Project description:Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2,112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters, and enrichment of co-localised functional elements. We found eQTLs for about 85% of analysed genes, 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 MB to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might often be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels, and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. We show for strongly heritable transcripts that a considerable gap still exists between total heritability resulting from all trans-chromosomes and explained variance of all identified trans-eSNPs. In contrast, the vast majority of most cis-heritability of these genes is already explained. Dissection of co-localised functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene-expression, pathways and disease related processes. Gene expression from human blood mononuclear cells from individuals of the Leipzig LIFE Heart Study was analyzed applying Illumina HT-12 v4 Expression BeadChips. After preprocessing, 28,295 expression probes for 2,112 individuals remained for analysis. In a population-based analysis, we identified associations between DNA variants and RNA expression levels and characterized these findings.

Project description:In the last 20 years, there has been significant research towards defining the genetic basis of lipid metabolism and meat quality related traits in pigs. Nowadays, the study of the transcriptome and its regulatory mechanisms allows going far beyond in the genetic dissection of these complex traits. In present study, a genome-wide eQTL scan aiming to detect pig genome regions regulating levels of skeletal muscle mRNA expression has been performed. This study has been conducted on a commercial Duroc population where a number of QTL for muscle fat deposition and fatty acid composition had been detected. GeneChip Porcine Genome® arrays (Affymetrix) were used to determine the gene expression levels of gluteus medius samples from 105 Duroc pigs belonging to two groups with divergent phenotypes for fatness traits. This experimental design aimed to favour detection of eQTL affecting genes related to lipid metabolism and meat quality traits. The whole genome scan with a panel of 110 microsatellites allowed us detecting 613 genome-wide significant eQTL unequally distributed across the pig genome, SSC5 and SSC3 harbouring the highest number of eQTL. Moreover, 11 genome regions with eQTL affecting the expression levels of a high number of genes (eQTL hot spots) have been described. After mapping target probes and discarding low quality probes, a total of 59 cis- and 396 trans-acting eQTL were retained for further analyses. The functional classification showed that lipid-related GO terms were not the most enriched by the list of eQTL-regulated genes. However, a number of regulated genes functionally related to lipid metabolism and fat deposition traits were identified, and their functional relationship with these phenotypes were further investigated. With this purpose, eQTL results were integrated with 1) QTL linkage maps and 2) correlation data between phenotypes and gene expression levels. As a result, a comprehensive list of 29 positional and functional candidate genes was elaborated. These results represent a valuable contribution to the comprehension of genetic regulation of skeletal muscle individual gene expression in swine species, and a first step towards disentangling gene networks and molecular mechanisms involved in lipid metabolism and meat quality traits. 105 gluteus medius samples from 105 animals belonging to two groups of 53 and 52 animals each: HIGH group had higher carcass, plasma and muscle fat content; LOW group had lower carcass, plasma and muscle fat content

Project description:ATR is a PI3K-like kinase protein, regulating checkpoint responses to DNA damage and replication stress. Apart from its checkpoint function in the nucleus, ATR actively engage in antiapoptotic role at mitochondria following DNA damage. The different functions of ATR in the nucleus and cytoplasm are carried out by two prolyl isomeric forms of ATR: trans- and cis-ATR, respectively. The isomerization occurs at the Pin1 Ser428-Pro429 motif of ATR. Here we investigated the structural basis of the subcellular location-specific functions of human ATR. Using a mass spectrometry-based footprinting approach, the surface accessibility of ATR lysine residues to sulfo-NHS-LC-biotin modification was monitored and compared between the cis and the trans-isomers. We have identified two biotin-modified lysine residues, K459 and K469, within the BH3-like domain of cis-ATR that were not accessible in trans-ATR, indicating a conformational change around the BH3 domain between cis- and trans-ATR. The conformational alteration also involved the N-terminal domain and the middle HEAT domain. Moreover, experimental results from an array of complementary assays show that cis-ATR with the accessible BH3 domain was able to bind to tBid while trans-ATR could not. In addition, both cis- and trans-ATR can directly form homodimers via their C-terminal domains without ATRIP, while nuclear (trans-ATR) in the presence of ATRIP forms dimer-dimer complexes involving both N- and C-termini of ATR and ATRIP after UV. Structural characteristics around the Ser428-Pro429 motif and the BH3 domain region are also analyzed by molecular modelling and dynamics simulation. In support, cis conformation was found to be significantly more energetically favourable than trans at Ser428-Pro429 bond in a 20-aa wild-type ATR peptide. Taken together, our results suggest that the isomerization-induced structural changes of ATR define both its subcellular location and compartment-specific functions and plays an essential role in promoting cell survival and DNA damage responses.

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Cobitis taenia

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