CNV-microRNA-target genes interaction network in autism.

<p>Saffron ellipses represent the target genes of miRNAs present in the CNV loci, while miRNAs are denoted by the blue coloured squares. Dashed blue lines represent the predicted interactions and solid black edges represent the validated interactions.</p

The genetic heterogeneity model of ASD.

<p>This figure summarizes the various mechanisms by which the dosage of critical genes involved in autism may be altered thereby contributing to the genetic heterogeneity. To elaborate, individual 1 may harbor CNVs that may cause deletion or duplication of a particular miRNA. In individual 2, the target gene(s) present in the CNV regions might show inverse correlation with the deletion/duplication status of the miRNAs altered in individual 1. In individual 3, some genes may be inactivated by mutation or promoter methylation and certain genes may be over expressed due to loss of miRNA control or increased transcriptional activity. Altered expression of miRNAs may directly affect a transcription factor which in-turn may control the downstream genes, with the phenotypic effect reducing down to those mentioned above.</p

Different modes of repression of target genes caused by miRNAs.

<p>A miRNA can directly repress its target genes or can repress the TF that governs the expression of the miRNA’s targets. In addition, the miRNA can repress the TF as well as its target genes thereby having dual effect on repression of the downstream target genes.</p

Insights on the Functional Impact of MicroRNAs Present in Autism-Associated Copy Number Variants

<div><p>Autism spectrum disorder is a complex neurodevelopmental disorder that appears during the first three years of infancy and lasts throughout a person’s life. Recently a large category of genomic structural variants, denoted as copy number variants (CNVs), were established to be a major contributor of the pathophysiology of autism. To date almost all studies have focussed only on the genes present in the CNV loci, but the impact of non-coding regulatory microRNAs (miRNAs) present in these regions remain largely unexplored. Hence we attempted to elucidate the biological and functional significance of miRNAs present in autism-associated CNV loci and their target genes by using a series of computational tools. We demonstrate that nearly 11% of the CNV loci harbor miRNAs and a few of these miRNAs were previously reported to be associated with autism. A systematic analysis of the CNV-miRNAs based on their interactions with the target genes enabled the identification of top 10 miRNAs namely hsa-miR-590-3p, hsa-miR-944, hsa-miR-570, hsa-miR-34a, hsa-miR-124, hsa-miR-548f, hsa-miR-429, hsa-miR-200b, hsa-miR-195 and hsa-miR-497 as hub molecules. Further, the CNV-miRNAs formed a regulatory loop with transcription factors and their downstream target genes, and annotation of these target genes indicated their functional involvement in neurodevelopment and synapse. Moreover, miRNAs present in deleted and duplicated CNV loci may explain the difference in dosage of the crucial genes controlled by them. These CNV-miRNAs can also impair the global processing and biogenesis of all miRNAs by targeting key molecules in the miRNA pathway. To our knowledge, this is the first report to highlight the significance of CNV-microRNAs and their target genes to contribute towards the genetic heterogeneity and phenotypic variability of autism.</p> </div

Functional annotation of the 326 genes targeted by miRNAs present in autism-associated CNV loci.

<p>The results for each enriched GO categories of the 326 genes targeted by the autism associated CNV-miRNAs are listed in this table. Each GO category belongs to one of the three sub-roots (<i>biological process, molecular function, or cellular component</i>). R is the ratio of enrichment. Adj P – P-value adjusted by multiple testing.</p

The genomic location of autism-associated CNV-microRNAs.

<p>The genomic locations of miRNAs present in the 41 CNV loci consistently associated with autism are indicated with arrow heads. The miRNAs labelled in red, green and black indicate the deleted, duplicated and deleted-duplicated categories, respectively.</p

The top 10 hub molecules in the autism CNV-microRNA-target gene network.

*<p>Only selected targets are shown. For the complete list of target genes, see supporting information <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056781#pone.0056781.s005" target="_blank">Table S5</a>.</p

Intersection analysis of the 326 genes targeted by miRNAs present in CNVs.

<p>The Venn diagram represents the distribution of genes targeted by microRNAs belonging to three CNV categories (deletion, duplication and deletion-duplication). The effect on the dosage/expression status of these genes is described along the sides of the figure with arrow mark indications.</p

Normalized density distribution of autism-associated CNVs across human chromosomes.

<p>The normalized CNV density is plotted in y-axis against the chromosomes in x-axis. For any given chromosome, a value above 1 indicates that it has accumulated more number of autism-associated CNVs compared to the mean of all chromosomal CNV densities. The error bars indicate the standard deviation.</p

CNV-miRNAs and their target genes involved in the microRNA processing and biogenesis pathways.

<p>Saffron ellipses represent the key components involved in miRNA processing and biogenesis, while miRNAs are denoted by the blue coloured squares. Dashed lines represent the validated interactions between the genes and CNV-miRNAs.</p