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Title: Origin of robustness in generating drug-resistant malaria parasites
Authors: Krittikorn Kümpornsin
Charin Modchang
Adina Heinberg
Eric H. Ekland
Piyaporn Jirawatcharadech
Pornpimol Chobson
Nattida Suwanakitti
Sastra Chaotheing
Prapon Wilairat
Kirk W. Deitsch
Sumalee Kamchonwongpaisan
David A. Fidock
Laura A. Kirkman
Yongyuth Yuthavong
Thanat Chookajorn
Mahidol University
Weill Cornell Medical College
Columbia University, College of Physicians and Surgeons
Thailand National Center for Genetic Engineering and Biotechnology
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Jan-2014
Citation: Molecular Biology and Evolution. Vol.31, No.7 (2014), 1649-1660
Abstract: Biological robustness allows mutations to accumulate while maintaining functional phenotypes. Despite its crucial role in evolutionary processes, the mechanistic details of how robustness originates remain elusive. Using an evolutionary trajectory analysis approach, we demonstrate how robustness evolved in malaria parasites under selective pressure from an antimalarial drug inhibiting the folate synthesis pathway. A series of four nonsynonymous amino acid substitutions at the targeted enzyme, dihydrofolate reductase (DHFR), render the parasites highly resistant to the antifolate drug pyrimethamine. Nevertheless, the stepwise gain of these four dhfr mutations results in tradeoffs between pyrimethamine resistance and parasite fitness. Here, we report the epistatic interaction between dhfr mutations and amplification of the gene encoding the first upstream enzyme in the folate pathway, GTP cyclohydrolase I (GCH1). gch1 amplification confers low level pyrimethamine resistance and would thus be selected for by pyrimethamine treatment. Interestingly, the gch1 amplification can then be co-opted by the parasites because it reduces the cost of acquiring drug-resistant dhfr mutations downstream in the same metabolic pathway. The compensation of compromised fitness by extra GCH1 is an example of how robustness can evolve in a system and thus expand the accessibility of evolutionary trajectories leading toward highly resistant alleles. The evolution of robustness during the gain of drug-resistant mutations has broad implications for both the development of new drugs and molecular surveillance for resistance to existing drugs. © The Author 2014.
ISSN: 15371719
Appears in Collections:Scopus 2011-2015

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