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Following the Dynamics of Structural Variants in Experimentally Evolved Populations
Published on: February 3, 2023
Mutation induced extinction in finite populations: lethal mutagenesis and lethal isolation
C Scott Wylie1, Eugene I Shakhnovich
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
Plos Computational Biology
|August 10, 2012
Summary
High mutation rates can cause extinction, especially in small populations. This study reveals that small population size and high mutation rates interact synergistically, impacting extinction dynamics and potentially aiding pathogen treatment.
Area of Science:
- Evolutionary biology
- Population genetics
- Theoretical biology
Background:
- Genomic replication introduces mutations, often detrimental to fitness.
- Lethal mutagenesis, extinction via high mutation rates (U), is relevant clinically for pathogen eradication.
- Existing models often assume infinite population size (N), neglecting drift and selection relaxation in smaller populations.
Purpose of the Study:
- To investigate the combined effects of population size (N) and mutation rate (U) on extinction time.
- To explore the interplay between lethal mutagenesis and population size dynamics.
- To provide a more realistic model for extinction phenomena in finite populations.
Main Methods:
- Analytical computation of mean extinction time (τ) in a simplified model with lethal or neutral mutations.
- Stochastic population-genetics simulations using a realistic fitness landscape based on protein folding biophysics and epistatic fitness effects.
- Examination of mutation effects on protein stability and unfolding.
Main Results:
- Identified two distinct extinction regimes: survival and extinction phases, with different scaling of τ with N.
- Demonstrated that decreasing N can induce phase transitions from survival to extinction, termed 'lethal isolation'.
- Found synergistic interactions between lethal mutagenesis and lethal isolation, with potential clinical implications.
Conclusions:
- Stably folded proteins necessitate sufficiently large population sizes.
- The interplay of N and U is critical for understanding extinction dynamics.
- Findings suggest novel therapeutic strategies by combining mutation-inducing drugs with population size reduction for pathogens.
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