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  1. Article ; Online: The evolutionary landscape of antifolate resistance in Plasmodium falciparum.

    Costanzo, Marna S / Hartl, Daniel L

    Journal of genetics

    2011  Volume 90, Issue 2, Page(s) 187–190

    Abstract: Resistance to antifolates in Plasmodium falciparum is well described and has been observed in clinical settings for decades. At the molecular level, point mutations in the dhfr gene that lead to resistance have been identified, and the crystal structure ... ...

    Abstract Resistance to antifolates in Plasmodium falciparum is well described and has been observed in clinical settings for decades. At the molecular level, point mutations in the dhfr gene that lead to resistance have been identified, and the crystal structure of the wildtype and mutant dihydrofolate reductase enzymes have been solved in complex with native substrate and drugs. However, we are only beginning to understand the complexities of the evolutionary pressures that lead to the evolution of drug resistance in this system. Microbial systems that allow heterologous expression of malarial proteins provide a tractable way to investigate patterns of evolution that can inform our eventual understanding of the more complex factors that influence the evolution of drug resistance in clinical settings. In this paper we will review work in Escherichia coli and Saccharomyces cerevisiae expression systems that explore the fitness landscape of mutations implicated in drug resistance and show that (i) a limited number of evolutionary pathways to resistance are followed with high probability; (ii) fitness costs associated with the maintenance of high levels of resistance are modest; and (iii) different antifolates may exert opposing selective forces.
    MeSH term(s) Adaptation, Biological ; Animals ; Drug Resistance/genetics ; Evolution, Molecular ; Folic Acid Antagonists/pharmacology ; Humans ; Malaria, Falciparum/drug therapy ; Mutation ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/genetics ; Protozoan Proteins/genetics ; Tetrahydrofolate Dehydrogenase/genetics
    Chemical Substances Folic Acid Antagonists ; Protozoan Proteins ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3)
    Language English
    Publishing date 2011-08-25
    Publishing country India
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 3039-9
    ISSN 0973-7731 ; 0958-8361 ; 0022-1333
    ISSN (online) 0973-7731
    ISSN 0958-8361 ; 0022-1333
    DOI 10.1007/s12041-011-0072-z
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  2. Article ; Online: Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.

    Costanzo, Marna S / Brown, Kyle M / Hartl, Daniel L

    PloS one

    2011  Volume 6, Issue 5, Page(s) e19636

    Abstract: Background: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential ... ...

    Abstract Background: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness.
    Methodology/principal findings: We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine.
    Conclusions/significance: Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.
    MeSH term(s) Drug Resistance ; Evolution, Molecular ; Folic Acid Antagonists/pharmacology ; Malaria, Falciparum/drug therapy ; Malaria, Falciparum/enzymology ; Malaria, Falciparum/parasitology ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/enzymology ; Proguanil/pharmacology ; Pyrimethamine/pharmacology ; Tetrahydrofolate Dehydrogenase/chemistry ; Tetrahydrofolate Dehydrogenase/metabolism ; Triazines/pharmacology
    Chemical Substances Folic Acid Antagonists ; Triazines ; cycloguanil (26RM326WVN) ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3) ; Proguanil (S61K3P7B2V) ; Pyrimethamine (Z3614QOX8W)
    Language English
    Publishing date 2011-05-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0019636
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  3. Article: Spatial learning and memory in African mole-rats: the role of sociality and sex.

    Costanzo, Marna S / Bennett, Nigel C / Lutermann, Heike

    Physiology & behavior

    2009  Volume 96, Issue 1, Page(s) 128–134

    Abstract: Spatial learning and memory is an important skill for the survival and fitness and may vary between the sexes depending on differences in space use. This is particularly true for animals that explore the subterranean niche as it is associated with high ... ...

    Abstract Spatial learning and memory is an important skill for the survival and fitness and may vary between the sexes depending on differences in space use. This is particularly true for animals that explore the subterranean niche as it is associated with high travelling costs. In subterranean rodents the complexity of burrow systems varies with differing degrees of sociality possibly posing stronger selective pressures regarding spatial abilities on species with more complex burrow structures. This could lead to superior abilities in spatial learning and memory in social compared to solitary subterranean species. We tested this hypothesis in two species of subterranean mole-rats, the eusocial Damaraland (Fukomys damarensis) and solitary Cape mole-rats (Georychus capensis) by comparing their ability to locate food in an artificial maze. Measurements of the time taken to the goal chamber, the number of wrong turns taken, and the average velocity at which animals travelled were used to compare performance between animals. We did not find marked sex-specific differences in either study species during the assessment of learning and memory retention. In accordance with our hypothesis significant differences between the species were apparent during both learning and memory trials with the social species exhibiting superior performances. However, in both species memory retention was generally high suggesting that the fossorial lifestyle poses a strong selective pressure on spatial abilities in subterranean mammals.
    MeSH term(s) Analysis of Variance ; Animals ; Learning/physiology ; Maze Learning/physiology ; Memory/physiology ; Mole Rats/physiology ; Sex Characteristics ; Social Behavior ; Spatial Behavior/physiology ; Species Specificity ; Statistics, Nonparametric
    Language English
    Publishing date 2009-01-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3907-x
    ISSN 1873-507X ; 0031-9384
    ISSN (online) 1873-507X
    ISSN 0031-9384
    DOI 10.1016/j.physbeh.2008.09.008
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  4. Article ; Online: Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.

