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Open Access Highly Accessed Research article

The relationship between the hierarchical position of proteins in the human signal transduction network and their rate of evolution

David Alvarez-Ponce

Author Affiliations

Department of Biology, National University of Ireland Maynooth, Maynooth, County Kildare, Ireland

Instituto de Biología Molecular y Celular de Plantas, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Politécnica de Valencia (UPV), Valencia, Spain

BMC Evolutionary Biology 2012, 12:192  doi:10.1186/1471-2148-12-192

Published: 28 September 2012



Proteins evolve at disparate rates, as a result of the action of different types and strengths of evolutionary forces. An open question in evolutionary biology is what factors are responsible for this variability. In general, proteins whose function has a great impact on organisms’ fitness are expected to evolve under stronger selective pressures. In biosynthetic pathways, upstream genes usually evolve under higher levels of selective constraint than those acting at the downstream part, as a result of their higher hierarchical position. Similar observations have been made in transcriptional regulatory networks, whose upstream elements appear to be more essential and subject to selection. Less well understood is, however, how selective pressures distribute along signal transduction pathways.


Here, I combine comparative genomics and directed protein interaction data to study the distribution of evolutionary forces across the human signal transduction network. Surprisingly, no evidence was found for higher levels of selective constraint at the upstream network genes (those occupying more hierarchical positions). On the contrary, purifying selection was found to act more strongly on genes acting at the downstream part of the network, which seems to be due to downstream genes being more highly and broadly expressed, performing certain functions and, in particular, encoding proteins that are more highly connected in the protein–protein interaction network. When the effect of these confounding factors is discounted, upstream and downstream genes evolve at similar rates. The trends found in the overall signaling network are exemplified by analysis of the distribution of purifying selection along the mammalian Ras signaling pathway, showing that upstream and downstream genes evolve at similar rates.


These results indicate that the upstream/downstream position of proteins in the signal transduction network has, in general, no direct effect on their rates of evolution, suggesting that upstream and downstream genes are similarly important for the function of the network. This implies that natural selection differently distributes across signal transduction networks and across biosynthetic and transcriptional regulatory networks, which might reflect fundamental differences in their function and organization.

Network evolution; Evolutionary rate; Selective constraint; Purifying selection; Signal transduction; Molecular pathways; Upstream and downstream position