Multiple molecular and cellular properties jointly affect protein and site-specific evolutionary rates
Anshul Saini1, Dinara R Usmanova1,2, Rydberg Supo Escalante1
1Department of Systems Biology, Columbia University; New York, NY, USA.
Biorxiv : the Preprint Server for Biology
|June 4, 2026
Summary
Protein evolutionary rates are influenced by molecular, cellular, and functional constraints. Neural networks reveal how these factors combine across scales to predict evolutionary rates, offering a unified framework for understanding protein evolution.
Area of Science:
- Evolutionary biology
- Computational biology
- Molecular evolution
Background:
- Protein evolutionary rates vary significantly due to diverse constraints.
- Understanding how protein-level (e.g., expression) and site-level (e.g., structural) constraints interact is challenging.
- Existing models struggle to disentangle correlated features and lack integration.
Purpose of the Study:
- To develop a unified predictive model for protein evolutionary rates across multiple scales.
- To investigate the combined influence of molecular, cellular, and site-specific features on evolutionary rates.
- To identify proteins with atypical evolutionary rates.
Main Methods:
- Utilized neural networks to predict protein evolutionary rates.
- Integrated molecular, cellular, and site-level structural/functional features as predictors.
- Analyzed data across multiple eukaryotic species, including humans.
Main Results:
- Protein-level features explained substantial variance in evolutionary rates (nearly 50% in humans).
- Site-level features explained a comparable fraction of variance in relative evolutionary rates.
- Integrated models explained up to 37% of site-specific evolutionary rate variance, showing additive effects.
Conclusions:
- Molecular and cellular properties set the evolutionary context for proteins.
- Site-specific structural and functional features modulate variation within proteins.
- The study provides a quantitative framework for understanding protein evolution across scales.
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