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In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with Autism risk genes

View ORCID ProfileXin Jin, Sean K. Simmons, Amy X. Guo, Ashwin S. Shetty, Michelle Ko, Lan Nguyen, Elise Robinson, Paul Oyler, Nathan Curry, Giulio Deangeli, Simona Lodato, View ORCID ProfileJoshua Z. Levin, Aviv Regev, Feng Zhang, Paola Arlotta
doi: https://doi.org/10.1101/791525
Xin Jin
1Society of Fellows, Harvard University, Cambridge, MA, USA
2Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
4McGovern Institute of Brain Science, Department of Brain and Cognitive Science, Department of Biological Engineering, MIT, Cambridge, MA, USA
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  • ORCID record for Xin Jin
  • For correspondence: paola_arlotta@harvard.edu zhang@broadinstitute.org aregev@broadinstitute.org xinjin@fas.harvard.edu
Sean K. Simmons
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Amy X. Guo
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Ashwin S. Shetty
2Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Michelle Ko
2Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA
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Lan Nguyen
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Elise Robinson
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
8Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Paul Oyler
2Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA
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Nathan Curry
2Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA
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Giulio Deangeli
2Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA
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Simona Lodato
7Department of Biomedical Sciences and IRCCS Humanitas Clinical and Research Center, Humanitas University, Milan, Italy
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Joshua Z. Levin
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Aviv Regev
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
9Koch Institute of Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA
10Howard Hughes Medical Institute
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  • For correspondence: paola_arlotta@harvard.edu zhang@broadinstitute.org aregev@broadinstitute.org xinjin@fas.harvard.edu
Feng Zhang
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
4McGovern Institute of Brain Science, Department of Brain and Cognitive Science, Department of Biological Engineering, MIT, Cambridge, MA, USA
10Howard Hughes Medical Institute
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  • For correspondence: paola_arlotta@harvard.edu zhang@broadinstitute.org aregev@broadinstitute.org xinjin@fas.harvard.edu
Paola Arlotta
2Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA
3Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • For correspondence: paola_arlotta@harvard.edu zhang@broadinstitute.org aregev@broadinstitute.org xinjin@fas.harvard.edu
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Abstract

The thousands of disease risk genes and loci identified through human genetic studies far outstrip our current capacity to systematically study their functions. New experimental approaches are needed for functional investigations of large panels of genes in a biologically relevant context. Here, we developed a scalable genetic screen approach, in vivo Perturb-Seq, and applied this method to the functional evaluation of 35 autism spectrum disorder (ASD) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes in pools, within the developing brain in utero, and then performed single-cell RNA-Seq in the postnatal brain. We identified cell type-specific gene signatures from both neuronal and glial cell classes that are affected by genetic perturbations, and pointed at elements of both convergent and divergent cellular effects across this cohort of ASD risk genes. In vivo Perturb-Seq pioneers a systems genetics approach to investigate at scale how diverse mutations affect cell types and states in the biologically relevant context of the developing organism.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 07, 2019.
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In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with Autism risk genes
Xin Jin, Sean K. Simmons, Amy X. Guo, Ashwin S. Shetty, Michelle Ko, Lan Nguyen, Elise Robinson, Paul Oyler, Nathan Curry, Giulio Deangeli, Simona Lodato, Joshua Z. Levin, Aviv Regev, Feng Zhang, Paola Arlotta
bioRxiv 791525; doi: https://doi.org/10.1101/791525
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In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with Autism risk genes
Xin Jin, Sean K. Simmons, Amy X. Guo, Ashwin S. Shetty, Michelle Ko, Lan Nguyen, Elise Robinson, Paul Oyler, Nathan Curry, Giulio Deangeli, Simona Lodato, Joshua Z. Levin, Aviv Regev, Feng Zhang, Paola Arlotta
bioRxiv 791525; doi: https://doi.org/10.1101/791525

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