Random or stochastic monoallelic expressed genes are enriched for neurodevelopmental disorder candidate genes.

Aaron R Jeffries,Sarah Curran,David A Collier,Caroline M Ogilvie,Evangelos Vassos,Jack Price,Michael Edward Zwick

doi:10.1371/journal.pone.0085093

Abstract

Random or stochastic monoallelic expressed genes (StMA genes) represent a unique form of monoallelic expression where allelic choice is made at random early in development. The consequential clonal diversity provides opportunity for functional heterozygosity in tissues such as the brain, and can impact on both development and disease. We investigate the relationship of StMA expressed genes previously identified in clonal neural stem cells with the neurodevelopmental disorders autism and schizophrenia. We found that StMA genes show an overrepresentation of schizophrenia risk candidates identified by genome wide association studies from the genetic association database. Similar suggestive enrichment was also found for genes from the NHGRI genome-wide association study catalog and a psychiatric genetics consortium schizophrenia dataset although these latter more robust gene lists did not achieve statistical significance. We also examined multiple sources of copy number variation (CNV) datasets from autism and schizophrenia cohorts. After taking into account total gene numbers and CNV size, both autism and schizophrenia associated CNVs appeared to show an enrichment of StMA genes relative to the control CNV datasets. Since the StMA genes were originally identified in neural stem cells, bias due to the neural transcriptome is possible. To address this, we randomly sampled neural stem cell expressed genes and repeated the tests. After a significant number of iterations, neural stem cell expressed genes did not show an overrepresentation in autism or schizophrenia CNV datasets. Therefore, irrespective of the neural derived transcriptome, StMA genes originally identified in neural stem cells show an overrepresentation in CNVs associated with autism and schizophrenia. If this association is functional, then the regulation (or dysregulation) of this form of allelic expression status within tissues such as the brain may be a contributory risk factor for neurodevelopmental disorders and may also influence disease discordance sometimes observed in monozygotic twins.

Highlights

Several forms of monoallelic gene expression have been identified
While the exact impact stochastic monoallelic expression has on development is unclear, our study of allelic expression in human neural stem cells identified a number of neurodevelopmental genes showing this form of allelic expression control [5]
We have demonstrated an associative link of neural stem cell identified stochastic monoallelic choice (StMA) genes with autism and schizophrenia GWAS and copy number variation (CNV) identified genes

Summary

Introduction

Several forms of monoallelic gene expression have been identified. Imprinting, a form of monoallelic gene expression based on parent-of-origin effects, is highly represented in the brain transcriptome [1], and several neurodevelopmental disorders are associated with the disruption of imprinted genes. Monoallelic expression of specific disease candidate genes has been observed in a small number of autism patient samples [3,4]. Another form of monoallelic gene expression, identified by global allelic expression profiling of clonal cell lines, is random or stochastic monoallelic choice (StMA), where the expressed allele within a cell is selected at random early in development and maintained in subsequent cellular progeny [5,6]. We asked whether stochastic monoallelic expressed genes have any potential significance as a risk factor in the neurodevelopmental disorders, autism and schizophrenia

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Results

Conclusion