analysis. MPD contains >3500 phenotype measurements or traits relevant to human health, including cancer, aging, cardiovascular disorders, obesity, infectious disease susceptibility, blood disorders, neurosensory disorders, drug addiction and toxicity. Since our 2012 NAR report, we have added >70 new data sets, including data from Collaborative Cross lines and Diversity Outbred mice. During this time we have completely revamped our homepage, improved search and navigational aspects of the MPD application, developed several web-enabled data analysis and visualization tools, annotated phenotype data to public ontologies, developed an ontology browser and released new single nucleotide polymorphism query functionality with much higher density coverage than before. Here, we summarize recent data acquisitions and describe our latest improvements.
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http://dx.doi.org/10.1093/nar/gkt1159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965087PMC
January 2014

Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice.

Mamm Genome 2012 Jun 30;23(5-6):322-35. Epub 2011 Dec 30.

Department of Genetics, University of North Carolina, Genomic Medicine Building, CB#7264, Chapel Hill, NC 27599-7264, USA.

Tardive dyskinesia (TD) is a debilitating, unpredictable, and often irreversible side effect resulting from chronic treatment with typical antipsychotic agents such as haloperidol. TD is characterized by repetitive, involuntary, purposeless movements primarily of the orofacial region. In order to investigate genetic susceptibility to TD, we used a validated mouse model for a systems genetics analysis geared toward detecting genetic predictors of TD in human patients. Phenotypic data from 27 inbred strains chronically treated with haloperidol and phenotyped for vacuous chewing movements were subject to a comprehensive genomic analysis involving 426,493 SNPs, 4,047 CNVs, brain gene expression, along with gene network and bioinformatic analysis. Our results identified ~50 genes that we expect to have high prior probabilities for association with haloperidol-induced TD, most of which have never been tested for association with human TD. Among our top candidates were genes regulating the development of brain motor control regions (Zic4 and Nkx6-1), glutamate receptors (Grin1 and Grin2a), and an indirect target of haloperidol (Drd1a) that has not been studied as well as the direct target, Drd2.
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http://dx.doi.org/10.1007/s00335-011-9385-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356790PMC
June 2012

Mouse Phenome Database (MPD).

Nucleic Acids Res 2012 Jan 18;40(Database issue):D887-94. Epub 2011 Nov 18.

The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.

The Mouse Phenome Project was launched a decade ago to complement mouse genome sequencing efforts by promoting new phenotyping initiatives under standardized conditions and collecting the data in a central public database, the Mouse Phenome Database (MPD; http://phenome.jax.org). MPD houses a wealth of strain characteristics data to facilitate the use of the laboratory mouse in translational research for human health and disease, helping alleviate problems involving experimentation in humans that cannot be done practically or ethically. Data sets are voluntarily contributed by researchers from a variety of institutions and settings, or in some cases, retrieved by MPD staff from public sources. MPD maintains a growing collection of standardized reference data that assists investigators in selecting mouse strains for research applications; houses treatment/control data for drug studies and other interventions; offers a standardized platform for discovering genotype-phenotype relationships; and provides tools for hypothesis testing. MPD improvements and updates since our last NAR report are presented, including the addition of new tools and features to facilitate navigation and data mining as well as the acquisition of new data (phenotypic, genotypic and gene expression).
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http://dx.doi.org/10.1093/nar/gkr1061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245053PMC
January 2012

Fine mapping in 94 inbred mouse strains using a high-density haplotype resource.

Genetics 2010 Jul 3;185(3):1081-95. Epub 2010 May 3.

Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

The genetics of phenotypic variation in inbred mice has for nearly a century provided a primary weapon in the medical research arsenal. A catalog of the genetic variation among inbred mouse strains, however, is required to enable powerful positional cloning and association techniques. A recent whole-genome resequencing study of 15 inbred mouse strains captured a significant fraction of the genetic variation among a limited number of strains, yet the common use of hundreds of inbred strains in medical research motivates the need for a high-density variation map of a larger set of strains. Here we report a dense set of genotypes from 94 inbred mouse strains containing 10.77 million genotypes over 121,433 single nucleotide polymorphisms (SNPs), dispersed at 20-kb intervals on average across the genome, with an average concordance of 99.94% with previous SNP sets. Through pairwise comparisons of the strains, we identified an average of 4.70 distinct segments over 73 classical inbred strains in each region of the genome, suggesting limited genetic diversity between the strains. Combining these data with genotypes of 7570 gap-filling SNPs, we further imputed the untyped or missing genotypes of 94 strains over 8.27 million Perlegen SNPs. The imputation accuracy among classical inbred strains is estimated at 99.7% for the genotypes imputed with high confidence. We demonstrated the utility of these data in high-resolution linkage mapping through power simulations and statistical power analysis and provide guidelines for developing such studies. We also provide a resource of in silico association mapping between the complex traits deposited in the Mouse Phenome Database with our genotypes. We expect that these resources will facilitate effective designs of both human and mouse studies for dissecting the genetic basis of complex traits.
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http://dx.doi.org/10.1534/genetics.110.115014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907194PMC
July 2010

Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels.

Aging Cell 2009 Jun 9;8(3):277-87. Epub 2009 Apr 9.

The Jackson Aging Center at The Jackson Laboratory, Bar Harbor, ME 04609, USA.

To better characterize aging in mice, the Jackson Aging Center carried out a lifespan study of 31 genetically-diverse inbred mouse strains housed in a specific pathogen-free facility. Clinical assessments were carried out every 6 months, measuring multiple age-related phenotypes including neuromuscular, kidney and heart function, body composition, bone density, hematology, hormonal levels, and immune system parameters. In a concurrent cross-sectional study of the same 31 strains at 6, 12, and 20 months, more invasive measurements were carried out followed by necropsy to assess apoptosis, DNA repair, chromosome fragility, and histopathology. In this report, which is the initial paper of a series, the study design, median lifespans, and circulating insulin-like growth factor 1 (IGF1) levels at 6, 12, and 18 months are described for the first cohort of 32 females and 32 males of each strain. Survival curves varied dramatically among strains with the median lifespans ranging from 251 to 964 days. Plasma IGF1 levels, which also varied considerably at each time point, showed an inverse correlation with a median lifespan at 6 months (R = -0.33, P = 0.01). This correlation became stronger if the short-lived strains with a median lifespan < 600 days were removed from the analysis (R = -0.53, P < 0.01). These results support the hypothesis that the IGF1 pathway plays a key role in regulating longevity in mice and indicates that common genetic mechanisms may exist for regulating IGF1 levels and lifespan.
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http://dx.doi.org/10.1111/j.1474-9726.2009.00478.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768517PMC
June 2009

Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans.

Genome Res 2009 Sep 5;19(9):1507-15. Epub 2009 May 5.

Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. We present a strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d x 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, we demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. Our results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.
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http://dx.doi.org/10.1101/gr.090241.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752130PMC
September 2009

Identification of mouse inbred strains through mitochondrial DNA single-nucleotide extension.

Electrophoresis 2008 Dec;29(23):4795-802

Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.

Inbred mouse strains are used as model organisms for biomedical research in laboratories throughout the world. The most widely used of these strains had their genome sequenced recently, and phylogenetic studies have been performed, namely, based on mitochondrial DNA (mtDNA). This has allowed determining that few polymorphisms distinguish the mtDNAs of the common inbred strains, but a high number of differences are observed among the wild-derived strains. Taking advantage of these observations, we here present a single base extension typing strategy that, with only a pair of multiplex reactions, allows the distinction between common inbred and wild-derived mice strains, and provides the identification of ten different common inbred and six wild-derived mice mtDNA haplotypes. Given that all the animals inside a strain present the same mtDNA, this strategy allows a rapid identification of the strains without the need for probability calculations. We further test this approach in an island population of wild mice, which provides both an indication on its applicability in wild mice, and a comparison of evolutionary processes on inbred and wild mice that are restricted to a limited space. Rapid genotyping methods that allow the distinction of the different strains are important for both the distinction of materials such as tissue and cell collections and to identify the origin of new strains. Moreover, it may also prove valuable in forensic identification of materials collected in laboratory accidents, as well as in cases of scientific fraud.
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http://dx.doi.org/10.1002/elps.200800313DOI Listing
December 2008

Mouse phenome database.

