Ultimate paths of least resistance: intrinsically disordered proteins as developmental resets in regulatory networks

Evolution requires flexibility, needed for exploration and adjustment, and stability, needed for function. In development, these conflicting requirements are met by regulatory complexes of factors that can transiently reassemble into functional groups at each successive context. Two hallmarks of these complexes-interchangeability and accessibility of binding partners-implicate intrinsically disordered proteins (IDPs) as likely key organizers. We test whether the binding plasticity of IDPs and their capacity to sustain phase-separated regulatory assemblies can reconcile developmental continuity with microevolutionary divergence in avian beak primordia. We found that the axes of the core regulatory network governing shifts between mechanical states of homogeneous cells in early development align with population divergence in this regulatory network, a pattern produced by IDPs' dosage-dependent binding plasticity. This disorder-enhanced connectivity converts the stochastic variation in protein concentration at each transition into discrete network configurations, resetting regulatory specializations and promoting plasticity and population divergence. Comparative analyses of avian proteomes confirm that binding promiscuity in regulatory IDPs broadens their interaction repertoires and accelerates their evolution. By enabling reversible transitions between specialized network states, IDPs can ensure developmental continuity and evolutionary persistence, reconciling precision with evolvability in avian beak diversification.