Abstract
One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving high specificity spatial interactomes compared to prior methods. The resulting native proximity interactomes are enriched for human genes dysregulated in the brain of autistic individuals and reveal unexpected and highly significant interactions with other lower-confidence autism 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 condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networks in vivo relevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.
Competing Interest Statement
SHS and YG have a patent application related to the HiUGE technology. The intellectual property was licensed to CasTag Biosciences. SHS 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. WCW is a consultant for Onsero Therapeutics.
Footnotes
New data has been added.