Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Ashok Patowary; Pan Zhang; Connor Jops; Celine K Vuong; Xinzhou Ge; Kangcheng Hou; Minsoo Kim; Naihua Gong; Michael Margolis; Daniel Vo; Xusheng Wang; Chunyu Liu; Bogdan Pasaniuc; Jingyi Jessica Li; Michael J Gandal; Luis de la Torre-Ubieta

doi:10.1126/science.adh7688

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Science. 2024 May 24;384(6698):eadh7688. doi: 10.1126/science.adh7688. Epub 2024 May 24.

Authors

Ashok Patowary^#^{1

2

3

4}, Pan Zhang^#^{1

2

3

4}, Connor Jops^#^{5

6

7}, Celine K Vuong^{1

2

3}, Xinzhou Ge⁸, Kangcheng Hou⁹, Minsoo Kim^{1

2

4}, Naihua Gong⁵, Michael Margolis⁴, Daniel Vo^{5

6

7}, Xusheng Wang^{10

11}, Chunyu Liu^{12

13}, Bogdan Pasaniuc^{4

9

14

15

16}, Jingyi Jessica Li^{4

8

9

16

17}, Michael J Gandal^{1

2

3

4

5

6

7}, Luis de la Torre-Ubieta^{1

2

3}

Affiliations

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.

^# Contributed equally.

PMID: 38781356
DOI: 10.1126/science.adh7688

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.

MeSH terms

Alternative Splicing
Genetic Predisposition to Disease
Humans
Mental Disorders* / genetics
Molecular Sequence Annotation
Neocortex* / embryology
Neocortex* / metabolism
Neurogenesis* / genetics
Protein Isoforms* / genetics
Protein Isoforms* / metabolism
RNA Splicing*
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Single-Cell Analysis*
Transcriptome*

Substances

Protein Isoforms
RNA-Binding Proteins

Grants and funding

R01 MH124018/MH/NIMH NIH HHS/United States