Autism and Increased Paternal Age Related Changes in Global Levels of Gene Expression Regulation

Mark D Alter,Theresa A Grebe,Keri E Ramsey,Dietrich A Stephan,Rene Hen,Josh J Jones,Raun D Melmed,Sharman Ober-Reynolds,J Blake Turner,David W Craig,R Curtis Bay,Rutwik Kharkar,Janet Kirwan,Joanna Bridger

doi:10.1371/journal.pone.0016715

Abstract

A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.

Highlights

Autism is a severe neurodevelopmental disorder with characteristic social and communication deficits and ritualistic or repetitive behaviors that appear by age three
Measurement of the variance in the distribution of gene expression levels assessed for differences at the global level of gene expression regulation
Because changes in a limited number of genes could not account for a change in the shape of the entire gene expression distribution, changes in variance suggest alterations at global levels of gene expression regulation

Summary

Introduction

Autism is a severe neurodevelopmental disorder with characteristic social and communication deficits and ritualistic or repetitive behaviors that appear by age three. The failure to identify specific gene variants for most cases of autism has been attributed to many potential factors including complex interactions of multiple genes, a heterogeneous disorder with multiple causes converging on the autistic phenotype, or epigenetic factors not related to specific genetic mutations or polymorphisms [2,3]. Valproate can adversely impact neurodevelopment in rodents and cause autism in humans [10,11,12,13] Both genetic and pharmacological studies suggest alterations in global levels of gene expression regulation can interfere with normal neurodevelopment. Additional studies of various HDAC inhibitors in rodents have shown that HDAC inhibitors may act by altering levels of synaptic plasticity and in this context HDAC inhibitors have been used to modify learning, memory, and emotional behavior underscoring the potentially pleiotropic effects of targeting global levels of gene expression regulation [14,15,16,17,18,19]

Methods

Results

Conclusion