Endogenous cell competition kills pathogenic de novo mutant cells but declines under pH stress

Abstract

Although endogenous cell competition safeguards embryonic development by eliminating unfit cells, the intrinsic origins of unfitness remain unclear. Here, zebrafish whole-genome sequencing and imaging reveal that endogenous cell competition removes cells with spontaneous de novo mutations in key developmental signalling pathways and in human disease-associated genes, such as those associated with Alzheimers disease, epilepsy, autism, and premature aging. These mutations arise frequently during normal development but are efficiently eliminated under physiological conditions, thereby preventing the clonal expansion of harmful cells. However, environmental pH stress disrupts this surveillance by dysregulating Ca2+ signals, allowing mutant cells to persist and resulting in tissue mispatterning and morphological defects. Our findings establish endogenous cell competition as an intercellular communication-dependent genome quality-control mechanism that removes pathogenic mutant cells before clonal expansion. This link between developmental robustness, environmental stress, and mosaic genetic disorders highlights how intrinsic mutations and extrinsic stressors together shape disease susceptibility across the lifespan.