Yin and Yang of disease genes and death genes between reciprocally scale-free biological networks

Hyun Wook Han,Jung Hun Ohn,Ju Han Kim,Jisook Moon

doi:10.1093/nar/gkt683

Hyun Wook Han, Jung Hun Ohn + Show 2 more

Open Access

https://doi.org/10.1093/nar/gkt683

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Abstract

Biological networks often show a scale-free topology with node degree following a power-law distribution. Lethal genes tend to form functional hubs, whereas non-lethal disease genes are located at the periphery. Uni-dimensional analyses, however, are flawed. We created and investigated two distinct scale-free networks; a protein–protein interaction (PPI) and a perturbation sensitivity network (PSN). The hubs of both networks exhibit a low molecular evolutionary rate (P < 8 × 10−12, P < 2 × 10−4) and a high codon adaptation index (P < 2 × 10−16, P < 2 × 10−8), indicating that both hubs have been shaped under high evolutionary selective pressure. Moreover, the topologies of PPI and PSN are inversely proportional: hubs of PPI tend to be located at the periphery of PSN and vice versa. PPI hubs are highly enriched with lethal genes but not with disease genes, whereas PSN hubs are highly enriched with disease genes and drug targets but not with lethal genes. PPI hub genes are enriched with essential cellular processes, but PSN hub genes are enriched with environmental interaction processes, having more TATA boxes and transcription factor binding sites. It is concluded that biological systems may balance internal growth signaling and external stress signaling by unifying the two opposite scale-free networks that are seemingly opposite to each other but work in concert between death and disease.

Highlights

Biological systems are often described as complex networks whose vertex connectivities follow a scale-free power-law distribution [1]
We investigated network topology, evolutionary pressure, distribution of classified genes, transcription factor binding site (TFBS) and functional enrichment and the interrelation of the two networks, protein–protein interaction (PPI) and perturbation sensitivity network (PSN)
We propose that disease genes are located in the functional hub of PSN but not in that of PPI, which is a reciprocal network to PSN

Summary

Introduction

Biological systems are often described as complex networks whose vertex connectivities follow a scale-free power-law distribution [1]. The scale-free topology of a network may arise from ‘network growth’ and ‘preferential attachment’, endowing the network with robustness against random errors owing to its relatively small number of functional hubs and many peripheral nodes. Robustness against random errors and attack vulnerability are associated with the lethality of mutations in the protein–protein interaction (PPI) network. Deleterious mutations of highly connected hub proteins in the PPI network of yeast are three times more likely to be lethal than those of less connected peripheral ones [3]. The scale-free topology of PPI network seems to have been shaped by evolutionary selection pressure, enabling organisms to be robust against random mutations and lethal only from disruptions of a few critical proteins with many interacting partners. Each gene’s contribution to sustain internal growth or ‘essentiality’ is well represented by the connectivities of protein interactome

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