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PubMed1997

One gene in diamondback moth confers resistance to four Bacillus thuringiensis toxins.

Environmentally benign insecticides derived from the soil bacterium Bacillus thuringiensis (Bt) are the most widely used biopesticides, but their success will be short-lived if pests quickly adapt to them. The risk of evolution of resistance by pests has increased, because transgenic crops producing insecticidal proteins from Bt are being grown commercially. Efforts to delay resistance with two or more Bt toxins assume that independent mutations are required to counter each toxin. Moreover, it generally is assumed that resistance alleles are rare in susceptible populations. We tested these assumptions by conducting single-pair crosses with diamondback moth (Plutella xylostella), the first insect known to have evolved resistance to Bt in open field populations. An autosomal recessive gene conferred extremely high resistance to four Bt toxins (Cry1Aa, Cry1Ab, Cry1Ac, and Cry1F). The finding that 21% of the individuals from a susceptible strain were heterozygous for the multiple-toxin resistance gene implies that the resistance allele frequency was 10 times higher than the most widely cited estimate of the upper limit for the initial frequency of resistance alleles in susceptible populations. These findings suggest that pests may evolve resistance to some groups of toxins much faster than previously expected.

Animals↗
PubMed2003

Rapid evolution and the cost of resistance to Bacillus thuringiensis in greenhouse populations of cabbage loopers, Trichoplusia ni.

The microbial insecticide Bacillus thuringiensis (Bt) has become the mainstay of non-chemical control of Lepidopteran pests, either as sprays or through the incorporation of Bt toxins into transgenic crops. Given the wide use of Bt, it is striking that currently only one pest species, Plutella xylostella, has been reported to have developed significant resistance to Bt outside the laboratory. By contrast, we report here the frequent and rapid development of resistance to B. thuringiensis kurstaki (Dipel, Abbott) in populations of cabbage loopers, Trichoplusia ni, in commercial greenhouses. Resistance to Bt appears to be costly and there is a rapid decline of resistance in populations collected from greenhouses and maintained in the laboratory without selection. Management of pests resistant to Bt in vegetable greenhouses will require sporadic use of Bt-based sprays or alternatively use of sprays containing other Bt toxins.

Animals↗
PubMed1997

Anthelmintic resistance.

Since the first reports of resistance to the broad spectrum anthelmintics were made some three decades ago, this phenomenon has changed from being considered merely as a parasitological curiosity to a state of industry crisis in certain livestock sectors. This extreme situation exists with the small ruminant industry of the tropical/sub-tropical region of southern Latin America where resistance to the entire broad spectrum anthelmintic arsenal now occurs. In contrast, the cattle industry does not appear to be threatened--or so it seems. Although field reports of resistance have been made to the range of broad spectrum anthelmintics in nematode parasites of cattle, it appears that the evolution of resistance in cattle parasites is not as dramatic as for sheep worms. However, one cannot remain confident that this state of affairs will remain static. Concern is shared amongst parasitologists that we have not looked closely enough. In regions of the world where internal parasites are considered a problem in cattle and drenching occurs frequently, no widespread surveys have been carried out. It appears that because of the very high costs and risks associated with taking a new active drug down the development track to marketing, that the pharmaceutical industry has, in general, turned away from this activity. By implication, the international small ruminant industry is too small for these companies to make the necessary investment. This begs two questions: What is the fate of the sheep (and goat) industries in those parts of the world where resistance is rampant and immediate ameliorative parasite control options are required? What will be the response if significant resistance is found in cattle parasites? There is a body of opinion which suggests that if resistance becomes an issue in the control of cattle parasites then the pharmaceutical industry will find it commercially attractive to re-enter the anthelmintic discovery and development business. This is based on the simple commercial fact that by far the greatest anthelmintic sales are associated with the cattle industry. However, this market is specific and sectoral, with by far the greatest sales in North America and Western Europe, where the prevalence of resistance is likely to be low and remain so, more-or-less indefinitely. So the chances of the above scenario occurring must be considered low. Remarkable developments have recently occurred in non-chemotherapeutic parasite control options, for example worm vaccines, host selection and biological control. Also, there seems to be greater acceptance of various grazing management practices designed to reduce the frequency of anthelmintic treatment. However, they collectively cannot be expected to offer immediate salvation to farmers now faced with chemotherapeutic failure to control nematode parasites in their flocks. The future for these farmers must be considered bleak, because compounded with these problems are the poor commodity prices for sheep and goat meat and fibre, resulting in relentless reductions in funding for research to support these industries. Perhaps the major social issues associated with re-structuring and possibly abandonment of sheep and goat farming in affected areas may precipitate action? As veterinary parasitologists, who in general have an interest and expertise in parasite control, we must promote the importance of the problem of anthelmintic resistance and ways to tackle it.

