MiRNA and miRNA target genes in copy number variations occurring in individuals with intellectual disability

Ying Qiao,Evica Rajcan-Separovic,Eloi Mercier,Paul Pavlidis,Suzanne Me Lewis,Chansonette Badduke

doi:10.1186/1471-2164-14-544

Abstract

BackgroundMicroRNAs (miRNAs) are a family of short, non-coding RNAs modulating expression of human protein coding genes (miRNA target genes). Their dysfunction is associated with many human diseases, including neurodevelopmental disorders. It has been recently shown that genomic copy number variations (CNVs) can cause aberrant expression of integral miRNAs and their target genes, and contribute to intellectual disability (ID).ResultsTo better understand the CNV-miRNA relationship in ID, we investigated the prevalence and function of miRNAs and miRNA target genes in five groups of CNVs. Three groups of CNVs were from 213 probands with ID (24 de novo CNVs, 46 familial and 216 common CNVs), one group of CNVs was from a cohort of 32 cognitively normal subjects (67 CNVs) and one group of CNVs represented 40 ID related syndromic regions listed in DECIPHER (30 CNVs) which served as positive controls for CNVs causing or predisposing to ID. Our results show that 1). The number of miRNAs is significantly higher in de novo or DECIPHER CNVs than in familial or common CNV subgroups (P < 0.01). 2). miRNAs with brain related functions are more prevalent in de novo CNV groups compared to common CNV groups. 3). More miRNA target genes are found in de novo, familial and DECIPHER CNVs than in the common CNV subgroup (P < 0.05). 4). The MAPK signaling cascade is found to be enriched among the miRNA target genes from de novo and DECIPHER CNV subgroups.ConclusionsOur findings reveal an increase in miRNA and miRNA target gene content in de novo versus common CNVs in subjects with ID. Their expression profile and participation in pathways support a possible role of miRNA copy number change in cognition and/or CNV-mediated developmental delay. Systematic analysis of expression/function of miRNAs in addition to coding genes integral to CNVs could uncover new causes of ID.

Highlights

MicroRNAs are a family of short, non-coding RNAs modulating expression of human protein coding genes
Our findings reveal an increase in Micro RNA (miRNA) and miRNA target gene content in de novo versus common copy number variations (CNVs) in subjects with intellectual disability (ID)
CNV detection and sub-classification Initially, we identified 24 de novo, 46 familial and 216 common CNVs from 213 cases with idiopathic ID, 67 common CNVs from 32 cognitively normal subjects, and 30 CNVs collected from 40 ID-related syndromic regions in DECIPHER database representing CNVs known to cause or predispose to developmental delay

Summary

Introduction

MicroRNAs (miRNAs) are a family of short, non-coding RNAs modulating expression of human protein coding genes (miRNA target genes). Their dysfunction is associated with many human diseases, including neurodevelopmental disorders. MicroRNAs (miRNAs) are an abundant class of short, non-coding, endogenous RNAs that regulate gene expression at the post-transcriptional level [1,2]. Single nucleotide polymorphisms (SNPs) in miRNA binding sequences have been shown to affect miRNA-mediated gene regulation and alter the expression of target genes [7]. The number of miRNA target genes in polymorphic CNVs is higher than in non-CNV regions, suggesting that genes integral to polymorphic CNVs are more likely to be regulated by miRNAs, in order to counteract their expression changes due to copy number variability of the region in which they reside [9]. Multiple cancer studies show that miRNAs integral to CNVs demonstrate gain or loss at the genomic level, and are associated with expression changes for ~10% -20% miRNAs [11,12]

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