Congenic dissection of a major QTL for methamphetamine sensitivity implicates epistasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE35139 | GEO | 2012/01/18
SECONDARY ACCESSION(S): PRJNA150701
REPOSITORIES: GEO
Similar Datasets
Project description:We identified a congenic mouse with an introgressed region from the A/J donor inbred strain on an inbred C57BL/6J background that showed a reduced locomotor stimulant response to methamphetamine. We conducted microarray analysis of the striatum from drug-naive female and male mice that were 6-9 weeks old. The congenic region is on chromosome 11 and spans approximately 84-96 Mb. There were two groups of mice used in the analysis: B6 control mice versus congenic mice. Congenic mice were collapsed across heterozygous and homozygous genotypes. All mice are on a C57BL/6J background. Congenic mice differ only on chromosome 11 where they contain the introgressed A/J alleles from 84-96 Mb. 14 C57BL/6J wildtype mice and 14 B6.A/J congenic mice (84-96 Mb region from A/J strain) were examined for gene expression differences using striatal tissue (left and right punches pooled). All mice were drug-naïve and were 6-9 weeks old at the time of sacrifice.
2012-01-18 | E-GEOD-35139 | biostudies-arrayexpress
Project description:Inbred congenic strain B6.C6.132.54/Vad was created using C57BL/6ByJ background and BALB/cJ donor strains. Flanking background markers at chr. 6: 75.9 Mb (rs4226008, NCBI Mouse Build 36 / dbSNP Build 126) and 122.3 Mb (rs3023093), and limiting donor markers at 81.9 Mb (rs4226024) and at 91.8 Mb (rs3712161) defined the introgressed region. We concluded the segment size must be between 9.9 Mb and 46.4 Mb. In a Quantitative Trait Gene identification study we compared brain (without cerebellum) gene expression between progenitors and congenics. Such comparisons can facilitate identification of cis-regulated genes and to establish genetic control of a complex phenotype whose expression is associated with the introgressed chromosome segment. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Keywords: strain comparison
2007-07-30 | GSE7155 | GEO
Project description:Inbred congenic strain B6.C6.132.54/Vad was created using C57BL/6ByJ background and BALB/cJ donor strains. Flanking background markers at chr. 6: 75.9 Mb (rs4226008, NCBI Mouse Build 36 / dbSNP Build 126) and 122.3 Mb (rs3023093), and limiting donor markers at 81.9 Mb (rs4226024) and at 91.8 Mb (rs3712161) defined the introgressed region. We concluded the segment size must be between 9.9 Mb and 46.4 Mb. In a Quantitative Trait Gene identification study we compared brain (without cerebellum) gene expression between progenitors and congenics. Such comparisons can facilitate identification of cis-regulated genes and to establish genetic control of a complex phenotype whose expression is associated with the introgressed chromosome segment. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Experiment Overall Design: Experiments were carried out in three batches. In each batch 10 animals per strain were used. After processing each hemisphere separately, 10 hemispheres were pooled for one high-density oligonucleotide microarray (Mouse Genome 430 2.0, Affymetrix, Santa Clara, CA). For each strain 3 oligonucleotide microarrays were used (n=3). We used adult, untreated, male mice (n=30, 90 mice in toto).
2008-06-15 | E-GEOD-7155 | biostudies-arrayexpress
Project description:Genetically engineered mice (GEM) are essential tools for understanding gene function and disease modeling. Due to historical reasons, gene targeting was at first done in embryonic stem cells (ESC) derived from the 129 family of inbred strains, leading to mixed background or congenic mice when crossed with C57BL/6 mice. Depending on the number of backcrosses and breeding strategies genomic segments from 129-derived ESC can be introgressed into the C57BL/6 genome at different levels, establishing a unique genetic makeup that needs characterization in order to obtain valid conclusions of experiments using GEM models. We sequenced wild-type (WT), heterozygous (Het) and knockout (KO) mouse embryonic fibroblasts (MEFs) from a knockout model of Sall2 (Sato A. et al, Zinc finger protein sall2 is not essential for embryonic and kidney development. Mol Cell Biol 2003, 23:62-69) maintained in a mixed background between C57BL/6J and 129P2OlaHsd mice. We also treated these cells with doxorubicin, as a global perturbation of the gene expression. With this schema, we aimed to detect genetic introgression of 129 mice onto C57BL/6J, KO-ligated variants (the so-called congenic footprint) and potential modifier genes.
