Chemical Engg. Seminar Series : Prof. Supreet Saini

A First-Principles Approach to Global Epistasis: How Metabolism Predicts and Constrains Evolution

Can we predict evolution using fundamental physical principles? Mutations drive evolution, but their effects depend on other genes—a phenomenon called epistasis. Since its discovery over a century ago, epistasis has remained difficult to understand mechanistically. In the past decade, researchers have identified global epistasis, a statistical pattern suggesting that mutation effects follow systematic trends. Yet, its underlying causes remain elusive.

In this talk, I will show how simple metabolic constraints naturally explain these patterns. Using a mathematical model of bacterial growth, we demonstrate that mutations in key metabolic steps exhibit predictable effects, while increasing genetic complexity reduces this predictability. This work provides a first-principles, mechanistic explanation of global epistasis, linking metabolism to evolutionary predictability. Beyond explaining observed evolutionary trends, our model generates testable hypotheses that can be validated experimentally, offering new insights into microbial adaptation.