对拼接变体的深度学习分析确定了PCP4与肌缩侧面硬化症的联系
Xuelin Tang1,2,3, Yan Chen4, Yongfei Ren5
1State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Clinical Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, 200331, Shanghai, China.
Brain : a journal of neurology
|January 24, 2025
概括
我们开发了Spliformer,这是一款深度学习工具,可以准确预测肌缩侧面硬化症 (ALS) 的RNA拼接缺陷. 这种工具确定了新的ALS相关基因,包括PCP4,为神经退行性疾病机制提供了新的见解.
科学领域:
- 遗传学 遗传学 是一个
- 神经科学是一个神经科学.
- 生物信息学是一种生物信息学.
背景情况:
- 肌缩侧面硬化症 (ALS) 是一种严重的运动神经元疾病,大多数零星病例的遗传原因不明.
- 异常的mRNA前拼接,特别是由于TAR DNA结合蛋白43 (TDP-43) 功能丧失,与ALS的发病有关.
- 内部变异在驱动ALS中的RNA错误拼接中的作用尚不清楚.
研究的目的:
- 开发和验证一个深度学习模型 (Spliformer) 来准确预测RNA拼接事件.
- 识别与ALS风险,进展和新型ALS相关基因相关的内基因变异.
- 研究确定ALS相关基因在神经元健康中的功能作用.
主要方法:
- 开发了基于转换器的深度学习模型Spliformer,用于RNA拼接预测,以GENCODE和RNA-seq数据进行训练.
- 与SpliceAI和Pangolin相比,基准分离器使用配对全基因组测序 (WGS) 和RNA-seq数据.
- 分析了ALS患者的Clinvar和WGS数据,以确定拼接变体和相关基因;使用小基因测试和功能研究验证了发现.
主要成果:
- 与现有的工具相比,Spliformer在预测拼接事件方面表现出更高的速度和准确性.
- 拼接器-动机成功识别了新的拼接监管动机.
- 分析揭示了与ALS病原性和进展相关的拼接变异,并确定了已知的ALS基因 (例如PTPRN2,CFAP410) 和TDP-43相关基因 (例如PTPRD) 中的罕见变异.
- PCP4和TMEM63A被提名为新型ALS相关基因,PCP4被证明对维持神经元脊柱密度至关重要.
结论:
- 分离器和分离器-动机提供准确的预测和解释前mRNA拼接.
- 内部遗传变异代表着一个重要的机制,驱动ALS的RNA错误拼接.
- PCP4被确定为一种与ALS相关的新型基因,对神经元功能至关重要.
相关概念视频
01:32RNA Splicing
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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...
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02:18Alternative RNA Splicing
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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...
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