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Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder


A universal challenge in genetic studies of autism spectrum disorders (ASDs) is determining whether a given DNA sequence alteration will manifest as disease. Among different population controls, we observed, for specific exons, an inverse correlation between exon expression level in brain and burden of rare missense mutations. For genes that harbor de novo mutations predicted to be deleterious, we found that specific critical exons were significantly enriched in individuals with ASD relative to their siblings without ASD (P < 1.13 × 10−38; odds ratio (OR) = 2.40). Furthermore, our analysis of genes with high exonic expression in brain and low burden of rare mutations demonstrated enrichment for known ASD-associated genes (P < 3.40 × 10−11; OR = 6.08) and ASD-relevant fragile-X protein targets (P < 2.91 × 10−157; OR = 9.52). Our results suggest that brain-expressed exons under purifying selection should be prioritized in genotype-phenotype studies for ASD and related neurodevelopmental conditions.

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Figure 1: Assembling an exon transcriptome-mutation contingency index.
Figure 2: Inverse correlation between the burden of rare missense mutations and exon expression levels.
Figure 3: Spatiotemporal association analysis of exon expression levels and burden of rare missense mutations for genes with de novo SNVs or indels predicted to be deleterious.
Figure 4: Highly expressed exons with de novo mutations.
Figure 5: Delineation and profiling of brain-critical exons.


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We thank the Centre for Applied Genomics for informatics support, the Allen Institute of Brain Science, the National Heart, Lung, and Blood Institute (NHLBI) and the Autism Genome Project for sharing data. We thank J. Buchanan for critical review and editing of the manuscript. This work was supported by grants from the University of Toronto McLaughlin Centre, NeuroDevNet, Genome Canada and the Ontario Genomics Institute (project 4445), the Canadian Institutes for Health Research (CIHR) (FRN 74527 and FRNXGG818), the Canadian Institute for Advanced Research, the Canada Foundation for Innovation, the government of Ontario (GL2-01-013), the Ontario Brain Institute and Autism Speaks. R.K.C.Y. holds an Autism Speaks Meixner Fellowship in Translational Research. K.T. holds a fellowship from the Swedish Research Council. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and the Hospital for Sick Children.

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Authors and Affiliations



M.U. and S.W.S. conceived the project, designed its components and contributed to the original concept of the project. K.T. performed quantitative PCR and RT-PCR analysis on brain tissues. M.U., G.P., D.M., P.H., R.K.C.Y., Z.W., D.P., L.L., T.N. and C.R.M. helped perform different components of the transcriptome and exome mutation analyses. M.U., G.P. and D.M. designed and performed the pathway analysis. B.A., B.J.F. and B.J.B. conducted the splicing code analysis. M.U., K.T. and S.W.S. coordinated the entire study and wrote the manuscript.

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Correspondence to Stephen W Scherer.

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Competing interests

The concept of an exon transcriptome-mutation contingency index for autism diagnosis has been filed under reference H8312944USP (US provisional application number 61/892920) with the US Patent and Trademark Office.

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Supplementary Note, Supplementary Figures 1–21 and Supplementary Tables 1–3, 5, 6 and 10 (PDF 5505 kb)

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Uddin, M., Tammimies, K., Pellecchia, G. et al. Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat Genet 46, 742–747 (2014).

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