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Identification of gene co-expression clusters in liver tissues from multiple porcine populations with high and low backfat androstenone phenotype.

ABSTRACT: Boar taint is principally caused by accumulation of androstenone and skatole in adipose tissues. Studies have shown high heritability estimates for androstenone whereas skatole production is mainly dependent on nutritional factors. Androstenone is a lipophilic steroid mainly metabolized in liver. Majority of the studies on hepatic androstenone metabolism focus only on a single breed and very few studies account for population similarities/differences in gene expression patterns. In this work, we concentrated on population similarities in gene expression to identify the common genes involved in hepatic androstenone metabolism of multiple pig populations. Based on androstenone measurements, publicly available gene expression datasets from three porcine populations were compiled into either low or high androstenone dataset. Gene expression correlation coefficients from these datasets were converted to rank ratios and joint probabilities of these rank ratios were used to generate dataset specific co-expression clusters. Finally, these networks were clustered using a graph clustering technique.Cluster analysis identified a number of statistically significant co-expression clusters in the dataset. Further enrichment analysis of these clusters showed that one of the clusters from low androstenone dataset was highly enriched for xenobiotic, drug, cholesterol and lipid metabolism and cytochrome P450 associated metabolism of drugs and xenobiotics. Literature references revealed that a number of genes in this cluster were involved in phase I and phase II metabolism. Physical and functional similarity assessment showed that the members of this cluster were dispersed across multiple clusters in high androstenone dataset, possibly indicating a weak co-expression of these genes in high androstenone dataset.Based on these results we hypothesize that majority of the genes in this cluster forms a signature co-expression cluster in low androstenone dataset in our experiment and that majority of the members of this cluster might be responsible for hepatic androstenone metabolism across all the three populations used in our study. We propose these results as a background work towards understanding breed similarities in hepatic androstenone metabolism. Additional large scale experiments using data from multiple porcine breeds are necessary to validate these findings.

SUBMITTER: Sahadevan S

PROVIDER: S-EPMC4365963 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Identification of gene co-expression clusters in liver tissues from multiple porcine populations with high and low backfat androstenone phenotype.

Sahadevan Sudeep S Tholen Ernst E Große-Brinkhaus Christine C Schellander Karl K Tesfaye Dawit D Hofmann-Apitius Martin M Cinar Mehmet Ulas MU Gunawan Asep A Hölker Michael M Neuhoff Christiane C

BMC genetics 20150228

<h4>Background</h4>Boar taint is principally caused by accumulation of androstenone and skatole in adipose tissues. Studies have shown high heritability estimates for androstenone whereas skatole production is mainly dependent on nutritional factors. Androstenone is a lipophilic steroid mainly metabolized in liver. Majority of the studies on hepatic androstenone metabolism focus only on a single breed and very few studies account for population similarities/differences in gene expression pattern ...[more]

PMID: 25884519

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Project description:Expression quantitative trait loci (eQTLs) represent genetic control points of gene expression, and can be categorized as cis- and trans-acting, reflecting local and distant regulation of gene expression respectively. Although there is evidence of co-regulation within clusters of trans-eQTLs, the extent of co-expression patterns and their relationship with the genotypes at eQTLs are not fully understood. We have mapped thousands of cis- and trans-eQTLs in four tissues (fat, kidney, adrenal and left ventricle) in a large panel of rat recombinant inbred (RI) strains. Here we investigate the genome-wide correlation structure in expression levels of eQTL transcripts and underlying genotypes to elucidate the nature of co-regulation within cis- and trans-eQTL datasets. Across the four tissues, we consistently found statistically significant correlations of cis-regulated gene expression to be rare (<0.9% of all pairs tested). Most (>80%) of the observed significant correlations of cis-regulated gene expression are explained by correlation of the underlying genotypes. In comparison, co-expression of trans-regulated gene expression is more common, with significant correlation ranging from 2.9%-14.9% of all pairs of trans-eQTL transcripts. We observed a total of 81 trans-eQTL clusters (hot-spots), defined as consisting of > or =10 eQTLs linked to a common region, with very high levels of correlation between trans-regulated transcripts (77.2-90.2%). Moreover, functional analysis of large trans-eQTL clusters (> or =30 eQTLs) revealed significant functional enrichment among genes comprising 80% of the large clusters. The results of this genome-wide co-expression study show the effects of the eQTL genotypes on the observed patterns of correlation, and suggest that functional relatedness between genes underlying trans-eQTLs is reflected in the degree of co-expression observed in trans-eQTL clusters. Our results demonstrate the power of an integrative, systematic approach to the analysis of a large gene expression dataset to uncover underlying structure, and inform future eQTL studies.

Project description:BACKGROUND: Boar taint is the unpleasant odour and flavour of the meat of uncastrated male pigs that is primarily caused by high levels of androstenone and skatole in adipose tissue. Androstenone is a steroid and its levels are mainly genetically determined. Studies on androstenone metabolism have, however, focused on a limited number of genes. Identification of additional genes influencing levels of androstenone may facilitate implementation of marker assisted breeding practices. In this study, microarrays were used to identify differentially expressed genes and pathways related to androstenone metabolism in the liver from boars with extreme levels of androstenone in adipose tissue. RESULTS: Liver tissue samples from 58 boars of the two breeds Duroc and Norwegian Landrace, 29 with extreme high and 29 with extreme low levels of androstenone, were selected from more than 2500 individuals. The samples were hybridised to porcine cDNA microarrays and the 1% most significant differentially expressed genes were considered significant. Among the differentially expressed genes were metabolic phase I related genes belonging to the cytochrome P450 family and the flavin-containing monooxygenase FMO1. Additionally, phase II conjugation genes including UDP-glucuronosyltransferases UGT1A5, UGT2A1 and UGT2B15, sulfotransferase STE, N-acetyltransferase NAT12 and glutathione S-transferase were identified. Phase I and phase II metabolic reactions increase the water solubility of steroids and play a key role in their elimination. Differential expression was also found for genes encoding 17beta-hydroxysteroid dehydrogenases (HSD17B2, HSD17B4, HSD17B11 and HSD17B13) and plasma proteins alpha-1-acid glycoprotein (AGP) and orosomucoid (ORM1). 17beta-hydroxysteroid dehydrogenases and plasma proteins regulate the availability of steroids by controlling the amount of active steroids accessible to receptors and available for metabolism. Differences in the expression of FMO1, NAT12, HSD17B2 and HSD17B13 were verified by quantitative real competitive PCR. CONCLUSION: A number of genes and pathways related to metabolism of androstenone in liver were identified, including new candidate genes involved in phase I oxidation metabolism, phase II conjugation metabolism, and regulation of steroid availability. The study is a first step towards a deeper understanding of enzymes and regulators involved in pathways of androstenone metabolism and may ultimately lead to the discovery of markers to reduce boar taint.

Dataset Information

Identification of gene co-expression clusters in liver tissues from multiple porcine populations with high and low backfat androstenone phenotype.

Publications

Identification of gene co-expression clusters in liver tissues from multiple porcine populations with high and low backfat androstenone phenotype.

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