Using deep long-read RNAseq in Alzheimer's disease brain to assess medical relevance of RNA isoform diversity.

Autor:	Heberle BA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY.; Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY., Brandon JA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY., Page ML; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY., Nations KA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY., Dikobe KI; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY., White BJ; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY., Gordon LA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY., Fox GA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY.; Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY., Wadsworth ME; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY., Doyle PH; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY.; Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY., Williams BA; Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY., Fox EJ; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Shantaraman A; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA., Ryten M; Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK., Goodwin S; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States., Ghiban E; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States., Wappel R; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States., Mavruk-Eskipehlivan S; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States., Miller JB; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY.; Division of Biomedical Informatics, Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY.; Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA.; Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY, USA., Seyfried NT; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Nelson PT; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY., Fryer JD; Department of Neuroscience, Mayo Clinic, Scottsdale, Arizona., Ebbert MTW; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY.; Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY.; Division of Biomedical Informatics, Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 11. Date of Electronic Publication: 2023 Dec 11.
DOI:	10.1101/2023.08.06.552162
Abstrakt:	Due to alternative splicing, human protein-coding genes average over eight RNA isoforms, resulting in nearly four distinct protein coding sequences per gene. Long-read RNAseq (IsoSeq) enables more accurate quantification of isoforms, shedding light on their specific roles. To assess the medical relevance of measuring RNA isoform expression, we sequenced 12 aged human frontal cortices (6 Alzheimer's disease cases and 6 controls; 50% female) using one Oxford Nanopore PromethION flow cell per sample. Our study uncovered 53 new high-confidence RNA isoforms in medically relevant genes, including several where the new isoform was one of the most highly expressed for that gene. Specific examples include WDR4 (61%; microcephaly), MYL3 (44%; hypertrophic cardiomyopathy), and MTHFS (25%; major depression, schizophrenia, bipolar disorder). Other notable genes with new high-confidence isoforms include CPLX2 (10%; schizophrenia, epilepsy) and MAOB (9%; targeted for Parkinson's disease treatment). We identified 1,917 medically relevant genes expressing multiple isoforms in human frontal cortex, where 1,018 had multiple isoforms with different protein coding sequences, demonstrating the need to better understand how individual isoforms from a single gene body are involved in human health and disease, if at all. Exactly 98 of the 1,917 genes are implicated in brain-related diseases, including Alzheimer's disease genes such as APP (Aβ precursor protein; five), MAPT (tau protein; four), and BIN1 (eight). As proof of concept, we also found 99 differentially expressed RNA isoforms between Alzheimer's cases and controls, despite the genes themselves not exhibiting differential expression. Our findings highlight the significant knowledge gaps in RNA isoform diversity and their medical relevance. Deep long-read RNA sequencing will be necessary going forward to fully comprehend the medical relevance of individual isoforms for a "single" gene. Competing Interests: Competing interests The authors report no competing interests.
Databáze:	MEDLINE
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