Evolvability-enhancing mutations in the fitness landscapes of an RNA and a protein

Abstract

Can evolvability—the ability to produce adaptive heritable variation—itself evolve through adaptive Darwinian evolution? If so, then Darwinian evolution may help create the conditions that enable Darwinian evolution. Here I propose a framework that is suitable to address this question with available experimental data on adaptive landscapes. I introduce the notion of an evolvability-enhancing mutation, which increases the likelihood that subsequent mutations in an evolving organism, protein, or RNA molecule are adaptive. I search for such mutations in the experimentally characterized and combinatorially complete fitness landscapes of a protein and an RNA molecule. I find that such evolvability-enhancing mutations indeed exist. They constitute a small fraction of all mutations, which shift the distribution of fitness effects of subsequent mutations towards less deleterious mutations, and increase the incidence of beneficial mutations. Evolving populations which experience such mutations can evolve significantly higher fitness. The study of evolvability-enhancing mutations opens many avenues of investigation into the evolution of evolvability.

Evolution of Evolvability In Rapidly Adapting Populations

“…using barcoded lineage tracking (8,(50)(51)(52) or mutation trap experiments (53). However, we have also shown that the important changes in this distribution will often occur in its high-fitness tail, and are poorly captured by existing heuristics like the mean mutational effect (42,54). They can also depend on external factors like the population size and the overall mutation rate.…”

Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape

“…These arguments are consistent with the decisive role of the stable epistatic hotspots Y501 and R498 in ACE2 binding and the presence of epistatic drift in other RBD sites that mediate immune evasion properties and may determine future "pockets" of evolutionary changes. Most recent studies have identified "evolvability-enhancing" mutations that could create a genetic background where subsequent mutations are more likely to be beneficial relative to mutations acquired on an ancestral background [131,132]. The relationships between epistatic interactions and evolution are complex and while the effects of some mutations follow predictable fitness-correlated patterns, these patterns depend on the biological system and on the physical underpinnings of particular phenotypes, such as protein binding.…”

Mutations that enhance evolvability may open doors to faster adaptation

“…In a new study published in Nature Communications , Andreas Wagner utilizes large data sets and computational tools to offer provocative ideas about the frequency, phenotypic effects, and evolutionary consequences of mutations that facilitate access to beneficial mutations and more efficient searches for fitness peaks 6 . Specifically, Wagner identifies “evolvability-enhancing” mutations that create a genetic background where subsequent mutations are more likely to be beneficial relative to mutations acquired on an ancestral background by virtue of their average mutational neighbor being of higher fitness (Fig.…”