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; Paola Arlotta

doi:10.1038/s41586-021-04358-6

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 BarrettNeville E. Sanjana, Xi Shi, Kwanghun Chung, Kasper Lage, Edward S. Boyden, Aviv Regev, Joshua Z. Levin, Paola Arlotta

Yonsei Advanced Science Institute

Research output: Contribution to journal › Article › peer-review

51 Citations (Scopus)

Abstract

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions^1–6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals^7,8. 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.

Original language	English
Pages (from-to)	268-273
Number of pages	6
Journal	Nature
Volume	602
Issue number	7896
DOIs	https://doi.org/10.1038/s41586-021-04358-6
Publication status	Published - 2022 Feb 10

Bibliographical note

Funding Information:
We thank J. R. Brown (from the P.A. laboratory) for input and assistance in editing the manuscript and all of the members of the Arlotta laboratory for discussions; M. Daly, E. Robinson and B. Neale for discussions on autism genetics; T. Nguyen (from the G.Q. laboratory) for support with organoid generation; X. Jin (from the P.A. laboratory) for helping with designing and sequencing edited lines; A. Shetty (from the P.A. laboratory) for help with scRNA-seq cell type classification; N. Haywood for help with scRNA-seq experiments; D. Di Bella (from the P.A. laboratory) for help with final edits of the manuscript; S. Andreadis and S. Getz (from the P.A. laboratory) for help with editing images; F. Zhang and J. Pan for supporting the creation of the HUES66 CHD8 -mutant line; members of the Talkowski laboratory for the GM08330 line; members of the Cohen laboratory for the Mito210 line; members of the Ricci laboratory for providing nanoblades for the generation of SUV420H1 edited cell lines; L. M. Daheron at the Harvard Stem Cell Facility for expanding edited lines; and B. Budnik at the Harvard Center for Mass Spectrometry for assisting with proteomics experiments. This work was supported by grants from the Stanley Center for Psychiatric Research, the Broad Institute of MIT and Harvard, the National Institutes of Health (R01-MH112940 to P.A. and J.Z.L.; P50MH094271, U01MH115727 and 1RF1MH123977 to P.A.), the Klarman Cell Observatory to J.Z.L. and A.R., and the Howard Hughes Medical Institute to A.R. A.R. was a Howard Hughes Medical Institute and a Koch Institute extramural member while conducting this study. The HUES66 CHD8 -mutant line was created with support from the Simons Foundation (346073 to F. Zhang) and the National Institutes of Health (MH099448 to J. Pan).

Funding Information:
We thank J. R. Brown (from the P.A. laboratory) for input and assistance in editing the manuscript and all of the members of the Arlotta laboratory for discussions; M. Daly, E. Robinson and B. Neale for discussions on autism genetics; T. Nguyen (from the G.Q. laboratory) for support with organoid generation; X. Jin (from the P.A. laboratory) for helping with designing and sequencing edited lines; A. Shetty (from the P.A. laboratory) for help with scRNA-seq cell type classification; N. Haywood for help with scRNA-seq experiments; D. Di Bella (from the P.A. laboratory) for help with final edits of the manuscript; S. Andreadis and S. Getz (from the P.A. laboratory) for help with editing images; F. Zhang and J. Pan for supporting the creation of the HUES66 CHD8-mutant line; members of the Talkowski laboratory for the GM08330 line; members of the Cohen laboratory for the Mito210 line; members of the Ricci laboratory for providing nanoblades for the generation of SUV420H1 edited cell lines; L. M. Daheron at the Harvard Stem Cell Facility for expanding edited lines; and B. Budnik at the Harvard Center for Mass Spectrometry for assisting with proteomics experiments. This work was supported by grants from the Stanley Center for Psychiatric Research, the Broad Institute of MIT and Harvard, the National Institutes of Health (R01-MH112940 to P.A. and J.Z.L.; P50MH094271, U01MH115727 and 1RF1MH123977 to P.A.), the Klarman Cell Observatory to J.Z.L. and A.R., and the Howard Hughes Medical Institute to A.R. A.R. was a Howard Hughes Medical Institute and a Koch Institute extramural member while conducting this study. The HUES66 CHD8-mutant line was created with support from the Simons Foundation (346073 to F. Zhang) and the National Institutes of Health (MH099448 to J. Pan).

