Assessing the Impact of Copy Number Variants on miRNA Genes in Autism by Monte Carlo Simulation

Abstract

Autism Spectrum Disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies have investigated the role of de novo Copy Number Variants (CNVs) and microRNAs as important but distinct etiological factors in ASD. We developed a novel computational procedure to assess the potential pathogenic role of microRNA genes overlapping de novo CNVs in ASD patients. Here we show that for chromosomes # 1, 2 and 22 the actual number of miRNA loci affected by de novo CNVs in patients was found significantly higher than that estimated by Monte Carlo simulation of random CNV events. Out of 24 miRNA genes over-represented in CNVs from these three chromosomes only hsa-mir-4436b-1 and hsa-mir-4436b-2 have not been detected in CNVs from non-autistic subjects as reported in the Database of Genomic Variants. Altogether the results reported in this study represent a first step towards a full understanding of how a dysregulated expression of the 24 miRNAs genes affect neurodevelopment in autism. We also propose that the procedure used in this study can be effectively applied to CNVs/miRNA genes association data in other genomic disorders beyond autism.

MicroRNA and Posttranscriptional Dysregulation in Psychiatry

“…Autistic traits also have been associated with miR-211 deletions and duplications at miRNA Dysregulation in Psychiatry (66). Finally, two groups of investigators used CNV database searches and reported a large number of miRNAs, including miR-211, that overlap with known autism-associated CNVs (67,68). Again, miR-132 has been associated with autism disorders several times, suggesting it could be a particularly important miRNA (Supplement 1).…”

Knowledge-Guided Bioinformatics Model for Identifying Autism Spectrum Disorder Diagnostic MicroRNA Biomarkers

“…and Vaishnavi et al . reported that copy number variants or single nucleotide polymorphisms in miRNAs were correlated with ASD67. Nguyen et al .…”

Ageing and epigenetics: linking neurodevelopmental and neurodegenerative disorders

“…Another neurodevelopmental disorder associated with epigenetic dysregulation related to paternal chromosomal mutations is Rett syndrome caused by MECP2 on the X-chromosome. 9 Such data support a background genetic landscape influencing epigenetic processes, but given the relative fluidity of these processes, the role of environmental factors and how these might impact on neurodevelopment also needs to be considered. Moreover, MECP2 preferentially binds at cytosine-phosphate-guanine sites and silences downstream-regulated genes, but mutated forms are far less effective; they appear to be specifically involved with a neuron-related set of genes and interact with DNA methylation.…”

“…Furthermore, microRNAs are affected more than would be expected in copy-number variation-associated autism spectrum disorder. 9 Such data support a background genetic landscape influencing epigenetic processes, but given the relative fluidity of these processes, the role of environmental factors and how these might impact on neurodevelopment also needs to be considered. In a rat model of cocaine exposure, drug na€ ıve male rats of cocaine-exposed sires have memory formation deficits associated with reduced hippocampal N-methyl-D-aspartate-receptor synaptic plasticity.…”