Mouse models of ocular diseases

The Jackson Laboratory, having the world's largest collection of mouse mutant stocks and genetically diverse inbred strains, is an ideal place to discover genetically determined eye variations and disorders. In this paper, we list and describe mouse models for ocular research available from Mouse Eye Mutant Resource at The Jackson Laboratory. While screening mouse strains and stocks at The Jackson Laboratory (TJL) for genetic mouse models of human ocular disorders, we have identified numerous spontaneous or naturally occurring mutants. We characterized these mutants using serial indirect ophthalmoscopy, fundus photography, electroretinography (ERG) and histology, and performed genetic analysis including linkage studies and gene identification. Utilizing ophthalmoscopy, electroretinography, and histology, to date we have discovered 109 new disorders affecting all aspects of the eye including the lid, cornea, iris, lens, and retina, resulting in corneal disorders, glaucoma, cataracts, and retinal degenerations. The number of known serious or disabling eye diseases in humans is large and affects millions of people each year. Yet research on these diseases frequently is limited by the obvious restrictions on studying pathophysiologic processes in the human eye. Likewise, many human ocular diseases are genetic in origin, but appropriate families often are not readily available for genetic studies. Mouse models of inherited ocular disease provide powerful tools for rapid genetic analysis, characterization, and gene identification. Because of the great similarity among mammalian genomes, these findings in mice have direct relevance to the homologous human conditions.

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A Large-Scale Mutagenesis and Strain Characterization Project To Identify Genetic Variability in Mice: Resources Available from the Jackson Laboratory Program for Genomic Applications (JAX PGA).

Blood ◽

10.1182/blood.v104.11.1578.1578 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1578-1578

Author(s):

Luanne L. Peters ◽

Orah S. Platt ◽

Karen L. Svenson ◽

Beverly J. Paigen ◽

Gary A. Churchill ◽

...

Keyword(s):

Genetic Variation ◽

Animal Models ◽

Hypothesis Testing ◽

Statistical Power ◽

Large Scale ◽

Inbred Strains ◽

Chromosome 1 ◽

Mouse Strains ◽

Strain Characterization ◽

Jackson Laboratory

Abstract Identifying the genes and gene products relevant to physiological systems and creating opportunities to elucidate their function are essential first steps in understanding the pathophysiology of disease. To dissect the genetic variation underlying hematopoietic, cardiovascular, lung, and sleep dysfunction, we established a Center for Mouse Models of Heart, Lung, Blood and Sleep (HLBS) Disorders at The Jackson Laboratory as part of the NHLBI Program for Genomic Applications (PGA). The major goal of the JAX PGA is to enable researchers to link both single-gene mutations and quantitative trait loci (QTL) to gene function and disease. To achieve this goal, we are generating new mutations in mice by chemical (ENU) mutagenesis, and characterizing the common inbred mouse strains to detect existing genetic variation. Here, we report an extensive body of hematologically relevant strain characterization data and the establishment of new animal models. All strain characterization data is deposited into the Mouse Phenome Database (MPD, http://www.jax.org/phenome), also accessible via the JAX PGA website (http://pga.jax.org). Data for up to 48 inbred strains are currently available and include complete blood counts and coagulation profiles (PT, aPTT, fibrinogen). These data allow investigators to identify the most appropriate strains for (a) physiological testing; (b) drug development; (c) progenitors in QTL crosses; (d) sensitized mutagenesis screens; and (e) direct hypothesis testing. For example, to maximize the potential for successful QTL identification, parental strains that differ substantially in the phenotype of interest, at least 2 standard deviations (SD), should be selected. We used our strain survey data to select parental strains for identification of QTL for baseline WBC count, an important risk factor for sickle cell disease severity. The strains C57BLKS/J and SM/J have WBC counts of 12.6 ± 1.6 and 3.3 ± 0.8 x 103/μL, respectively, a difference much greater the 2 SD, indicating a high statistical power. We identified a highly significant QTL (LOD = 7) on chromosome 1 in an initial genome wide scan of 279 F2 animals. Moreover, the availability of extensive phenotypic data across the inbred strains in conjunction with the availability of saturated sslp and SNP maps has allowed us to identify QTL in silico. As an example of the utility of the MPD in hypothesis testing, a modifier gene associated with decreased VWF levels is present in 5 of the 6 MPD strains showing the highest aPTT levels (see abstract by Johnsen et al). In total, 44 different phenotypic projects, each consisting of large datasets, can be freely accessed through the MPD. The JAX PGA mutagenesis effort in C57BL/6J mice has likewise yielded valuable resources. Nearly 100 new mutant strains are in various stages of development, including strains with phenotypes of interest to the hematology community (e. g., anemia, thrombocytopenia, leukopenia, leukocytosis). These animal models and all other JAX PGA resources (protocols, software, QTL locations) are freely available to the scientific community.