Nucleic Acids Res 2009 Jan 5;37(Database issue):D720-30. Epub 2008 Nov 5.

The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.

The Mouse Phenome Database (MPD; http://www.jax.org/phenome) is an open source, web-based repository of phenotypic and genotypic data on commonly used and genetically diverse inbred strains of mice and their derivatives. MPD is also a facility for query, analysis and in silico hypothesis testing. Currently MPD contains about 1400 phenotypic measurements contributed by research teams worldwide, including phenotypes relevant to human health such as cancer susceptibility, aging, obesity, susceptibility to infectious diseases, atherosclerosis, blood disorders and neurosensory disorders. Electronic access to centralized strain data enables investigators to select optimal strains for many systems-based research applications, including physiological studies, drug and toxicology testing, modeling disease processes and complex trait analysis. The ability to select strains for specific research applications by accessing existing phenotype data can bypass the need to (re)characterize strains, precluding major investments of time and resources. This functionality, in turn, accelerates research and leverages existing community resources. Since our last NAR reporting in 2007, MPD has added more community-contributed data covering more phenotypic domains and implemented several new tools and features, including a new interactive Tool Demo available through the MPD homepage (quick link: http://phenome.jax.org/phenome/trytools).
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http://dx.doi.org/10.1093/nar/gkn778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2686531PMC
January 2009

Enhanced thymic selection of FoxP3+ regulatory T cells in the NOD mouse model of autoimmune diabetes.

Proc Natl Acad Sci U S A 2007 Nov 8;104(46):18181-6. Epub 2007 Nov 8.

Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

FoxP3(+)CD4(+) regulatory T cells (Tregs) play a key role in the maintenance of peripheral self-tolerance, and it has been suggested that diabetes-susceptible nonobese diabetic (NOD) mice are defective in the generation and numbers of Tregs. We found thymic selection of Tregs to be under genetic control. Fetal thymic organ cultures on the NOD background required 3- to 10-fold more antigen than corresponding cultures on the B6 background for optimal induction of Tregs, but once the threshold for induction was reached the NOD background yielded close to 10-fold more Tregs. This increased selection of Tregs was also found in nontransgenic NOD mice in fetal through adult stages. This trait did not map to the MHC, idd3, or the chromosome 3 (Chr3) regions that control clonal deletion, but mainly to two regions on Chr1 and Chr11. Thus, NOD mice do not have a global defect in the generation or maintenance of Tregs; if anything, they show the opposite.
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http://dx.doi.org/10.1073/pnas.0708899104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2084317PMC
November 2007

A sequence-based variation map of 8.27 million SNPs in inbred mouse strains.

Nature 2007 Aug 29;448(7157):1050-3. Epub 2007 Jul 29.

Perlegen Sciences, 2021 Stierlin Court, Mountain View, California 94043, USA.

A dense map of genetic variation in the laboratory mouse genome will provide insights into the evolutionary history of the species and lead to an improved understanding of the relationship between inter-strain genotypic and phenotypic differences. Here we resequence the genomes of four wild-derived and eleven classical strains. We identify 8.27 million high-quality single nucleotide polymorphisms (SNPs) densely distributed across the genome, and determine the locations of the high (divergent subspecies ancestry) and low (common subspecies ancestry) SNP-rate intervals for every pairwise combination of classical strains. Using these data, we generate a genome-wide haplotype map containing 40,898 segments, each with an average of three distinct ancestral haplotypes. For the haplotypes in the classical strains that are unequivocally assigned ancestry, the genetic contributions of the Mus musculus subspecies--M. m. domesticus, M. m. musculus, M. m. castaneus and the hybrid M. m. molossinus--are 68%, 6%, 3% and 10%, respectively; the remaining 13% of haplotypes are of unknown ancestral origin. The considerable regional redundancy of the SNP data will facilitate imputation of the majority of these genotypes in less-densely typed classical inbred strains to provide a complete view of variation in additional strains.
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http://dx.doi.org/10.1038/nature06067DOI Listing
August 2007

Mouse Phenotype Database Integration Consortium: integration [corrected] of mouse phenome data resources.

Mamm Genome 2007 Mar 10;18(3):157-63. Epub 2007 Apr 10.

