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PubMed2003

Mutational and selective pressures on codon and amino acid usage in Buchnera, endosymbiotic bacteria of aphids.

We have explored compositional variation at synonymous (codon usage) and nonsynonymous (amino acid usage) positions in three complete genomes of Buchnera, endosymbiotic bacteria of aphids, and also in their orthologs in Escherichia coli, a close free-living relative. We sought to discriminate genes of variable expression levels in order to weigh the relative contributions of mutational bias and selection in the genomic changes following symbiosis. We identified clear strand asymmetries, distribution biases (putative high-expression genes were found more often on the leading strand), and a residual slight codon bias within each strand. Amino acid usage was strongly biased in putative high-expression genes, characterized by avoidance of aromatic amino acids, but above all by greater conservation and resistance to AT enrichment. Despite the almost complete loss of codon bias and heavy mutational pressure, selective forces are still strong at nonsynonymous sites of a fraction of the genome. However, Buchnera from Baizongia pistaciae appears to have suffered a stronger symbiotic syndrome than the two other species.

Amino Acids↗
PubMed1996

Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile) HIV-1 mutants.

The quinoxaline nonnucleoside RT inhibitor (NNRTI) (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4- dihydroquinoxaline-2(1H)-thione (HBY 097) was used to select for drug-resistant HIV-1 variants in vitro. The viruses first developed mutations affecting the NNRTI-binding pocket, and five of six strains displayed the RT G190-->E substitution, which is characteristic for HIV-1 resistance against quinoxalines. In one variant, a new mutant (G190-->Q) most likely evolved from preexisting G190-->E mutants. The negative charge introduced by the G190-->E substitution was maintained at that site of the pocket by simultaneous selection for V179-->D together with G190-->Q. After continued exposure to the drug, mutations at positions so far known to be specific for resistance against nucleoside RT inhibitors (NRTIs) (L74-->V/I and V75-->L/I) were consistently detected in all cultures. The inhibitory activities of the cellular conversion product of 2',3'-dideoxyinosine (ddI, didanosine), 2',3'-dideoxyadenosine (ddA) and of 2',3'-didehydro-3'-deoxythymidine (d4T, stavudine) against these late-passage viruses were shown to be enhanced with the L74-->V/I RT mutant virus as compared with the wild-type (wt) HIV-1MN isolate. Clonal analysis proved linkage of the codon 74 and codon 75 mutations to the NNRTI-specific mutations in all RT gene fragments. The nonnucleoside- and nucleoside-resistance mutation sites are separated by approximately 35 A. We propose that the two sites "communicate" through the template-primer which is situated in the DNA-binding cleft between these two sites. Quinoxalines cause high selective pressure on HIV-1 replication in vitro; however, the implication of these findings for the treatment of HIV-1 infection has yet to be determined.

Antiviral Agents↗
PubMed1995

Influence of the nature of the reporter gene and selection pressure on stability of avian retrovirus vectors.

We have compared the long-term stability of 2 avian non-replicative retroviral vectors in an infected permanent cell line from quail fibroblasts (QT6). Vectors NL53 and NPL, expressing both the neo and LacZ genes under control of cis-acting elements originated from avian erythroblastosis virus (AEV), are similar to each other except for the presence of the phleomycin-resistance SHble gene fused upstream the reporter LacZ gene, in NPL vector. The use of such vectors, with an uniform backbone, to infect QT6 cells, allowed us to demonstrate that stability of the beta-galactosidase activity encoded by the SHble-LacZ fusion gene remains higher than that encoded by the native LacZ gene, as determined in the same conditions of culture. Moreover, stability of the provirus was dependent on the selection pressure. Here we show that stability of beta-galactosidase activity in infected QT6 cells was obtained with high dose selection for the selectable SHble-LacZ fusion gene.

Alpharetrovirus↗
PubMed1999

Selective pressure as an essential force in molecular evolution of myeloid leukemic clones: a view from the window of Fanconi anemia.

Specific chromosomal deletions are commonly found in bone marrow cells of children with Fanconi anemia (FA) whose disease has evolved to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Identical deletions are found in adults with MDS/AML with a history of exposure to alkylating agents (secondary MDS/AML). While deleted chromosomal regions likely harbor genes encoding proteins with tumor suppressor (TS) function, such genes have not been identified and the environmental forces by which these mutant clones are selected remain unclear. A consistent signaling abnormality in cells bearing mutations of the Fanconi anemia complementation group C (FA-C) gene (FANCC) has revealed a potential selective force. Hematopoietic progenitor cells from patients and mice with FANCC mutations are hypersensitive to the inhibitory effects of IFNgamma and TNFalpha. Consequently, clonal outgrowths in FA likely result from strong selective pressure for stem and/or progenitor cells resistant to these inhibitory cytokines. Additional mutations that inactivate signaling pathways for these inhibitors would create a cell with a profound proliferative advantage over its apoptosis-prone counterparts. Here, we present preliminary evidence supporting a selection-based model of leukemic evolution and argue that MDS in FA patients is a de facto model of secondary MDS in non-FA adults.

