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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

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
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Temporal constraints on the incorporation of regulatory mutants in evolutionary pathways.

Brown, Kyle M / Depristo, Mark A / Weinreich, Daniel M / Hartl, Daniel L

Molecular biology and evolution

2009 Volume 26, Issue 11, Page(s) 2455–2462

Abstract: Understanding the molecular details of the sequence of events in multistep evolutionary pathways can reveal the extent to which natural selection exploits regulatory mutations affecting expression, amino acid replacements affecting the active site, amino ...

Abstract	Understanding the molecular details of the sequence of events in multistep evolutionary pathways can reveal the extent to which natural selection exploits regulatory mutations affecting expression, amino acid replacements affecting the active site, amino acid replacements affecting protein folding or stability, or variations affecting gene copy number. In experimentally exploring the adaptive landscape of the evolution of resistance to beta-lactam antibiotics in enteric bacteria, we noted that a regulatory mutation that increases beta-lactamase expression by about 2-fold has a very strong tendency to be fixed at or near the end of the evolutionary pathway. This pattern contrasts with previous experiments selecting for the utilization of novel substrates, in which regulatory mutations that increase expression are often fixed early in the process. To understand the basis of the difference, we carried out experiments in which the expression of beta-lactamase was under the control of a tunable arabinose promoter. We find that the fitness effect of an increase in gene expression is highly dependent on the catalytic activity of the coding sequence. An increase in expression of an inefficient enzyme has a negligible effect on drug resistance; however, the effect of an increase in expression of an efficient enzyme is very large. The contrast in the temporal incorporation of regulatory mutants between antibiotic resistance and the utilization of novel substrates is related to the nature of the function that relates enzyme activity to fitness. A mathematical model of beta-lactam resistance is examined in detail and shown to be consistent with the observed results.
MeSH term(s)	Directed Molecular Evolution ; Drug Resistance, Microbial/genetics ; Escherichia coli/classification ; Escherichia coli/genetics ; Evolution, Molecular ; Kinetics ; Microbial Sensitivity Tests ; Mutation/genetics ; beta-Lactamases/genetics
Chemical Substances	beta-Lactamases (EC 3.5.2.6)
Language	English
Publishing date	2009-07-14
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/msp151
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Article ; Online: Cascading transcriptional effects of a naturally occurring frameshift mutation in Saccharomyces cerevisiae.

Brown, Kyle M / Landry, Christian R / Hartl, Daniel L / Cavalieri, Duccio

Molecular ecology

2008 Volume 17, Issue 12, Page(s) 2985–2997

Abstract: Gene-expression variation in natural populations is widespread, and its phenotypic effects can be acted upon by natural selection. Only a few naturally segregating genetic differences associated with expression variation have been identified at the ... ...

Abstract	Gene-expression variation in natural populations is widespread, and its phenotypic effects can be acted upon by natural selection. Only a few naturally segregating genetic differences associated with expression variation have been identified at the molecular level. We have identified a single nucleotide insertion in a vineyard isolate of Saccharomyces cerevisiae that has cascading effects through the gene-expression network. This allele is responsible for about 45% (103/230) of the genes that show differential gene expression among the homozygous diploid progeny produced by a vineyard isolate. Using isogenic laboratory strains, we confirm that this allele causes dramatic differences in gene-expression levels of key genes involved in amino acid biosynthesis. The mutation is a frameshift mutation in a mononucleotide run of eight consecutive T's in the coding region of the gene SSY1, which encodes a key component of a plasma-membrane sensor of extracellular amino acids. The potentially high rate of replication slippage of this mononucleotide repeat, combined with its relatively mild effects on growth rate in heterozygous genotypes, is sufficient to account for the persistence of this phenotype at low frequencies in natural populations.
MeSH term(s)	Alleles ; Frameshift Mutation ; Gene Expression Regulation, Fungal ; Gene Frequency ; Genetic Complementation Test ; Genotype ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins/genetics ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/growth & development ; Saccharomyces cerevisiae Proteins/genetics ; Sequence Analysis, DNA ; Transcription, Genetic
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; SSY1 protein, S cerevisiae ; Saccharomyces cerevisiae Proteins
Language	English
Publishing date	2008-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/j.1365-294X.2008.03765.x
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Article: The impact of microsatellite electromorph size homoplasy on multilocus population structure estimates in a tropical tree (Corythophora alta) and an anadromous fish (Morone saxatilis).

Adams, Rachel I / Brown, Kyle M / Hamilton, Matthew B

Molecular ecology

2004 Volume 13, Issue 9, Page(s) 2579–2588

Abstract: Microsatellite allelic states are determined by electrophoretic sizing of polymerase chain reaction fragments to define electromorphs. Numerous studies have documented that identical microsatellite electromorphs are potentially heterogeneous at the DNA ... ...

