Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes of metabolic syndrome in rats
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PROVIDER: PRJEB22045 | ENA |
REPOSITORIES: ENA
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Project description:We developed a method to prioritise strain-specific haplotypes by integrating genomic variation and genomic regulatory data predicted to be involved in specific phenotypes. To identify genomic regions associated with metabolic syndrome (MetS), a disorder of energy utilization and storage affecting several organ systems, we compared two Lyon rat strains, LH/Mav which is susceptible to MetS, and LL/Mav, which is susceptible to obesity as an intermediate MetS phenotype, with a third strain (LN/Mav) that is resistant to both MetS and obesity. Applying a novel metric, we ranked the identified strain-specific haplotypes using evolutionary conservation of the occupancy three liver-specific transcription factors (HNF4A, CEBPA, and FOXA1) in five rodents including rat. We generated RNA-seq expression data from liver of LL rats and from kidney of all three Lyon strains (5 biological replicates) and integrated these with relevant existing data including the level of regulatory conservation for three liver-specific transcription factors (CEBPA, FOXA1 and HNF4A between rat and five related mouse species and strains. We also used RNA-seq expression data from liver of LH and LN rats previously generated (GSE50027). Our results show that the use of functional regulatory conservation is a potentially effective approach to select strain-specific genomic regions associated with phenotypic differences among Lyon rats and could be extended to other systems.
2017-08-03 | E-MTAB-5939 | biostudies-arrayexpress
Project description:The genomes of laboratory rat strains are characterised by a mosaic haplotype structure caused by their unique breeding history. These mosaic haplotypes have been recently mapped by extensive sequencing of key strains. Comparison of genomic variation between two closely related rat strains with different phenotypes has been proposed as an effective strategy for the discovery of candidate strain-specific regions involved in phenotypic differences. We developed a method to prioritise strain-specific haplotypes by integrating genomic variation and genomic regulatory data predicted to be involved in specific phenotypes. Specifically, we aimed to identify genomic regions associated with Metabolic Syndrome (MetS), a disorder of energy utilization and storage affecting several organ systems.We compared two Lyon rat strains, Lyon Hypertensive (LH) which is susceptible to MetS, and Lyon Low pressure (LL), which is susceptible to obesity as an intermediate MetS phenotype, with a third strain (Lyon Normotensive, LN) that is resistant to both MetS and obesity. Applying a novel metric, we ranked the identified strain-specific haplotypes using evolutionary conservation of the occupancy three liver-specific transcription factors (HNF4A, CEBPA, and FOXA1) in five rodents including rat. Consideration of regulatory information effectively identified regions with liver-associated genes and rat orthologues of human GWAS variants related to obesity and metabolic traits. We attempted to find possible causative variants and compared them with the candidate genes proposed by previous studies. In strain-specific regions with conserved regulation, we found a significant enrichment for published evidence to obesity-one of the metabolic symptoms shown by the Lyon strains-amongst the genes assigned to promoters with strain-specific variation.Our results show that the use of functional regulatory conservation is a potentially effective approach to select strain-specific genomic regions associated with phenotypic differences among Lyon rats and could be extended to other systems.
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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.
2009-07-11 | E-GEOD-12066 | biostudies-arrayexpress
Project description:Morphotypes of Brassica oleracea are the result of a dynamic interaction between the genes that regulate the transition between vegetative and reproductive stages and those that regulate leaf morphology and plant architecture. In kales ornate leaf patterns, flowering delaying and nutrient quality are some of the characters were potentially selected by humans during domestication. Understanding candidate genes responsible for kale domestication is of importance to ultimately improve crop production. We aim to identify candidate genes that are responsible for kale leaf shape diversity and the evolution of domestic kale. Here we look at the global pattern of expressed genes during one single phase of development in kale, cabbage and TO1000 to gain an understanding of the genome-wide differences among some of the vegetative B. oleracea phenotypes. We identified gene expression patterns that are shared among the phenotypes and estimate the contribution of morphotype-specific gene expression patterns that set each of them apart. Differentially expressed developmental genes that regulate the vegetative to reproductive transition were abundant and present in all comparisons.
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2008-07-14 | E-MEXP-976 | biostudies-arrayexpress
Project description:The minor spliceosome is evolutionarily conserved in higher eukaryotes, but its biological significance remains poorly understood. Here, by precise CRISPR/Cas9-mediated disruption of the U12 and U6atac snRNAs, we report that a defective minor spliceosome is responsible for spinal muscular atrophy (SMA) associated phenotypes in Drosophila. Using a newly developed bioinformatic approach, we identified a large set of minor spliceosome-sensitive splicing events and demonstrate that three sensitive intron-containing neural genes, Pcyt2, Zmynd10, and Fas3, directly contribute to disease development as evidenced by the ability of their cDNAs to rescue the SMA-associated phenotypes in muscle development, neuromuscular junctions, and locomotion. Interestingly, many splice sites in sensitive introns are recognizable by both minor and major spliceosomes, suggesting a new mechanism of splicing regulation through competition between minor and major spliceosomes. These findings reveal a vital contribution of the minor spliceosome to SMA and to regulated splicing in animals.
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