Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model

Abstract

This article is available online at http://www.jlr.org lated to body composition, leanness, and obesity. Traits related to fatness are important not only as economic factors in pork production but also because of their association with serious diseases in humans ( 1, 2 ). Pigs share many similarities with humans in physiology and genomes and, therefore, provide a good model to study the genetic determination of complex traits ( 3 ). The study of a porcine model is benefi cial because a number of fatness traits (e.g., "fat area") can be determined quantitatively with great accuracy and reproducibility post mortem, and RNA samples are available for transcriptomic approaches. In humans, indices for obesity are obtained intra vitam (i.e., body mass index or body fat percentage are estimated based on statistical models of measures of near-infrared interactance, body average density measurement, bioelectrical impedance analysis, or anthropometric methods) ( 4 ).Functional genomics provides an insight into the molecular processes underlying phenotypic differences. The analysis of trait-correlated expression levels reveals genes belonging to pathways or networks relevant for the control of quantitative traits. However, holistic expression profi ling does not often discriminate differential expression of the genes as either an effect or a cause of variation.Genome-wide association studies (GWAS) in large natural populations of unrelated individuals have resulted in the association of many genes with complex traits (http:// www. genome.gov/gwastudies). Unfortunately, for a conAbstract Traits related to fatness, important as economic factors in pork production, are associated with serious diseases in humans. Genetical genomics is a useful approach for studying the effects of genetic variation at the molecular level in biological systems. Here we applied a whole-genome association analysis to hepatic gene expression traits, focusing on transcripts with expression levels that correlated with fatness traits in a porcine model. A total of 150 crossbred pigs [Pietrain×(German Large White × German Landrace)] were studied for transcript levels in the liver. The 24K Affymetrix expression microarrays and 60K Illumina single nucleotide polymorphism (SNP) chips were used for genotyping. A total of 663 genes, whose expression signifi cantly correlated with the trait "fat area," were analyzed for enrichment of functional annotation groups as defi ned in the Ingenuity Pathways Knowledge Base (IPKB). Genes involved in metabolism of various macromolecules and nutrients as well as functions related to dynamic cellular processes correlated with fatness traits. Regions affecting the transcription levels of these genes were mapped and revealed 4,727 expression quantitative trait loci (eQTL) at P < 10 The metabolic activities of the liver are essential for providing fuel to the peripheral organs. Most components absorbed by the intestine pass through the liver, which enables it to regulate the levels of many metabolites in the blood. Storage, ...

Genetically regulated hepatic transcripts and pathways orchestrate haematological, biochemical and body composition traits

“…We observed a highly significant enrichment of transcripts associated with LXR/RXR, PXR/RXR and FXR/RXR activation among those transcripts correlated with biochemical and body composition traits, consistent with a previous study on liver expression relation to body composition in other pig breeds6. These pathways play an important regulatory role in the metabolism of carbohydrates, fatty acids and cholesterol60.…”

“…Knowledge of the position of the analyzed genes and markers enables the differentiation of cis- and trans-eQTLs4. We have previously shown that the detection of trait-dependent expressed genes in a relevant tissue facilitates the identification of genes associated with complex traits, such as muscle and meat properties and coping behaviors; these genes represent strong candidate genes56. Studies of eQTLs in the human liver have led to the identification of genes associated with clinical phenotypes and provide a foundation for pharmacogenomics7.…”

Developmental Stage, Muscle and Genetic Type Modify Muscle Transcriptome in Pigs: Effects on Gene Expression and Regulatory Factors Involved in Growth and Metabolism

“…In agreement, biological functions related to glucose metabolism and lipid accumulation, as concentration of lipid , concentration of fatty acid and concentration of triacylglycerol (Fig 4), were enriched in growing IB pigs. Moreover, the LPS/IL-1 Mediated Inhibition of RXR pathway, enriched in those pigs was reported to positively correlate with fat area [85]. …”

Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues

“…37 It has been reported that the reduction of proteins related to the LPS/IL-1–mediated inhibition of RXR function pathway can lead to impaired metabolism, transport or biosynthesis of lipid, cholesterol, bile acid, and xenobiotics. 38,39 In APAs, genes related to this pathway were mainly upregulated, suggesting perhaps a role in the metabolism, transport, and biosynthesis of cholesterol, a key precursor of aldosterone. On the contrary, genes associated with this pathway were downregulated in ZG (Table S16), suggesting decrease of corticosteroid synthesis, which is in agreement with our previous finding of ZG selective genes regulating aldosterone negatively and the low patchy staining of CYP11B2 in ZG.…”