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Isoform transcriptome of developing human brain provides new insights into autism risk variants

Kevin Chau, Pan Zhang, Jorge Urresti, Megha Amar, Akula Bala Pramod, Amy Thomas, Roser Corominas, Guan Ning Lin, View ORCID ProfileLilia M. Iakoucheva
doi: https://doi.org/10.1101/2020.06.27.175489
Kevin Chau
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
2Department of Biology, University of California San Diego, La Jolla, CA, USA
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Pan Zhang
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
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Jorge Urresti
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
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Megha Amar
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
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Akula Bala Pramod
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
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Amy Thomas
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
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Roser Corominas
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
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Guan Ning Lin
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
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Lilia M. Iakoucheva
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
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  • ORCID record for Lilia M. Iakoucheva
  • For correspondence: lilyak@ucsd.edu
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Summary

Alternative splicing plays important role in brain development, however its global contribution to human neurodevelopmental diseases (NDD) has not been fully investigated. Here, we examined the relationships between splicing isoforms expression in the brain and de novo loss-of-function mutations identified in the patients with NDDs. We constructed isoform transcriptome of the developing human brain, and observed differentially expressed isoforms and isoform co-expression modules undetectable by the gene-level analyses. These isoforms were enriched in loss-of-function mutations and microexons, co-expressed with a unique set of partners, and had higher prenatal expression. We experimentally tested the impact of splice site mutations in five NDD risk genes, including SCN2A, DYRK1A and BTRC, and demonstrated exon skipping. Furthermore, our results suggest that the splice site mutation in BTRC reduces translational efficiency, likely impacting Wnt signaling through impaired degradation of β-catenin. We propose that functional effect of mutations associated with human diseases should be investigated at isoform-rather than gene-level resolution.

Highlights

  • Differential isoform expression analysis of human brain transcriptome reveals neurodevelopmental processes and pathways undetectable by differential gene expression analyses.

  • Splicing isoforms impacted by neurodevelopmental disease (NDD) risk mutations exhibit higher prenatal expression, are enriched in microexons and involved in neuronal-related functions.

  • Isoform co-expression network analysis identifies modules with splicing and synaptic functions that are enriched in NDD mutations.

  • Splice site mutations impacting NDD risk genes cause exon skipping and produce novel isoforms with altered biological properties.

  • Functional impact of mutations should be investigated at isoform-rather than gene-level resolution

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 27, 2020.
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Isoform transcriptome of developing human brain provides new insights into autism risk variants
Kevin Chau, Pan Zhang, Jorge Urresti, Megha Amar, Akula Bala Pramod, Amy Thomas, Roser Corominas, Guan Ning Lin, Lilia M. Iakoucheva
bioRxiv 2020.06.27.175489; doi: https://doi.org/10.1101/2020.06.27.175489
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Isoform transcriptome of developing human brain provides new insights into autism risk variants
Kevin Chau, Pan Zhang, Jorge Urresti, Megha Amar, Akula Bala Pramod, Amy Thomas, Roser Corominas, Guan Ning Lin, Lilia M. Iakoucheva
bioRxiv 2020.06.27.175489; doi: https://doi.org/10.1101/2020.06.27.175489

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