scholarly journals High Throughput Computational Mouse Genetic Analysis

2020 ◽  
Author(s):  
Ahmed Arslan ◽  
Yuan Guan ◽  
Xinyu Chen ◽  
Robin Donaldson ◽  
Wan Zhu ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Mitochondrial Targeting ◽  
Phenotypic Data ◽  
Factors Affecting ◽  
Wide Range ◽  
Allelic Differences

AbstractBackgroundGenetic factors affecting multiple biomedical traits in mice have been identified when GWAS data, which measured responses in panels of inbred mouse strains, was analyzed using haplotype-based computational genetic mapping (HBCGM). Although this method was previously used to analyze one dataset at a time; but now, a vast amount of mouse phenotypic data is now publicly available, which could enable many more genetic discoveries.ResultsHBCGM and a whole genome SNP map covering 43 inbred strains was used to analyze 8300 publicly available datasets of biomedical responses (1.52M individual datapoints) measured in panels of inbred mouse strains. As proof of concept, causative genetic factors affecting susceptibility for eye, metabolic and infectious diseases were identified when structured automated methods were used to analyze the output. One analysis identified a novel genetic effector mechanism; allelic differences within the mitochondrial targeting sequence affected the subcellular localization of a protein. We also found allelic differences within the mitochondrial targeting sequences of many murine and human proteins, and these could affect a wide range of biomedical phenotypes.ImplicationsThese initial results indicate that genetic factors affecting biomedical responses could be identified through analysis of very large datasets, and they provide an early indication of how this type of ‘augmented intelligence’ can facilitate genetic discovery.

scholarly journals Analysis of Structural Variation Among Inbred Mouse Strains Identifies Genetic Factors for Autism-Related Traits

2021 ◽  
Author(s):  
Ahmed Arslan ◽  
Zhuoqing Fang ◽  
Meiyue Wang ◽  
Zhuanfen Cheng ◽  
Boyoung Yoo ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Sequence Data ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Autism Spectrum ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Genetic Traits ◽  
Long Read ◽  
Short Read Sequence

AbstractThe genomes of six inbred strains were analyzed using long read (LR) sequencing. The results revealed that structural variants (SV) were very abundant within the genome of inbred mouse strains (4.8 per gene), which indicates that they could impact genetic traits. Analysis of the relationship between SNP and SV alleles across 53 inbred strains indicated that we have a very limited ability to infer whether SV are present using short read sequence data, even when nearby SNP alleles are known. The benefit of having a more complete map of the pattern of genetic variation was demonstrated by identifying at least three genetic factors that could underlie the unique neuroanatomic and behavioral features of BTBR mice that resemble human Autism Spectrum Disorder (ASD). Similar to the genetic findings in human ASD cohorts, the identified BTBR-unique alleles are very rare, and they cause high impact changes in genes that play a role in neurodevelopment and brain function.

scholarly journals Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains

2010 ◽  
Vol 42A (2) ◽  
pp. 103-113 ◽  
Author(s):  
Matthew S. Barnabei ◽  
Nathan J. Palpant ◽  
Joseph M. Metzger
Keyword(s):  
Cardiac Function ◽  
Genetic Divergence ◽  
Ex Vivo ◽  
Inbred Mouse ◽  
Critical Role ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Cardiac Decompensation

