RT Journal Article SR Electronic T1 Transcriptome variation in human tissues revealed by long-read sequencing JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.01.22.427687 DO 10.1101/2021.01.22.427687 A1 Dafni A Glinos A1 Garrett Garborcauskas A1 Paul Hoffman A1 Nava Ehsan A1 Lihua Jiang A1 Alper Gokden A1 Xiaoguang Dai A1 Francois Aguet A1 Kathleen L. Brown A1 Kiran Garimella A1 Tera Bowers A1 Maura Costello A1 Kristin Ardlie A1 Ruiqi Jian A1 Nathan R Tucker A1 Patrick T Ellinor A1 Eoghan D Harrington A1 Hua Tang A1 Michael Snyder A1 Sissel Juul A1 Pejman Mohammadi A1 Daniel G MacArthur A1 Tuuli Lappalainen A1 Beryl Cummings YR 2021 UL http://biorxiv.org/content/early/2021/01/23/2021.01.22.427687.abstract AB Regulation of transcript structure generates transcript diversity and plays an important role in human disease. The advent of long-read sequencing technologies offers the opportunity to study the role of genetic variation in transcript structure. In this paper, we present a large human long-read RNA-seq dataset using the Oxford Nanopore Technologies platform from 88 samples from GTEx tissues and cell lines, complementing the GTEx resource. We identified just under 100,000 new transcripts for annotated genes, and validated the protein expression of a similar proportion of novel and annotated transcripts. We developed a new computational package, LORALS, to analyze genetic effects of rare and common variants on the transcriptome via allele-specific analysis of long reads. We called allele-specific expression and transcript structure events, providing novel insights into the specific transcript alterations caused by common and rare genetic variants and highlighting the resolution gained from long-read data. We were able to perturb transcript structure upon knockdown of PTBP1, an RNA binding protein that mediates splicing, thereby finding genetic regulatory effects that are modified by the cellular environment. Finally, we use this dataset to enhance variant interpretation and study rare variants leading to aberrant splicing patterns.Competing Interest StatementXD, EDH, and SJ are employees of Oxford Nanopore Technologies and are shareholders and/or share option holders. FA holds stock in Pacific Biosciences. TL is an advisor of Variant Bio, Goldfinch Bio, and GSK and holds stock in Variant Bio. BC is currently employed at Maze Therapeutics.