The ENCODE4 long-read RNA-seq collection reveals distinct classes of transcript structure diversity

作者：Fairlie Reese, Brian A. Williams, Gabriela Balderrama-Gutierrez, Dana Wyman, Muhammed Hasan Çelik, Elisabeth Rebboah, Narges Rezaie, Diane Trout, Milad Razavi-Mohseni, Yunzhe Jiang, Beatrice Borsari, Samuel Morabito, Heidi Yahan Liang, Cassandra McGill, Sorena Rahmanian, Jasmine Sakr, Shan Jiang, Weihua Zeng, Klébea Carvalho, Annika K. Weimer, Louise A. Dionne, Ariel McShane, Karan Bedi, Shaimae I. Elhajjajy, Sean Upchurch, Jennifer Jou, Ingrid Youngworth, Idan Gabdank, Paul Sud, Otto Jolanki, J. Seth Strattan, Meenakshi S. Kagda, M Snyder, Ben C. Hitz, Jill E. Moore, Zhiping Weng, David A. Bennett, Laura G. Reinholdt, Mats Ljungman, M Beer, Mark Gerstein, Lior Pachter, Roderic Guigó, B Wold, A Mortazavi · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2023 · DOI：10.1101/2023.05.15.540865 · 被引用次数：65 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、RNA Research and Splicing

The majority of mammalian genes encode multiple transcript isoforms that result from differential promoter use, changes in exonic splicing, and alternative 3' end choice. Detecting and quantifying transcript isoforms across tissues, cell types, and species has been extremely challenging because transcripts are much longer than the short reads normally used for RNA-seq. By contrast, long-read RNA-seq (LR-RNA-seq) gives the complete structure of most transcripts. We sequenced 264 LR-RNA-seq PacBio libraries totaling over 1 billion circular consensus reads (CCS) for 81 unique human and mouse samples. We detect at least one full-length transcript from 87.7% of annotated human protein coding genes and a total of 200,000 full-length transcripts, 40% of which have novel exon junction chains. To capture and compute on the three sources of transcript structure diversity, we introduce a gene and transcript annotation framework that uses triplets representing the transcript start site, exon junction chain, and transcript end site of each transcript. Using triplets in a simplex representation demonstrates how promoter selection, splice pattern, and 3' processing are deployed across human tissues, with nearly half of multi-transcript protein coding genes showing a clear bias toward one of the three diversity mechanisms. Evaluated across samples, the predominantly expressed transcript changes for 74% of protein coding genes. In evolution, the human and mouse transcriptomes are globally sim...