Inbred mouse strains play a critical role in biomedical research. Genetic homogeneity within inbred strains and their general amenability to genetic manipulation have made them an ideal resource for dissecting the physiological function(s) of individual genes. However, the inbreeding that makes inbred mice so useful also results in genetic divergence between them. This genetic divergence is often unaccounted for but may be a confounding factor when comparing studies that have utilized distinct inbred strains. Here, we compared the cardiac function of C57BL/6J mice to seven other commonly used inbred mouse strains: FVB/NJ, DBA/2J, C3H/HeJ, BALB/cJ, 129X1/SvJ, C57BL/10SnJ, and 129S1/SvImJ. The assays used to compare cardiac function were the ex vivo isolated Langendorff heart preparation and in vivo real-time hemodynamic analysis using conductance micromanometry. We report significant strain-dependent differences in cardiac function between C57BL/6J and other commonly used inbred strains. C57BL/6J maintained better cardiac function than most inbred strains after ex vivo ischemia, particularly compared with 129S1/SvImJ, 129X1/SvJ, and C57BL/10SnJ strains. However, during in vivo acute hypoxia 129X1/SvJ and 129S1/SvImJ maintained relatively normal cardiac function, whereas C57BL/6J animals showed dramatic cardiac decompensation. Additionally, C3H/HeJ showed rapid and marked cardiac decompensation in response to esmolol infusion compared with effects of other strains. These findings demonstrate the complex effects of genetic divergence between inbred strains on cardiac function. These results may help inform analysis of gene ablation or transgenic studies and further demonstrate specific quantitative traits that could be useful in discovery of genetic modifiers relevant to cardiac health and disease.

scholarly journals Mouse Susceptibility to Anthrax Lethal Toxin Is Influenced by Genetic Factors in Addition to Those Controlling Macrophage Sensitivity

2004 ◽  
Vol 72 (8) ◽  
pp. 4439-4447 ◽  
Author(s):  
Mahtab Moayeri ◽  
Nathaniel W. Martinez ◽  
Jason Wiggins ◽  
Howard A. Young ◽  
Stephen H. Leppla
Keyword(s):  
Genetic Factors ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Lethal Toxin ◽  
Cytokine Response ◽  
Mouse Strains ◽  
Anthrax Lethal Toxin ◽  
Toll Like Receptor 4 ◽  
Oxide Synthase

ABSTRACT Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages (Mφ) derived from certain inbred strains. We used nine inbred strains and two inducible nitric oxide synthase (iNOS) knockout C57BL/6J strains polymorphic for the LT Mφ sensitivity Kif1C locus to analyze the role of Mφ sensitivity (to lysis) in LT-mediated cytokine responses and lethality. LT-mediated induction of cytokines KC, MCP-1/JE, MIP-2, eotaxin, and interleukin-1β occurred only in mice having LT-sensitive Mφ. However, while iNOS knockout C57BL/6J mice having LT-sensitive Mφ were much more susceptible to LT than the knockout mice with LT-resistant Mφ, a comparison of susceptibilities to LT in the larger set of inbred mouse strains showed a lack of correlation between Mφ sensitivity and animal susceptibility to toxin. For example, C3H/HeJ mice, harboring LT-sensitive Mφ and having the associated LT-mediated cytokine response, were more resistant than mice with LT-resistant Mφ and no cytokine burst. Toll-like receptor 4 (Tlr4)-deficient, lipopolysaccharide-nonresponsive mice were not more resistant to LT. We also found that CAST/Ei mice are uniquely sensitive to LT and may provide an economical bioassay for toxin-directed therapeutics. The data indicate that while the cytokine response to LT in mice requires Mφ lysis and while Mφ sensitivity in the C57BL/6J background is sufficient for BALB/cJ-like mortality of that strain, the contribution of Mφ sensitivity and cytokine response to animal susceptibility to LT differs among other inbred strains. Thus, LT-mediated lethality in mice is influenced by genetic factors in addition to those controlling Mφ lysis and cytokine response and is independent of Tlr4 function.

scholarly journals Large-scale, high-throughput screening for coagulation and hematologic phenotypes in mice*

2002 ◽  
Vol 11 (3) ◽  
pp. 185-193 ◽  
Author(s):  
Luanne L. Peters ◽  
Eleanor M. Cheever ◽  
Heather R. Ellis ◽  
Phyllis A. Magnani ◽  
Karen L. Svenson ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Large Scale ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Sample Volume ◽  
Small Sample ◽  
Mouse Strains ◽  
Phenotypic Data ◽  
Multiple Tests

