使用LeafCutter2进行非生产性拼接的遗传和功能分析
bioRxiv : the preprint server for biology
|April 28, 2025
概括
LeafCutter2识别了非生产性拼接,这是一个降低蛋白质水平并影响基因调节的过程. 该工具揭示了在发育过程中保存的拼接变化,并将非生产性拼接与阿尔茨海默病风险基因联系起来.
科学领域:
- 基因组学就是基因组学.
- 分子生物学分子生物学
- 生物信息学是一种生物信息学.
背景情况:
- 替代拼接会产生具有过早终止子的非生产性mRNA转录,从而通过无意义中介衰变 (NMD) 导致降解.
- 这些事件可以降低蛋白质表达,影响基因调节和疾病发病.
- 目前分析来自RNA测序数据的非生产性拼接的方法有限.
研究的目的:
- 介绍LeafCutter2,一个新的计算工具,用于从短读RNA测序数据中识别和量化非生产性拼接事件.
- 研究跨物种,组织和发育阶段的非生产性拼接的景观和调节.
- 探索非生产性拼接在阿尔茨海默病 (AD) 和其遗传基础中的作用.
主要方法:
- LeafCutter2使用最小的基因注释 (启动和停止编码) 来识别NMD诱导的拼接事件.
- 该工具允许在样本组之间对非生产性拼接进行差异分析,并绘制非生产性拼接定量特征位置 (u-sQTL).
- 应用于来自多种人类和非人类物种的RNA-seq数据,包括AD患者队列.
主要成果:
- LeafCutter2成功地在各种物种和组织中识别和量化了非生产性拼接事件,揭示了显著的差异.
- 在丸成熟期间观察到非生产性剪接的保存,发育调节的增加.
- 在18个阿尔茨海默氏症风险基因中发现了非生产性拼接事件,这表明它在调解阿尔茨海默氏症遗传风险方面发挥了作用.
结论:
- LeafCutter2是分析非生产性拼接及其对基因表达的功能后果的强大工具.
- 非生产性拼接在基因调节,发育和疾病中发挥着重要作用,提供了超越传统表达量化特征位点 (eQTL) 分析的见解.
- 这些发现强调了考虑非生产性拼接在理解AD等复杂疾病的遗传贡献方面的重要性.
相关概念视频
Pre-mRNA Processing: RNA Splicing
5.1K
5.1K
Alternative RNA Splicing
3.6K
3.6K
Chromatin Structure and RNA Splicing
2.7K
2.7K
Pre-mRNA Processing: Modification of pre-mRNA Ends
9.1K
In eukaryotic cells, transcripts made by RNA polymerase are modified and processed before exiting the nucleus. Unprocessed RNA is called precursor mRNA or pre-mRNA to distinguish it from mature mRNA.
Once about 20-40 ribonucleotides have been joined together by RNA polymerase, a group of enzymes adds a cap to the 5' end of the growing transcript. In this process, a 5' phosphate is replaced by modified guanosine that has a methyl group attached (7-methyl guanosine). This 5' cap helps...
Once about 20-40 ribonucleotides have been joined together by RNA polymerase, a group of enzymes adds a cap to the 5' end of the growing transcript. In this process, a 5' phosphate is replaced by modified guanosine that has a methyl group attached (7-methyl guanosine). This 5' cap helps...
9.1K
RNA Editing
8.8K
RNA editing is a post-transcriptional modification where a precursor mRNA (pre-mRNA) nucleotide sequence is changed by base insertion, deletion, or modification. The extent of RNA editing varies from a few hundred bases, in mitochondrial DNA of trypanosomes, to a just single base, in nuclear genes of mammals. Even a single base change in the pre-mRNA can convert a codon for one amino acid into the codon for another amino acid or a stop codon. This type of re-coding can significantly affect the...
8.8K
Nonsense-mediated mRNA Decay
10.3K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
10.3K


