A pivot mutation impedes reverse evolution across an adaptive landscape for drug resistance in Plasmodium vivax

Malaria Journal
C Brandon Ogbunugafor, Daniel L Hartl

Abstract

The study of reverse evolution from resistant to susceptible phenotypes can reveal constraints on biological evolution, a topic for which evolutionary theory has relatively few general principles. The public health catastrophe of antimicrobial resistance in malaria has brought these constraints on evolution into a practical realm, with one proposed solution: withdrawing anti-malarial medication use in high resistance settings, built on the assumption that reverse evolution occurs readily enough that populations of pathogens may revert to their susceptible states. While past studies have suggested limits to reverse evolution, there have been few attempts to properly dissect its mechanistic constraints. Growth rates were determined from empirical data on the growth and resistance from a set of combinatorially complete set of mutants of a resistance protein (dihydrofolate reductase) in Plasmodium vivax, to construct reverse evolution trajectories. The fitness effects of individual mutations were calculated as a function of drug environment, revealing the magnitude of epistatic interactions between mutations and genetic backgrounds. Evolution across the landscape was simulated in two settings: starting from the population fixed for...Continue Reading

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Citations

Oct 14, 2016·PLoS Computational Biology·C Brandon Ogbunugafor, Daniel L Hartl
May 8, 2018·Journal of Mathematical Biology·Caitlin LienkaemperAlex Gavryushkin
Dec 21, 2017·ELife·Kristina CronaNiko Beerenwinkel
Aug 16, 2017·Nature Ecology & Evolution·C Brandon Ogbunugafor, Margaret J Eppstein
Aug 17, 2019·Evolution; International Journal of Organic Evolution·Anne E HallFrancisco B-G Moore
Jul 23, 2020·Proceedings. Biological Sciences·Steven M Van BelleghemRiccardo Papa
Mar 22, 2021·Molecular Biology and Evolution·Kedar KarkareTim F Cooper

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