Transcriptome variation in human tissues revealed by long-read sequencing.
Transcriptome variation in human tissues revealed by long-read sequencing.
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长阅读测序揭示了人体组织中的转录组变化。
DOI：
10.1038/s41586-022-05035-y
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发表时间：
2022-08
期刊：
影响因子：
64.8
通讯作者：
Cummings, Beryl
中科院分区：
文献类型：
--
作者：
Glinos, Dafni A.;Garborcauskas, Garrett;Hoffman, Paul;Ehsan, Nava;Jiang, Lihua;Gokden, Alper;Dai, Xiaoguang;Aguet, Francois;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
转录本结构的调控产生了转录本多样性，在人类疾病中起着重要作用。长读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。在本文中，我们利用牛津纳米孔技术平台从88个GTEx组织和细胞系样本中提供了一个大型的人类长读RNA-seq数据集，补充了GTEx资源。我们鉴定了超过70,000个新转录本的注释基因，并验证了10%的新转录本的蛋白质表达。我们开发了一个新的计算包，LORALS，通过长读取的等位基因特异性分析来分析罕见和常见变异对转录组的遗传影响。我们称之为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，并突出了从长读数据中获得的分辨率。我们能够通过敲低PTBP1（一种介导剪接的RNA结合蛋白）来扰乱转录本结构，从而发现被细胞环境修饰的遗传调控效应。最后，我们使用该数据集来增强变异解释，并研究导致异常剪接模式的罕见变异。
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 over 70,000 new transcripts for annotated genes, and validated the protein expression of 10% of novel transcripts. We developed a new computational package, LORALS, to analyse 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.
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影响因子：
12.3
作者：
Castel SE;Levy-Moonshine A;Mohammadi P;Banks E;Lappalainen T
通讯作者：
Lappalainen T
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Jiang L;Wang M;Lin S;Jian R;Li X;Chan J;Dong G;Fang H;Robinson AE;GTEx Consortium;Snyder MP
通讯作者：
Snyder MP
影响因子：
17.1
作者：
Cummings BB;Marshall JL;Tukiainen T;Lek M;Donkervoort S;Foley AR;Bolduc V;Waddell LB;Sandaradura SA;O'Grady GL;Estrella E;Reddy HM;Zhao F;Weisburd B;Karczewski KJ;O'Donnell-Luria AH;Birnbaum D;Sarkozy A;Hu Y;Gonorazky H;Claeys K;Joshi H;Bournazos A;Oates EC;Ghaoui R;Davis MR;Laing NG;Topf A;Genotype-Tissue Expression Consortium;Kang PB;Beggs AH;North KN;Straub V;Dowling JJ;Muntoni F;Clarke NF;Cooper ST;Bönnemann CG;MacArthur DG
通讯作者：
MacArthur DG
影响因子：
7
作者：
Battle A;Mostafavi S;Zhu X;Potash JB;Weissman MM;McCormick C;Haudenschild CD;Beckman KB;Shi J;Mei R;Urban AE;Montgomery SB;Levinson DF;Koller D
通讯作者：
Koller D