Animals↗
PubMed2003

Molecular description of evolving paclitaxel resistance in the SKOV-3 human ovarian carcinoma cell line.

Ovarian cancer is currently the most lethal gynecological malignancy in the United States. Although effective therapies exist, the acquisition of multidrug resistance within persisting tumor cells renders curative therapies elusive for the majority of women with ovarian cancer. In an attempt to better define the evolution of paclitaxel resistance, three SKOV-3 sublines were selected during successive rounds of exposure to increasing paclitaxel concentrations. The sublines were selected to represent early (0.003 micro M), intermediate (0.03 micro M), and late (0.3 micro M) paclitaxel resistance. RNA from these cell lines, SKOV-3(0.003TR), SKOV-3(0.03TR), and SKOV-3(0.3TR), as well as the parent cell line SKOV-3, was analyzed by cDNA array to evaluate transcript expression profiles. Arrays were performed using Affymetrix HG-U95Av2 arrays, which contain probes for approximately 9600 known human genes. Signal intensities were calculated by Microarray Suite 5.0 (Affymetrix, Santa Clara, CA). Expression patterns were analyzed by Affymetrix Data Mining Tool 3.0 with filtering of expression patterns for fold change in expression (maximum divided by minimum expression value/gene) and for variation of expression (maximum minus minimum expression value/gene). This analysis dismissed approximately 11,000 of approximately 12,000 expression patterns. The remaining approximately 1000 expression patterns were normalized and segregated into 20 partitions of a self-organizing map (SOM). The resulting SOM discriminates between genes, which are differentially expressed in early versus intermediate versus late paclitaxel resistance. For example, multidrug resistance 1 transcript expression is not elevated in SKOV-3(0.003TR) as compared with parental SKOV-3 but demonstrates elevated expression in SKOV-3(0.03TR) and SKOV-3(0.3TR). In contrast, SOM analysis demonstrates early (SKOV-3(0.003TR)) transcriptional changes in a wide variety of genes, including gene families involved in cell growth/maintenance, cell structure, signal transduction, and inflammatory response. The use of array analysis with SOMs in sublines with progressive paclitaxel resistance can successfully define an evolution of resistance. Such an analysis may be useful at defining candidate gene families involved in the early-drug resistance phenotype.

Algorithms↗
PubMed2005

Resistance in the mosquito, Culex quinquefasciatus, and possible mechanisms for resistance.

Two mosquito strains of Culex quinquefasciatus (Say), MAmCq(G0) and HAmCq(G0), were collected from Mobile and Huntsville, Alabama, respectively. MAmCq(G0) and HAmCq(G0) were further selected in the laboratory with permethrin for one and three generations, respectively. The levels of resistance to permethrin in MAmCq(G1) (after one-generation selection) and HAmCq(G3) (after three-generation selection) increased rapidly. Resistance to permethrin in MAmCq(G1) and HAmCq(G3) was partially suppressed by piperonyl butoxide (PBO), S,S,S-tributylphosphorotrithioate (DEF) and diethyl maleate (DEM), inhibitors of cytochrome P450 monooxygenases, hydrolases and glutathione S-transferases (GST), respectively, suggesting these three enzyme families are important in conferring permethrin resistance in both strains. A substitution of leucine to phenylalanine (L to F) resulting from a single nucleotide polymorphism (SNP), termed the kdr mutation, in the para-homologous sodium channel gene has been reported as a very common mutation associated with pyrethroid resistance of insects. A 341-bp sodium channel gene fragment, where the kdr mutation resides, was generated by PCR from genomic DNAs of Cx. quinquefasciatus strains. We found that the kdr mutation was present in both permethrin-selected and unselected HAmCq and MAmCq mosquito populations, suggesting that the kdr mutation plays the role in permethrin resistance. There was no significant change in the frequency and heterozygosity of the A to T SNP for the kdr allele between permethrin-selected and unselected MAmCq and HAmCq mosquitoes, indicating that other mechanisms are involved in the evolution of resistance in mosquitoes selected by permethrin in the laboratory.