Acute Disease↗
PubMed2003

Antibiotic selective pressure for the maintenance of antibiotic resistant genes in coliform bacteria isolated from the aquatic environment.

Coliform bacteria isolated from the aquatic environment were investigated for antibiotic susceptibility and detailed structures of class 1 integrons. A high proportion of isolates were found to be resistant to sulfamethoxazole, aminoglycosides, and beta-lactams. The 750 (53.6%) isolates were resistant to one or more of the antibiotics tested out of 1,400 coliform bacteria. Based on the MIC of antibiotics and antibiogram, 150 isolates were selected and further studied for class 1 integrons. The intI1 gene was found in 36 (24.0%) of the 150 isolates. Twelve isolates carried the gene cassettes responsible for antibiotic resistance, while no gene cassettes were found in 24 isolates. Seven different genes, dfrA5, dfrA7, dfrA12, dfrA17, aaA2, aaA5, and aad(3'), were detected in gene cassettes. The dfrA and aad genes located on class 1 integrons were responsible for resistance to trimethoprim and aminoglycosides. The remaining 24 coliform bacteria had the incomplete or non-functional class 1 integrons. These results indicated that antibiotic selective pressures may play an important role to maintain gene cassettes of class 1 integrons and in the absence of sustained antibiotic pressures, such as the aquatic environment, coliform bacteria may carry empty or non-functional class 1 integrons.

Drug Resistance, Microbial↗
PubMed2003

Contrasting selection pressures on components of the Ras-mediated signal transduction pathway in Drosophila.

The molecular genetics of several signal transduction pathways is well characterized, providing an opportunity to address the nature of the population genetic forces acting on functionally related suites of pleiotropic regulatory genes. Signal transduction is the process by which signals are transmitted from the cell surface to the nucleus or other cellular structures. It plays a fundamental role in regulating a wide range of developmental and physiological processes, many of which are likely to be subject to buffering mechanisms. Here we infer that contrasting selection pressures act on six components of the Ras signal transduction pathway by comparing sequences obtained from 25 alleles of Drosophila melanogaster with one allele of the sibling species D. simulans. The three most upstream components of the cascade, Ras, Drk and polehole, experience strong purifying selection, as they show no fixed amino acid differences between the species and just a handful of rare replacement polymorphisms within D. melanogaster. This portion of the pathway is likely to act as a control point in signal transduction, because the more downstream components Dsor1, corkscrew and Ksr, each show several amino acid replacements between the species. Furthermore, Ksr is nearly monomorphic within D. melanogaster, and application of the HKA and McDonald and Kreitman tests indicate that this gene may have experienced a recent selective sweep, suggesting that modifiers of Ras kinase signalling are the most likely source of quantitative variation associated with this core regulatory pathway.

Animals↗
PubMed2026

Evaluating Patient Satisfaction and Oral Health Impact Profile-14 (OHIP-14): A Multicenter Crossover Study Comparing Selective Pressure Impression Conventional Dentures with Mucostatic Digital Dentures.

PURPOSE: To compare patient satisfaction and oral health impact between individuals receiving complete dentures made by digital methods and those using conventional techniques. MATERIALS AND METHODS: In this randomized crossover clinical trial, 23 patients aged 40 years and older with completely edentulous arches were enrolled at three treatment centers. Each participant received two sets of complete dentures: one set created using conventional methods (selective pressure impression) and the other through digital techniques (mucostatic digital impression). The order of denture placement was randomized, with each set used for 4 weeks. A trained specialist administered treatments alongside research tools, including a general information questionnaire, a denture satisfaction survey, and the OHIP-14 interview tool. Statistical analysis was conducted using Mann-Whitney U test. RESULTS: Participants with digital dentures reported significantly higher satisfaction regarding treatment duration, comfort, confidence, chewing ability, esthetics, and overall satisfaction compared to those with conventional dentures. There were no significant differences in satisfaction concerning speech and pronunciation. Overall, the oral health impact on quality of life was similar between denture types, but participants indicated improved quality of life while using dentures compared to being edentulous. CONCLUSIONS: Patients with digital dentures exhibited greater satisfaction across various domains compared to those with conventional dentures, despite similar satisfaction levels in speech and pronunciation. The impact on quality of life was comparable between both types, as measured by the OHIP-14.

