Origin of robustness in generating drug-resistant malaria parasites. Academic Article uri icon

Overview

MeSH

  • Amino Acid Substitution
  • Antimalarials
  • Epistasis, Genetic
  • Genes, Protozoan
  • Genetic Fitness
  • Humans
  • Malaria, Falciparum
  • Pyrimethamine
  • Signal Transduction

MeSH Major

  • Biological Evolution
  • Drug Resistance
  • GTP Cyclohydrolase
  • Plasmodium falciparum
  • Tetrahydrofolate Dehydrogenase

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. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

publication date

  • July 2014

has subject area

  • Amino Acid Substitution
  • Antimalarials
  • Biological Evolution
  • Drug Resistance
  • Epistasis, Genetic
  • GTP Cyclohydrolase
  • Genes, Protozoan
  • Genetic Fitness
  • Humans
  • Malaria, Falciparum
  • Plasmodium falciparum
  • Pyrimethamine
  • Signal Transduction
  • Tetrahydrofolate Dehydrogenase

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4069624

Digital Object Identifier (DOI)

  • 10.1093/molbev/msu140

PubMed ID

  • 24739308

Additional Document Info

start page

  • 1649

end page

  • 1660

volume

  • 31

number

  • 7