Animals↗
PubMed2026

Multiomic study of cutaneous T-cell lymphoma reveals single-cell clonal evolution in progression and therapy resistance.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multiomics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. Here, we present a comprehensive multiomics view of CTCL clonal evolution, incorporating exome, whole-genome, epigenome, bulk, single-cell T-cell receptor, and single-cell RNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 patients with CTCL. We leveraged this extensive data set to define the molecular underpinnings of CTCL progression in individual patients at single-cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, phosphoinositide 3-kinase inhibitor signaling, and programmed cell death protein 1 (PD-1) checkpoint pathways as evasion tactics deployed by malignant T cells. We identified a gain-of-function mutation in STAT3 (D661Y) and demonstrated, using cleavage under targets and release using nuclease (CUT&RUN) and RNA sequencing, that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in histone deacetylase inhibitor-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely used for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision-making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.

Multiomics↗
PubMed2000

Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria.

In the absence of the selecting drugs, chromosomal mutations for resistance to antibiotics and other chemotheraputic agents commonly engender a cost in the fitness of microorganisms. Recent in vivo and in vitro experimental studies of the adaptation to these "costs of resistance" in Escherichia coli, HIV, and Salmonella typhimurium found that evolution in the absence of these drugs commonly results in the ascent of mutations that ameliorate these costs, rather than higher-fitness, drug-sensitive revertants. To ascertain the conditions under which this compensatory evolution, rather than reversion, will occur, we did computer simulations, in vitro experiments, and DNA sequencing studies with low-fitness rpsL (streptomycin-resistant) mutants of E. coli with and without mutations that compensate for the fitness costs of these ribosomal protein mutations. The results of our investigation support the hypothesis that in these experiments, the ascent of intermediate-fitness compensatory mutants, rather than high-fitness revertants, can be attributed to higher rates of compensatory mutations relative to that of reversion and to the numerical bottlenecks associated with serial passage. We argue that these bottlenecks are intrinsic to the population dynamics of parasitic and commensal microbes and discuss the implications of these results to the problem of drug resistance and adaptive evolution in parasitic and commmensal microorganisms in general.

Adaptation, Biological↗
PubMed1985

Natural selection for resistance to mercury pollution.

The survival under conditions of mercury pollution of two natural populations of the marine gastropod Cerithium rupestre, derived from mercury-polluted and mercury-free sites, was tested in the laboratory. The results indicate a significantly higher survival rate for animals derived from the mercury-polluted site, in each of six repetitive experiments. We conclude that mercury resistance in marine organisms is reinforced in mercury polluted sites, presumably by natural selection for increased resistance. The evolution of metal tolerance in marine organisms may be as fast as that of metal tolerance in plants and the evolution of industrial melanisms in moths.

Animals↗
PubMed2004

The maintenance of extreme amino acid diversity at the disease resistance gene, RPP13, in Arabidopsis thaliana.

We have used the naturally occurring plant-parasite system of Arabidopsis thaliana and its common parasite Peronospora parasitica (downy mildew) to study the evolution of resistance specificity in the host population. DNA sequence of the resistance gene, RPP13, from 24 accessions, including 20 from the United Kingdom, revealed amino acid sequence diversity higher than that of any protein coding gene reported so far in A. thaliana. A significant excess of amino acid polymorphism segregating within this species is localized within the leucine-rich repeat (LRR) domain of RPP13. These results indicate that single alleles of the gene have not swept through the population, but instead, a diverse collection of alleles have been maintained. Transgenic complementation experiments demonstrate functional differences among alleles in their resistance to various pathogen isolates, suggesting that the extreme amino acid polymorphism in RPP13 is maintained through continual reciprocal selection between host and pathogen.

Alleles↗
PubMed1986

Genetic and biochemical basis of resistance of Enterobacteriaceae to beta-lactam antibiotics.

Resistance to beta-lactam drugs is usually determined by genes mediating the production of beta-lactamases. These genes can be located on resistance plasmids or on the chromosome. Resistance to drugs which have been available for many years is mostly transposable. Although the origin of these genes is not known, it is possible to draw a hypothetical flow diagram of the evolution of resistance genes in general. The mechanism of resistance although mediated in Gram-negative bacteria mostly by beta-lactamases cannot be simply described as the hydrolytic function of the enzyme. It is a complex interaction involving the affinity of the drug for the target and the lactamase, the amount of drug in the periplasmic space, the amount of enzyme and the number of lethal target sites. Usually one of these factors is predominant.

