Genome mutations and environmental perturbations reshape the epigenomic topology to drive functional collapse in digital cells

Understanding how genetic and environmental perturbations drive cellular dysfunction remains a challenge. Using digital somatic cells, we evaluate the functionality of over eight thousand genomes across thousands of environments alongside systematic mutational screens. We find that environmental perturbations induce loss of function with a higher probability than point mutations. Crucially, however, most mutations causing loss of function, rather than acting as direct sequence-level damage, converge with environmental stress by triggering reorganization of the epigenomic topology. Our data suggest that loss of functionality is best understood not as cumulative damage, but as a perturbation-driven state transition within a reconfigurable epigenetic landscape