Russo Christopher Joel, Husain Kabir, Ranganathan Rama, Pincus David, Murugan Arvind
Program in Biophysical Sciences, University of Chicago, Chicago, IL, USA.
James Franck Institute, University of Chicago, Chicago, IL, USA.
ArXiv. 2025 Jul 16:arXiv:2507.11973v1.
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 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.
生物系统具有许多相互作用的组件，面临着高维环境波动，范围从各种营养物质剥夺到毒素、药物和物理应激。然而，许多生物控制机制是“简单的”——它们通过系统高维状态的低维表示来恢复内稳态。低维控制器如何在高维系统中维持内稳态？我们为波动环境中的复杂系统开发了一个易于分析处理的积分反馈模型。我们发现，对内稳态的选择导致出现一种软模式，该模式为简单控制器的运行提供所需的降维。我们的理论预测，缓冲环境扰动的简单控制器（例如应激反应途径）也将缓冲突变扰动，我们使用酵母基因敲除文库中5000个菌株的实验数据对这种等效性进行了测试。我们还做出了违反直觉的预测，即敲除一个简单控制器将增加对环境变化的反应维度；我们概述了转录组学测试以验证这一点。我们的工作表明了软模式的进化起源，其功能本身是用于降维，而不是像变构那样的直接功能，其影响范围从隐秘遗传变异到全局上位性。