Anti-Bacterial Agents↗
PubMed2005

Insecticide resistance in Culex pipiens from New York.

Insecticides are the primary means to control Culex pipiens, an enzootic vector of West Nile virus, in the USA. To better understand how the evolution of resistance might impact control of this insect, we investigated the levels of resistance in populations collected from 2 metropolitan areas (Albany and Syracuse, NY) to 4 larvicides (methoprene, phenothrin, Bacillus sphaericus [Bs], and Bacillus thuringiensis israelensis [Bti]) and 1 adulticide (phenothrin) registered for mosquito control in New York State. High levels of resistance were found only to Bti, and only at 1 site (Syracuse). Resistance levels to the other insecticides were less than 10-fold. Given the large difference in Bti resistance between Syracuse and Albany, it appears these populations of Cx. pipiens do not rapidly mix, leading to localization of resistant populations.

Animals↗
PubMed2006

Absence of resistance mutations in antiretroviral-naive patients treated with ritonavir-boosted saquinavir.

BACKGROUND: There are few data on the selection of resistance by ritonavir-boosted saquinavir (SQV/r), particularly in antiretroviral (ARV)-naive patients. OBJECTIVE: To assess the incidence of virological failure and evolution of resistance in ARV-naive individuals receiving SQV/r in the induction phase of the Staccato trial. METHODS: ARV-naive subjects (n = 272) received SQV/r 1,600/100 mg once daily with two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 24 weeks. Patients were defined as having virological failure (VF) when there were two consecutive HIV-1 RNA measurements > 500 copies/ml after week 12. Viral genotypes (reverse transcriptase [RT] and protease [PRO]) were determined at baseline in all patients and as close as possible to the time of initial failure in patients experiencing VF. RESULTS: VF was observed in 9/272 patients receiving SQV/r 1,600/100 mg once daily with two NRTIs (3.3%) and occurred 19-48 weeks after treatment initiation. Eight of these patients were evaluable at failure. No major PRO mutations were detected, but 2/8 displayed single new minor PRO substitutions (M36I, L10I) at VF that were known or suspected not to have been present at baseline; both these substitutions exist as natural polymorphisms. A third patient displayed a single new RT mutation (M184I). CONCLUSIONS: SQV/r plus two NRTIs (1,600/100 mg once daily) is an effective initial treatment option for ARV-naive patients, resulting in a low rate of viral rebound (3.3%). Furthermore, no major protease mutations were detected following VF, suggesting that future treatment options are preserved.

Adult↗
PubMed2006

Planting transgenic insecticidal corn based on economic thresholds: consequences for integrated pest management and insect resistance management.

A simulation model of the western corn rootworm, Diabrotica virgifera virgifera LeConte, was used to investigate whether sampling and economic thresholds can improve integrated pest management (IPM) and insect resistance management (IRM) when transgenic insecticidal crops are used for insect pest management. When transgenic corn killed at least 80% of susceptible larvae, the calculated economic threshold increased linearly as the proportion of susceptible beetles surviving the toxin increased. The use of economic thresholds slightly slowed the evolution of resistance to transgenic insecticidal crops. In areas with or without rotation-resistant western corn rootworm phenotypes, the use of sampling and economic thresholds generated similar returns compared with strategies of planting transgenic corn, Zea mays L., every season. Because transgenic crops are extremely effective, farmers may be inclined to plant transgenic crops every season rather than implementing costly and time-consuming sampling protocols.

Agriculture↗
PubMed2006

Sensory exploitation and sexual conflict.

Much of the literature on male-female coevolution concerns the processes by which male traits and female preferences for these can coevolve and be maintained by selection. There has been less explicit focus on the origin of male traits and female preferences. Here, I argue that it is important to distinguish origin from subsequent coevolution and that insights into the origin can help us appreciate the relative roles of various coevolutionary processes for the evolution of diversity in sexual dimorphism. I delineate four distinct scenarios for the origin of male traits and female preferences that build on past contributions, two of which are based on pre-existing variation in quality indicators among males and two on exploitation of pre-existing sensory biases among females. Recent empirical research, and theoretical models, suggest that origin by sensory exploitation has been widespread. I argue that this points to a key, but perhaps transient, role for sexually antagonistic coevolution (SAC) in the subsequent evolutionary elaboration of sexual traits, because (i) sensory exploitation is often likely to be initially costly for individuals of the exploited sex and (ii) the subsequent evolution of resistance to sensory exploitation should often be associated with costs due to selective constraints. A review of a few case studies is used to illustrate these points. Empirical data directly relevant to the costs of being sensory exploited and the costs of evolving resistance is largely lacking, and I stress that such data would help determining the general importance of sexual conflict and SAC for the evolution of sexual dimorphism.

