Marginal specificity in protein interactions constrains evolution of a paralogous family

The evolution of novel functions in biology relies heavily on gene duplication and divergence, creating large paralogous protein families. Selective pressure to avoid detrimental cross-talk often results in paralogs that exhibit exquisite specificity for their interaction partners. But how robust or sensitive is this specificity to mutation? Here, using deep mutational scanning, we demonstrate that a paralogous family of bacterial signaling proteins exhibits marginal specificity, such that many individual substitutions give rise to substantial cross-talk between normally insulated pathways. Our results indicate that sequence space is locally crowded despite overall sparseness, and we provide evidence that this crowding has constrained the evolution of bacterial signaling proteins. These findings underscore how evolution selects for good enough rather than optimized phenotypes, leading to restrictions on the subsequent evolution of paralogs.

Automated summary

The evolution of novel functions in biology relies on gene duplication and divergence, creating large paralogous protein families. However, the specificity of these paralogs to their interaction partners can be sensitive to mutation. Through deep mutational scanning, it was demonstrated that a family of bacterial signaling proteins exhibits marginal specificity, with individual substitutions leading to substantial cross-talk between pathways. These findings suggest that the evolution of bacterial signaling proteins is constrained by sequence space crowding, and that evolution selects for good enough rather than optimized phenotypes in paralogs.