Higher-Order Epistasis Is Unpredictable From Molecular Wiring
The Composition Gap: Higher-Order Knockout Epistasis Is Unpredictable From Molecular Wiring
Higher-order knockout epistasis is unpredictable from molecular wiring: exhaustive 2n sweeps across 28 Boolean networks show that the strongest local interactions produce the weakest global effects. The gap between pairwise and higher-order epistasis grows with knockout order, and no topological feature of the network — degree, betweenness, clustering coefficient, motif participation — predicts which gene combinations will interact.
ODE-validated on continuous-time dynamics to confirm that the composition gap is not an artifact of the Boolean discretization. The result implies that predicting higher-order genetic interactions from pathway topology alone is a structurally hard problem, not a data-limited one.