Genetic architecture modulates diet-induced hepatic mRNA and miRNA expression profiles in Diversity Outbred mice

Authors: Que, Excel; JAMES, KRISTEN - University Of California, Davis; COFFEY, ALISHA - University Of North Carolina; SMALLWOOD, TANGI - University Of North Carolina; ALBRIGHT, JODY - North Carolina State University; POMP, DANIEL - University Of North Carolina; SETHUPATHY, PRAVEEN - Cornell University; Bennett, Brian

Submitted to: Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/27/2020
Publication Date: 9/1/2020
Citation: Que, E.S., James, K.L., Coffey, A., Smallwood, T.L., Albright, J., Pomp, D., Sethupathy, P., Bennett, B.J. 2020. Genetic architecture modulates diet-induced hepatic mRNA and miRNA expression profiles in Diversity Outbred mice. Genetics. 216(1):241-259. https://doi.org/10.1534/genetics.120.303481.
DOI: https://doi.org/10.1534/genetics.120.303481

Interpretive Summary: Alterations in diet can affect the expression of genes and the expression of genes is known to be affected by one’s genetics. What isn’t clear is how genetics interacts with diet to affect the expression of genes. Here we perform global genetic analysis in a population of Diversity Outbred (DO) mice fed two different diets. We identified several key features of genetic architecture, and focus on 2 types of RNA, messenger RNA (mRNA) and microRNA (miRNA). mRNA are regulated by genetic variants close to their physical location in approximately 50% of occurrences while mirRNA are less frequently regulated by genetic variants near their location, ~25% occurrences. Detailed analysis describes the general amount of variation explained by genetics for each miRNA and mRNA detected and the overall effect size of an individual variant on a miRNA or mRNA. We highlight how diet affects each of these parameters. 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.

Technical 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 perform global 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 regulations (cis/trans) between mRNA and miRNA. mirQTL are regulated by a trans-acting factor in approximately 50% of mirQTL occurrences while eQTL for mRNA are less frequently trans-acting, only ~25% of eQTL occurrences. 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, investigate the effect of diet on the genetic architecture of eQTL and mirQTL which highlight the critical effects the environment has 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.