The Limited Information Capacity of Cross-Reactive Sensors Drives the Evolutionary Expansion of Signaling.

Signaling systems expand by duplications of various components, be it receptors or downstream effectors. However, whether and how duplicated components contribute to higher signaling capacity is unclear, especially because in most cases, their specificities overlap. Using information theory, we found that augmentation of capacity by an increase in the copy number is strongly limited by logarithmic diminishing returns. Moreover, counter to conventional biochemical wisdom, refinements of the response mechanism, e.g., by cooperativity or allostery, do not increase the overall signaling capacity. However, signaling capacity nearly doubles when a promiscuous, non-cognate ligand becomes explicitly recognized via duplication and partial divergence of signaling components. Our findings suggest that expansion of signaling components via duplication and enlistment of promiscuously acting cues is virtually the only accessible evolutionary strategy to achieve overall high-signaling capacity despite overlapping specificities and molecular noise. This mode of expansion also explains the highly cross-wired architecture of signaling pathways.