University of California, San Francisco (UCSF) - Quantitative Biosciences Institute; QBI Coronavirus Research Group (QCRG); University of California, San Francisco (UCSF) - Department of Cellular and Molecular Pharmacology; Gladstone Institutes - Gladstone Institute of Data Science and Biotechnology
University of California, San Francisco (UCSF) - Quantitative Biosciences Institute; QBI Coronavirus Research Group (QCRG); University of California, San Francisco (UCSF) - Department of Cellular and Molecular Pharmacology; Gladstone Institutes - Gladstone Institute of Data Science and Biotechnology
University of California, San Francisco (UCSF) - Quantitative Biosciences Institute; QBI Coronavirus Research Group (QCRG); University of California, San Francisco (UCSF) - Department of Cellular and Molecular Pharmacology; Gladstone Institutes - Gladstone Institute of Data Science and Biotechnology
University of California, San Francisco (UCSF) - Quantitative Biosciences Institute; QBI Coronavirus Research Group (QCRG); University of California, San Francisco (UCSF) - Department of Cellular and Molecular Pharmacology; Gladstone Institutes - Gladstone Institute of Data Science and Biotechnology
University of California, San Francisco (UCSF) - Quantitative Biosciences Institute; QBI Coronavirus Research Group (QCRG); University of California, San Francisco (UCSF) - Department of Cellular and Molecular Pharmacology; Gladstone Institutes - Gladstone Institute of Data Science and Biotechnology
QBI Coronavirus Research Group (QCRG); Gladstone Institutes - Gladstone Institute of Data Science and Biotechnology; University of California, San Francisco (UCSF) - Quantitative Biosciences Institute; University of California, San Francisco (UCSF) - Department of Cellular and Molecular Pharmacology; University of California, San Francisco (UCSF)
Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification. A PPI map of 54 patient-derived missense variants identified differential physical interactions, and we leveraged AlphaFold-Multimer predictions to prioritize direct PPIs and specific variants for interrogation in Xenopus tropicalis and human forebrain organoids. A mutation in the transcription factor FOXP1 led to reconfiguration of DNA binding sites and altered development of deep cortical layer neurons in forebrain organoids. This work offers new insights into molecular mechanisms underlying ASD and describes a powerful platform to develop and test therapeutic strategies for many genetically-defined conditions.
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Funding Information: This research was funded by grants from the National Institutes of Health to N.J.K, A.J.W, M.W.S, T.I. and T.J.N (U01MH115747), A.J.W. and M.W.S (U01MH116487), N.J.K and T.I. (1OT2OD032742, U54CA274502), and T.J.N (R01MH128364, R01NS123263, SF810018). This study was also supported by the Weill Institute for Neurosciences (Startup Funding to A.J.W.), the Quantitative Biosciences Institute (QBI) at UCSF, the Overlook International Foundation (to M.W.S. and A.J.W.), gifts from Schmidt Futures and the William K. Bowes Jr Foundation (to T.J.N), the Sergey Brin Family Foundation (to M.W.S) and the Sorensen Foundation Career Award in Child & Adolescent Psychiatry (to B.W.). T.J.N. is a New York Stem Cell Foundation Robertson Neuroscience Investigator; H.R.W. is a Chan Zuckerberg Biohub - San Francisco Investigator.
Conflict of Interests: The Krogan Laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. Nevan Krogan has a financially compensated consulting agreement with Maze Therapeutics and has previously held financially compensated consulting agreements with the Icahn School of Medicine at Mount Sinai, New York and Twist Bioscience Corp.. He is on the Board of Directors of Rezo Therapeutics, and a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, GEn1E Lifesciences and Interline Therapeutics. All other authors declare no competing interests.
Wang, Belinda and Vartak, Rasika and Zaltsman, Yefim and Naing, Zun Zar Chi and Hennick, Kelsey and Polacco, Benjamin and Bashir, Ali and Eckhardt, Manon and Bouhaddou, Mehdi and Xu, Jiewei and Sun, Nawei and Lasser, Micaela and Zhou, Yuan and Mcketney, Justin and Guiley, Keelan and Chan, Una and Kaye, Julia A. and Chadha, Nishant and Cakir, Merve and Gordon, Martin and Khare, Prachi and Drake, Sam and Drury, Vanessa and Burke, David and Gonzalez, Silvano and Alkhairy, Sahar and Thomas, Reuben and Lam, Stephanie and Morris, Montana and Bader, Ethel and Seyler, Meghan and Baum, Tierney and Krasnoff, Rebecca and Wang, Sheng and Pham, Presley and Arbelaez, Juan and Pratt, Dexter and Chag, Shivali and Mahmood, Nadir and Rolland, Thomas and Bourgeron, Thomas and Finkbeiner, Steve and Swaney, Danielle L. and Bandyopadhay, Sourav and Ideker, Trey and Beltrao, Pedro and Willsey, Helen and Obernier, Kirsten and Nowakowski, Tomasz J. and Huttenhain, Ruth and State, Matthew W. and Willsey, Jeremy and Krogan, Nevan J., A Foundational Atlas of Autism Protein Interactions Reveals Molecular Convergence. Available at SSRN: https://ssrn.com/abstract=4663951 or http://dx.doi.org/10.2139/ssrn.4663951
This version of the paper has not been formally peer reviewed.
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