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Invited Review: Identifying new mouse models of cardiovascular disease: a review of high-throughput screens of mutagenized and inbred strains

Journal of Applied Physiology ◽

10.1152/japplphysiol.01029.2003 ◽

2003 ◽

Vol 94 (4) ◽

pp. 1650-1659 ◽

Cited By ~ 49

Author(s):

Karen L. Svenson ◽

Molly A. Bogue ◽

Luanne L. Peters

Keyword(s):

Cardiovascular Disease ◽

Mouse Models ◽

High Throughput ◽

Human Disease ◽

Early Stage ◽

Inbred Mouse ◽

Inbred Strains ◽

Mouse Strains ◽

Complex Disorders ◽

Lung Dysfunction

The mouse is a proven model for studying human disease. Many strains exist that exhibit either natural or engineered genetic variation and thereby enable the elucidation of pathways involved in the development of cardiovascular disease. Although those mouse models have been fundamental to advancing our knowledge base, we are still at an early stage in understanding how genes contribute to complex disorders. There remains a need for new animal models that closely represent human disease. To expedite their development, we have established the Center for New Mouse Models of Heart, Lung, Blood, and Sleep Disorders at The Jackson Laboratory. We are using a phenotype-driven approach to identify mutations leading to atherosclerosis, hypertension, obesity, blood disorders, lung dysfunction, thrombosis, and disordered sleep. Our high-throughput, comprehensive phenotyping draws from two sources for new models: 1) the natural variation among over 40 inbred mouse strains and 2) chemically induced, whole-genome mutagenized mice. Here, we review our cardiovascular screens and present some hypertensive, obese, and cardiovascular models identified with this approach.

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Translating Mouse Models

Toxicologic Pathology ◽

10.1177/0192623316675767 ◽

2016 ◽

Vol 45 (1) ◽

pp. 134-145 ◽

Cited By ~ 16

Author(s):

Rani S. Sellers

Keyword(s):

Immune Response ◽

Mouse Models ◽

Inbred Mouse ◽

Laboratory Mouse ◽

Inbred Strains ◽

Mouse Strains ◽

Genetic Mutations ◽

Response Patterns ◽

Human Immune System ◽

Models Of Disease

Mice and humans branched from a common ancestor approximately 80 million years ago. Despite this, mice are routinely utilized as animal models of human disease and in drug development because they are inexpensive, easy to handle, and relatively straightforward to genetically manipulate. While this has led to breakthroughs in the understanding of genotype–phenotype relationships and in the identification of therapeutic targets, translation of beneficial responses to therapeutics from mice to humans has not always been successful. In a large part, these differences may be attributed to variations in the alignment of protein expression and signaling in the immune systems between mice and humans. Well-established inbred strains of “The Laboratory Mouse” vary in their immune response patterns as a result of genetic mutations and polymorphisms arising from intentional selection for research relevant traits, and even closely related substrains vary in their immune response patterns as a result of genetic mutations and polymorphisms arising from genetic drift. This article reviews some of the differences between the mouse and human immune system and between inbred mouse strains and shares examples of how these differences can impact the usefulness of mouse models of disease.

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Genetic Control of Mammalian Meiotic Recombination. I. Variation in Exchange Frequencies Among Males From Inbred Mouse Strains

Genetics ◽

10.1093/genetics/162.1.297 ◽

2002 ◽

Vol 162 (1) ◽

pp. 297-306 ◽

Cited By ~ 13

Author(s):

Kara E Koehler ◽

Jonathan P Cherry ◽

Audrey Lynn ◽

Patricia A Hunt ◽

Terry J Hassold

Keyword(s):

Meiotic Recombination ◽

Inbred Mouse ◽

Inbred Strains ◽

Male Meiosis ◽

Mouse Strains ◽

Recombination Rates ◽

The Mean ◽

Genetic Background Effects ◽

Exchange Patterns ◽

Positive Interference

AbstractGenetic background effects on the frequency of meiotic recombination have long been suspected in mice but never demonstrated in a systematic manner, especially in inbred strains. We used a recently described immunostaining technique to assess meiotic exchange patterns in male mice. We found that among four different inbred strains—CAST/Ei, A/J, C57BL/6, and SPRET/Ei—the mean number of meiotic exchanges per cell and, thus, the recombination rates in these genetic backgrounds were significantly different. These frequencies ranged from a low of 21.5 exchanges in CAST/Ei to a high of 24.9 in SPRET/Ei. We also found that, as expected, these crossover events were nonrandomly distributed and displayed positive interference. However, we found no evidence for significant differences in the patterns of crossover positioning between strains with different exchange frequencies. From our observations of >10,000 autosomal synaptonemal complexes, we conclude that achiasmate bivalents arise in the male mouse at a frequency of 0.1%. Thus, special mechanisms that segregate achiasmate chromosomes are unlikely to be an important component of mammalian male meiosis.

