Do deleterious mutations act synergistically? Metabolic control theory provides a partial answer

Area of Science:

• Biochemistry
• Evolutionary Biology
• Systems Biology

Background:

• Deleterious mutations can impact metabolic pathway dynamics and organismal fitness.
• Understanding the synergistic or antagonistic effects of multiple mutations is crucial for evolutionary and systems biology.

Purpose of the Study:

• To apply Metabolic Control Theory to determine conditions for synergistic effects of two deleterious mutations in metabolic pathways.
• To analyze how different fitness objectives influence the epistasis (gene interaction) between metabolic mutations.

Main Methods:

• Utilized Metabolic Control Theory to model the effects of mutations on metabolic pathways.
• Analyzed four distinct fitness criteria: maximal flux, maximal intermediate concentration, optimal flux, and optimal pool size.

Main Results:

• Mutations reducing the activity of the same enzyme tend to act synergistically.
• Antagonistic epistasis is predicted for maximal flux selection, while synergistic epistasis is more likely for optimal flux or pool size selection.
• Different fitness objectives lead to varied predictions for mutation effects in prokaryotes versus eukaryotes.

Conclusions:

• The interplay between mutation location, fitness objectives, and epistasis shapes the evolutionary impact of metabolic mutations.
• The model's predictions align with observations of mosaic gene structures in bacteria, suggesting clonal populations can accumulate diverse genetic elements.