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Transcriptome variation in human tissues revealed by long-read sequencing
Nature ( IF 64.8 ) Pub Date : 2022-08-03 , DOI: 10.1038/s41586-022-05035-y
Dafni A Glinos 1, 2 , Garrett Garborcauskas 3 , Paul Hoffman 1 , Nava Ehsan 4 , Lihua Jiang 5 , Alper Gokden 1 , Xiaoguang Dai 6 , François Aguet 7 , Kathleen L Brown 1, 8 , Kiran Garimella 7 , Tera Bowers 7 , Maura Costello 7 , Kristin Ardlie 7 , Ruiqi Jian 5 , Nathan R Tucker 9, 10 , Patrick T Ellinor 10 , Eoghan D Harrington 6 , Hua Tang 5 , Michael Snyder 5 , Sissel Juul 6 , Pejman Mohammadi 4, 11 , Daniel G MacArthur 3, 12, 13 , Tuuli Lappalainen 1, 2, 14 , Beryl B Cummings 3
Affiliation  

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.



中文翻译:

长读长测序揭示人体组织转录组变异

转录本结构的调节产生转录本多样性,并在人类疾病中发挥重要作用1,2,3,4,5,6,7。长读长测序技术的出现为研究转录本结构中遗传变异的作用提供了机会8,9,10,11,12,13,14,15,16。在本文中,我们使用 Oxford Nanopore Technologies 平台展示了来自基因型组织表达 (GTEx) 组织和细胞系的 88 个样本的大型人类长读 RNA-seq 数据集,补充了 GTEx 资源。我们鉴定了 70,000 多个注释基因的新转录本,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,通过长读长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。我们表征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。我们能够在敲低 PTBP1(一种介导剪接的 RNA 结合蛋白)后扰乱转录物结构,从而发现细胞环境改变的遗传调控效应。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。

更新日期:2022-08-03
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