在肝脏中通过ATAC-seq定义的足迹QTL结合转录因子的非编码变异的表征
Max F Dudek1,2, Brandon M Wenz3,4, Christopher D Brown2,3,4
1Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
bioRxiv : the preprint server for biology
|October 10, 2024
概括
我们通过分析转录因子结合在人类肝脏DNA中来确定足迹定量特征位点 (fpQTLs). 这些fpQTLs有助于在全基因组关联研究 (GWAS) 中确定因果变异,推动疾病研究.
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:
- 全基因组关联研究 (GWAS) 将非编码变体与调控元素和转录因子 (TF) 结合动机联系起来.
- 干扰 cis 调节序列与疾病相关.
- ATAC-seq通过"足迹"来检测TF的占用,其中绑定的TF阻止了转化酶插入.
研究的目的:
- 为了确定与人类肝脏中TF结合相关的"足迹定量特征位点" (fpQTLs).
- 利用fpQTL进行精细映射GWAS位置和理解非编码变异函数.
主要方法:
- 从170个人类肝脏样本中生成的ATAC-seq数据.
- 从ATAC-seq读数计算使用"足迹分数"来量化TF结合概率.
- 在全基因组测序数据中测试了基因型和足迹得分之间的关联.
主要成果:
- 发现了693个与TF结合相关的fpQTL,错误发现率 (FDR) < 5%.
- fpQTLs精确地确定了广的GWAS位置内的TF活动.
- 肝脏的fpQTLs显示在ChIP-seq峰值,eQTL和GWAS位点中的丰富,TF结合和动机效应之间有80%的一致性.
结论:
- fpQTLs可以识别因果GWAS变异,并阐明TF结合部位中断在疾病中的作用.
- 这种方法提供了对非编码变体的功能洞察,可能为常见疾病的新疗法提供信息.
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