Modeling Protein Evolution with Generative Models: from Extant Sequence Data to Evolutionary Dynamics

Abstract

Protein sequences carry a record of evolutionary history shaped by mutation, selection, drift, and epistasis. Recent generative models trained on homologous sequence families offer a new way to read this record: they define probabilistic landscapes that score sequences, generate viable variants, and capture constraints that are difficult to measure experimentally. In this review, we discuss how such landscapes can be used not only for protein design or mutation-effect prediction, but also for modeling evolutionary dynamics. We focus particularly on Direct Coupling Analysis as an interpretable and experimentally validated framework, while placing it in the broader context of generative sequence modeling. We first describe how generative sequence landscapes are inferred and assessed, then review how they can be coupled to population-genetic or substitution-model dynamics to simulate protein evolution across experimental and phylogenetic timescales. Applications include viral evolution, laboratory drift experiments, historical contingency, entrenchment, epistatic drift over time, and long-term sequence-space exploration. We conclude by discussing open challenges, including score-fitness calibration, phylogenetic structure, codon-level mutation biases, indels, and the integration of experimental data.