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.
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.
Project description:Novel, systems-based approach to mouse genetics. Expression Profiles from 99 strains of inbred and recombinant inbred mice. Most assayed in triplicate. Two of 288 chips were excluded from the final analysis due to low QC scores.
Project description:Strain differences in gene expression in the hypothalamus of BXD recombinant inbred mice We used microarrays to evaluate genetic and sex-specific differences in gene expression in the hypothalamus
Project description:We used a systems genetics approach in the BXD genetic reference population of mice and assembled a comprehensive experimental knowledge base comprising a deep ‘sleep-wake’ phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation.
Project description:Individual genetic variation affects gene expression and cell phenotype by acting within complex molecular circuits, but this relationship is still largely unknown. Here, we combine genomic and meso-scale profiling with novel computational methods to detect genetic variants that affect the responsiveness of gene expression to stimulus (responsiveness QTLs) and position them in circuit diagrams. We apply this approach to study individual variation in transcriptional responsiveness to three different pathogen components in the model response of primary bone marrow dendritic cells (DCs) from recombinant inbred mice strains. We show that reQTLs are common both in cis (affecting a single target gene) and in trans (pleiotropically affecting co-regulated gene modules) and are specific to some stimuli but not others. Leveraging the stimulus-specific activity of reQTLs and the differential responsiveness of their associated targets, we show how to position reQTLs within the context of known pathways in this regulatory circuit. For example, we find that a pleiotropic trans-acting genetic factor in chr1:129-165Mb affects the responsiveness of 35 anti-viral genes only during an anti-viral like stimulus. Using RNAi we uncover RGS16 the likely causal gene in this interval, and an activator of the antiviral response. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in other complex circuits in primary mammalian cells. The transcriptional response of DCs to pathogen components in the context of the mouse BXD recombinant inbred lines. We isolated DCs from individual age-synchronized female mice of different BXD and parental strains. We measured 30 global transcription profiles in resting and stimulated DCs from two parental strains (B6 and D2) and six BXD strains. We used bone marrow derived primary DCs from a panel of recombinant inbred (RI) BXD mice derived from a cross of the parental C57BL/6J (B6) and DBA/2J (D2) strains. We measured transcriptional responses in DCs from each of two parental strains and 6 BXD strains stimulated by three ligands of Toll-like receptors: LPS (TLR4 ligand), Pam3CSK ('PAM', TLR2 ligand) and poly IC (TLR3/RIG-I ligand).
Project description:In order to elucidate the molecular mechanisms underlying individual variation in sensitivity to ethanol we profiled the prefrontal cortex transcriptomes of two inbred strains that exhibit divergent responses to acute ethanol, the C57BL6/J (B6) and DBA/2J (D2) strains, as well as 27 members of the BXD recombinant inbred panel, which was derived from a B6 x D2 cross. With this dataset we were able to identify several gene co-expression networks that were robustly altered by acute ethanol across the BXD panel. These ethanol-responsive gene-enriched networks were heavily populated by genes regulating synaptic transmission and neuroplasticity, and showed strong genetic linkage to discreet chromosomal loci. Network-based measurements of node importance identified several hub genes as established regulators of ethanol response phenotypes, while other hubs represent novel candidate modulators of ethanol responses.
2011-12-01 | GSE28515 | GEO
Project description:Whole-genome sequencing of the BXD recombinant inbred family