Molecular signatures of autism genes and 16p11.2 deletion

  • Awarded: 2012
  • Award Type: Research
  • Award #: 240021

Mutation in many different genes has been found in individuals with autism, suggesting that there are many different ways to trigger the disorder. James Gusella and his colleagues previously found a number of autism genes whose normal function involves regulating the expression of other genes1,2. This finding led them to consider that some effects of inactivating mutations in different autism genes might produce overlapping changes in overall gene expression. In this way, quite different genetic mutations might lead to autism by disrupting the same neurodevelopmental mechanisms.

Gusella and his group tested this possibility in two ways, using mRNA sequencing to simultaneously measure expression of all human genes. First they compared the effects of chromosomal region 16p11.2 deletion, 16p11.2 duplication and controls on gene expression, using human cell lines and brain tissue from mice in which the mutations had been engineered3. The researchers found the expected change in the level of expression of genes within the deletion or duplication region but also observed that these mutations caused changes in expression of genes elsewhere in the genome. The genes whose expression was changed included a number of known autism genes, suggesting disruption of an interconnected autism network of gene expression.

Second, in human neural progenitor cells, Gusella and his team specifically reduced the expression of CHD8 to mimic the effects of inactivating one copy of this well-established autism gene, which has also been implicated in cancer4.

Because the CHD8 protein’s function in regulating gene expression involves binding to chromatin at specific sites in the genome, the researchers mapped out these sites to compare them with the locations of genes showing altered expression. This comparison revealed that the subset of genes without CHD8 binding sites whose expression was reduced indirectly by decreasing CHD8 levels was highly enriched in genes previously implicated in autism. Genes that bound CHD8 but did not show altered expression were also mildly enriched for a second set of autism genes, which were identified by discovery of a new inactivating mutation in individuals with autism.

Cancer genes were highly enriched among genes that bound CHD8, particularly the subset whose expression was upregulated due to reducing CHD8 levels. In subsequent comparisons with suppression of two other autism genes, TCF4 and SATB2, Gusella and his group further demonstrated the network interconnectedness of these and other autism genes, along with several 16p11.2 genes.

Their findings support the view that different autism genes converge on a limited array of mechanisms to disrupt normal neurodevelopment.



1.Talkowski M.E. et al. Am. J. Hum. Genet. 89, 551-563 (2011) PubMed
2.Talkowski M.E. et al. Cell 149, 525-537 (2012) PubMed
3.Blumenthal I. et al. Am. J. Hum. Genet. 94, 870-883 (2014) PubMed
4.Sugathan A. et al. Proc. Natl. Acad. Sci. USA 111, E4468-4477 (2014) PubMed
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