Humans↗
PubMed1993

B epitopes and selection pressures in feline immunodeficiency virus envelope glycoproteins.

In order to map linear B epitopes in feline immunodeficiency virus (FIV) envelope glycoproteins (Env), a random library of FIV Env polypeptides fused to beta-galactosidase and expressed in Escherichia coli was screened by using sera from experimentally FIV-infected cats. We mapped five antibody-binding domains in the surface envelope glycoprotein (SU1 to SU5) and four in the transmembrane envelope glycoprotein (TM1 to TM4). Immunological analysis with 48 serum samples from naturally or experimentally infected cats of diverse origins revealed a broad group reactivity for epitopes SU2, TM2, and TM3, whereas SU3 appeared as strictly type specific. To study selection pressures acting on the identified immunogenic domains, we analyzed structural constraints and distribution of synonymous and nonsynonymous mutations (amino acids unchanged or changed). Two linear B epitopes (SU3 and TM4) appeared to be submitted to positive selection for change, a pattern of evolution predicting their possible involvement in antiviral protection. These experiments provide a pertinent choice of oligopeptides for further analysis of the protective response against FIV envelope glycoproteins, as a model to understand the role of antibody escape in lentiviral persistence and to design feline AIDS vaccines.

Animals↗
PubMed1999

Pattern of mutations that results in loss of reduced folate carrier function under antifolate selective pressure augmented by chemical mutagenesis.

Chemical mutagenesis with N-methyl-N-nitrosourea was employed to study the pattern of mutations in the reduced folate carrier (RFC1) that results in transport-related methotrexate resistance and to identify amino acid residues that are critical to carrier structure and/or function. Thirty-four methotrexate transport-defective L1210 leukemia cell lines were isolated with folic acid as the sole folate source under antifolate selective pressure. The RFC1 mRNA levels were comparable with, or not substantially decreased, in most of these cell lines relative to wild-type L1210 cells. The molecular basis for the transport defects was investigated by sequencing multiple RFC1 cDNA clones isolated from these mutants by reverse transcription-polymerase chain reaction, which encompassed the entire coding region. The mutations identified were further confirmed either by direct sequencing or, when applicable, by restriction analysis of total reverse transcription-polymerase chain reaction products. The majority of mutations (21) led to single amino acid substitutions that were in, or near, 9 of 12 predicted transmembrane domains, with the highest frequencies in the first, fifth, and eighth. There were no mutations in the sixth, ninth, and twelfth transmembrane domains. Glycine, serine, and arginine were the most frequently mutated residues. These data suggest that several transmembrane domains, rather than the amino- and carboxyl-termini, and the large intracellular loop between the sixth and seventh transmembrane domains play key roles as sites for RFC1 inactivation because of single point mutations. This panel of mutated cell lines offers an important resource for studies on RFC1 structure-function and for the evaluation of transport-related cross-resistance patterns with new-generation antifolate inhibitors of tetrahydrofolate cofactor-dependent enzymes.

Animals↗
PubMed2004

Antibiotic selection pressure and resistance in Streptococcus pneumoniae and Streptococcus pyogenes.

We correlated outpatient antibiotic use with prevalence of penicillin-nonsusceptible Streptococcus pneumoniae (PNSP), macrolide-resistant S. pneumoniae (MRSP), and macrolide-resistant S. pyogenes (MRGAS) in 20 countries. Total antibiotic use was correlated with PNSP (r = 0.75; p < 0.001), as was macrolide use with MRSP (r = 0.88; p < 0.001) and MRGAS (r = 0.71; p = 0.004). Streptococcal resistance is directly associated with antibiotic selection pressure on a national level.

Anti-Bacterial Agents↗
PubMed1988

Selection pressure and altered hepatocellular islands after a single injection of aflatoxin B1.

Development of glutathione S-transferase placental form (GST-P)-positive focal populations was investigated subsequent to single injections of the hepatocarcinogens aflatoxin B1 (AfB1), dimethylnitrosamine (DMN) and diethylnitrosamine (DEN). While DEN proved far more potent at inducing putative initiated hepatocytes, the AfB1 treatment was associated with a very rapid (3 weeks) development of lesions approaching nodular proportions. Autoradiographic investigation revealed selective incorporation of label into GST-P-positive hepatocytes and oval cells at the day 7 time point following AfB1 treatment. Administration of butylated hydroxyanisole (BHA) subsequent to carcinogen injection was associated with a decrease in the final yield of lesions and increased tritiated thymidine incorporation in perivenular zone 3 background hepatocytes. The results suggest that 'selection pressure', resulting in rapid growth and development of putative preneoplastic lesions, is inherent in a single injection of the mycotoxin and indicate that variations of the present short-term model may be useful for elucidating the mechanisms underlying AfB1-induced hepatocarcinogenesis.

