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Chemico-genetic Analysis of Native Autism Proteomes Reveals Shared Biology Predictive of Functional Modifiers

Yudong Gao, Matthew Trn, Daichi Shonai, Jieqing Zhao, Erik J. Soderblom, S. Alexandra Garcia-Moreno, Charles A. Gersbach, William C. Wetsel, Geraldine Dawson, Dmitry Velmeshev, Yong-hui Jiang, Laura Sloofman, View ORCID ProfileJoseph D. Buxbaum, View ORCID ProfileScott H. Soderling
doi: https://doi.org/10.1101/2022.10.06.511211
Yudong Gao
1Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA
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Matthew Trn
1Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA
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Daichi Shonai
2Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
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Jieqing Zhao
3Department of Biology, Duke University, Durham, NC, USA
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Erik J. Soderblom
4Department of Cell Biology, Proteomics and Metabolomics Shared Resource, Duke University School of Medicine, Durham, NC, USA
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S. Alexandra Garcia-Moreno
5Department of Biomedical Engineering, Duke University, Durham, NC, USA
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Charles A. Gersbach
5Department of Biomedical Engineering, Duke University, Durham, NC, USA
6Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA; Department of Surgery, Duke University Medical Center, Durham, NC, USA
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William C. Wetsel
7Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University School of Medicine, Durham, NC, USA
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Geraldine Dawson
8Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA
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Dmitry Velmeshev
9Department of Neurobiology, Duke University School of Medicine, Durham, NC, USA
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Yong-hui Jiang
10Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
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Laura Sloofman
11Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Joseph D. Buxbaum
11Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
12The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Scott H. Soderling
1Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA
9Department of Neurobiology, Duke University School of Medicine, Durham, NC, USA
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  • For correspondence: Scott.Soderling@duke.edu
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Abstract

One of the main drivers of autism spectrum disorder (ASD) are risk alleles within hundreds of genes, which may interact within shared biological processes through as-yet unclear mechanisms. Here we develop a high-throughput genome-editing-mediated approach to target 14 high-confidence ASD genes within the mouse brain for proximity-based proteomics of endogenous interactomes. The resulting interactomes are enriched for human genes dysregulated in the brain of ASD patients and reveal unexpected, but highly significant, interactions with other lower confidence ASD-risk gene products, positing new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the disorder. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two ASD models, demonstrating new functional interactions that modulate mechanisms of their dysregulation. Together, our results reveal native protein-interaction networks in ASD, providing new inroads for understanding its cellular neurobiology.

Competing Interest Statement

SS and YG have a patent related to the HiUGE technology. The intellectual property was licensed to CasTag Biosciences. SS is a founder of CasTag Biosciences; Duke University as an institution holds equity in CasTag Biosciences. CAG is an inventor on patents and patent applications related to CRISPR-based gene activation, is a co-founder of Tune Therapeutics, Locus Biosciences, and Element Genomics, and is an advisor to Sarepta Therapeutics. GD Dr. Dawson is on the Scientific Advisory Boards of Akili Interactive, Inc, and Tris Pharma, is a consultant to Apple, Gerson Lehrman Group, and Guidepoint Global, Inc. GD has developed autism-related technology, data, and/or products that have been licensed to Apple, Inc. and Cryocell, Inc. and Dawson and Duke University have benefited financially. JDB is a consultant for Bridgebio.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 07, 2022.
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Chemico-genetic Analysis of Native Autism Proteomes Reveals Shared Biology Predictive of Functional Modifiers
Yudong Gao, Matthew Trn, Daichi Shonai, Jieqing Zhao, Erik J. Soderblom, S. Alexandra Garcia-Moreno, Charles A. Gersbach, William C. Wetsel, Geraldine Dawson, Dmitry Velmeshev, Yong-hui Jiang, Laura Sloofman, Joseph D. Buxbaum, Scott H. Soderling
bioRxiv 2022.10.06.511211; doi: https://doi.org/10.1101/2022.10.06.511211
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Chemico-genetic Analysis of Native Autism Proteomes Reveals Shared Biology Predictive of Functional Modifiers
Yudong Gao, Matthew Trn, Daichi Shonai, Jieqing Zhao, Erik J. Soderblom, S. Alexandra Garcia-Moreno, Charles A. Gersbach, William C. Wetsel, Geraldine Dawson, Dmitry Velmeshev, Yong-hui Jiang, Laura Sloofman, Joseph D. Buxbaum, Scott H. Soderling
bioRxiv 2022.10.06.511211; doi: https://doi.org/10.1101/2022.10.06.511211

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