Minimising mutation load as a mechanism for low-dose hyper-radiosensitivity and induced radioresistance.

Low-dose hyper-radiosensitivity (HRS) and induced radioresistance (IRR) are unexpected features of cellular survival curves that challenge classical radiobiological models. While often interpreted phenomenologically, their underlying biological purpose remains unclear. Here we propose that these effects reflect an evolved strategy by which tissues minimise mutational burden through context-dependent cell elimination. We introduce the Minimum Mutation Load (MML) model, a principle-based framework in which irradiated cells assess their survival based on local intercellular signals that reflect neighbourhood damage. This cooperative behaviour balances the benefit of removing highly damaged cells with the mutational cost of their replacement. Using a curated dataset of 99 clonogenic survival experiments, we show that the MML model replicates key features of HRS and IRR across diverse conditions, with an average adjusted R² of 0.74, and performs comparably to the established Induced Repair (IR) model. Unlike the IR model, which is phenomenological, the MML model provides biologically interpretable parameters with independent theoretical grounding. The model suggests that mutation minimisation may be an organising principle of tissue homeostasis. These findings support a new conceptual framework in which tissue-level cooperation, rather than purely cell-intrinsic responses, governs somatic maintenance and cancer suppression.