Multiple peaks and reciprocal sign epistasis in an empirically determined genotype-phenotype landscape

Abstract

Insight into the ruggedness of adaptive landscapes is central to understanding the mechanisms and constraints that shape the course of evolution. While empirical data on adaptive landscapes remain scarce, a handful of recent investigations have revealed genotype-phenotype and genotype-fitness landscapes that appeared smooth and single peaked. Here, we used existing in vivo measurements on lac repressor and operator mutants in Escherichia coli to reconstruct the genotype-phenotype map that details the repression value of this regulatory system as a function of two key repressor residues and four key operator base pairs. We found that this landscape is multipeaked, harboring in total 19 distinct optima. Analysis showed that all direct evolutionary pathways between peaks involve significant dips in the repression value. Consistent with earlier predictions, we found reciprocal sign epistatic interactions at the repression minimum of the most favorable paths between two peaks. These results suggest that the occurrence of multiple peaks and reciprocal epistatic interactions may be a general feature in coevolving systems like the repressor-operator pair studied here.

Breaking evolutionary constraint with a tradeoff ratchet

“…Note that the repression ability (R) is, thus, not the inverse of the expression ability (E). We constructed four lac repressor-operator variants that have been predicted (45)(46)(47)(48) to display binding: PK:agga, PS: acca, MK:acca, and YQ:tggt, where the first two letters indicate the controlling repressor residues and the last four letters indicate the controlling operator bases ( Fig. 1 A and B).…”

Delayed commitment to evolutionary fate in antibiotic resistance fitness landscapes

“…These studies show that only a limited number of pathways to the highly adapted genotype are feasible (continuously increasing in fitness), suggesting that epistatic interactions impose constraints that may render evolution more predictable 1,2,11 . However, adaptive landscapes can often have multiple distinct adaptive peaks, of which some may be more readily attainable than others 5,12,13 . Key to the predictability of evolution is whether and how early does evolution commit to a final genotypic state.…”

The Valley-of-Death: Reciprocal sign epistasis constrains adaptive trajectories in a constant, nutrient limiting environment

“…Is it a protein’s activity [14] or its cofactor binding affinity [15]? Is it the regulatory response of a repressor-operator pair [16] or is it the rate of a process such as CO 2 assimilation [9]? And if it actually is true Darwinian fitness, is fitness estimated in terms of differential reproduction [17] or in terms of differential survivorship [7], or as is possible in microbial studies, both?…”

“…But how often do empirical fitness landscapes exhibit such topography? Analysis of in vivo data on repressor-operator pairs in the lac system of Escherichia coli reveals 19 distinct peaks [16]. Multiple, deep fitness valleys have recently been demonstrated in adaptation of HIV-1 to its secondary cell-surface chemokine co-receptor, CXCR4 [30, 31].…”