Abstract
The pattern of how gene co-regulation varies across tissues determines human health. However, inferring tissue-specific regulatory networks and associating them with human phenotypes represent a substantial challenge because multi-tissue projects, including the GTEx, typically contain expression data measured only at one time point from highly heterogeneous donors. Here, we implement an interdisciplinary framework for assembling and programming genomic data from multiple tissues into fully informative gene networks, encapsulated by a complete set of bi-directional, signed, and weighted interactions, from static expression data. This framework can monitor how gene networks change simultaneously across tissues and individuals, infer gene-driven inter-tissue wiring networks, compare and test topological alterations of gene/tissue networks between health states, and predict how regulatory networks evolve across spatiotemporal gradients. Our framework provides a tool to catalogue a comprehensive encyclopedia of mechanistic gene networks that walk medical researchers through tissues in each individual and through individuals for each tissue, facilitating the translation of multi-tissue data into clinical practices.
Highlights
Fundamental questions in modern biomedicine include how human diseases result from alterations of gene expression and how these alterations are instructed by the human genome
Our approach capitalizes on a system of quasi-dynamic ordinary differential equations (ODEs) and uniquely combines three features: full recovery of interactions, gene classification, and sample-specific networking
As the most influential multi-tissue project, the GTEx database contains gene expression data on more than 12,000 samples across 53 tissues from nearly 1,000 human donors. This invaluable database has been extensively analyzed by researchers worldwide, successfully identifying a variety of significant genes that distinguish among tissues and subjects (Fagny et al, 2017; Yang et al, 2017; Gamazon et al, 2018)
Summary
Fundamental questions in modern biomedicine include how human diseases result from alterations of gene expression and how these alterations are instructed by the human genome. Mounting evidence suggests that gene expression is differentially regulated across tissues or cell types during the developmental stage of diseases (Melé et al, 2015; Sonawane et al, 2017; Gamazon et al, 2018). To reveal the cellular mechanisms that underlie complex human diseases and traits, many multi-tissue projects, such as the GTEx (TheEx Consortium, 2015; TheEx Consortium, 2017), have been launched to monitor transcriptional profiles across an array of tissues of the human body. These projects have established resource databases and associated tissue biobanks to study how genes behave in all major human tissues across individuals. With the increasing identification of individual significant genes, it has become clear that the way human cells perform common or unique functions across tissues is determined by gene co-expression networks (Saha et al, 2017; Girousse et al, 2018)
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