Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

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

Subjects

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).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J et al. De novo gene disruptions in children on the autistic spectrum. Neuron 2012; 74: 285–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012; 485: 242–245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012; 485: 246–250.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485: 237–241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 2012; 337: 64–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kang HJ, Kawasawa YI, Cheng F, Zhu Y, Xu X, Li M et al. Spatio-temporal transcriptome of the human brain. Nature 2011; 478: 483–489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yoo AS, Crabtree GR . ATP-dependent chromatin remodeling in neural development. Curr Opin Neurobiol 2009; 19: 120–126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kleefstra T, Kramer JM, Neveling K, Willemsen MH, Koemans TS, Vissers LE et al. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am J Hum Genet 2012; 91: 73–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

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

    E Ben-David & S Shifman

Authors
  1. E Ben-David
    View author publications

    Search author on:PubMed Google Scholar

  2. S Shifman
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to S Shifman.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/mp.2012.148

This article is cited by

Search

Advanced search

Quick links