论文标题

Granger的因果推断DAGS鉴定了调节转录的基因组基因座

Granger causal inference on DAGs identifies genomic loci regulating transcription

论文作者

Singh, Rohit, Wu, Alexander P., Berger, Bonnie

论文摘要

当可以将动态系统建模为一系列观测系统时,Granger因果关系是检测其变量之间预测相互作用的强大方法。但是,传统的Granger因果推论在需要以定向的无环图(DAG)而不是线性序列(例如与细胞分化轨迹)表示动力学的域中有限的效用。在这里,我们提出网格网络,这是一个基于图形神经网络的框架,其滞后消息传递了Granger因果关系的推断,该框架推断了DAG结构化系统。我们激励的应用是对单细胞多模式数据的分析,以识别介导特定基因调节的基因组基因座。据我们所知,网格网络是第一个说明基因组基因座变得可访问的时间滞后与其对靶基因表达的下游效应之间的时间滞后的单细胞分析工具。我们将网格NET应用于多模式的单细胞测定,即在同一细胞中介绍了染色质访问性(ATAC-SEQ)和基因表达(RNA-SEQ),并表明它极大地优于推断监管基因座链接的现有方法,可与基于独立遗传学的估计量相吻合,达到71%的估计均高达71%。通过将Granger因果关系扩展到DAG结构的动力学系统,我们的工作可以为因果分析提供新的领域,更具体地说,为阐明与细胞分化和复杂人类疾病相关的基因调节相互作用打开了一条途径。

When a dynamical system can be modeled as a sequence of observations, Granger causality is a powerful approach for detecting predictive interactions between its variables. However, traditional Granger causal inference has limited utility in domains where the dynamics need to be represented as directed acyclic graphs (DAGs) rather than as a linear sequence, such as with cell differentiation trajectories. Here, we present GrID-Net, a framework based on graph neural networks with lagged message passing for Granger causal inference on DAG-structured systems. Our motivating application is the analysis of single-cell multimodal data to identify genomic loci that mediate the regulation of specific genes. To our knowledge, GrID-Net is the first single-cell analysis tool that accounts for the temporal lag between a genomic locus becoming accessible and its downstream effect on a target gene's expression. We applied GrID-Net on multimodal single-cell assays that profile chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) in the same cell and show that it dramatically outperforms existing methods for inferring regulatory locus-gene links, achieving up to 71% greater agreement with independent population genetics-based estimates. By extending Granger causality to DAG-structured dynamical systems, our work unlocks new domains for causal analyses and, more specifically, opens a path towards elucidating gene regulatory interactions relevant to cellular differentiation and complex human diseases at unprecedented scale and resolution.

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