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EVIDENCE THAT TWO LOCI PREDOMINANTLY DETERMINE THE DIFFERENCE IN SUSCEPTIBILITY TO THE HIGH PRESSURE NEUROLOGIC SYNDROME TYPE I SEIZURE IN MICE

Genetics ◽

10.1093/genetics/99.2.285 ◽

1981 ◽

Vol 99 (2) ◽

pp. 285-307

Author(s):

R D McCall ◽

D Frierson

Keyword(s):

High Pressure ◽

Inbred Mouse ◽

Inbred Strains ◽

Chromosome 17 ◽

Seizure Threshold ◽

Mouse Strains ◽

Compression Rate ◽

Type I ◽

Major Locus ◽

The Difference

ABSTRACT Most mammals tested, when exposed to increasing pressure in helium/oxygen atmospheres, exhibit progressive motor disturbances culminating in two, usually successive, well-differentiated convulsive seizures. The seizures are highly reproducible components of the constellation of events that collectively constitute the High Pressure Neurologic Syndrome (HPNS). In the present study, we present evidence that the mean difference in seizure threshold pressures of the first seizure to occur (HPNS Type I) between inbred mouse strains DBA/2J and C57BL/6J is predominantly determined (> 60%) by the expression of a major locus—possibly linked to the H-2 locus on chromosome 17—and a minor locus, probably unlinked. This outcome is derived from applications of the maximum likelihood modeling procedure of Elston and Stewart (1973) and Stewart and Elston (1973) to eleven models of genetic determinacy and tests (including breeding tests) of "preferred" models so derived using BXD recombinant inbred strains that show the following: The major locus exhibits conditional dominance characteristics depending upon compression rate and minor locus genotype. At a constant mean compression rate of 100 atm hr-1, the major locus manifests strong, though incomplete, dominance apparently independent of minor locus genotype. Its expression is, however, highly sensitive to compression rate, losing its dominance altogether at a linear rate of 1,000 atm hr-1. The major locus interacts with the weakly dominant and relatively compression-rate-insensitive minor locus to retain dominance at fast compression only when the dominant alleles of both loci are present. A principal finding of this study is that employing two compression rates permits fuller genetic characterization of murine high-pressure seizure susceptibility differences than could be achieved by use of a single compression rate.

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Discovery and refinement of muscle weight QTLs in B6 × D2 advanced intercross mice

Physiological Genomics ◽

10.1152/physiolgenomics.00055.2014 ◽

2014 ◽

Vol 46 (16) ◽

pp. 571-582 ◽

Cited By ~ 9

Author(s):

P. Carbonetto ◽

R. Cheng ◽

J. P. Gyekis ◽

C. C. Parker ◽

D. A. Blizard ◽

...

Keyword(s):

Inbred Strains ◽

Mouse Strains ◽

Missense Mutations ◽

Muscle Weight ◽

Hindlimb Muscles ◽

Hindlimb Muscle ◽

Causal Genes ◽

Snp Panel ◽

Genomic Regions ◽

Genetic Contributions

The genes underlying variation in skeletal muscle mass are poorly understood. Although many quantitative trait loci (QTLs) have been mapped in crosses of mouse strains, the limited resolution inherent in these conventional studies has made it difficult to reliably pinpoint the causal genetic variants. The accumulated recombination events in an advanced intercross line (AIL), in which mice from two inbred strains are mated at random for several generations, can improve mapping resolution. We demonstrate these advancements in mapping QTLs for hindlimb muscle weights in an AIL ( n = 832) of the C57BL/6J (B6) and DBA/2J (D2) strains, generations F8–F13. We mapped muscle weight QTLs using the high-density MegaMUGA SNP panel. The QTLs highlight the shared genetic architecture of four hindlimb muscles and suggest that the genetic contributions to muscle variation are substantially different in males and females, at least in the B6D2 lineage. Out of the 15 muscle weight QTLs identified in the AIL, nine overlapped the genomic regions discovered in an earlier B6D2 F2 intercross. Mapping resolution, however, was substantially improved in our study to a median QTL interval of 12.5 Mb. Subsequent sequence analysis of the QTL regions revealed 20 genes with nonsense or potentially damaging missense mutations. Further refinement of the muscle weight QTLs using additional functional information, such as gene expression differences between alleles, will be important for discerning the causal genes.

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A comprehensive SNP-based genetic analysis of inbred mouse strains

Mammalian Genome ◽

10.1007/s00335-005-0001-7 ◽

2005 ◽

Vol 16 (7) ◽

pp. 476-480 ◽

Cited By ~ 31

Author(s):

Shirley Tsang ◽

Zhonghe Sun ◽

Brian Luke ◽

Claudia Stewart ◽

Nicole Lum ◽

...

