Joint gene network construction by single-cell RNA sequencing data.

Abstract

In contrast to differential gene expression analysis at the single-gene level, gene regulatory network (GRN) analysis depicts complex transcriptomic interactions among genes for better understandings of underlying genetic architectures of human diseases and traits. Recent advances in single-cell RNA sequencing (scRNA-seq) allow constructing GRNs at a much finer resolution than bulk RNA-seq and microarray data. However, scRNA-seq data are inherently sparse, which hinders the direct application of the popular Gaussian graphical models (GGMs). Furthermore, most existing approaches for constructing GRNs with scRNA-seq data only consider gene networks under one condition. To better understand GRNs across different but related conditions at single-cell resolution, we propose to construct Joint Gene Networks with scRNA-seq data (JGNsc) under the GGMs framework. To facilitate the use of GGMs, JGNsc first proposes a hybrid imputation procedure that combines a Bayesian zero-inflated Poisson model with an iterative low-rank matrix completion step to efficiently impute zero-inflated counts resulted from technical artifacts. JGNsc then transforms the imputed data via a nonparanormal transformation, based on which joint GGMs are constructed. We demonstrate JGNsc and assess its performance using synthetic data. The application of JGNsc on two cancer clinical studies of medulloblastoma and glioblastoma gains novel insights in addition to confirming well-known biologicalresults.