Project description:A QTL analysis between inbred mouse strains MRL/MpJ and SM/J was performed to identify genetic loci influencing high-density lipoprotein (HDL) cholesterol and triglycerides (TG) at eight weeks of age in F2 mice fed a chow diet. In order to narrow down lists of candidate genes, expression levels from liver tissue were used to test for differential expression among parental and F1 strains and to scan for eQTL in F2 animals. We provide evidence for Mppe1 (Chr 18) as an HDL QTL candidate gene and Cyp2d26 (Chr 15) as a TG QTL candidate gene.
Project description:A C57BL6/J (B6) x CAST/Ei (CAST) strain intercross has revealed a new quantitative trait locus (QTL) on Chromosome (Chr) 17 controlling total food volume (Tfv1; LOD=7.6). Compared with B6, the CAST mice consume 39% more food volume per body weight in a macronutrient diet selection paradigm. Linkage analyses of total food volume revealed the presence of suggestive QTL on Chrs 2, 6, and 15 and a significant locus on Chr 17. An interval-specific congenic strain, B6.CAST-17, was then developed which verified the QTL. Microarray analysis of stomach in congenic and wildtype B6 mice revealed Glp1r as an expression candidate with physiological relevance to food intake. Further functional analysis of this gene revealed this gene as potential candidate for total food volume trait in mice Keywords: Comparative gene expression analysis
Project description:We used Affymetrix Mouse Exon 1.0 ST arrays to identify potential changes in alternative splicing between a subcongenic interval of the QTL Sicd2 on Chr 15 and their FVB-like littermates. Results implicate novel candidate genes conferring susceptibility to seizure-induced cell death.
Project description:Bone mineral density and structure candidate gene analysis in alcohol-non-preferring (NP), alcohol-preferring (P), congenic NP (NP.P) and congenic P (P.NP) rats Genetic mapping in alcohol-preferring (P) and alcohol-non-preferring (NP) rats has identified a major quantitative trait locus (QTL) in the region between q22 – q34 on chromosome (Chr) 4 for alcohol preference. In a separate genome-wide linkage study, using inbred Fischer 344 (F344) and Lewis (LEW) rats, several QTL linked to bone density and structure were identified at the same location suggesting that bone mass and strength genes might co-segregate with genes that regulate the alcohol preference trait. The aim of this study is to identify the genes segregating for skeletal phenotypes and alcohol trait in congenic P/NP rats. We compared bone mineral content (BMC), areal/volumetric bone mineral density (aBMD/vBMD) and biomechanical strength at different skeletal sites from 6-month-old inbred and congenic P/NP rats. Transfer of the NP Chr 4 QTL into P background significantly increased body weight but decreased BMC, aBMD/vBMD in whole body, cranium, femur, and lumbar vertebrae. On the other hand, transfer of P Chr 4 QTL into NP background significantly decreased body weight but increased BMC and aBMD in the same skeletal sites. Microarray analysis was performed from the femurs of 4-week-old rats (n = 5 per strain) using Affymetrix Rat Genome 230 2.0 arrays. A total of 53 genes, including 41 candidate genes and 12 predicted genes, were differentially expressed among all strains of rats with a false discovery rate (FDR) less than 10%. Several candidate genes from microarray analysis were found to be were strongly correlated (r2>0.50) with different skeletal phenotypes. Gene expression of top 3 candidate genes from microarray profiling was validated by quantitative real-time PCR (qRT-PCR). Ingenuity pathway analysis revealed relationships among the candidate genes related to bone metabolism including pathways related to beta-estradiol, tumor necrosis factor and androgen receptor. Keywords: Comparison of gene expression profiles between NP, P, NP.P and P.NP rats
Project description:Several studies have shown that bone mineral density (BMD), a clinically measurable predictor of osteoporotic fracture, is the sum of genetic and environmental influences. In addition, serum IGF-1 levels have been correlated to both BMD and fracture risk. We previously identified a Quantitative Trait Locus (QTL) for Bone Mineral Density (BMD) on mouse Chromosome (Chr) 6 that overlaps a QTL for serum IGF-1. The B6.C3H-6T (6T) congenic mouse is homozygous for C57BL/6J (B6) alleles across the genome except for a 30 cM region on Chr 6 that is homozygous for C3H/HeJ (C3H) alleles. This mouse was created to study biology behind both the BMD and the serum IGF-1 QTLs and to identify the gene(s) underlying these QTLs. Female 6T mice have lower BMD and lower serum IGF-1 levels at all ages measured. As the liver is the major source of serum IGF-1, we examined differential expression in the livers of fasted female B6 and 6T mice by microarray. Keywords: Genetic variation
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.
