Description
- Abstract:
- As a malaria patient takes and metabolizes weekly doses of an anti-malarial pyrimethamine, there is a periodic change in drug concentration. The growth rate, or “fitness,” of a genotype changes with the drug concentration. Previous drug resistance research has considered the time-averaged fitness a suitable statistic, but defining the fitness of a genotype as a dynamic variable can change the outcome of evolution. Generally, there is a fitness trade-off for drug resistance: increased drug resistance comes with a drop in growth rate in the drugless environment. The drug resistant genotype will “win” while drug concentration is high, but if the drug concentration drops, that genotype will “lose” to other, less drug resistant genotypes. This is why changing drug concentration is meaningful. To explore this system, we simulate the evolution of drug resistance of a 16-genotype malaria population within a single human host as the drug concentration changes periodically. The simulation attempts to capture the randomness that exists in vivo: it is stochastic in both reproduction and mutation. We also compare several single- and multi-locus positive controls to classical analytic predictions. The simulation is generalized for an array of evolution questions. We expand on classical evolution theory and use the simulation to evaluate our mathematical results for multi-locus, haploid predictions for probability of fixation and heterozygosity. Our investigation of pyrimethamine resistance in malaria suggests that the changing drug concentration in the host does not affect the outcome of evolution because there is no fitness trade-off over clinically relevant, in vivo drug concentrations.
- Notes:
- Senior thesis (ScB)--Brown University, 2019
- Concentration: Applied Mathematics-Biology
Access Conditions
- Rights
- In Copyright
- Restrictions on Use
- Collection is open for research.
Citation
Bronson, Ryan,
"A Stochastic Simulation for Evolution in a Changing Environment: Understanding Pyrimethamine Resistance in Plasmodium falciparum."
(2019).
Applied Mathematics Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/rwz4-qj54
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Applied Mathematics Theses and Dissertations
Theses and Dissertations for the Applied Mathematics department....