Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms-Reference-Cited by-同舟云学术

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Published:2024-05-24 Issue:6698 Volume:384 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Patowary Ashok¹²³⁴^ORCID,Zhang Pan¹²³⁴^ORCID,Jops Connor⁵⁶⁷^ORCID,Vuong Celine K.¹²³^ORCID,Ge Xinzhou⁸,Hou Kangcheng⁹^ORCID,Kim Minsoo¹²⁴^ORCID,Gong Naihua⁵^ORCID,Margolis Michael⁴^ORCID,Vo Daniel⁵⁶⁷^ORCID,Wang Xusheng¹⁰¹¹^ORCID,Liu Chunyu¹²¹³^ORCID,Pasaniuc Bogdan⁴⁹¹⁴¹⁵¹⁶,Li Jingyi Jessica⁴⁸⁹¹⁶¹⁷^ORCID,Gandal Michael J.¹²³⁴⁵^ORCID,de la Torre-Ubieta Luis¹²³^ORCID

Affiliation:

1. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

2. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, 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.

4. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

5. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

6. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

7. Lifespan Brain Institute at Penn Med and the Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.

8. Department of Statistics, University of California Los Angeles, Los Angeles, CA 90095, USA.

9. Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA.

10. Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38103, USA.

11. Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

12. Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

13. Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China.

14. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

15. Institute for Precision Health, 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.

17. Department of Biostatistics, University of California Los Angeles, Los Angeles, CA 90095, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adh7688

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