RETRACTED: Genetic Architecture Modulates Diet-Induced Hepatic mRNA and miRNA Expression Profiles in Diversity Outbred Mice

Abstract

Genetic approaches in model organisms have consistently demonstrated that molecular traits such as gene expression are under genetic regulation, similar to clinical traits. The resulting expression quantitative trait loci (eQTL) have revolutionized our understanding of genetic regulation and identified numerous candidate genes for clinically-relevant traits. More recently, these analyses have been extended to other molecular traits such as protein abundance, metabolite levels, and miRNA expression. Here we performed global hepatic eQTL and miRNA expression quantitative trait loci (mirQTL) analysis in a population of Diversity Outbred (DO) mice fed two different diets. We identified several key features of eQTL and mirQTL, namely differences in the mode of genetic regulation (cis or trans) between mRNA and miRNA. Approximately 50% of mirQTL are regulated by a trans-acting factor compared to ~25% of eQTL. We note differences in the heritability of mRNA and miRNA expression and variance explained by each eQTL or mirQTL. In general, cis-acting variants affecting mRNA or miRNA expression explain more phenotypic variance than trans-acting variants. Lastly, we investigated the effect of diet on the genetic architecture of eQTL and mirQTL highlighting the critical effects of environment on both eQTL and mirQTL. Overall, these data underscore the complex genetic regulation of two well-characterized RNA classes (mRNA and miRNA) that have critical roles in the regulation of clinical traits and disease susceptibility.

Altered macronutrient composition and genetics influence the complex transcriptional network associated with adiposity in the Collaborative Cross

“…Probes and transcript cluster IDs (TC IDs) were first filtered as described [70], resulting in the total number of 24,004 unique probes post-filter corresponding to 23,626 genes. Next, TC IDs were kept for analysis if their median expression was above the mean of all TC ID medians or if their median expression was above the mean of all TC ID medians in over 12.5% of samples, based on the assumption that by chance, one of the 8 founders may be contributing low/no expression alleles.…”

“…Module eigengenes were calculated, and Spearman's correlations were performed between module eigengenes and measured phenotypes. KEGG pathway enrichment and gene ontology analyses were performed on genes within each module using Enrichr as described [70] to see which modules contained genes associated with biological function or diseases. Cytoscape [77] was used to generate a visualization of the relationship between genes within a module, using the magenta module as an example.…”

Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross

“…The genetic and phenotypic diversity of the combined eight founder strains is similar to the interindividual diversity of the human population. The utilization of the genomic sequence of the eight CC founder strains provides an unprecedented unique resource for genetic mapping and correlation studies (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) Here, we evaluate the variability of metabolic traits and perform global liver transcriptomics from the eight CC founder strains fed a standard purified diet or an atherogenic diet. Our studies focus on female mice as a number of studies have reported that female mice are generally more susceptible to atherosclerosis than male mice (30,32,(35)(36)(37)(38).…”