Epistatic hotspots boost antibody evolvability
ORAL
Abstract
Interaction between mutations yields rugged sequence-to-function maps and constrains adaptive paths available. Widely used random landscape models do not describe the counterintuitive observation that empirical fitness landscapes are both strongly rugged and highly navigable, that is, increased ruggedness appears not to reduce, and may even enhance, 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 confers global smoothness to the stability landscape and boosts protein evolvability. Our results suggest a broad role of sparse epistatic hotspots in organizing high-dimensional solution space that permits efficient exploration.
*SW gratefully acknowledges funding support from the NSF via MCB-2225947 and an NSF CAREER Award PHY-2146581.
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Presenters
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Shenshen Wang
- University of California, Los Angeles