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© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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10.1038/s41586-021-04358-6

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Paulsen, B., Velasco, S., Kedaigle, A. J., Pigoni, M., Quadrato, G., Deo, A. J., Adiconis, X., Uzquiano, A., Sartore, R., Yang, S. M., Simmons, S. K., Symvoulidis, P., Kim, K., Tsafou, K., Podury, A., Abbate, C., Tucewicz, A., Smith, S. N., Albanese, A., ... Arlotta, P. (2022). Autism genes converge on asynchronous development of shared neuron classes. Nature, 602(7896), 268-273. https://doi.org/10.1038/s41586-021-04358-6

@article{5bf8020d2c4d410490eb29cfa7e4f5fb,

title = "Autism genes converge on asynchronous development of shared neuron classes",

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.",

author = "Bruna Paulsen and Silvia Velasco and Kedaigle, {Amanda J.} and Martina Pigoni and Giorgia Quadrato and Deo, {Anthony J.} and Xian Adiconis and Ana Uzquiano and Rafaela Sartore and Yang, {Sung Min} and Simmons, {Sean K.} and Panagiotis Symvoulidis and Kwanho Kim and Kalliopi Tsafou and Archana Podury and Catherine Abbate and Ashley Tucewicz and Smith, {Samantha N.} and Alexandre Albanese and Lindy Barrett and Sanjana, {Neville E.} and Xi Shi and Kwanghun Chung and Kasper Lage and Boyden, {Edward S.} and Aviv Regev and Levin, {Joshua Z.} and Paola Arlotta",

note = "Funding Information: We thank J. R. Brown (from the P.A. laboratory) for input and assistance in editing the manuscript and all of the members of the Arlotta laboratory for discussions; M. Daly, E. Robinson and B. Neale for discussions on autism genetics; T. Nguyen (from the G.Q. laboratory) for support with organoid generation; X. Jin (from the P.A. laboratory) for helping with designing and sequencing edited lines; A. Shetty (from the P.A. laboratory) for help with scRNA-seq cell type classification; N. Haywood for help with scRNA-seq experiments; D. Di Bella (from the P.A. laboratory) for help with final edits of the manuscript; S. Andreadis and S. Getz (from the P.A. laboratory) for help with editing images; F. Zhang and J. Pan for supporting the creation of the HUES66 CHD8 -mutant line; members of the Talkowski laboratory for the GM08330 line; members of the Cohen laboratory for the Mito210 line; members of the Ricci laboratory for providing nanoblades for the generation of SUV420H1 edited cell lines; L. M. Daheron at the Harvard Stem Cell Facility for expanding edited lines; and B. Budnik at the Harvard Center for Mass Spectrometry for assisting with proteomics experiments. This work was supported by grants from the Stanley Center for Psychiatric Research, the Broad Institute of MIT and Harvard, the National Institutes of Health (R01-MH112940 to P.A. and J.Z.L.; P50MH094271, U01MH115727 and 1RF1MH123977 to P.A.), the Klarman Cell Observatory to J.Z.L. and A.R., and the Howard Hughes Medical Institute to A.R. A.R. was a Howard Hughes Medical Institute and a Koch Institute extramural member while conducting this study. The HUES66 CHD8 -mutant line was created with support from the Simons Foundation (346073 to F. Zhang) and the National Institutes of Health (MH099448 to J. Pan). Funding Information: We thank J. R. Brown (from the P.A. laboratory) for input and assistance in editing the manuscript and all of the members of the Arlotta laboratory for discussions; M. Daly, E. Robinson and B. Neale for discussions on autism genetics; T. Nguyen (from the G.Q. laboratory) for support with organoid generation; X. Jin (from the P.A. laboratory) for helping with designing and sequencing edited lines; A. Shetty (from the P.A. laboratory) for help with scRNA-seq cell type classification; N. Haywood for help with scRNA-seq experiments; D. Di Bella (from the P.A. laboratory) for help with final edits of the manuscript; S. Andreadis and S. Getz (from the P.A. laboratory) for help with editing images; F. Zhang and J. Pan for supporting the creation of the HUES66 CHD8-mutant line; members of the Talkowski laboratory for the GM08330 line; members of the Cohen laboratory for the Mito210 line; members of the Ricci laboratory for providing nanoblades for the generation of SUV420H1 edited cell lines; L. M. Daheron at the Harvard Stem Cell Facility for expanding edited lines; and B. Budnik at the Harvard Center for Mass Spectrometry for assisting with proteomics experiments. This work was supported by grants from the Stanley Center for Psychiatric Research, the Broad Institute of MIT and Harvard, the National Institutes of Health (R01-MH112940 to P.A. and J.Z.L.; P50MH094271, U01MH115727 and 1RF1MH123977 to P.A.), the Klarman Cell Observatory to J.Z.L. and A.R., and the Howard Hughes Medical Institute to A.R. A.R. was a Howard Hughes Medical Institute and a Koch Institute extramural member while conducting this study. The HUES66 CHD8-mutant line was created with support from the Simons Foundation (346073 to F. Zhang) and the National Institutes of Health (MH099448 to J. Pan). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

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day = "10",

doi = "10.1038/s41586-021-04358-6",

language = "English",

volume = "602",

pages = "268--273",

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Paulsen, B, Velasco, S, Kedaigle, AJ, Pigoni, M, Quadrato, G, Deo, AJ, Adiconis, X, Uzquiano, A, Sartore, R, Yang, SM, Simmons, SK, Symvoulidis, P, Kim, K, Tsafou, K, Podury, A, Abbate, C, Tucewicz, A, Smith, SN, Albanese, A, Barrett, L, Sanjana, NE, Shi, X, Chung, K, Lage, K, Boyden, ES, Regev, A, Levin, JZ & Arlotta, P 2022, 'Autism genes converge on asynchronous development of shared neuron classes', Nature, vol. 602, no. 7896, pp. 268-273. https://doi.org/10.1038/s41586-021-04358-6

TY - JOUR

T1 - Autism genes converge on asynchronous development of shared neuron classes

AU - Paulsen, Bruna

AU - Velasco, Silvia

AU - Kedaigle, Amanda J.

