Robustness and evolvability of the human signaling network

PLoS Comput Biol. 2014 Jul 31;10(7):e1003763. doi: 10.1371/journal.pcbi.1003763. eCollection 2014 Jul.

Abstract

Biological systems are known to be both robust and evolvable to internal and external perturbations, but what causes these apparently contradictory properties? We used Boolean network modeling and attractor landscape analysis to investigate the evolvability and robustness of the human signaling network. Our results show that the human signaling network can be divided into an evolvable core where perturbations change the attractor landscape in state space, and a robust neighbor where perturbations have no effect on the attractor landscape. Using chemical inhibition and overexpression of nodes, we validated that perturbations affect the evolvable core more strongly than the robust neighbor. We also found that the evolvable core has a distinct network structure, which is enriched in feedback loops, and features a higher degree of scale-freeness and longer path lengths connecting the nodes. In addition, the genes with high evolvability scores are associated with evolvability-related properties such as rapid evolvability, low species broadness, and immunity whereas the genes with high robustness scores are associated with robustness-related properties such as slow evolvability, high species broadness, and oncogenes. Intriguingly, US Food and Drug Administration-approved drug targets have high evolvability scores whereas experimental drug targets have high robustness scores.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Drug Discovery
  • Evolution, Molecular*
  • Humans
  • Models, Biological*
  • Signal Transduction / genetics*
  • Signal Transduction / physiology*

Grants and funding

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government, the Ministry of Science, ICT & Future Planning (2010-0017662 and 2013M3A9A7046303) and Science Foundation Ireland (SFI) funding award 06/CE/B1129. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.