    Marna S Costanzo / Kyle M Brown / Daniel L Hartl

    PLoS ONE, Vol 6, Iss 5, p e

    2011  Volume 19636

    Abstract: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the ... ...

    Abstract Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness.We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine.Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Malaria: a peek at the var variorum.

    Chookajorn, Thanat / Costanzo, Marna S / Hartl, Daniel L / Deitsch, Kirk W

    Trends in parasitology

    2007  Volume 23, Issue 12, Page(s) 563–565

    Abstract: Geneticists encountering the diversity of the malaria parasite's var gene family for the first time often complain that its complexity is a nightmare. A new article by Barry et al. presents the latest and most systematic attempt to date to decipher the ... ...

    Abstract Geneticists encountering the diversity of the malaria parasite's var gene family for the first time often complain that its complexity is a nightmare. A new article by Barry et al. presents the latest and most systematic attempt to date to decipher the var variorum. This important work, combined with other recent articles on var global variation such as that by Kraemer et al., suggests that only the tip of the var diversity iceberg is currently in view. In this article, we discuss these recent results and provide an overview of current understanding of var diversity.
    MeSH term(s) Animals ; Evolution, Molecular ; Genes, Protozoan ; Genetic Variation ; Humans ; Malaria, Falciparum/parasitology ; Plasmodium falciparum/genetics
    Language English
    Publishing date 2007-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2036227-4
    ISSN 1471-5007 ; 1471-4922
    ISSN (online) 1471-5007
    ISSN 1471-4922
    DOI 10.1016/j.pt.2007.08.022
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  6. Article ; Online: Compensatory mutations restore fitness during the evolution of dihydrofolate reductase.

    Brown, Kyle M / Costanzo, Marna S / Xu, Wenxin / Roy, Scott / Lozovsky, Elena R / Hartl, Daniel L

    Molecular biology and evolution

    2010  Volume 27, Issue 12, Page(s) 2682–2690

    Abstract: Whether a trade-off exists between robustness and evolvability is an important issue for protein evolution. Although traditional viewpoints have assumed that existing functions must be compromised by the evolution of novel activities, recent research has ...

    Abstract Whether a trade-off exists between robustness and evolvability is an important issue for protein evolution. Although traditional viewpoints have assumed that existing functions must be compromised by the evolution of novel activities, recent research has suggested that existing phenotypes can be robust to the evolution of novel protein functions. Enzymes that are targets of antibiotics that are competitive inhibitors must evolve decreased drug affinity while maintaining their function and sustaining growth. Utilizing a transgenic Saccharomyces cerevisiae model expressing the dihydrofolate reductase (DHFR) enzyme from the malarial parasite Plasmodium falciparum, we examine the robustness of growth rate to drug-resistance mutations. We assay the growth rate and resistance of all 48 combinations of 6 DHFR point mutations associated with increased drug resistance in field isolates of the parasite. We observe no consistent relationship between growth rate and resistance phenotypes among the DHFR alleles. The three evolutionary pathways that dominate DHFR evolution show that mutations with increased resistance can compensate for initial declines in growth rate from previously acquired mutations. In other words, resistance mutations that occur later in evolutionary trajectories can compensate for the fitness consequences of earlier mutations. Our results suggest that high levels of resistance may be selected for without necessarily jeopardizing overall fitness.
    MeSH term(s) Alleles ; Antimalarials/pharmacology ; Drug Resistance ; Evolution, Molecular ; Genes, Protozoan ; Genetic Fitness ; Models, Genetic ; Phenotype ; Plasmodium falciparum/enzymology ; Plasmodium falciparum/genetics ; Point Mutation ; Pyrimethamine/pharmacology ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/genetics ; Tetrahydrofolate Dehydrogenase/genetics ; Tetrahydrofolate Dehydrogenase/metabolism
    Chemical Substances Antimalarials ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3) ; Pyrimethamine (Z3614QOX8W)
    Language English
    Publishing date 2010-06-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 998579-7
    ISSN 1537-1719 ; 0737-4038
    ISSN (online) 1537-1719
    ISSN 0737-4038
    DOI 10.1093/molbev/msq160
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