Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms
RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type–specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-rea...
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| Published in | Science (American Association for the Advancement of Science) Vol. 384; no. 6698; p. eadh7688 |
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| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
The American Association for the Advancement of Science
24.05.2024
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| Subjects | |
| Online Access | Get full text |
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| Abstract | RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type–specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity—regulated by RNA binding proteins—in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders. |
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| AbstractList | RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type-specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity-regulated by RNA binding proteins-in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders.RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type-specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity-regulated by RNA binding proteins-in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders. RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type-specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity-regulated by RNA binding proteins-in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders. RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type–specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity—regulated by RNA binding proteins—in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders. An isoform-centric transcriptome of the developing human neocortex informs mechanisms of neuropsychiatric disease. We provide a systematic characterization of transcript-isoform diversity in the developing human neocortex at tissue and single-cell resolution using long-read Iso-Seq. The bracket pointing out from a schematic summarizing data generation indicates major analyses performed in this study. We identified thousands of isoforms with specific regional (GZ or CP) and cell type expression coalescing into networks driven by cell type identity and RBP regulation. This resource reveals substantial contributions of isoform switching to cellular identity and elucidates genetic risk mechanisms for neurodevelopmental and neuropsychiatric disorders, including a reannotation of thousands of de novo rare variants with potential clinical implications. SCZ, schizophrenia. [Figure created with BioRender] INTRODUCTIONThe development of the human brain is regulated by precise molecular mechanisms driving spatiotemporal and cell type–specific transcript expression programs. Alternative splicing—a major mechanism increasing transcript diversity—is highly prevalent in the human brain, influences many aspects of brain development, and has strong links to neuropsychiatric disorders. Despite this, the cell type–specific transcript-isoform diversity of the developing human brain has not been systematically investigated.RATIONALEShort-read sequencing, the prevalent technology for transcriptome profiling, is not well suited to capturing alternative splicing and isoform diversity. To address this, we used third-generation long-read sequencing, which enables the capture of complete RNA molecules, to profile the full-length transcriptome of the germinal zone (GZ) and cortical plate (CP) regions of the developing human neocortex at tissue and single-cell resolution.RESULTSWe profiled microdissected GZ and CP regions of postconception week (PCW) 15 to 17 human neocortex across six subjects using high-fidelity long-read sequencing. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode v33), and >7000 novel exons, expanding the proteome by 92,422 putative proteoforms. We uncovered thousands of isoform switches during cortical neurogenesis predicted to affect RNA regulatory domains or protein structure and implicating previously uncharacterized RNA binding proteins (RBPs) in cellular identity and neuropsychiatric disease. At the single-cell level, early-stage excitatory neurons exhibited the greatest isoform diversity, and isoform-centric single-cell clustering led to the identification of previously uncharacterized cell states. We systematically assessed the contribution of transcriptomic features and localized cell and spatiotemporal transcript expression signatures across neuropsychiatric disorders. This revealed predominant enrichments in dynamic isoform expression and utilization patterns and that the number and complexity of isoforms per gene were strongly predictive of disease. Leveraging this resource, we reprioritized thousands of rare de novo risk variants associated with autism spectrum disorders (ASDs), intellectual disability, and neurodevelopmental disorders (NDDs) to potentially more-severe consequences and revealed a larger proportion of cryptic splice variants than previously reported.CONCLUSIONOur study offers a comprehensive landscape of isoform diversity in the human neocortex during development. This extensive cataloging of isoforms and splicing events sheds light on the underlying mechanisms of NDDs and presents an opportunity to explore rare genetic variants linked to these conditions. Our findings also provide crucial insights into the molecular basis of developmental brain disorders and pave the way for targeted therapeutic interventions. To facilitate exploration of this dataset we developed an online portal (https://sciso.gandallab.org/). |
| Author | Patowary, Ashok Zhang, Pan Pasaniuc, Bogdan de la Torre-Ubieta, Luis Jops, Connor Li, Jingyi Jessica Vo, Daniel Liu, Chunyu Vuong, Celine K. Gong, Naihua Wang, Xusheng Ge, Xinzhou Margolis, Michael Hou, Kangcheng Kim, Minsoo Gandal, Michael J. |
| AuthorAffiliation | 10 Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38103, USA 5 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 12 Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA 3 Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA 16 Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA 9 Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA 8 Department of Statistics, University of California Los Angeles, Los Angeles, CA 90095, USA 7 Lifespan Brain Institute at Penn Med and the Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA 14 Department of Pathology and Laboratory Medicine, |
