Full-length transcript sequencing of human and mouse cerebral cortex identifies widespread isoform diversity and alternative splicing
Szi Kay Leung,
Aaron R. Jeffries,
Isabel Castanho,
Ben T. Jordan,
Karen Moore,
Jonathan P. Davies,
Emma L. Dempster,
Nicholas J. Bray,
Paul O’Neill,
Elizabeth Tseng,
Zeshan Ahmed,
David A. Collier,
Erin D. Jeffery,
Shyam Prabhakar,
Leonard Schalkwyk,
Connor Jops,
Michael J. Gandal,
Gloria M. Sheynkman,
Eilis Hannon,
Jonathan Mill
Affiliations
Szi Kay Leung
University of Exeter, Exeter, UK
Aaron R. Jeffries
University of Exeter, Exeter, UK
Isabel Castanho
University of Exeter, Exeter, UK; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Ben T. Jordan
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA
Karen Moore
University of Exeter, Exeter, UK
Jonathan P. Davies
University of Exeter, Exeter, UK
Emma L. Dempster
University of Exeter, Exeter, UK
Nicholas J. Bray
School of Medicine, Cardiff University, Cardiff, UK
Paul O’Neill
University of Exeter, Exeter, UK
Elizabeth Tseng
Pacific Biosciences, Menlo Park, CA, USA
Zeshan Ahmed
Eli Lilly & Co., Windlesham, UK
David A. Collier
Eli Lilly & Co., Windlesham, UK
Erin D. Jeffery
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA
Shyam Prabhakar
Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
Leonard Schalkwyk
School of Life Sciences, University of Essex, Colchester, UK
Connor Jops
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA
Michael J. Gandal
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA
Gloria M. Sheynkman
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; UVA Cancer Center, University of Virginia, Charlottesville, VA, USA
Eilis Hannon
University of Exeter, Exeter, UK
Jonathan Mill
University of Exeter, Exeter, UK; Corresponding author
Summary: Alternative splicing is a post-transcriptional regulatory mechanism producing distinct mRNA molecules from a single pre-mRNA with a prominent role in the development and function of the central nervous system. We used long-read isoform sequencing to generate full-length transcript sequences in the human and mouse cortex. We identify novel transcripts not present in existing genome annotations, including transcripts mapping to putative novel (unannotated) genes and fusion transcripts incorporating exons from multiple genes. Global patterns of transcript diversity are similar between human and mouse cortex, although certain genes are characterized by striking differences between species. We also identify developmental changes in alternative splicing, with differential transcript usage between human fetal and adult cortex. Our data confirm the importance of alternative splicing in the cortex, dramatically increasing transcriptional diversity and representing an important mechanism underpinning gene regulation in the brain. We provide transcript-level data for human and mouse cortex as a resource to the scientific community.
