How the Structure of Signaling Regulation Evolves: Insights From an Evolutionary Model

Area of Science:

• Evolutionary biology
• Systems biology
• Molecular biology

Background:

• Signaling pathways use negative feedback loops (NFLs) to regulate cellular responses to environmental changes.
• NFLs can function upstream (reducing input) or downstream (reducing output) of signaling cascades.
• Downstream NFLs regulate gene expression directly, unlike upstream NFLs involving intermediate proteins.

Purpose of the Study:

• To test the hypothesis that downstream NFLs evolve under more stringent selection than upstream NFLs.
• To investigate the evolutionary dynamics and robustness of different NFL architectures.
• To understand the factors influencing the evolution of NFLs in signaling pathways.

Main Methods:

• Developed a minimal model of immune signaling.
• Analyzed the evolutionary rates of genes encoding upstream and downstream NFLs.
• Simulated the evolution of NFLs under varying model parameters, including signaling cost and protein half-life.

Main Results:

• Genes encoding downstream NFLs evolve at a slower, more consistent rate, indicating stronger selective pressure.
• Upstream NFLs evolve more rapidly and variably, suggesting weaker or context-specific selection.
• The number of signaling steps to activate a downstream NFL is influenced by the cost of signaling.
• Model predicts upstream NFLs favor shorter protein half-lives, absence of co-evolution, and high infection rates.

Conclusions:

• Downstream NFLs exhibit more robust evolutionary trajectories compared to upstream NFLs.
• Evolutionary pressures on NFLs are influenced by signaling pathway architecture and environmental factors.
• Findings provide insights into the evolution of regulatory mechanisms in biological signaling.