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Pathway based analysis of genes and interactions influencing porcine testis samples from boars with divergent androstenone content in back fat.

ABSTRACT: One of the primary factors contributing to boar taint is the level of androstenone in porcine adipose tissues. A majority of the studies performed to identify candidate biomarkers for the synthesis of androstenone in testis tissues follow a reductionist approach, identifying and studying the effect of biomarkers individually. Although these studies provide detailed information on individual biomarkers, a global picture of changes in metabolic pathways that lead to the difference in androstenone synthesis is still missing. The aim of this work was to identify major pathways and interactions influencing steroid hormone synthesis and androstenone biosynthesis using an integrative approach to provide a bird's eye view of the factors causing difference in steroidogenesis and androstenone biosynthesis. For this purpose, we followed an analysis procedure merging together gene expression data from boars with divergent levels of androstenone and pathway mapping and interaction network retrieved from KEGG database. The interaction networks were weighted with Pearson correlation coefficients calculated from gene expression data and significant interactions and enriched pathways were identified based on these networks. The results show that 1,023 interactions were significant for high and low androstenone animals and that a total of 92 pathways were enriched for significant interactions. Although published articles show that a number of these enriched pathways were activated as a result of downstream signaling of steroid hormones, we speculate that the significant interactions in pathways such as glutathione metabolism, sphingolipid metabolism, fatty acid metabolism and significant interactions in cAMP-PKA/PKC signaling might be the key factors determining the difference in steroidogenesis and androstenone biosynthesis between boars with divergent androstenone levels in our study. The results and assumptions presented in this study are from an in-silico analysis done at the gene expression level and further laboratory experiments at genomic, proteomic or metabolomic level are necessary to validate these findings.

SUBMITTER: Sahadevan S

PROVIDER: S-EPMC3948775 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Pathway based analysis of genes and interactions influencing porcine testis samples from boars with divergent androstenone content in back fat.

Sahadevan Sudeep S Gunawan Asep A Tholen Ernst E Große-Brinkhaus Christine C Tesfaye Dawit D Schellander Karl K Hofmann-Apitius Martin M Cinar Mehmet Ulas MU Uddin Muhammad Jasim MJ

PloS one 20140310 3

One of the primary factors contributing to boar taint is the level of androstenone in porcine adipose tissues. A majority of the studies performed to identify candidate biomarkers for the synthesis of androstenone in testis tissues follow a reductionist approach, identifying and studying the effect of biomarkers individually. Although these studies provide detailed information on individual biomarkers, a global picture of changes in metabolic pathways that lead to the difference in androstenone ...[more]

PMID: 24614349

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Project description:BACKGROUND: Androstenone is one of the major compounds responsible for boar taint, a pronounced urine-like odor produced when cooking boar meat. Several studies have identified quantitative trait loci (QTL) for androstenone level on Sus scrofa chromosome (SSC) 6. For one of the candidate genes in the region SULT2A1, a difference in expression levels in the testis has been shown at the protein and RNA level. RESULTS: Haplotypes were predicted for the QTL region and their effects were estimated showing that haplotype 1 was consistently related with a lower level, and haplotype 2 with a higher level of androstenone. A recombinant haplotype allowed us to narrow down the QTL region from 3.75 Mbp to 1.94 Mbp. An RNA-seq analysis of the liver and testis revealed six genes that were differentially expressed between homozygotes of haplotypes 1 and 2. Genomic sequences of these differentially expressed genes were checked for variations within potential regulatory regions. We identified one variant located within a CpG island that could affect expression of SULT2A1 gene. An allele-specific expression analysis in the testis did not show differential expression between the alleles of SULT2A1 located on the different haplotypes in heterozygous animals. However a synonymous mutation C166T (SSC6: 49,117,861 bp in Sscrofa 10.2; C/T) was identified within the exon 2 of SULT2A1 for which the haplotype 2 only had the C allele which was higher expressed than the T allele, indicating haplotype-independent allelic-imbalanced expression between the two alleles. A phylogenetic analysis for the 1.94 Mbp region revealed that haplotype 1, associated with low androstenone level, originated from Asia. CONCLUSIONS: Differential expression could be observed for six genes by RNA-seq analysis. No difference in the ratio of C:T expression of SULT2A1 for the haplotypes was found by the allele-specific expression analysis, however, a difference in expression between the C over T allele was found for a variation within SULT2A1, showing that the difference in androstenone levels between the haplotypes is not caused by the SNP in exon 2.

Project description:Boar taint is an offensive odour and flavour from developed in a proportion of non-castrated male pigs (boars). Surgical castration is an effective solution but is under debate due to animal welfare concerns. Gene-based selection for low boar taint has been proposed as concentrations of the main compounds responsible for boar taint (androstenone, skatole and indole [ASI]) exhibit heritability but candidate biomarkers are lacking. The aims of this study were to identify expression quantitative trait loci (eQTLs) associated with ASI in order to aid development of candidate biomarkers and to generate insights into biological pathways. Gene expression profiles were obtained by RNA-Seq from testis of Danish Duroc × Landrace/Yorkshire boars fed either a control or chicory-added diet and genotyping was conducted with a high density SNP panel. A tendency (P = 0.052) of lowered ASI concentrations was found in the chicory group. Furthermore, a high correlation was found between estimated breeding values (EBVs) of androstenone and androstenone concentrations (r2 = 0.48). A total of 213 eQTLs, representing 125 unique genes including MVP, COX1, MAP2K4 and RDH16, contained genotypes associated with summed ASI concentrations and of these, six genes were also differentially expressed across ASI/diet groups. The genes were functionally associated with membrane localised proteins, extracellular exosomes, ATP binding, MAPK cascade and oxidative stress. The highest densities of the eQTLs were on pig chromosomes (SSC) SSC18, SSC12, SSC2, SSC7 and SSC14, in that order. A total of 42 known porcine traits were enriched by the genomic coordinates, including health, meat quality and one reproduction trait. A total of 33 candidate eQTLs enriched known genomic coordinates for androstenone and odour intensity in fat. Our findings suggests that careful monitoring of important productions parameters is necessary, if gene-based selection is performed with markers located within the genomic coordinates of the candidate eQTLs or the eQTLs themselves.

