Epistatic hotspots organize antibody fitness landscape and boost evolvability.

The course of evolution is strongly shaped by interaction between mutations. Such epistasis can yield rugged sequence-function maps and constrain the availability of adaptive paths. While theoretical intuition is often built on global statistics of large, homogeneous model landscapes, mutagenesis measurements necessarily probe a limited neighborhood of a reference genotype. It is unclear to what extent local topography of a real epistatic landscape represents its global shape. Here, we demonstrate that epistatic landscapes can be heterogeneously rugged and this heterogeneity may render biomolecules more evolvable. By characterizing a multipeaked fitness landscape of a SARS-CoV-2 antibody mutant library, we show that heterogeneous ruggedness arises from sparse epistatic hotspots, whose mutation impacts the fitness effect of numerous sequence sites. Surprisingly, mutating an epistatic hotspot may enhance, rather than reduce, the accessibility of the fittest genotype, while increasing the overall ruggedness. Further, migratory constraints in real space alleviate mutational constraints in sequence space, which not only diversify direct paths taken but may also turn a road-blocking fitness peak into a stepping stone leading toward the global optimum. Our results suggest that a hierarchy of epistatic hotspots may organize the fitness landscape in such a way that path-orienting ruggedness confers global smoothness.