Animals↗
PubMed1997

Influence of Exposure to Single versus Multiple Toxins of Bacillus thuringiensis subsp. israelensis on Development of Resistance in the Mosquito Culex quinquefasciatus (Diptera: Culicidae).

The impending widespread use of transgenic crop plants encoding a single insecticidal toxin protein of Bacillus thuringiensis has focused attention on the perceived risk of rapid selection of resistance in target insects. We have used Bacillus thuringiensis subsp. israelensis toxins as a model system and determined the speed and magnitude of evolution of resistance in colonies of the mosquito Culex quinquefasciatus during selection for 28 consecutive generations with single or multiple toxins. The parental strain was synthesized by combining approximately 500 larvae from each of 19 field collections obtained from the states of California, Oregon, Louisiana, and Tennessee. At least 10,000 larvae were selected in each generation of each line at an average mortality level of 84%. The susceptibilities of the parental and selected lines were compared in parallel tests in every third generation by using fresh suspensions of toxin powders. The normal toxin complement of B. thuringiensis subsp. israelensis consists of four toxins, CryIVA, CryIVB, CryIVD, and CytA. Resistance became evident first in the line that was selected with a single toxin (CryIVD), attaining the highest level (resistance ratio [RR], >913 at 95% lethal concentration) by generation F(inf28) when the study was completed. Resistance evolved more slowly and to a lower level (RR, >122 by F(inf25)) in the line selected with two toxins (CryIVA+CryIVB) and lower still (RR, 91 by F(inf28)) in the line selected with three toxins (CryIVA+CryIVB+ CryIVD). Resistance was remarkably low (RR, 3.2) in the line selected with all four toxins. The results reveal the importance of the full complement of toxins found in natural populations of B. thuringiensis subsp. israelensis as an effective approach to resistance management.

Journal Article↗
PubMed2002

On the implications of endogenous resistance to medications.

Uniform treatment guidelines are often used in medicine to ensure that all physicians prescribe a safe, efficacious, and cost-effective drug in treating a medical condition. The main message of this paper is that a policy of uniform treatment based on the standard cost-effectiveness criterion may be inappropriate when drug resistance is endogenous, and selection pressure imposed by the use of any single drug (antibiotic, antiviral, or antimalarial) leads sooner or later to the evolution of resistance (by bacteria, viruses, or parasites) to that drug. The paper shows that a mixed treatment policy of multiple drug use is generally desirable, and characterizes analytically the conditions under which it is optimal.

Anti-Bacterial Agents↗
PubMed1999

A sodium channel point mutation is associated with resistance to DDT and pyrethroid insecticides in the peach-potato aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae).

The voltage-gated sodium channel is the primary target site of DDT and pyrethroid insecticides, and point mutations in the domain II region of the channel protein have been implicated in the knockdown resistant (kdr ) phenotype of several insect species. Here, we report that one of these mutations, a leucine-to-phenylalanine replacement in transmembrane segment IIS6, is also found in certain insecticide-resistant clones of the peach-potato aphid, Myzus persicae. The mutation was present in four clones with amplified E4 esterase genes, but was absent from both susceptible clones and those with amplified FE4 genes. The inferred presence of kdr-type resistance in the four E4 clones was subsequently confirmed by bioassays that showed this to be the primary mechanism of resistance to deltamethrin and DDT, although the esterase-based mechanism also contributes to the overall level of deltamethrin resistance. The kdr mutation on its own conferred 35-fold resistance to deltamethrin and this was enhanced up to 540-fold when it was present in a high (E4) esterase background. The esterase (FE4) mechanism was far less effective without the kdr mutation, conferring just 3-4-fold resistance to deltamethrin. These findings, and the linkage disequilibrium of the kdr mutation within clones overproducing the E4 esterase, have important implications for the evolution of resistance in this insect and for the use of pyrethroid sprays in the management of M. persicae populations in the field.

Amino Acid Sequence↗