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Updated: Sep 5, 2026

Following the Dynamics of Structural Variants in Experimentally Evolved Populations
Published on: February 3, 2023
Sequence-free landscape inference for directed evolution
Sebastian Towers1, Jessica James1, Harrison Steel1
1Department of Engineering Science, University of Oxford, Oxford, United Kingdom.
Abstract:
Directed evolution is a method for engineering biological systems or components, such as proteins, wherein desired traits are optimised through iterative rounds of mutagenesis and selection of fit variants. The process of protein directed evolution can be envisaged as navigation over high-dimensional optimisation landscapes with numerous local maxima. The performance of any strategy in navigating such a landscape is dependent on the ruggedness of that landscape. However, this information is generally unavailable at the outset of an experiment. Here we propose SLIDE, Sequence-free Landscape Inference for Directed Evolution, which consists of two parts. First, SLIDE provides an estimation of landscape ruggedness from a mutating population using only population-level phenotypic data and an estimate of the mutation rate. Such ruggedness information in itself is valuable in protein design, for instance in predicting evolutionary stability. Second, SLIDE offers a framework for using the estimated ruggedness metric to identify high-performing selection strategies for directed evolution. Using theoretical NK landscapes and four empirical protein fitness landscapes, we demonstrate consistent in silico improvement upon the performance of fixed-parameter strategies, using a pipeline that could also be combined with emerging AI-based methods for driving directed evolution.
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