Transcriptome variation in human tissues revealed by long-read sequencing

Dafni A. Glinos (), Garrett Garborcauskas (), Paul Hoffman, Nava Ehsan, Lihua Jiang, Alper Gokden, Xiaoguang Dai, François Aguet, Kathleen L. Brown, Kiran Garimella, Tera Bowers, Maura Costello, Kristin Ardlie, Ruiqi Jian, Nathan R. Tucker, Patrick T. Ellinor, Eoghan D. Harrington, Hua Tang, Michael Snyder, Sissel Juul, Pejman Mohammadi, Daniel G. MacArthur, Tuuli Lappalainen () and Beryl B. Cummings ()
Additional contact information
Dafni A. Glinos: New York Genome Center
Garrett Garborcauskas: The Broad Institute of MIT and Harvard
Paul Hoffman: New York Genome Center
Nava Ehsan: The Scripps Research Institute
Lihua Jiang: Stanford University
Alper Gokden: New York Genome Center
Xiaoguang Dai: Oxford Nanopore Technology
François Aguet: Broad Institute of MIT and Harvard
Kathleen L. Brown: New York Genome Center
Kiran Garimella: Broad Institute of MIT and Harvard
Tera Bowers: Broad Institute of MIT and Harvard
Maura Costello: Broad Institute of MIT and Harvard
Kristin Ardlie: Broad Institute of MIT and Harvard
Ruiqi Jian: Stanford University
Nathan R. Tucker: Masonic Medical Research Institute
Patrick T. Ellinor: The Broad Institute of Harvard and MIT
Eoghan D. Harrington: Oxford Nanopore Technology
Hua Tang: Stanford University
Michael Snyder: Stanford University
Sissel Juul: Oxford Nanopore Technology
Pejman Mohammadi: The Scripps Research Institute
Daniel G. MacArthur: The Broad Institute of MIT and Harvard
Tuuli Lappalainen: New York Genome Center
Beryl B. Cummings: The Broad Institute of MIT and Harvard

Nature, 2022, vol. 608, issue 7922, 353-359

Abstract: Abstract Regulation of transcript structure generates transcript diversity and plays an important role in human disease1–7. The advent of long-read sequencing technologies offers the opportunity to study the role of genetic variation in transcript structure8–16. In this Article, we present a large human long-read RNA-seq dataset using the Oxford Nanopore Technologies platform from 88 samples from Genotype-Tissue Expression (GTEx) tissues and cell lines, complementing the GTEx resource. We identified just over 70,000 novel transcripts for annotated genes, and validated the protein expression of 10% of novel transcripts. We developed a new computational package, LORALS, to analyse the genetic effects of rare and common variants on the transcriptome by allele-specific analysis of long reads. We characterized allele-specific expression and transcript structure events, providing new 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 the 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 used this dataset to enhance variant interpretation and study rare variants leading to aberrant splicing patterns.

Date: 2022
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DOI: 10.1038/s41586-022-05035-y

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