美国博德研究所Beryl B. Cummings等研究人员合作利用长读测序揭示人类组织的转录组变化。这一研究成果于2022年8月3日在线发表在国际学术期刊《自然》上。
研究人员利用牛津纳米孔技术平台提出了一个大型的人类长读RNA-seq数据集，该数据集来自于基因型-组织表达（GTEx）组织和细胞系的88个样本，并补充了GTEx资源。研究人员确定了超过70,000个被注释基因的新转录本，并验证了10%新转录本的蛋白质表达。研究人员开发了一个新的计算包，LORALS，通过长读数的等位基因特异性分析来揭示罕见和常见变异对转录组的遗传影响。
研究人员描述了等位基因特异性表达和转录本结构事件，为常见和罕见遗传变异引起的特定转录本改变提供了新的见解，并强调了从长读数据中获得的分辨率。研究人员能够在敲除PTBP1（一种介导剪接的RNA结合蛋白）后扰乱转录本结构，从而发现被细胞环境改变的遗传调节效应。最后，研究人员用这个数据集来加强了变体解释，并研究了导致异常剪接模式的罕见变体。
据介绍，转录本结构的调控产生了转录本的多样性，并在人类疾病中发挥着重要作用。长度测序技术的出现为研究遗传变异在转录本结构中的作用提供了机会。
附：英文原文
Title: Transcriptome variation in human tissues revealed by long-read sequencing
Author: Glinos, Dafni A., Garborcauskas, Garrett, Hoffman, Paul, Ehsan, Nava, Jiang, Lihua, Gokden, Alper, Dai, Xiaoguang, Aguet, Franois, Brown, Kathleen L., Garimella, Kiran, Bowers, Tera, Costello, Maura, Ardlie, Kristin, Jian, Ruiqi, Tucker, Nathan R., Ellinor, Patrick T., Harrington, Eoghan D., Tang, Hua, Snyder, Michael, Juul, Sissel, Mohammadi, Pejman, MacArthur, Daniel G., Lappalainen, Tuuli, Cummings, Beryl B.
Issue&Volume: 2022-08-03
Abstract: Regulation of transcript structure generates transcript diversity and plays an important role in human disease1,2,3,4,5,6,7. The advent of long-read sequencing technologies offers the opportunity to study the role of genetic variation in transcript structure8,9,10,11,12,13,14,15,16. 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.
DOI: 10.1038/s41586-022-05035-y
Source: https://www.nature.com/articles/s41586-022-05035-y
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
