将遗传变异与深度学习相结合,为影响胚胎发生过程中转录因子结合的变异提供了背景
Olga M Sigalova1, Mattia Forneris1, Frosina Stojanovska2,3
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
Genome research
|April 15, 2025
概括
遗传变异显著影响转录因子 (TF) 的结合,影响疾病风险. 我们的研究揭示了基因差异如何改变TF结合部位,并提供了预测这些效应的工具.
科学领域:
- 基因组学就是基因组学.
- 分子生物学分子生物学
- 发育生物学 发展生物学
背景情况:
- 了解遗传变异对转录因子 (TF) 结合的影响,对于模拟疾病至关重要.
- 当前的方法在准确地分析异位基因特异性TF结合时面临挑战.
研究的目的:
- 研究遗传变异如何影响Drosophila胚胎发生过程中的TF结合.
- 开发和完善用于检测和解释基因特异性TF结合的计算工具.
主要方法:
- 使用具有多样性遗传背景的受控F1交叉来定位基因特异性TF结合概况.
- 扩展了WASP工具以检测indels,提高了对基失衡的TF结合峰值的识别.
- 训练了一个卷积神经网络 (Basenji) 来预测来自DNA序列的TF结合和模型等位基因失衡.
主要成果:
- 鉴定了受基因变异影响的9-18%的TF-bound地区,即使对于基本的TFs.
- 使用增强的WASP工具增加了30%-50%的基失衡峰值的检测.
- 巴森吉模型准确地预测了TF结合和基失衡,为变异效应提供了机理性的洞察力.
结论:
- 遗传变异在调节TF结合动态方面发挥着重要作用.
- 开发了先进的计算方法,用于精确识别和解释影响TF结合的遗传变异.
- 发现了新的TF关系和组织特异性的结合机制,包括CTCF.
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