Epistatic interactions between mutations are thought to constrain evolution since they make an adaptive landscape in sequence space very rugged. However, an increasing variety of empirical fitness landscapes appear to be both strongly rugged and highly navigable. That is, increased ruggedness tends not to reduce, and may even enhance, the evolutionary accessibility of the fittest genotype. By mapping a combinatorially complete antibody folding-stability landscape, we find that mutating an epistatic hotspot—an outgoing hub of epistatic interactions—generates heterogeneous ruggedness, which “funnels” the landscape toward its global optimum. Our results suggest that sparse hierarchical epistatic hotspots may render high-dimensional solution spaces easy to navigate, potentially underlying biomolecular evolvability and cell-fate plasticity alike.
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