Project description:BACKGROUND: Boar taint is a major obstacle when using uncastrated male pigs for swine production. One of the main compounds causing this taint is androstenone, a pheromone produced in porcine testis. Here we use microarrays to study the expression of thousands of genes simultaneously in testis of high and low androstenone boars. The study allows identification of genes and pathways associated with elevated androstenone levels, which is essential for recognising potential molecular markers for breeding purposes. RESULTS: Testicular tissue was collected from 60 boars, 30 with extreme high and 30 with extreme low levels of androstenone, from each of the two breeds Duroc and Norwegian Landrace. The samples were hybridised to porcine arrays containing 26,877 cDNA clones, detecting 563 and 160 genes that were differentially expressed (p < 0.01) in Duroc and Norwegian Landrace, respectively. Of these significantly up- and down-regulated clones, 72 were found to be common for the two breeds, suggesting the possibility of both general and breed specific mechanisms in regulation of, or response to androstenone levels in boars. Ten genes were chosen for verification of expression patterns by quantitative real competitive PCR and real-time PCR. As expected, our results point towards steroid hormone metabolism and biosynthesis as important biological processes for the androstenone levels, but other potential pathways were identified as well. Among these were oxidoreductase activity, ferric iron binding, iron ion binding and electron transport activities. Genes belonging to the cytochrome P450 and hydroxysteroid dehydrogenase families were highly up-regulated, in addition to several genes encoding different families of conjugation enzymes. Furthermore, a number of genes encoding transcription factors were found both up- and down-regulated. The high number of clones belonging to ferric iron and iron ion binding suggests an importance of these genes, and the association between these pathways and androstenone levels is not previously described. CONCLUSION: This study contributes to the understanding of the complex genetic system controlling and responding to androstenone levels in pig testis. The identification of new pathways and genes involved in the biosynthesis and metabolism of androstenone is an important first step towards finding molecular markers to reduce boar taint.

Project description:BackgroundBoar taint is an unpleasant odor and flavor of the meat and occurs in a high proportion of uncastrated male pigs. Androstenone, a steroid produced in testis and acting as a sex pheromone regulating reproductive function in female pigs, is one of the main compounds responsible for boar taint. The primary goal of the present investigation was to determine the differential gene expression of selected candidate genes related to levels of androstenone in pigs.ResultsAltogether 2560 boars from the Norwegian Landrace and Duroc populations were included in this study. Testicle samples from the 192 boars with most extreme high or low levels of androstenone in fat were used for RNA extraction, and 15 candidate genes were selected and analyzed by real-competitive PCR analysis. The genes Cytochrome P450 c17 (CYP17A1), Steroidogenic acute regulatory protein (STAR), Aldo-keto reductase family 1 member C4 (AKR1C4), Short-chain dehydrogenase/reductase family member 4 (DHRS4), Ferritin light polypeptide (FTL), Sulfotransferase family 2A, dehydroepiandrosterone-preferring member 1 (SULT2A1), Cytochrome P450 subfamily XIA polypeptide 1 (CYP11A1), Cytochrome b5 (CYB5A), and 17-beta-Hydroxysteroid dehydrogenase IV (HSD17B4) were all found to be significantly (P < 0.05) up-regulated in high androstenone boars in both Duroc and Landrace. Furthermore, Cytochrome P450 c19A2 (CYP19A2) was down-regulated and progesterone receptor membrane component 1 (PGRMC1) was up-regulated in high-androstenone Duroc boars only, while CYP21 was significantly down-regulated (2.5) in high-androstenone Landrace only. The genes Nuclear Receptor co-activator 4 (NCOA4), Sphingomyrlin phosphodiesterase 1 (SMPD1) and 3beta-hydroxysteroid dehydrogenase (HSD3B) were not significantly differentially expressed in any breeds. Additionally, association studies were performed for the genes with one or more detected SNPs. Association between SNP and androstenone level was observed in CYB5A only, suggesting cis-regulation of the differential transcription in this gene.ConclusionA large pig material of highly extreme androstenone levels is investigated. The current study contributes to the knowledge about which genes that is differentially expressed regard to the levels of androstenone in pigs. Results in this paper suggest that several genes are important in the regulation of androstenone level in boars and warrant further evaluation of the above mentioned candidate genes, including analyses in different breeds, identification of causal mutations and possible gene interactions.

Dataset Information

Pathway based analysis of genes and interactions influencing porcine testis samples from boars with divergent androstenone content in back fat.

Publications

Pathway based analysis of genes and interactions influencing porcine testis samples from boars with divergent androstenone content in back fat.

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