TBR1 regulates autism risk genes in the developing neocortex
- James H. Notwell1,
- Whitney E. Heavner2,3,
- Siavash Fazel Darbandi4,
- Sol Katzman5,
- William L. McKenna6,
- Christian F. Ortiz-Londono6,
- David Tastad6,
- Matthew J. Eckler6,
- John L.R. Rubenstein4,
- Susan K. McConnell3,
- Bin Chen6 and
- Gill Bejerano1,2,7
- 1Department of Computer Science, Stanford University, Stanford, California 94305, USA;
- 2Department of Developmental Biology, Stanford University, Stanford, California 94305, USA;
- 3Department of Biology, Stanford University, Stanford, California 94305, USA;
- 4Department of Psychiatry, University of California, San Francisco, San Francisco, California 94143, USA;
- 5Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, California 95064, USA;
- 6Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California 95064, USA;
- 7Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, California 94305, USA
- Corresponding authors: bejerano{at}stanford.edu, bchen{at}ucsc.edu
Abstract
Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the nine ASD genes examined, seven were misexpressed in the cortices of Tbr1 knockout mice, including six with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.203612.115.
- Received December 20, 2015.
- Accepted June 17, 2016.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
