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Probing the Limits of Egg Recognition Using Egg Rejection Experiments Along Phenotypic Gradients

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Functional bottlenecks can emerge from non-epistatic underlying traits.

Anna Ottavia Schulte¹, Samar Alqatari², Saverio Rossi¹

¹Dipartimento di Fisica, Sapienza Università di Roma, Rome, Italy.

Plos Computational Biology

|March 16, 2026

Summary

Protein fitness landscapes with global epistasis can form functional bottlenecks, which are critical pathways between distinct phenotypes. Proper calibration and a balance of neutral and non-neutral mutations are essential for their emergence.

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Area of Science:

Evolutionary biology
Biophysics
Computational biology

Background:

Protein fitness landscapes often display epistasis, where mutation effects are context-dependent, increasing complexity and leading to multiple fitness peaks.
Global epistasis models fitness as a non-linear function of an additive trait, contrasting with more complex network epistasis involving residue interactions.

Purpose of the Study:

To introduce and analyze a stylized model of global epistasis with an additive underlying trait.
To investigate the conditions under which functional bottlenecks emerge in protein fitness landscapes.

Main Methods:

Analysis of a stylized model of global epistasis.
Mathematical modeling of protein sequence space and fitness landscapes.

Main Results:

Functional bottlenecks arise with high probability in the calibrated global epistasis model.
A balanced ratio of neutral and non-neutral mutations is crucial for the formation of functional bottlenecks.

Conclusions:

Global epistasis, under specific conditions, can generate the complex topologies of functional bottlenecks observed in protein evolution.
The balance between neutral and non-neutral mutations is a key factor in shaping protein fitness landscapes and enabling evolutionary pathways.