Keyword(s):

Genetic Analysis ◽

Inbred Mouse ◽

Mouse Strains ◽

Inbred Mouse Strains

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Effect of murine strain on metabolic pathways of glucose production after brief or prolonged fasting

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00601.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. E53-E61 ◽

Cited By ~ 46

Author(s):

Shawn C. Burgess ◽

F. Mark H. Jeffrey ◽

Charles Storey ◽

Angela Milde ◽

Natasha Hausler ◽

...

Keyword(s):

Genetic Manipulation ◽

Glucose Production ◽

Tca Cycle ◽

Inbred Strains ◽

Mouse Strains ◽

Background Strain ◽

Metabolic Fluxes ◽

Inbred Strains Of Mice ◽

Total Glucose

Background strain is known to influence the way a genetic manipulation affects mouse phenotypes. Despite data that demonstrate variations in the primary phenotype of basic inbred strains of mice, there is limited data available about specific metabolic fluxes in vivo that may be responsible for the differences in strain phenotypes. In this study, a simple stable isotope tracer/NMR spectroscopic protocol has been used to compare metabolic fluxes in ICR, FVB/N (FVB), C57BL/6J (B6), and 129S1/SvImJ (129) mouse strains. After a short-term fast in these mice, there were no detectable differences in the pathway fluxes that contribute to glucose synthesis. However, after a 24-h fast, B6 mice retain some residual glycogenolysis compared with other strains. FVB mice also had a 30% higher in vivo phospho enolpyruvate carboxykinase flux and total glucose production from the level of the TCA cycle compared with B6 and 129 strains, while total body glucose production in the 129 strain was ∼30% lower than in either FVB or B6 mice. These data indicate that there are inherent differences in several pathways involving glucose metabolism of inbred strains of mice that may contribute to a phenotype after genetic manipulation in these animals. The techniques used here are amenable to use as a secondary or tertiary tool for studying mouse models with disruptions of intermediary metabolism.

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Expression of a monoclonal antibody-defined, B-lineage transformation antigen specifically identifies Abelson-diseased animals. Genetically determined resistance to Abelson murine leukemia virus acts before induction of gp160(6C3).

Journal of Experimental Medicine ◽

10.1084/jem.164.4.1356 ◽

1986 ◽

Vol 164 (4) ◽

pp. 1356-1361 ◽

Cited By ~ 3

Author(s):

G F Tidmarsh ◽

M O Dailey ◽

I L Weissman

Keyword(s):

Recombinant Inbred ◽

Recombinant Inbred Lines ◽

Leukemia Virus ◽

Neoplastic Transformation ◽

Inbred Strains ◽

Inbred Lines ◽

Abelson Murine Leukemia Virus ◽

B Lineage ◽

Genetically Determined ◽

Murine Leukemia

Mice genetically susceptible or genetically resistant to the leukemogenic effects of A-MuLV(Mo) were tested for their expression of the B-lineage neoplastic transformation-associated antigen, 6C3Ag. Genetically resistant inbred strains and recombinant inbred lines developed neither cells expressing high levels of 6C3Ag (6C3Aghi) in their hematolymphoid tissues nor Abelson leukemias. Genetically susceptible inbred strains and recombinant inbred lines developed high percentages of 6C3Aghi hematolymphoid cells concomitant with development of Abelson leukemias and lymphomas. Thus the genetically-determined resistance to A-MuLV(Mo) leukemogenesis appears to act at some step(s) after virus infection but before the stage of malignant progression, which is marked by 6C3Ag expression.

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GENETIC ANALYSIS OF PLASMA CORTICOSTERONE LEVELS IN TWO INBRED STRAINS OF MICE

Journal of Endocrinology ◽

10.1677/joe.0.0550415 ◽

1972 ◽

Vol 55 (2) ◽

pp. 415-420 ◽

Cited By ~ 36

Author(s):

B. E. ELEFTHERIOU ◽

D. W. BAILEY

Keyword(s):

Genetic Analysis ◽

Recombinant Inbred ◽

Epistatic Interaction ◽

Genetic Model ◽

Inbred Strains ◽

Plasma Corticosterone ◽

Experimental Results ◽

Recombinant Inbred Strains ◽

Inbred Strains Of Mice

SUMMARY Plasma corticosterone levels were determined fluorometrically in mice of two unrelated highly inbred strains, C57BL/6By and BALB/cBy, and in seven of their derived recombinant-inbred strains as well as their F1 hybrid and backcross generations necessary to arrive at a genetic model for plasma corticosterone levels. It was concluded that the simplest genetic model, and one which fits the experimental results, was one which assumed that plasma corticosterone levels are controlled genetically by two loci with the epistatic interaction indicating dependency of pathways of action for the two genes.

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