在西班牙ASD (自闭症谱系障碍) 队列中进行替代拼接分析:in silico预测和表征
S Dominguez-Alonso1, M Tubío-Fungueiriño1, J González-Peñas2
1Grupo de Medicina Xenómica, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
Scientific reports
|March 29, 2025
概括
这项研究使用计算工具识别了自闭症谱系障碍 (ASD) 中的拼接变体,揭示了潜在的组织特异性影响和独特的分子通路. 这些发现凸显了替代拼接在ASD病变发生过程中的作用.
科学领域:
- 遗传学和基因组学 遗传学和基因组学
- 神经发育障碍 神经发育障碍
- 计算生物学 计算生物学
背景情况:
- 自闭症谱系障碍 (ASD) 是一种复杂的神经发育状况,具有异质的遗传基础.
- 替代拼接 (AS) 越来越多地被认为是ASD病原体的贡献者,但其在大型基因组研究中的作用仍未得到充分探索.
研究的目的:
- 在西班牙ASD队列中以计算方式识别,预测和验证拼接变体.
- 调查这些拼接变体对ASD病因及其组织特异性影响的潜在贡献.
主要方法:
- 利用SpliceAI在360个西班牙自闭症三组中进行高可信度拼接变体识别 (值 Δ ≥ 0.8).
- 使用SpliceVault进行了in silico验证,使用335,663个RNA测序数据集 (GTEx v8,SRA) 和使用ABSplice进行直角确认.
- 进行基因验证和基因本体学 (GO) 分析,使用来自42,000多例自闭症病例的互补数据集.
主要成果:
- 在包括CACNA1I,CBLB,CLTB,DLGAP1,DVL3,KIAA0513,OFD1,PKD1,SLC13A3和SCN2A在内的基因中发现了拼接变异的潜在贡献.
- 揭示了拼接变体的组织特异性影响,特别是在脂肪组织,丸和大脑中.
- 拼接基因主要与突触组织和传播有关,与与染色体重塑相关的非拼接ASD基因形成鲜明对比.
结论:
- 这项研究促进了对替代拼接在ASD病变发生过程中的作用的理解.
- 研究结果表明,特定的组织和分子通路,包括突触功能,都与ASD有关.
- 进一步的体外验证和多组合的整合是有必要的,以阐明功能角色和监管相互作用.
相关概念视频
01:32RNA Splicing
Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
02:18Alternative RNA Splicing
Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
01:32Pre-mRNA Processing: RNA Splicing
Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
02:18Alternative RNA Splicing
Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...