Simple biological controllers drive the evolution of soft modes

TL;DR

This paper develops a model showing how simple biological controllers evolve to reduce system complexity, enabling effective homeostasis in high-dimensional fluctuating environments, and validates predictions with experimental data.

Contribution

It introduces an analytically tractable model linking evolutionary selection for homeostasis to the emergence of soft modes for dimensionality reduction in biological systems.

Findings

Selection for homeostasis leads to soft modes enabling low-dimensional control.

Simple controllers buffer environmental and mutational perturbations.

Knocking out controllers decreases the system's response dimensionality.

Abstract

Biological systems, with many interacting components, face high-dimensional environmental fluctuations, ranging from diverse nutrient deprivations to toxins, drugs, and physical stresses. Yet, many biological control mechanisms are `simple' -- they restore homeostasis through low-dimensional representations of the system's high-dimensional state. How do low-dimensional controllers maintain homeostasis in high-dimensional systems? We develop an analytically tractable model of integral feedback for complex systems in fluctuating environments. We find that selection for homeostasis leads to the emergence of a soft mode that provides the dimensionality reduction required for the functioning of simple controllers. Our theory predicts that simple controllers that buffer environmental perturbations (e.g., stress response pathways) will also buffer mutational perturbation, an equivalence we test using experimental data across ~5000 strains in the yeast knockout collection. We also predict, counterintuitively, that knocking out a simple controller will \emph{decrease} the dimensionality of the response to environmental change; we outline transcriptomics tests to validate this. Our work suggests an evolutionary origin of soft modes whose function is for dimensionality reduction in and of itself rather than direct function like allostery, with implications ranging from cryptic genetic variation to global epistasis.