2018-12-01 | GSE123168 | GEO
Project description:Differential gene expression between mouse distal chromsome 1 congenic and background and reciprocal congenic and background Genetic factors significantly affect vulnerability to alcohol dependence (alcoholism). We previously identified a quantitative trait locus on chromosome 1 (Adw1) with a large effect on predisposition to alcohol physiological dependence and associated withdrawal following both chronic and acute alcohol exposure in mice. We fine-mapped these loci to a 1.1-1.7 Mb interval syntenic with human 1q23.2-23.3. Adw1 interval genes show remarkable genetic variation among mice derived from the C57BL/6J and DBA/2J strains, the two most widely studied genetic animal models for alcohol-related traits. Here, we report the creation of a novel recombinant Adw1 congenic model (R2) in which the Adw1 interval from a donor C57BL/6J strain is introgressed onto a uniform, inbred DBA/2J genetic background. As expected, R2 mice demonstrate significantly less severe alcohol withdrawal compared to wild-type littermates. Additionally, comparing R2 and background strain animals, as well as reciprocal congenic (R8) and appropriate background strain animals, we assessed Adw1 dependent brain gene expression using microarray and quantitative PCR analyses. To our knowledge this includes the first Weighted Gene Co-expression Network Analysis using reciprocal congenic models. Importantly, this allows detection of co-expression patterns limited to one or common to both genetic backgrounds with high and low predisposition to alcohol withdrawal severity. The gene expression patterns (modules) in common contain genes related to oxidative phosphorylation, building upon human and animal model studies that implicate involvement of oxidative phosphorylation in alcohol use disorders. Finally, we demonstrate that administration of N-acetylcysteine, an FDA-approved antioxidant, significantly reduces symptoms of alcohol withdrawal (convulsions) in mice, thus validating a phenotypic role for this network. Taken together, these studies support the importance of mitochondrial oxidative homeostasis in alcohol withdrawal and identify this network as a valuable therapeutic target in human alcohol use disorders.
2017-03-08 | GSE89281 | GEO
Project description:We previously utilized interval-specific congenic lines derived from C57BL/6J (B6) and DBA/2J (D2) alleles to fine map a quantitative trait locus (QTL) influencing methamphetamine (MA)- induced locomotor activity. We identified a 0.23 MB critical interval on chromosome 11 containing only two protein coding genes, Rufy1 and Hnrnph1. Notably, Rufy1 contains three missense SNPs and Hnrnph1 contains 1 SNP near the 5’ UTR. In an effort to identify the molecular mechanisms that bridge genetic variation with behavior, we conducted transcriptome analysis via mRNA sequencing (RNA-seq) in a B6.D2 congenic line (chr.11: 50-60 Mb) that captures the QTL. There was an overrepresentation of cis-regulated, differentially expressed genes within the congenic interval (4 out of 92 differentially expressed genes; FDR < 0.05) and widespread genomic regulation on all autosomes.
2015-12-11 | GSE66366 | GEO
Project description:Previous studies of congenic lines of C57BL/6J-DBA/2J mice compared to C57BL/6 mice revealed a 0.23 QTL for sensitivity to methamphetamine on chromosome 11, which contains two protein coding genes, Rufy1 and Hnrnph1. Subsequent transcription activator-like effector nucleases (TALENs)-mediated introduction of frameshift deletions in the first coding exon of one copy of Hnrnph1 of C57BL/6J mice, revealed comparable association to phenotype. Analysis of the transcriptome and splicesome between these Hnrnph1 heterozygous knockouts and C57BL/6J mice revealed genome-wide differentially expression and exon usage of more than 1000 genes in either.
