Robustness and lethality in multilayer biological molecular networks

Xueming Liu,Joseph Loscalzo,Amitabh Sharma,Rashmi B Prasad,Arda Halu,Enrico Maiorino,Kimberly Glass,Jianxi Gao

doi:10.1038/s41467-020-19841-3

Abstract

Robustness is a prominent feature of most biological systems. Most previous related studies have been focused on homogeneous molecular networks. Here we propose a comprehensive framework for understanding how the interactions between genes, proteins and metabolites contribute to the determinants of robustness in a heterogeneous biological network. We integrate heterogeneous sources of data to construct a multilayer interaction network composed of a gene regulatory layer, a protein–protein interaction layer, and a metabolic layer. We design a simulated perturbation process to characterize the contribution of each gene to the overall system’s robustness, and find that influential genes are enriched in essential and cancer genes. We show that the proposed mechanism predicts a higher vulnerability of the metabolic layer to perturbations applied to genes associated with metabolic diseases. Furthermore, we find that the real network is comparably or more robust than expected in multiple random realizations. Finally, we analytically derive the expected robustness of multilayer biological networks starting from the degree distributions within and between layers. These results provide insights into the non-trivial dynamics occurring in the cell after a genetic perturbation is applied, confirming the importance of including the coupling between different layers of interaction in models of complex biological systems.

Highlights

Robustness is a prominent feature of most biological systems
We propose an analytical method to determine two equivalent coupling strengths[23], qG, and qP, to quantify, respectively, the fraction of genes that depend on proteins of the protein–protein interaction (PPI) network, and the fraction of proteins that depend on genes of the gene regulatory network
To uncover how the couplings between molecular networks influence their biological functions, we propose a minimalist model of multilayer molecular networks encompassing regulatory, protein–protein, and metabolic interactions, and develop a theoretical framework for analyzing the system’s robustness

Summary

Introduction

Robustness is a prominent feature of most biological systems. Most previous related studies have been focused on homogeneous molecular networks. We analytically derive the expected robustness of multilayer biological networks starting from the degree distributions within and between layers These results provide insights into the non-trivial dynamics occurring in the cell after a genetic perturbation is applied, confirming the importance of including the coupling between different layers of interaction in models of complex biological systems. Klosik et al.[40] designed a vast, directed, biological molecular network, called the interdependent network of gene regulation and metabolism, which is composed of three types of biological molecules: genes, proteins, and metabolites For multicellular organisms such as humans, Didier et al.[41] and Valdeolivas et al.[42] investigated the community structure in multiplex biological molecular networks, which is composed of three or four biological networks sharing the same set of genes/proteins, with the nodes in each layer connected by different types of interactions, such as co-expression or physical interactions

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Results

Conclusion