Understanding the functions encoded in the mouse genome will be central to an understanding of the genetic basis of human disease. To achieve this it will be essential to be able to characterize the phenotypic consequences of variation and alterations in individual genes. Data on the phenotypes of mouse strains are currently held in a number of different forms (detailed descriptions of mouse lines, first-line phenotyping data on novel mutations, data on the normal features of inbred lines) at many sites worldwide. For the most efficient use of these data sets, we have initiated a process to develop standards for the description of phenotypes (using ontologies) and file formats for the description of phenotyping protocols and phenotype data sets. This process is ongoing and needs to be supported by the wider mouse genetics and phenotyping communities to succeed. We invite interested parties to contact us as we develop this process further.
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http://dx.doi.org/10.1007/s00335-007-9004-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230762PMC
March 2007

mtDNA phylogeny and evolution of laboratory mouse strains.

Genome Res 2007 Mar 6;17(3):293-8. Epub 2007 Feb 6.

Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-465 Porto, Portugal.

Inbred mouse strains have been maintained for more than 100 years, and they are thought to be a mixture of four different mouse subspecies. Although genealogies have been established, female inbred mouse phylogenies remain unexplored. By a phylogenetic analysis of newly generated complete mitochondrial DNA sequence data in 16 strains, we show here that all common inbred strains descend from the same Mus musculus domesticus female wild ancestor, and suggest that they present a different mitochondrial evolutionary process than their wild relatives with a faster accumulation of replacement substitutions. Our data complement forthcoming results on resequencing of a group of priority strains, and they follow recent efforts of the Mouse Phenome Project to collect and make publicly available information on various strains.
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http://dx.doi.org/10.1101/gr.5941007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1800920PMC
March 2007

Mouse Phenome Database (MPD).

Nucleic Acids Res 2007 Jan 6;35(Database issue):D643-9. Epub 2006 Dec 6.

The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.

The Mouse Phenome Database (MPD; http://www.jax.org/phenome) is a repository of phenotypic and genotypic data on commonly used and genetically diverse inbred strains of mice. Strain characteristics data are contributed by members of the scientific community. Electronic access to centralized strain data enables biomedical researchers to choose appropriate strains for many systems-based research applications, including physiological studies, drug and toxicology testing and modeling disease processes. MPD provides a community data repository and a platform for data analysis and in silico hypothesis testing. The laboratory mouse is a premier genetic model for understanding human biology and pathology; MPD facilitates research that uses the mouse to identify and determine the function of genes participating in normal and disease pathways.
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http://dx.doi.org/10.1093/nar/gkl1049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781116PMC
January 2007

Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice.

Cancer Res 2006 May;66(10):5029-38

Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Secondary malignancies are a serious adverse consequence of alkylator chemotherapy. The risk of developing an alkylator-associated malignancy is influenced by genetic background, although the relevant genetic factors are poorly understood. To screen for novel susceptibility factors, we established a mouse model of alkylator-induced malignancy. We exposed mice from 20 inbred strains to the prototypical alkylating agent, N-nitroso-N-ethylurea (ENU). ENU was a potent carcinogen in many of the strains tested, inducing 140 tumors in 240 ENU-treated mice (66% incidence of at least one tumor in evaluable mice), compared with a background incidence of 8% spontaneous tumors in 240 strain-, age-, and sex-matched control mice (relative risk, 8.4; P < 0.0001). A wide variety of tumor histologies were noted, including epithelial carcinomas, soft tissue sarcomas, and hematopoietic tumors. Cancer susceptibility was a heritable trait for the most common tumor types, lung adenocarcinoma (H(2) = 0.25), T cell lymphoma (H(2) = 0.19), and myeloid malignancies (H(2) = 0.10). Quantitative trait locus mapping identified regions on chromosomes 3, 6, 9, and 15 containing candidate genes associated with lung adenoma, lung carcinoma, and lymphoma susceptibility. This novel mouse model recapitulates many features of human alkylator-associated cancer and supports the hypothesis that susceptibility to this syndrome is influenced by inherited polymorphisms that could be used to make informed clinical treatment decisions.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-3404DOI Listing
May 2006
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