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Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism

Molecular Psychiatry volume 18, pages 1054–1056 (2013)Cite this article

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Four recent studies of the coding regions of the human genome (the ‘exome’), suggest that new (de novo) mutations in hundreds of genes may contribute to the risk of autism spectrum disorder (ASD).1, 2, 3, 4 While the experimental strategy in the different efforts is almost identical, the four studies were published independently, and no integrative analysis has yet been reported. Notably, limited conclusions regarding the specific systems of genes disrupted by de novo mutations can be drawn based on each study alone. This stems from the relatively small fraction of mutations identified in each study in which there is a clear functional phenotype at the protein level. Here we show that upon combining the evidence from the different studies and integrating it with gene expression data from the developing human brain, a large group of genes emerges that is involved in regulation of expression during prenatal brain development. This suggests a prominent role in ASD for the genes involved in transcription regulation during brain development, specifically chromatin regulators.

We analyzed the complete collection of de novo single-nucleotide variations (SNVs) that were identified in 965 probands, sequenced in the four studies.1, 2, 3, 4 We gathered 121 genes that are most likely to be disrupted, containing de novo SNVs, which are nonsense, frameshift or splice site mutations. To characterize the genes, we first analyzed the enrichment of cellular processes and gene ontology (GO), using the Database for Annotation, Visualization and Integrated Discovery (DAVID). We found a significant enrichment for ‘chromatin regulator’ (UniProtKB; corrected P=0.021; Enrichment Score=2.04). Among the genes in this category, the chromatin remodeling gene CHD8 harbored two mutations in separate individuals (a frameshift and a nonsense mutation).

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Acknowledgements

This research was supported by a grant from the National Institute for Psychobiology in Israel.

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  1. Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

    E Ben-David & S Shifman

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  1. E Ben-David
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  2. S Shifman
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Correspondence to S Shifman.

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Ben-David, E., Shifman, S. Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. Mol Psychiatry 18, 1054–1056 (2013). https://doi.org/10.1038/mp.2012.148

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