| AuthorAffiliation_xml | – name: 2 Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 10 Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38103, USA – name: 5 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – name: 8 Department of Statistics, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 4 Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 15 Institute for Precision Health, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 6 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – name: 7 Lifespan Brain Institute at Penn Med and the Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA – name: 16 Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 13 Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China – name: 1 Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 3 Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 14 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 11 Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA – name: 12 Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA – name: 17 Department of Biostatistics, University of California Los Angeles, Los Angeles, CA 90095, USA – name: 9 Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA |
| Author_xml | – sequence: 1 givenname: Ashok orcidid: 0000-0001-7507-3907 surname: Patowary fullname: Patowary, Ashok organization: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA., Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA., Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA – sequence: 2 givenname: Pan orcidid: 0000-0002-2233-9019 surname: Zhang fullname: Zhang, Pan organization: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA., Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA., Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA – sequence: 3 givenname: Connor orcidid: 0000-0003-3813-2407 surname: Jops fullname: Jops, Connor organization: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Lifespan Brain Institute at Penn Med and the Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA – sequence: 4 givenname: Celine K. orcidid: 0000-0002-8269-0660 surname: Vuong fullname: Vuong, Celine K. organization: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA., Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA – sequence: 5 givenname: Xinzhou surname: Ge fullname: Ge, Xinzhou organization: Department of Statistics, University of California Los Angeles, Los Angeles, CA 90095, USA – sequence: 6 givenname: Kangcheng orcidid: 0000-0001-7110-5596 surname: Hou fullname: Hou, Kangcheng organization: Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA – sequence: 7 givenname: Minsoo orcidid: 0000-0001-6657-8786 surname: Kim fullname: Kim, Minsoo organization: Department of Psychiatry and Biobehavioral Sciences, David Geffen 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Philadelphia, PA 19104, USA., Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Lifespan Brain Institute at Penn Med and the Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA – sequence: 11 givenname: Xusheng orcidid: 0000-0002-1759-9588 surname: Wang fullname: Wang, Xusheng organization: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38103, USA., Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA – sequence: 12 givenname: Chunyu orcidid: 0000-0002-5986-4415 surname: Liu fullname: Liu, Chunyu organization: Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA., Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China – sequence: 13 givenname: Bogdan surname: Pasaniuc fullname: Pasaniuc, Bogdan organization: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA., Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Institute for Precision Health, University of California Los Angeles, Los Angeles, CA 90095, USA., Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA – sequence: 14 givenname: Jingyi Jessica orcidid: 0000-0002-9288-5648 surname: Li fullname: Li, Jingyi Jessica organization: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Department of Statistics, University of California Los Angeles, Los Angeles, CA 90095, USA., Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA., Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Department of Biostatistics, University of California Los Angeles, Los Angeles, CA 90095, USA – sequence: 15 givenname: Michael J. orcidid: 0000-0001-5800-5128 surname: Gandal fullname: Gandal, Michael J. organization: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA., Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA., Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA – sequence: 16 givenname: Luis orcidid: 0000-0001-8059-6243 surname: de la Torre-Ubieta fullname: de la Torre-Ubieta, Luis organization: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA., Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38781356$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author contributions: A.P., M.J.G., and L.d.l.T.-U. conceived and designed the study. C.K.V. and L.d.l.T.-U. collected and processed the tissue specimens and dissected the samples for processing. A.P. and L.d.l.T.-U. generated the library for scIso-Seq. A.P. processed the single-cell raw data and performed the validation experiments. C.J. and A.P. analyzed bulk tissue Iso-Seq data; C.J. and M.J.G. analyzed bulk tissue isoform switching; P.Z., X.W., and C.L. performed the proteomic analysis; N.G. performed the APA analysis; C.K.V. performed the RBP-associated analysis; C.K.V., L.d.l.T.-U., and M.J.G. conducted network analyses; A.P., C.J., and M.M. performed scIso-Seq analysis; and M.K., D.V., and A.P. performed single-cell isoform-switch analysis. X.G. and J.J.L. performed single-cell DTU analysis; A.P. and L.d.l.T.-U. analyzed the DTU results; and M.J.G., L.d.l.T.-U., P.Z., K.H., C.J., A.P., and B.P. performed the disease enrichment analysis. A.P., C.K.V., M.J.G., and L.d.l.T.-U. interpreted the data. A.P., C.K.V., P.Z., M.J.G., and L.d.l.T.-U. wrote the manuscript. These authors contributed equally to this work. |
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| Snippet | RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type–specific splicing and... RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type-specific splicing and... INTRODUCTIONThe development of the human brain is regulated by precise molecular mechanisms driving spatiotemporal and cell type–specific transcript expression... |
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| SubjectTerms | Alternative Splicing Autism Autism Spectrum Disorders Brain Cellular structure Cerebral cortex Clustering Disorders Exons Gene expression Gene sequencing Genetic diversity Genetic Predisposition to Disease Genetic variance Humans Intellectual disabilities Isoforms Mental disorders Mental Disorders - genetics Molecular modelling Molecular Sequence Annotation Neocortex Neocortex - embryology Neocortex - metabolism Neurodevelopmental disorders Neurogenesis Neurogenesis - genetics Protein Isoforms - genetics Protein Isoforms - metabolism Protein structure Proteins Proteomes Ribonucleic acid RNA RNA Splicing RNA-binding protein RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Single-Cell Analysis Therapeutic applications Transcriptome Transcriptomes Transcriptomics Transcripts (Written Records) |
| Title | Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms |
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