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bioRxiv · 10.1101/2025.09.05.674565

Fundamental restriction on epistasis detection and fitness valleys in virus evolution

Likhachev, I. V.·Rouzine, I. M.
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Abstract

Probabilistic prognosis of virus evolution, vital for the design of effective vaccines and antiviral drugs, requires the knowledge of adaptive landscape including epistatic interactions. Although epistatic interactions can, in principle, be inferred from abundant sequencing data by various methods, it has been shown previously that genetic linkage between evolving sites obscures their signature and requires averaging over several independent populations. Here we probe the limits of epistasis detection based on pairwise correlations conditioned on the state of a third site on synthetic sequences evolved in a Monte Carlo algorithm with known epistatic pairs in two scenarios: an initially diverse population in the presence of recombination and mutation, with a uniform epistatic network, and an initially-uniform population in the presence of mutation and a fitness valley. In either scenario, the detection error decreases with the number of independent populations and increases with the sequence length. In the first scenario, the accuracy is enhanced by moderate recombination and is maximal, when epistasis magnitude approaches the point of full compensation. In the second scenario, simulation predicts the spontaneous crossing of a fitness valley and forming a new large strain.. The method is then applied to several thousands of sequences of SARS-CoV-2. Results obtained under equal sampling from world regions are consistent with the existence of fitness valleys connecting groups of viral variants. SIGNIFICANCEThe few epistatic pairs of genomic sites hide in genomic data among numerous random correlations caused by common phylogenetic history. We test a method of epistasis detection designed to compensate for this noise. The accuracy is tested using synthetic sequences generated by a Monte Carlo algorithm with known epistatic pairs. The method is applied to several thousands of sequences of SARS-CoV-2 sampled in two different ways. Results obtained under equal sampling from world regions imply the existence of fitness valleys connecting groups of viral variants.

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Likhachev, I. V., Rouzine, I. M.. 2025-09-08. Fundamental restriction on epistasis detection and fitness valleys in virus evolution. https://doi.org/10.1101/2025.09.05.674565

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