Loading...
THE MECHANISTIC ROLE OF EPISTASIS IN EVOLUTIONARY RATE VARIATION AND NEUTRAL THEORY
Schmelkin, Lisa
Schmelkin, Lisa
Citations
Altmetric:
Genre
Thesis/Dissertation
Date
2025-05
Advisor
Committee member
Group
Department
Biology
Subject
Permanent link to this record
Collections
Research Projects
Organizational Units
Journal Issue
DOI
https://doi.org/10.34944/eym9-rx74
Abstract
Direct coupling analysis infers pairwise interactions between sites of a protein, enabling the study of molecular evolution with epistasis and advancing substitution models beyond the unrealistic assumption that sites evolve independently. These Potts Hamiltonian (PH) models have been used to simulate protein domain evolution and investigate the emergent properties of neutral evolution. However, previous studies have considered the evolution simulated to be neutral simply because of purifying selection against mutations which did not preserve structural homology, despite the models being inferred from a large collection of domains found in paralogous proteins that evolved via gene duplication events and have distinct functions.
In this dissertation, I first construct alignments of orthologous domains that evolved by speciation and have the same function, which are the primary focus of Neutral Theory. I find that the statistical properties of orthologs are dramatically different than non-orthologs. This key observation motivates me to build a novel Neutral-with-Epistasis (NxE) simulation framework which induces purifying selection against substitutions that are predicted to be non-neutral if they do not conserve the statistical energy of the domain. Using my model, I test the hypothesis that epistasis provides a mechanistic explanation for the excess variation in evolutionary rates that has been a long-standing challenge to Neutral Theory.
To further understand the role of epistasis in neutral substitutions, I investigate the contingency of evolutionary rates in NxE lineages, i.e., if early substitutions can result in evolutionary speed-ups or slow-downs as additional substitutions accumulate. I then assess whether ancestral residues become unfavorable over time, a phenomenon referred to as evolutionary Stokes shift, that has been frequently attributed to epistasis. The methods and results herein advance our understanding of Neutral Theory and demonstrate how a wide range of outcomes can be a result of epistasis without invoking a non-neutral explanation. Therefore, emergent properties of the NxE model can serve as a new null baseline of neutrality, improving methods of detecting bouts of positive selection and adaptive change.
Description
Citation
Citation to related work
Has part
ADA compliance
For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu