Biphasic response as a mechanism against mutant takeover in tissue homeostasis circuits

Abstract

Tissues use feedback circuits in which cells send signals to each other to control their growth and survival. We show that such feedback circuits are inherently unstable to mutants that misread the signal level: Mutants have a growth advantage to take over the tissue, and cannot be eliminated by known cell‐intrinsic mechanisms. To resolve this, we propose that tissues have biphasic responses in which the signal is toxic at both high and low levels, such as glucotoxicity of beta cells, excitotoxicity in neurons, and toxicity of growth factors to T cells. This gives most of these mutants a frequency‐dependent selective disadvantage, which leads to their elimination. However, the biphasic mechanisms create a new unstable fixed point in the feedback circuit beyond which runaway processes can occur, leading to risk of diseases such as diabetes and neurodegenerative disease. Hence, glucotoxicity, which is a dangerous cause of diabetes, may have a protective anti‐mutant effect. Biphasic responses in tissues may provide an evolutionary stable strategy that avoids invasion by commonly occurring mutants, but at the same time cause vulnerability to disease. image Tissue homeostasis feedback circuits are inherently susceptible to mis‐sensing mutants. Biphasic signal response increases resistance to mis‐sensing mutants, at the cost of reduced dynamic stability. Tissue feedback circuits are inherently susceptible to mutant invasion. Biphasic signal response increases resistance to mis‐sensing mutants. Resistance to mis‐sensing mutants trades‐off with dynamic stability. Biphasic mechanisms explain observations in physiological circuits such as circuits of pancreatic beta cells, stem cells and immune cells.