The Mouse Phenome Project is an international effort to systematically gather phenotypic data for a defined set of inbred mouse strains. For such large-scale projects the development of high-throughput screening protocols that allow multiple tests to be performed on a single mouse is essential. Here we report hematologic and coagulation data for more than 30 inbred strains. Complete blood counts were performed using an Advia 120 analyzer. For coagulation testing, we successfully adapted the Dade Behring BCS automated coagulation analyzer for use in mice by lowering sample and reagent volume requirements. Seven automated assay procedures were developed. Small sample volume requirements make it possible to perform multiple tests on a single animal without euthanasia, while reductions in reagent volume requirements reduce costs. The data show that considerable variation in many basic hematological and coagulation parameters exists among the inbred strains. These data, freely available on the World Wide Web, allow investigators to knowledgeably select the most appropriate strain(s) to meet their individual study designs and goals.

scholarly journals Hydronephrosis in inbred strains of mice with particular reference to the BRVR strain

1973 ◽  
Vol 7 (3) ◽  
pp. 229-236 ◽  
Author(s):  
D. M. Taylor ◽  
H. Fraser
Keyword(s):  
Inbred Mouse ◽  
Inbred Strains ◽  
The Other ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Concomitant Infection ◽  
Inbred Strains Of Mice ◽  
Dietary Variation

Hydronephrosis occurred in 6 of the 13 inbred mouse strains maintained in the same colony. Its incidence was high only in the BRVR strain, where about half of the cases could only be detected microscopically. There was no concomitant infection even in severely abnormal BRVR kidneys and the incidence of the condition was not influenced by dietary variation. The hydronephrosis found, less frequently, in 5 of the other strains was of a different type from that in BRVR mice.

Epigenetic and genetic factors affect transgene methylation imprinting

Development ◽  
1989 ◽  
Vol 107 (1) ◽  
pp. 165-168 ◽  
Author(s):  
C. Sapienza ◽  
J. Paquette ◽  
T.H. Tran ◽  
A. Peterson
Keyword(s):  
Dna Methylation ◽  
Genetic Factors ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Maternal Genome ◽  
Two Factors ◽  
In Trans ◽  
In Cis ◽  
Transgene Locus

In some lines of transgenic mice, the methylation of MspI sites within or adjacent to the transgene locus is affected by the sex of the parent from which the transgene is inherited. These differences are consistent with a role for DNA methylation in genome imprinting. In a previous report, we noted that in one such line, all offspring of females exhibited hypermethylation of the transgene while only some offspring of males carried a hypomethylated transgene. In this report, we provide evidence that this phenomenon is controlled by at least two factors, one of which acts in cis and is dependent on the transgene locus, and one of which acts in trans and is supplied by the maternal genome. We also provide evidence that there are genetic differences between inbred mouse strains in the trans-acting factor.

scholarly journals A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains

2019 ◽  
Author(s):  
Corey T. Watson ◽  
Justin T. Kos ◽  
William S. Gibson ◽  
Leah Newman ◽  
Gintaras Deikus ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Inbred Mouse ◽  
Disease Model ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Strain Variation ◽  
In The Wild ◽  
Model Strain ◽  
Novel Allele

