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Sign Epistasis Can be Absent in Multi-peaked Landscapes With Neutral Mutations.

Dmitry N Ivankov1, Evgenii M Zorin1

  • 1Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, Russia.

Genome Biology and Evolution
|January 29, 2026
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Summary
This summary is machine-generated.

Neutral mutations can obscure reciprocal sign epistasis (RSE) in multi-peaked fitness landscapes. Compensatory mutations may not be adjacent, posing challenges for detecting RSE in noisy, real-world data.

Keywords:
compensatory evolutionfitnessfitness landscapemulti-peaked landscapereciprocal sign epistasissign epistasis

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Area of Science:

  • Evolutionary Biology
  • Theoretical Biology
  • Genetics

Background:

  • Fitness landscapes model evolutionary dynamics and epistasis, a key challenge in genotype-phenotype prediction.
  • A foundational theorem by Poelwijk et al. (2011) stated that multi-peaked landscapes must have reciprocal sign epistasis (RSE), assuming no neutral mutations.
  • Neutral mutations, or genotypes with equal fitness, are common in biological systems but were excluded from prior theoretical frameworks.

Purpose of the Study:

  • To extend the analysis of epistasis in fitness landscapes by incorporating neutral mutations.
  • To investigate the impact of neutral mutations on the presence and detectability of reciprocal sign epistasis (RSE).
  • To assess the practical implications for identifying RSE in empirical fitness data with experimental noise.

Main Methods:

  • Mathematical modeling of fitness landscapes incorporating neutral mutations.
  • Analysis of theoretical conditions for the presence of pairwise and composite reciprocal sign epistasis (RSE).
  • Evaluation of the impact of statistical noise on RSE detection in simulated multi-peaked landscapes.

Main Results:

  • Reciprocal sign epistasis (RSE) may be absent in multi-peaked landscapes when neutral mutations are present.
  • RSE is guaranteed only when considering composite mutations, not pairwise interactions.
  • Experimental noise can prevent statistically significant detection of RSE, even with composite mutation analysis.

Conclusions:

  • The presence of neutral mutations alters the conditions for reciprocal sign epistasis (RSE) in evolutionary systems.
  • Compensatory mutations in multi-peaked landscapes with neutral drift need not be adjacent.
  • Detecting RSE in empirical fitness landscapes is fundamentally limited by noise and the presence of neutral evolution.