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Systems genetics approach to low dose radiation sensitivity in BXD recombinant inbred mice

ABSTRACT: The immune system illustrates the challenges of assigning risk to low dose radiation (LDR) exposure in a population. While high radiation doses clearly suppress immune function, a number of studies have shown that LDR affects immune cell subpopulations in ways that could be beneficial. In the intact organism, defining the consequences of LDR is further complicated by the impact of genetic background, particularly in systems such as the immune system for which both radiosensitivity and genetic effects are profound. We employed a systems genetics approach to test for heritable differences in LDR responses. Mice from 39 BXD recombinant inbred (RI) strains were exposed to 10cGy gamma radiation to determine effects on immune function and oxidative stress 48h after irradiation. LDR significantly enhanced neutrophil phagocytosis in a manner that was independent of genetic background. In contrast, genetic background significantly impacted LDR-induced changes in spleen superoxide dismutase activity. Transcriptome data from spleens of the BXD parental strains highlighted the impact of genetic background on LDR responses and also indicate that genetic variation in radiosensitivity is further unmasked at low radiation doses. Taken together, these data highlight the need to consider genetic variation when assessing LDR outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE21562 | GEO | 2011/04/01

SECONDARY ACCESSION(S): PRJNA126185

REPOSITORIES: GEO

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Systems genetics approach to low dose radiation sensitivity in BXD recombinant inbred mice

Project description:The immune system illustrates the challenges of assigning risk to low dose radiation (LDR) exposure in a population. While high radiation doses clearly suppress immune function, a number of studies have shown that LDR affects immune cell subpopulations in ways that could be beneficial. In the intact organism, defining the consequences of LDR is further complicated by the impact of genetic background, particularly in systems such as the immune system for which both radiosensitivity and genetic effects are profound. We employed a systems genetics approach to test for heritable differences in LDR responses. Mice from 39 BXD recombinant inbred (RI) strains were exposed to 10cGy gamma radiation to determine effects on immune function and oxidative stress 48h after irradiation. LDR significantly enhanced neutrophil phagocytosis in a manner that was independent of genetic background. In contrast, genetic background significantly impacted LDR-induced changes in spleen superoxide dismutase activity. Transcriptome data from spleens of the BXD parental strains highlighted the impact of genetic background on LDR responses and also indicate that genetic variation in radiosensitivity is further unmasked at low radiation doses. Taken together, these data highlight the need to consider genetic variation when assessing LDR outcomes. Adult C57BL/6J and DBA/2J mice (10 weeks old) were exposed to low dose (10cGy) or high dose (1Gy) gamma radiation. Mice were sacrificed 24h after radiation or sham exposure & spleens were harvested for transcriptomic analysis.

2011-04-01 | E-GEOD-21562 | biostudies-arrayexpress

Low dose rate radiation induced secretion of TGF-β3 together 2 with an activator in small extracellular vesicles modifies low 3 dose hyper-radiosensitivity through ALK1 binding

Project description:Hyper-radiosensitivity (HRS) is the increased sensitivity to low doses of ionizing radiation 12 observed in most cell lines. We previously demonstrated that HRS is permanently abolished in cells irradiated at a low dose rate (LDR), in a mechanism dependent on transforming growth factor β3 (TGF-β3). In this study, we aimed to elucidate the activation and receptor binding of TGF-β3 in this mechanism. T-47D cells were pre-treated with inhibitors of potential receptors and activators of TGF-β3, along with addition of small extracellular vesicles (sEVs) from LDR primed cells, before their radiosensitivity was assessed by the clonogenic assay. The protein content of sEVs from LDR primed cells was analyzed with mass spectrometry. Our results show that sEVs contain TGF-β3 regardless of priming status, but only sEVs from LDR primed cells remove HRS in reporter cells. Inhibition of the matrix metalloproteinase (MMP) family prevents removal of HRS, suggesting an MMP-dependent activation of TGF-β3 in the LDR primed cells. We demonstrate a functional interaction between TGF-β3 and activin receptor like kinase 1 (ALK1), by showing that TGF-β3 removes HRS through ALK1 binding, independent of ALK5 and TGF-βRII. These results are an important contribution to a more comprehensive understanding of the mechanism behind TGF-β3 mediated removal of HRS.

2022-08-12 | PXD035010 | Pride

AD-BXD [Ntg dataset 2]

Project description:Cg.5XFAD females (MMRRC Stock No #34848-JAX) were bred to males from BXD strains. The resulting F1 progeny were monitored throughout their lifepan to evaluate the effect of genetic background on cognitive and pathological traits. Samples here come from various Ntg-BXD lines at either 6 or 14 months of age. An earlier dataset of similar design (plus Non-transgenic littermates) was deposited as GSE101144. AD littermates of mice sampled here will be deposited as a separate GEO series.

2020-08-17 | GSE119408 | GEO

Transcriptional profiling of BXD dorsal root ganglia

Project description:We sequenced dorsal root ganglia mRNA from 25 BXD recombinant inbred mouse strains to determine their variation in gene expression.