Aflatoxin B1↗
PubMed2006

Insights into the selective pressures restricting Pelargonium flower break virus genome variability: Evidence for host adaptation.

The molecular diversity of Pelargonium flower break virus (PFBV) was assessed using a collection of isolates from different geographical origins, hosts, and collecting times. The genomic region examined was 1,828 nucleotides (nt) long and comprised the coding sequences for the movement (p7 and p12) and the coat (CP) proteins, as well as flanking segments including the entire 3' untranslated region (3' UTR). Some constraints limiting viral heterogeneity could be inferred from sequence analyses, such as the conservation of the amino acid sequences of p7 and of the shell domain of the CP, the maintenance of a leucine zipper motif in p12, and the preservation of a particular folding in the 3' UTR. A remarkable covariation, involving five specific amino acid sites, was found in the CP of isolates largely propagated in the local lesion host Chenopodium quinoa and in the progeny of a PFBV variant subjected to serial passages in this host. Concomitant with this covariation, up to 30 nucleotide substitutions in a 1,428-nt region of the viral RNA could be attributable to C. quinoa-specific adaptation, representing one of the most outstanding cases of host-driven genome variation for a plant virus. Globally, the results indicate that the selective pressures exerted by the host play a critical role in shaping PFBV populations and that these populations are likely being selected for at both protein and RNA levels.

3' Untranslated Regions↗
PubMed1990

Mutations with multiple independent origins in surface antigens mark the targets of biological selective pressure.

This manuscript documents the existence and importance of a small subset of mutations in Plasmodium falciparum genes that continually reoccur in separated populations. Here we describe how to identify recurrent mutations using a novel application of pre-existing computer programs designed to trace genealogy. Perhaps the most striking example of this phenomenon occurs in the cytotoxic T-cell epitope of a malaria surface antigen, the circumsporozoite (CS) protein of P. falciparum, where identical sequence types clearly have multiple independent origins. The importance of this observation is that it conclusively demonstrates selective pressure on these sequences and indicates that there is a significant natural mechanism relating to the circumsporozoite protein that affects the success of malaria sporozoites.

Animals↗
PubMed2001

Ehrlichia ruminantium major antigenic protein gene (map1) variants are not geographically constrained and show no evidence of having evolved under positive selection pressure.

In a search for tools to distinguish antigenic variants of Ehrlichia ruminantium, we sequenced the major antigenic protein genes (map1 genes) of 21 different isolates and found that the sequence polymorphisms were too great to permit the design of probes which could be used as markers for immunogenicity. Phylogenetic comparison of the 21 deduced MAP1 sequences plus another 9 sequences which had been previously published did not reveal any geographic clustering among the isolates. Maximum likelihood analysis of codon and amino acid changes over the phylogeny provided no statistical evidence that the gene is under positive selection pressure, suggesting that it may not be important for the evasion of host immune responses.

Amino Acid Sequence↗
PubMed1990

Enhanced preneoplastic liver lesion development under 'selection pressure' conditions after administration of deoxycholic or lithocholic acid in the initiation phase in rats.

The initiating potential of the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), for rat hepatocarcinogenesis was investigated using the development of hyperplastic nodules and/or glutathione S-transferase placental form (GST-P)-positive liver foci as the end point. Five week old male F344 rats were given either basal diet, or diets containing 0.5% DCA or 0.5% LCA for 3 weeks in conjunction with partial hepatectomy performed midway, followed by a selection regimen consisting of 2 weeks feeding of 0.02% 2-acetylaminofluorene diet and a single gastric intubation of carbon tetrachloride. The animals were then placed on either basal diet or a diet containing 0.05% phenobarbital (PB) for 52 weeks. Significantly higher numbers of hyperplastic liver nodules developed in the DCA-treated rats irrespective of PB promotion as compared with the respective control groups. No such increase was evident in the LCA-treated rats. In contrast, both DCA and LCA treatments enhanced the development of GST-P-positive liver foci with or without subsequent PB promotion. Only one hepatocellular carcinoma was diagnosed in a control group animal. The present data indicate that a short period of feeding of DCA and LCA in the initiation stage in conjunction with partial hepatectomy results in enhanced development of preneoplastic liver lesions under selection pressure conditions with or without subsequent PB promotion. They thus confirm and extend our previous finding of enhanced gamma-glutamyltranspeptidase-positive liver foci development in a short-term assay of DCA and LCA, and suggest that these secondary bile acids either possess possible initiating activity or some other priming effect for rat hepatocarcinogenesis.

