Predictive modeling of miRNA-mediated predisposition to alcohol-related phenotypes in mouse

Pratyaydipta Rudra,Wen J Shi,Pamela Russell,Katerina Kechris,Paula Hoffman,Boris Tabakoff,Laura Saba,Brian Vestal

doi:10.1186/s12864-018-5004-3

Abstract

BackgroundMicroRNAs (miRNAs) are small non-coding RNAs that bind messenger RNAs and promote their degradation or repress their translation. There is increasing evidence of miRNAs playing an important role in alcohol related disorders. However, the role of miRNAs as mediators of the genetic effect on alcohol phenotypes is not fully understood. We conducted a high-throughput sequencing study to measure miRNA expression levels in alcohol naïve animals in the LXS panel of recombinant inbred (RI) mouse strains. We then combined the sequencing data with genotype data, microarry gene expression data, and data on alcohol-related behavioral phenotypes such as ’Drinking in the dark’, ’Sleep time’, and ’Low dose activation’ from the same RI panel. SNP-miRNA-gene triplets with strong association within the triplet that were also associated with one of the 4 alcohol phenotypes were selected and a Bayesian network analysis was used to aggregate results into a directed network model.ResultsWe found several triplets with strong association within the triplet that were also associated with one of the alcohol phenotypes. The Bayesian network analysis found two networks where a miRNA mediates the genetic effect on the alcohol phenotype. The miRNAs were found to influence the expression of protein-coding genes, which in turn influences the quantitative phenotypes. The pathways in which these genes are enriched have been previously associated with alcohol-related traits.ConclusionThis work enhances association studies by identifying miRNAs that may be mediating the association between genetic markers (SNPs) and the alcohol phenotypes. It suggests a mechanism of how genetic variants are affecting traits of interest through the modification of miRNA expression.

Highlights

MicroRNAs are small non-coding RNAs that bind messenger RNAs and promote their degradation or repress their translation
Low dose activation (LDA) is negatively correlated with the expression of the gene Ano5 (Anoctamin 5) and the miRNA miR-7057-5p, and positively associated with the Inbred short sleep (ISS) allele (Fig. 3a)
Loss of righting reflex (LORR) is negatively correlated with the expression of the gene Terf2 (Telomeric repeat binding factor 2) and the ISS allele, but positively correlated with the novel miRNA (Fig. 3b)

Summary

Introduction

MicroRNAs (miRNAs) are small non-coding RNAs that bind messenger RNAs and promote their degradation or repress their translation. There is increasing evidence of miRNAs playing an important role in alcohol related disorders. Non-coding RNAs are defined as biologically functional RNAs that are not translated into proteins They have a variety of functions including the regulation of the expression of protein coding genes. MicroRNAs (miRNA) are small non-coding RNAs that bind messenger RNAs (mRNA) and promote degradation or repress translation by post-transcriptional silencing of the target mRNA [1]. The influence of genetic background on alcohol-related traits, shown by several behavioral Quantitative Trait Loci (bQTL) studies [10, 11], and on miRNA expression shown

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Discussion

Conclusion