Effects of genetic variations on microRNA: target interactions.

Chaochun Liu,Jijun Cheng,C Steven Carmack,William A Rennie,Jun Lu,Ye Ding,Shaveta Kanoria

doi:10.1093/nar/gku675

Chaochun Liu, Jijun Cheng + Show 5 more

Open Access

https://doi.org/10.1093/nar/gku675

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Abstract

Genetic variations within microRNA (miRNA) binding sites can affect miRNA-mediated gene regulation, which may lead to phenotypes and diseases. We perform a transcriptome-scale analysis of genetic variants and miRNA:target interactions identified by CLASH. This analysis reveals that rare variants tend to reside in CDSs, whereas common variants tend to reside in the 3′ UTRs. miRNA binding sites are more likely to reside within those targets in the transcriptome with lower variant densities, especially target regions in which nucleotides have low mutation frequencies. Furthermore, an overwhelming majority of genetic variants within or near miRNA binding sites can alter not only the potential of miRNA:target hybridization but also the structural accessibility of the binding sites and flanking regions. These suggest an interpretation for certain associations between genetic variants and diseases, i.e. modulation of miRNA-mediated gene regulation by common or rare variants within or near miRNA binding sites, likely through target structure alterations. Our data will be valuable for discovering new associations among miRNAs, genetic variations and human diseases.

Highlights

Genetic variations within gene regulatory elements may affect gene expression levels in an allele-specific manner and thereby contribute to the variation in complex human phenotypes and diseases
Several studies have systematically identified the genetic variants within human miRNA target sites [16,17,18,19,20,21] and performed part or all of the following analyses: (i) investigation of natural selection via statistical analysis of the frequency of single nucleotide polymorphisms (SNPs) within miRNA seed (2–7 nt) complementary regions, miRNA binding sites and the 3 untranslated regions (3 UTRs) of messenger RNAs (mRNAs) or the entire mRNAs [17,18,19,20,21]; (ii) measurement of the SNP-induced effect on miRNA binding by hybridization energy change [16,17]; and (iii) association of the miRNA-related SNPs with human phenotypes or diseases [16,17,20]
We focus on presenting results using the common minor allele frequencies (MAFs) thresholds of 1% defining common variants and rare variants

Summary

Introduction

Genetic variations within gene regulatory elements may affect gene expression levels in an allele-specific manner and thereby contribute to the variation in complex human phenotypes and diseases. Several studies have systematically identified the genetic variants within human miRNA target sites [16,17,18,19,20,21] and performed part or all of the following analyses: (i) investigation of natural selection via statistical analysis of the frequency of single nucleotide polymorphisms (SNPs) within miRNA seed (2–7 nt) complementary regions, miRNA binding sites and the 3 untranslated regions (3 UTRs) of mRNAs or the entire mRNAs [17,18,19,20,21]; (ii) measurement of the SNP-induced effect on miRNA binding by hybridization energy change [16,17]; and (iii) association of the miRNA-related SNPs with human phenotypes or diseases [16,17,20] For some of these studies, a small fraction of miRNA binding sites were experimentally validated. Common genetic variants have been a focus of disease association studies, some rare variants may have significant impact on an individual’s risk of certain phenotypes

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