Autism genes converge on asynchronous development of shared neuron classes

Bruna Paulsen, Silvia Velasco (), Amanda J. Kedaigle, Martina Pigoni, Giorgia Quadrato, Anthony J. Deo, Xian Adiconis, Ana Uzquiano, Rafaela Sartore, Sung Min Yang, Sean K. Simmons, Panagiotis Symvoulidis, Kwanho Kim, Kalliopi Tsafou, Archana Podury, Catherine Abbate, Ashley Tucewicz, Samantha N. Smith, Alexandre Albanese, Lindy Barrett, Neville E. Sanjana, Xi Shi, Kwanghun Chung, Kasper Lage, Edward S. Boyden, Aviv Regev, Joshua Z. Levin and Paola Arlotta ()
Additional contact information
Bruna Paulsen: Harvard University
Silvia Velasco: Harvard University
Amanda J. Kedaigle: Harvard University
Martina Pigoni: Harvard University
Giorgia Quadrato: Harvard University
Anthony J. Deo: Harvard University
Xian Adiconis: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Ana Uzquiano: Harvard University
Rafaela Sartore: Harvard University
Sung Min Yang: Harvard University
Sean K. Simmons: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Panagiotis Symvoulidis: Massachusetts Institute of Technology (MIT)
Kwanho Kim: Harvard University
Kalliopi Tsafou: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Archana Podury: Massachusetts Institute of Technology (MIT)
Catherine Abbate: Harvard University
Ashley Tucewicz: Harvard University
Samantha N. Smith: Harvard University
Alexandre Albanese: Massachusetts Institute of Technology (MIT)
Lindy Barrett: Harvard University
Neville E. Sanjana: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Xi Shi: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Kwanghun Chung: Massachusetts Institute of Technology (MIT)
Kasper Lage: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Edward S. Boyden: Massachusetts Institute of Technology (MIT)
Aviv Regev: Broad Institute of MIT and Harvard
Joshua Z. Levin: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Paola Arlotta: Harvard University

Nature, 2022, vol. 602, issue 7896, 268-273

Abstract: Abstract Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1–6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes—SUV420H1 (also known as KMT5B), ARID1B and CHD8—in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages—γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons—but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

Date: 2022
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DOI: 10.1038/s41586-021-04358-6

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