ABSTRACTThe genomes of classical inbred mouse strains include genes derived from all three major subspecies of the house mouse, Mus musculus. We recently posited that genetic diversity in the immunoglobulin heavy chain (IGH) gene loci of C57BL/6 and BALB/c mice reflect differences in subspecies origin. To investigate this hypothesis, we conducted high-throughput sequencing of IGH gene rearrangements to document IGH variable (IGHV), joining (IGHJ), and diversity (IGHD) genes in four inbred wild-derived mouse strains (CAST/EiJ, LEWES/EiJ, MSM/MsJ, and PWD/PhJ), and a single disease model strain (NOD/ShiLtJ), collectively representing genetic backgrounds of several major mouse subspecies. A total of 341 germline IGHV sequences were inferred in the wild-derived strains, including 247 not curated in the International Immunogenetics Information System. In contrast, 83/84 inferred NOD IGHV genes had previously been observed in C57BL/6 mice. Variability among the strains examined was observed for only a single IGHJ gene, involving a description of a novel allele. In contrast, unexpected variation was found in the IGHD gene loci, with four previously unreported IGHD gene sequences being documented. Very few IGHV sequences of C57BL/6 and BALB/c mice were shared with strains representing major subspecies, suggesting that their IGH loci may be complex mosaics of genes of disparate origins. This suggests a similar level of diversity is likely present in the IGH loci of other classical inbred strains. This must now be documented if we are to properly understand inter-strain variation in models of antibody-mediated disease.

scholarly journals A QUANTITATIVE ANALYSIS OF THE GENETICS OF RESTING BLOOD LACTIC ACID LEVELS IN MICE

Genetics ◽  
1973 ◽  
Vol 75 (1) ◽  
pp. 191-198
Author(s):  
Patricia L Hatchell ◽  
James W MacInnes
Keyword(s):  
Lactic Acid ◽  
Genetic Factors ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Environment Interaction ◽  
Genotype X Environment ◽  
Generation Means ◽  
Nonallelic Interactions ◽  
Lactate Levels

ABSTRACT Resting blood lactate levels were measured in inbred mouse strains, their F1, and several of their segregating generations to determine whether the level of lactic acid is influenced by genetic factors. The inbred strains in each of the two sets used differed significantly from one another for this character. Only one strain showed a significant sex difference. The data could not be fully analyzed because of the failure to fulfill Mather's first criterion for an adequate scale. Nonallelic interactions, in particular, additive x dominance and dominance x dominance, were found to influence the generation means. Genotype x environment interaction was detected and eliminated by log transformation. Negative heterosis was exhibited by all but one noninbred generation.—The data suggest that genes influencing the character are dispersed between the parental lines and that interactions are predominantly of the duplicate kind. A buffering system by which lactate levels are kept at a minimum is proposed.

scholarly journals Multiple trait measurements in 43 inbred mouse strains capture the phenotypic diversity characteristic of human populations

2007 ◽  
Vol 102 (6) ◽  
pp. 2369-2378 ◽  
Author(s):  
Karen L. Svenson ◽  
Randy Von Smith ◽  
Phyllis A. Magnani ◽  
Heather R. Suetin ◽  
Beverly Paigen ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Phenotypic Diversity ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Human Populations ◽  
Large Set ◽  
Inbred Mouse Strains ◽  
High Fat ◽  
Mineral Density

The breadth of genetic and phenotypic variation among inbred strains is often underappreciated because assessments include only a limited number of strains. Evaluation of a larger collection of inbred strains provides not only a greater understanding of this variation but collectively mimics much of the variation observed in human populations. We used a high-throughput phenotyping protocol to measure females and males of 43 inbred strains for body composition (weight, fat, lean tissue mass, and bone mineral density), plasma triglycerides, high-density lipoprotein and total cholesterol, glucose, insulin, and leptin levels while mice consumed a high-fat, high-cholesterol diet. Mice were fed a chow diet until they were 6–8 wk old and then fed the high-fat diet for an additional 18 wk. As expected, broad phenotypic diversity was observed among these strains. Significant variation between the sexes was also observed for most traits measured. Additionally, the response to the high-fat diet differed considerably among many strains. By the testing of such a large set of inbred strains for many traits, multiple phenotypes can be considered simultaneously and thereby aid in the selection of certain inbred strains as models for complex human diseases. These data are publicly available in the web-accessible Mouse Phenome Database ( http://www.jax.org/phenome ), an effort established to promote systematic characterization of biochemical and behavioral phenotypes of commonly used and genetically diverse inbred mouse strains. Data generated by this effort builds on the value of inbred mouse strains as a powerful tool for biomedical research.

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