2017-02-01 | GSE76929 | GEO
Project description:We previously utilized interval-specific congenic lines derived from C57BL/6J (B6) and DBA/2J (D2) alleles to fine map a quantitative trait locus (QTL) influencing methamphetamine (MA)- induced locomotor activity. We identified a 0.23 MB critical interval on chromosome 11 containing only two protein coding genes, Rufy1 and Hnrnph1. Notably, Rufy1 contains three missense SNPs and Hnrnph1 contains 1 SNP near the 5â UTR. In an effort to identify the molecular mechanisms that bridge genetic variation with behavior, we conducted transcriptome analysis via mRNA sequencing (RNA-seq) in a B6.D2 congenic line (chr.11: 50-60 Mb) that captures the QTL. There was an overrepresentation of cis-regulated, differentially expressed genes within the congenic interval (4 out of 92 differentially expressed genes; FDR < 0.05) and widespread genomic regulation on all autosomes. For this study, 3mm punches from both striatal hemispheres were collected and pooled from 16 mice (8 controls and 8 B6.D2 congenics), and RNA was extracted and prepared for cDNA library preparation using the Illumina TruSeq (oligo-dT; 50bp single-end reads). Samples 1-16, consisting of alternating B6 and B6.D2 congenics were run in four lanes total, with samples 1-8 run in duplicate across lanes 5 and 6 and samples 9-16 acorss lanes 7 and 8, respectively. Raw samples provided are labeled with the "CB-" prefix, followed by the sample number and the lane that it was run in is described at the tail end as "_L00#" with # being either lane 5, 6, 7 or 8. In this study, all odd samples (e.g. CB-1,3,5 etc.) are C57BL/6J littermate controls, while all even samples are B6.D2 congenics. Note that the lane 7 replicate for Sample CB-13 (CB-13_L007.fastq.gz) was not processed due to technical difficulties with the file.
2015-12-11 | E-GEOD-66366 | biostudies-arrayexpress
Project description:We previously constructed a congenic mouse, B6.S-D2Mit194-D2Mit311 (B6.S-2) with SPRET/Ei donor DNA on distal chromosome 2 in a C57BL/6J background that captured an obesity quantitative trait locus (QTL). Mice homozygous for SPRET/Ei alleles at the donor region had decreased body weight and obesity related phenotypes. The B6.S-2 congenic donor region spanned a minimum of 26 Mb. In this study, we constructed five overlapping subcongenics with smaller SPRET/Ei donor regions to fine map the underlying gene(s). One of the five subcongenic lines derived from the B6.S-2 founding congenic, B6.S-2A, captures most of the body weight and adiposity phenotypes in a donor region with a maximum size of 7.4 Mb. Homozygous SPRET/Ei donor alleles in both the founding congenic and the derived B6.S-2A subcongenic exhibit significant decreases in body weight, multiple fat pad weights with the greatest decrease in mesenteric fat pad weight, and Adiposity Index (total fat pad weight divided by body weight). Interval specific microarray analysis in four tissues for donor region genes from the founding B6.S-2 congenic identified several differentially expressed genes mapping to the B6.S-2A subcongenic donor region, including prohormone convertase 2 (PC2). Quantitative real-time PCR confirmed a modest decrease of PC2 expression in whole brains of mice homozygous for SPRET/Ei donor alleles. Analysis of the relative levels of mRNA for B6 and SPRET/Ei in heterozygous congenic mice showed differentially higher expression of the C57BL/6J allele over the SPRET/Ei allele indicating a cis regulation of differential expression. Using subcongenic mapping, we have successfully narrowed a body weight and obesity QTL interval and identified PC2 as a positional candidate gene. Keywords: Two strain comparison for gene discovery
2008-09-22 | GSE6115 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent form of hepatic disease and feeding mice a High-Fat, High-Caloric (HFHC) diet is a standard model of NAFLD. In order to better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. 265 (A/J × C57BL/6J) F2 male mice were fed a HFHC diet for 8 weeks. QTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1 and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb). C57BL/6J-Chr 11A/J/ NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (p<0.05), while C57BL/6J-Chr 1A/J/ NaJ mice retained the C57BL/6 phenotype. In addition, we replicated the eQTLs on Chr 1 and 12 (LOD scores ? 3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and 11, and consomic mice confirmed that replacing the C57BL/6 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases.
2014-08-02 | GSE56987 | GEO