Project description:We used Affymetrix Mouse Exon 1.0 ST arrays to identify potential changes in alternative splicing between a subcongenic interval of the QTL Sicd2 on Chr 15 and their FVB-like littermates. Results implicate novel candidate genes conferring susceptibility to seizure-induced cell death. Total RNA was extracted from the hippocampus of 8 Sicd2-ISCL4 subcongenic mice and 8 FVB-like littermates.
Project description:A QTL analysis between inbred mouse strains MRL/MpJ and SM/J was performed to identify genetic loci influencing high-density lipoprotein (HDL) cholesterol and triglycerides (TG) at eight weeks of age in F2 mice fed a chow diet. In order to narrow down lists of candidate genes, expression levels from liver tissue were used to test for differential expression among parental and F1 strains and to scan for eQTL in F2 animals. We provide evidence for Mppe1 (Chr 18) as an HDL QTL candidate gene and Cyp2d26 (Chr 15) as a TG QTL candidate gene. MRL/MpJ (MRL) mice were crossed with male SM/J (SM) mice; their progeny were intercrossed to produce 371 F2 animals. Of these, 282 F2 males and females were profiled with Affy Mouse Gene 1.0 ST arrays for an eQTL study. Three animals from each parental and the F1 strains from each sex, i.e. 18 in total, were also profiled for testing differential expression. A total of 300 samples are included in the dataset. The mice were weaned at 3 weeks on a chow diet. At 13 weeks of age, mice were single housed for 3 days and fasted for 4 hours prior to being sacrificed. Tissue collection was performed between noon and 1pm to avoid variations due to circadian rhythm.
Project description:Children with Down syndrome (DS) have a 20-fold increased risk of developing B cell acute lymphoblastic leukemia (B-ALL). Polysomy 21 (i.e., extra copies of chr.21) is also the most frequent somatic aneuploidy among all B-ALLs. Additional B-ALLs harbor intrachromosomal amplifications of chr.21q22 (iAMP21). Yet, the mechanistic links between chr.21q22 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 is sufficient to confer murine B cell self-renewal in vitro, B cell maturation defects in vivo, and B-ALL in concert with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in murine progenitor B cells and B-ALLs, and ÒbivalentÓ genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes known to be marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q22, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo. These data implicate HMGN1 overexpression and loss of H3K27me3 in progenitor B cell transformation and suggest strategies to target leukemias with polysomy 21.
Project description:Bone mineral density and structure candidate gene analysis in alcohol-non-preferring (NP), alcohol-preferring (P), congenic NP (NP.P) and congenic P (P.NP) rats; Genetic mapping in alcohol-preferring (P) and alcohol-non-preferring (NP) rats has identified a major quantitative trait locus (QTL) in the region between q22 â?? q34 on chromosome (Chr) 4 for alcohol preference. In a separate genome-wide linkage study, using inbred Fischer 344 (F344) and Lewis (LEW) rats, several QTL linked to bone density and structure were identified at the same location suggesting that bone mass and strength genes might co-segregate with genes that regulate the alcohol preference trait. The aim of this study is to identify the genes segregating for skeletal phenotypes and alcohol trait in congenic P/NP rats. We compared bone mineral content (BMC), areal/volumetric bone mineral density (aBMD/vBMD) and biomechanical strength at different skeletal sites from 6-month-old inbred and congenic P/NP rats. Transfer of the NP Chr 4 QTL into P background significantly increased body weight but decreased BMC, aBMD/vBMD in whole body, cranium, femur, and lumbar vertebrae. On the other hand, transfer of P Chr 4 QTL into NP background significantly decreased body weight but increased BMC and aBMD in the same skeletal sites. Microarray analysis was performed from the femurs of 4-week-old rats (n = 5 per strain) using Affymetrix Rat Genome 230 2.0 arrays. A total of 53 genes, including 41 candidate genes and 12 predicted genes, were differentially expressed among all strains of rats with a false discovery rate (FDR) less than 10%. Several candidate genes from microarray analysis were found to be were strongly correlated (r2>0.50) with different skeletal phenotypes. Gene expression of top 3 candidate genes from microarray profiling was validated by quantitative real-time PCR (qRT-PCR). Ingenuity pathway analysis revealed relationships among the candidate genes related to bone metabolism including pathways related to beta-estradiol, tumor necrosis factor and androgen receptor. Experiment Overall Design: Comparison of differentially expressed genes between 4q22-4q34 on chromosome 4 in NP, P, NP.P and P.NP rats.