2015-06-11 | GSE69374 | GEO

Identifying genetic loci and spleen gene coexpression networks driving immunophenotypes in the BXD panel

Project description:The immune system plays a pivotal role in susceptibility to and progression of a variety of diseases. Due to its strong genetic basis, heritable differences in immune function may contribute to differential disease susceptibility between individuals. Genetic reference populations, such as the BXD (C57BL/6J X DBA/2J) panel of recombinant inbred (RI) mouse strains, provide a unique model through which to integrate baseline phenotypes in healthy individuals with heritable risk for disease because of the ability to combine data collected from these populations across multiple studies and time. We performed basic immunophenotyping (e.g. percentage of circulating B and T lymphocytes and CD4+ and CD8+ T cell subpopulations) in peripheral blood of healthy mice from 41 BXD RI strains to define the phenotypic variation in this model system and to characterize the genetic architecture that unlerlies these traits. Significant QTL models that explained the majority (50-77%) of phenotypic variance were derived for each trait and for the T:B cell and CD4+:CD8+ ratios. Combining QTL mapping with spleen gene expression data uncovered two quantitative trait transcripts (QTTs), Ptprk and Acp1, that which are candidates for heritable differences in the relative abundance of helper and cytotoxic T cells. These data will be valuable in extracting genetic correlates of the immune system in the BXD panel. In addition, they will be a useful resource in prospective, phenotype-driven model selection to test hypotheses about differential disease or environmental susceptibility between individuals with baseline differences in the composition of the immune system.

2010-03-31 | GSE19935 | GEO

Transcriptional profiling of BXD dorsal root ganglia

Project description:We sequenced dorsal root ganglia mRNA from 25 BXD recombinant inbred mouse strains to determine their variation in gene expression. Dorsal root ganglia mRNA profiles of recombinant inbred mouse strains

2015-06-11 | E-GEOD-69374 | biostudies-arrayexpress

The effect of genetic background on cognitive and pathological traits: AD-BXD [dataset 2]

Project description:Cg.5XFAD females (MMRRC Stock No #34848-JAX) were bred to males from BXD strains. The resulting F1 progeny were monitored throughout their lifepan to evaluate the effect of genetic background on cognitive and pathological traits. Samples here come from various AD-BXD lines at either 6 or 14 months of age. An earlier dataset of similar design (plus Non-transgenic littermates) was deposited as GSE101144. Ntg littermates of mice sampled here will be deposited as a separate GEO series.

2019-01-29 | GSE119215 | GEO

BXD Mouse Liver Gene Expression

Project description:The liver is the primary site for the metabolism of nutrients, drugs, and chemical agents. Although metabolic pathways are complex and tightly regulated, genetic variation among individuals, reflected in variations in gene expression levels, introduces complexity into research on liver disease. This study dissected genetic networks that control liver gene expression through the combination of large-scale quantitative mRNA expression analysis with genetic mapping in a reference population of BXD recombinant inbred mouse strains for which extensive single-nucleotide polymorphism, haplotype, and phenotypic data are publicly available. We profiled gene expression in livers of naive mice of both sexes from C57BL/6J, DBA/2J, B6D2F1, and 41 BXD strains using Agilent oligonucleotide microarrays. These data were used to map quantitative trait loci (QTLs) responsible for variations in the expression of about 19,000 transcripts. We identified polymorphic local and distant QTLs, including several loci that control the expression of large numbers of genes in liver, by comparing the physical transcript position with the location of the controlling QTL. CONCLUSION: The data are available through a public web-based resource (www.genenetwork.org) that allows custom data mining, identification of coregulated transcripts and correlated phenotypes, cross-tissue, and cross-species comparisons, as well as testing of a broad array of hypotheses.

2009-08-06 | GSE17522 | GEO

The effect of genetic background on cognitive and pathological traits: AD-BXD

Project description:Female C57BL/6J mice hemizygous for the 5XFAD transgene (MMRRC Stock No #34848-JAX) were bred to males from BXD strains, which do not carry the 5XFAD transgene. The resulting F1 progeny were monitored throughout their lifespan to evaluate the effect of genetic background on cognitive and pathological traits. All of the mice were fear conditioned and sacrificed within 30 minutes of testing. On the sample records, the characteristics: age field provides the age at which fear conditioning, sacrifice, and tissue collection occurred. Samples here come from various AD-BXD lines and their non-transgenic (Ntg) littermate counterparts at either 6 or 14 months of age.

2018-12-14 | GSE101144 | GEO

Intra- and inter-individual genetic differences in gene expression (BXD Brain)

Project description:Genetic variation is known to influence the amount of mRNA produced by a gene. Because molecular machines control mRNA levels of multiple genes, we expect genetic variation in components of these machines would influence multiple genes in a similar fashion. We show that this assumption is correct by using correlation of mRNA levels measured from multiple tissues in mouse strain panels to detect shared genetic influences. These correlating groups of genes (CGGs) have collective properties that on average account for 52â79% of the variability of their constituent genes and can contain genes that encode functionally related proteins. We show that the genetic influences are essentially tissue-specific and, consequently, the same genetic variations in one animal may upregulate a CGG in one tissue but downregulate the CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. Thus, this class of genetic variation can result in complex inter- and intra-individual differences. This will create substantial challenges in humans, where multiple tissues are not readily available. Each sample is a single hybridisation from a given BxD strain to a C57BL/6J reference sample. Two-colour glass arrays were used. No dye swaps were employed. Data from whole brain.

2010-06-25 | E-GEOD-8355 | biostudies-arrayexpress

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