Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq

Bernardo Aguzzoli Heberle, J. Anthony Brandon, Madeline L. Page, Kayla A. Nations, Ketsile I. Dikobe, Brendan J. White, Lacey A. Gordon, Grant A. Fox, Mark E. Wadsworth, Patricia H. Doyle, Brittney A. Williams, Edward J. Fox, Anantharaman Shantaraman, Mina Ryten, Sara Goodwin, Elena Ghiban, Robert Wappel, Senem Mavruk-Eskipehlivan, Justin B. Miller, Nicholas T. SeyfriedPeter T. Nelson, John D. Fryer, Mark T.W. Ebbert

Research output: Contribution to journalArticlepeer-review

Abstract

Determining whether the RNA isoforms from medically relevant genes have distinct functions could facilitate direct targeting of RNA isoforms for disease treatment. Here, as a step toward this goal for neurological diseases, we sequenced 12 postmortem, aged human frontal cortices (6 Alzheimer disease cases and 6 controls; 50% female) using one Oxford Nanopore PromethION flow cell per sample. We identified 1,917 medically relevant genes expressing multiple isoforms in the frontal cortex where 1,018 had multiple isoforms with different protein-coding sequences. Of these 1,018 genes, 57 are implicated in brain-related diseases including major depression, schizophrenia, Parkinson’s disease and Alzheimer disease. Our study also uncovered 53 new RNA isoforms in medically relevant genes, including several where the new isoform was one of the most highly expressed for that gene. We also reported on five mitochondrially encoded, spliced RNA isoforms. We found 99 differentially expressed RNA isoforms between cases with Alzheimer disease and controls.

Original languageEnglish
JournalNature Biotechnology
DOIs
StateAccepted/In press - 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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