AU - Pigoni, Martina

AU - Quadrato, Giorgia

AU - Deo, Anthony J.

AU - Adiconis, Xian

AU - Uzquiano, Ana

AU - Sartore, Rafaela

AU - Yang, Sung Min

AU - Simmons, Sean K.

AU - Symvoulidis, Panagiotis

AU - Kim, Kwanho

AU - Tsafou, Kalliopi

AU - Podury, Archana

AU - Abbate, Catherine

AU - Tucewicz, Ashley

AU - Smith, Samantha N.

AU - Albanese, Alexandre

AU - Barrett, Lindy

AU - Sanjana, Neville E.

AU - Shi, Xi

AU - Chung, Kwanghun

AU - Lage, Kasper

AU - Boyden, Edward S.

AU - Regev, Aviv

AU - Levin, Joshua Z.

AU - Arlotta, Paola

N1 - Funding Information: We thank J. R. Brown (from the P.A. laboratory) for input and assistance in editing the manuscript and all of the members of the Arlotta laboratory for discussions; M. Daly, E. Robinson and B. Neale for discussions on autism genetics; T. Nguyen (from the G.Q. laboratory) for support with organoid generation; X. Jin (from the P.A. laboratory) for helping with designing and sequencing edited lines; A. Shetty (from the P.A. laboratory) for help with scRNA-seq cell type classification; N. Haywood for help with scRNA-seq experiments; D. Di Bella (from the P.A. laboratory) for help with final edits of the manuscript; S. Andreadis and S. Getz (from the P.A. laboratory) for help with editing images; F. Zhang and J. Pan for supporting the creation of the HUES66 CHD8 -mutant line; members of the Talkowski laboratory for the GM08330 line; members of the Cohen laboratory for the Mito210 line; members of the Ricci laboratory for providing nanoblades for the generation of SUV420H1 edited cell lines; L. M. Daheron at the Harvard Stem Cell Facility for expanding edited lines; and B. Budnik at the Harvard Center for Mass Spectrometry for assisting with proteomics experiments. This work was supported by grants from the Stanley Center for Psychiatric Research, the Broad Institute of MIT and Harvard, the National Institutes of Health (R01-MH112940 to P.A. and J.Z.L.; P50MH094271, U01MH115727 and 1RF1MH123977 to P.A.), the Klarman Cell Observatory to J.Z.L. and A.R., and the Howard Hughes Medical Institute to A.R. A.R. was a Howard Hughes Medical Institute and a Koch Institute extramural member while conducting this study. The HUES66 CHD8 -mutant line was created with support from the Simons Foundation (346073 to F. Zhang) and the National Institutes of Health (MH099448 to J. Pan). Funding Information: We thank J. R. Brown (from the P.A. laboratory) for input and assistance in editing the manuscript and all of the members of the Arlotta laboratory for discussions; M. Daly, E. Robinson and B. Neale for discussions on autism genetics; T. Nguyen (from the G.Q. laboratory) for support with organoid generation; X. Jin (from the P.A. laboratory) for helping with designing and sequencing edited lines; A. Shetty (from the P.A. laboratory) for help with scRNA-seq cell type classification; N. Haywood for help with scRNA-seq experiments; D. Di Bella (from the P.A. laboratory) for help with final edits of the manuscript; S. Andreadis and S. Getz (from the P.A. laboratory) for help with editing images; F. Zhang and J. Pan for supporting the creation of the HUES66 CHD8-mutant line; members of the Talkowski laboratory for the GM08330 line; members of the Cohen laboratory for the Mito210 line; members of the Ricci laboratory for providing nanoblades for the generation of SUV420H1 edited cell lines; L. M. Daheron at the Harvard Stem Cell Facility for expanding edited lines; and B. Budnik at the Harvard Center for Mass Spectrometry for assisting with proteomics experiments. This work was supported by grants from the Stanley Center for Psychiatric Research, the Broad Institute of MIT and Harvard, the National Institutes of Health (R01-MH112940 to P.A. and J.Z.L.; P50MH094271, U01MH115727 and 1RF1MH123977 to P.A.), the Klarman Cell Observatory to J.Z.L. and A.R., and the Howard Hughes Medical Institute to A.R. A.R. was a Howard Hughes Medical Institute and a Koch Institute extramural member while conducting this study. The HUES66 CHD8-mutant line was created with support from the Simons Foundation (346073 to F. Zhang) and the National Institutes of Health (MH099448 to J. Pan). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022/2/10

Y1 - 2022/2/10

N2 - 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.

AB - 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.

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JF - Nature

IS - 7896

ER -

Autism genes converge on asynchronous development of shared neuron classes

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