Abstract	Microsatellite allelic states are determined by electrophoretic sizing of polymerase chain reaction fragments to define electromorphs. Numerous studies have documented that identical microsatellite electromorphs are potentially heterogeneous at the DNA sequence level, a phenomenon called electromorph size homoplasy. Few studies have examined the impact of electromorph size homoplasy on estimates of population genetic parameters. We investigated the frequency of microsatellite electromorph size homoplasy for 12 loci in the tropical tree Corythophora alta and 11 loci in the anadromous fish Morone saxatilis by sequencing 14-23 homozygotes per locus sampled from multiple populations for a total of 453 sequences. Sequencing revealed no homoplasy for M. saxatilis loci. Seven C. alta loci exhibited homoplasy, including single and compound repeat motifs both with and without interruptions. Between 12.5 and 42.9% of electromorphs sampled per locus showed size homoplasy. Two methods of correction for homoplasy in C. alta generally produced little or no change in single-locus estimates of RST, except for two loci in which some additional differentiation among populations was revealed. Twelve-locus estimates of RST (including the seven loci corrected for homoplasy) were slightly greater than estimates from uncorrected data, although the 95% confidence intervals overlapped. The frequency of methodological errors such as clerical mistakes or sample mislabelling per genotype scored was estimated at 5.4 and 7.3% for C. alta and M. saxatilis, respectively. Simulations showed that the increase in RST produced by homoplasy correction was only slightly larger than variation in RST estimates expected to be caused by methodological errors.
MeSH term(s)	Alleles ; Animals ; Base Sequence ; Bass/genetics ; Computer Simulation ; Genetic Variation ; Genetics, Population ; Lecythidaceae/genetics ; Microsatellite Repeats/genetics ; Molecular Sequence Data ; Population Dynamics ; Research Design ; Sequence Analysis, DNA
Language	English
Publishing date	2004-09
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/j.1365-294X.2004.02256.x
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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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Article: Cascading transcriptional effects of a naturally occurring frameshift mutation in Saccharomyces cerevisiae

BROWN, KYLE M / LANDRY, CHRISTIAN R / HARTL, DANIEL L / CAVALIERI, DUCCIO

Molecular ecology. 2008 June, v. 17, no. 12

2008

Abstract	Gene-expression variation in natural populations is widespread, and its phenotypic effects can be acted upon by natural selection. Only a few naturally segregating genetic differences associated with expression variation have been identified at the molecular level. We have identified a single nucleotide insertion in a vineyard isolate of Saccharomyces cerevisiae that has cascading effects through the gene-expression network. This allele is responsible for about 45% (103/230) of the genes that show differential gene expression among the homozygous diploid progeny produced by a vineyard isolate. Using isogenic laboratory strains, we confirm that this allele causes dramatic differences in gene-expression levels of key genes involved in amino acid biosynthesis. The mutation is a frameshift mutation in a mononucleotide run of eight consecutive T's in the coding region of the gene SSY1, which encodes a key component of a plasma-membrane sensor of extracellular amino acids. The potentially high rate of replication slippage of this mononucleotide repeat, combined with its relatively mild effects on growth rate in heterozygous genotypes, is sufficient to account for the persistence of this phenotype at low frequencies in natural populations.
Keywords	gene expression ; population genetics ; wine yeasts ; metagenomics
Language	English
Dates of publication	2008-06
Size	p. 2985-2997.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/j.1365-294X.2008.03765.x
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Article: Stepwise acquisition of pyrimethamine resistance in the malaria parasite

Lozovsky, Elena R / Chookajorn, Thanat / Brown, Kyle M / Imwong, Mallika / Shaw, Philip J / Kamchonwongpaisan, Sumalee / Neafsey, Daniel E / Weinreich, Daniel M / Hartl, Daniel L

Proceedings of the National Academy of Sciences of the United States of America. 2009 July 21, v. 106, no. 29

2009

Abstract: The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which ... ...

Abstract	The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa.
Keywords	Escherichia coli ; Plasmodium falciparum ; amino acids ; dihydrofolate reductase ; drug resistance ; evolution ; malaria ; parasites ; pyrimethamine ; site-directed mutagenesis ; Africa ; South America ; South Asia ; South East Asia
Language	English
Dates of publication	2009-0721
Size	p. 12025-12030.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0905922106
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Article ; Online: Stepwise acquisition of pyrimethamine resistance in the malaria parasite.

Lozovsky, Elena R / Chookajorn, Thanat / Brown, Kyle M / Imwong, Mallika / Shaw, Philip J / Kamchonwongpaisan, Sumalee / Neafsey, Daniel E / Weinreich, Daniel M / Hartl, Daniel L

Proceedings of the National Academy of Sciences of the United States of America

2009 Volume 106, Issue 29, Page(s) 12025–12030

Abstract	The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa.
MeSH term(s)	Alleles ; Animals ; Biological Assay ; Drug Resistance/drug effects ; Evolution, Molecular ; Inhibitory Concentration 50 ; Malaria, Falciparum/parasitology ; Parasites/drug effects ; Parasites/enzymology ; Parasites/genetics ; Parasites/growth & development ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/enzymology ; Plasmodium falciparum/genetics ; Plasmodium falciparum/growth & development ; Polymorphism, Genetic/drug effects ; Pyrimethamine/pharmacology ; Tetrahydrofolate Dehydrogenase/genetics
Chemical Substances	Tetrahydrofolate Dehydrogenase (EC 1.5.1.3) ; Pyrimethamine (Z3614QOX8W)
Language	English
Publishing date	2009-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0905922106
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