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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues

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Published on: July 14, 2015

Contingency and entrenchment in protein evolution under purifying selection.

Premal Shah¹, David M McCandlish¹, Joshua B Plotkin²

¹Department of Biology, University of Pennsylvania, Philadelphia, PA 19104.

Proceedings of the National Academy of Sciences of the United States of America

|June 10, 2015

Summary

Epistasis, where gene effects depend on other genes, is common in protein evolution. Even under purifying selection, mutations become contingent on prior changes, impacting evolutionary pathways.

Keywords:

coevolution intragenic epistasis near neutrality protein stability

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Mutagenesis and Functional Selection Protocols for Directed Evolution of Proteins in E. coli

Mutagenesis and Functional Selection Protocols for Directed Evolution of Proteins in E. coli

Published on: March 16, 2011

Area of Science:

Evolutionary biology
Molecular biology
Genetics

Background:

Epistasis, where gene effects depend on other genes, influences population evolution and protein divergence.
Epistasis under purifying selection is less understood than under adaptive selection.

Purpose of the Study:

To explore the structure of epistasis in protein sequence evolution under purifying selection.
To investigate how epistasis affects mutation fixation and evolutionary history.

Main Methods:

Computational models of thermodynamic stability in a ligand-binding protein.
Simulations of protein sequence evolution.

Main Results:

Mutations that fix under purifying selection are enriched for epistasis, despite random mutations being largely additive.
Fixing mutations are contingent on previous substitutions, being nearly neutral at fixation but deleterious without prior changes.
Substitutions are entrenched by later epistasis, becoming more deleterious to revert over time.

Conclusions:

Protein sequence evolution under purifying selection is historically contingent.
The phenotypic effects of mutations depend on the genetic background and cannot be predicted solely from the ancestral state.