Animals↗
PubMed2001

The structure of a local population of phytopathogenic Pseudomonas brassicacearum from agricultural soil indicates development under purifying selection pressure.

Among the isolates of a bacterial community from a soil sample taken from an agricultural plot in northern Germany, a population consisting of 119 strains was obtained that was identified by 16S rDNA sequencing and genomic fingerprinting as belonging to the recently described species Pseudomonas brassicacearum. Analysis of the population structure by allozyme electrophoresis (11 loci) and random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR; four primers) showed higher resolution with the latter method. Both methods indicated the presence of three lineages, one of which dominated strongly. Stochastic tests derived from the neutral theory of evolution (including Slatkin's exact test, Watterson's homozygosity test and the Tajima test) indicated that the population had developed under strong purifying selection pressure. The presence of strains clearly divergent from the majority of the population can be explained by in situ evolution or by influx of strains as a result of migration or both. Phytopathogenicity of a P. brassicacearum strain determined with tomato plants reached the level obtained with the type strain of the known pathogen Pseudomonas corrugata. The results show that a selective sweep was identified in a local population. Previously, a local selective sweep had not been seen in several populations of different bacterial species from a variety of environmental habitats.

Agriculture↗
PubMed1986

Role of selective pressure by screening organisms in the development of producer mutant isolates of different antibiotic markers.

The phenotypes of producer mutant isolates when obtained after mutagenesis of the spontaneous degenerate Aspergillus versicolor N5 by screening on Trichophyton rubrum and those on A. niger G3Br were found to be markedly different. In respect of phenotypic character anti-T. rubrum producer mutant isolates resembled the parental type more closely (which is specifically active against T. rubrum and generally against dermatophytes) than anti-A. niger mutant isolates. This clearly indicates not only the role of selective pressure of the screening organism in the development of a given producer mutant isolate but also shows the possibility of recovery of a producer type of the lost antibiotic marker.

Anti-Bacterial Agents↗
PubMed2005

Variable selection pressures across lineages in Trichodesmium and related cyanobacteria based on the heterocyst differentiation protein gene hetR.

Due to the irreversible inhibition of nitrogenase by O2, N2 fixation is incompatible with the oxygenic photosynthesis of cyanobacteria. These organisms have therefore evolved various strategies for growing diazotrophically. One group of N2-fixing cyanobacteria has specialized cells, heterocysts, which contain the nitrogenase, lack the oxygenic photosystem II, and are virtually anoxic inside as the result of respiratory activity and a thick glycolipid cell wall. The hetR gene encodes a serine protease which is thought to be involved in the regulation of heterocyst development and in DNA binding. Although hetR is also present in many non-heterocystous N2-fixing cyanobacteria, its function in these organisms is unknown. In this study, hetR sequences of the N2-fixing, non-heterocystous cyanobacterium Trichodesmium spp. and related genera were examined for signatures of selection. In parsimony- or distance-based hetR phylogenies, the filamentous non-heterocystous cyanobacteria Symploca sp. and Leptolyngbya sp. were closest to Trichodesmium sp. However, accommodating molecular attributes of hetR such as nucleotide frequencies and rate heterogeneity in phylogenetic analyses suggested that many other genera could not be excluded as sister taxa of Trichodesmium. Maximum likelihood analysis of the dN/dS ratio (omega) showed that-irrespective of the use of Symploca, Leptolyngbya, or more distant taxa as an outgroup-the lineage between an outgroup and Trichodesmium (omega1=0.02-0.05) and a lineage leading to Trichodesmium erythraeum (omega1=0.02) were under much stronger purifying selection than the other lineages in Trichodesmium (omega0=0.13-0.32). Although the results from the maximum likelihood analyses are most trustworthy because of codon usage bias in Trichodesmium, the results from a simpler tree-based McDonald-Kreitman test were in general agreement. Due to their quite different assumptions, the combination of these two methods of analysis circumvents multiple testing which, in general, is problematic when using branch models. Although the causal selective forces underlying the substitution patterns in hetR have not yet been identified, these findings parallel the variety of physiological, molecular, and behavioral differences in cyanobacteria related to N2 fixation. The heterogeneity of selection pressures in Trichodesmium is more surprising, because multiple adaptation mechanisms have not been described in this genus.

Bacterial Proteins↗