Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Ensemble epistasis: thermodynamic origins of non-additivity between mutations

View ORCID ProfileAnneliese J. Morrison, View ORCID ProfileDaria R. Wonderlick, View ORCID ProfileMichael J. Harms
doi: https://doi.org/10.1101/2020.10.14.339671
Anneliese J. Morrison
1Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403
2Institute for Molecular Biology, University of Oregon, Eugene, OR 97403
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Anneliese J. Morrison
Daria R. Wonderlick
1Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403
2Institute for Molecular Biology, University of Oregon, Eugene, OR 97403
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Daria R. Wonderlick
Michael J. Harms
1Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403
2Institute for Molecular Biology, University of Oregon, Eugene, OR 97403
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michael J. Harms
  • For correspondence: harms@uoregon.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Data/Code
  • Preview PDF
Loading

Abstract

Non-additivity between mutations—epistasis—profoundly shapes evolution. It can be difficult to understand its mechanistic origins. Here we show that “ensemble epistasis” is likely a universal feature of macromolecules. Using a simple analytical model, we found that epistasis arises when two conditions are met: 1) a macro-molecule populates at least three structures and 2) mutations have differential effects on a least two of the inactive structures. To explore the relative magnitude of ensemble epistasis, we performed a virtual deep-mutational scan of the allosteric Ca2+ signaling protein S100A4. We found that 27% of mutation pairs gave ensemble epistasis with a magnitude on the order of thermal fluctuations, 1 kT. We observed many forms of epistasis: magnitude, sign, and reciprocal sign epistasis. Depending on the effector concentration, the same mutation pair could even exhibit different forms of epistasis. The ubiquity of ensembles in biology and its pervasiveness in our dataset suggests that ensemble epistasis may be a universal mechanism of epistasis.

Significance statement Addressing the mechanistic origins of evolutionary unpredictability is critical to understanding how mutations combine to determine phenotype. Here we lay the theoretical foundations and investigate the plausibility of a potentially universal mechanism of unpredictability in macromolecules. Macromolecules often adopt a set of interchanging structures, called a thermodynamic ensemble. Mutations can change the relative population of each structure, introducing unpredictability in the mapping between genotype and phenotype. The conditions under which we expect this to arise are common in macromolecules, suggesting that this form of unpredictability may be pervasive in evolution. We conclude that the thermodynamic ensemble bakes unpredictability into biology and that future attempts to address it might incorporate this mechanistic insight.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/harmslab/ensemble_epistasis.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
Back to top
PreviousNext
Posted October 14, 2020.
Download PDF

Supplementary Material

Data/Code
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Ensemble epistasis: thermodynamic origins of non-additivity between mutations
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Ensemble epistasis: thermodynamic origins of non-additivity between mutations
Anneliese J. Morrison, Daria R. Wonderlick, Michael J. Harms
bioRxiv 2020.10.14.339671; doi: https://doi.org/10.1101/2020.10.14.339671
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Ensemble epistasis: thermodynamic origins of non-additivity between mutations
Anneliese J. Morrison, Daria R. Wonderlick, Michael J. Harms
bioRxiv 2020.10.14.339671; doi: https://doi.org/10.1101/2020.10.14.339671

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Biophysics
Subject Areas
All Articles
  • Animal Behavior and Cognition (3512)
  • Biochemistry (7352)
  • Bioengineering (5329)
  • Bioinformatics (20277)
  • Biophysics (10026)
  • Cancer Biology (7749)
  • Cell Biology (11319)
  • Clinical Trials (138)
  • Developmental Biology (6440)
  • Ecology (9958)
  • Epidemiology (2065)
  • Evolutionary Biology (13336)
  • Genetics (9362)
  • Genomics (12592)
  • Immunology (7714)
  • Microbiology (19046)
  • Molecular Biology (7447)
  • Neuroscience (41063)
  • Paleontology (300)
  • Pathology (1231)
  • Pharmacology and Toxicology (2139)
  • Physiology (3164)
  • Plant Biology (6866)
  • Scientific Communication and Education (1274)
  • Synthetic Biology (1898)
  • Systems Biology (5318)
  • Zoology (1089)