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Results for “Positive selection”

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PubMed1995

Evidence for the promotion of positive selection of thymocytes by Ah receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ligand for the arylhydrocarbon receptor (Ah receptor), abundant in the murine thymus. In the thymus immunocompetent T cells develop. Upon exposure of murine fetal thymi in organ cultures to TCDD the distribution of mature and immature thymocytes is skewed towards apparently mature, prospective cytotoxic cells of the CD4-CD8+T cell receptor+ phenotype. The normally abundant CD4+ CD8+ cells are decreased. Proliferation of the most immature thymocyte subpopulations is inhibited and maturation of thymocytes appears accelerated by TCDD. Eventually the thymocyte number is significantly decreased. Selective treatment of stroma cells showed them to be the primary target cells of TCDD action. Thymus stroma plays a pivotal role in thymocyte maturation and is indispensable for the selection of thymocytes bearing T cell receptors specific for foreign antigen in the context of self. We tested whether the effects of TCDD on thymocyte differentiation and maturation has further consequences for the selection processes by analysing (a) the repertoire of V beta genes used as a measure for negative selection and (b) the expression of CD69 and bcl-2 by thymocytes as a parameter of positive selection. Our data indicate that TCDD does not cause gross disturbance of negative selection but provide evidence for more cells auditioning for positive selection by TCDD exposure.

Animals↗

PubMed2001

Reliabilities of parsimony-based and likelihood-based methods for detecting positive selection at single amino acid sites.

The reliabilities of parsimony-based and likelihood-based methods for inferring positive selection at single amino acid sites were studied using the nucleotide sequences of human leukocyte antigen (HLA) genes, in which positive selection is known to be operating at the antigen recognition site. The results indicate that the inference by parsimony-based methods is robust to the use of different evolutionary models and generally more reliable than that by likelihood-based methods. In contrast, the results obtained by likelihood-based methods depend on the models and on the initial parameter values used. It is sometimes difficult to obtain the maximum likelihood estimates of parameters for a given model, and the results obtained may be false negatives or false positives depending on the initial parameter values. It is therefore preferable to use parsimony-based methods as long as the number of sequences is relatively large and the branch lengths of the phylogenetic tree are relatively small.

Amino Acid Substitution↗

PubMed1990

Positive selection of transgenic receptor-bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding.

A specific interaction between the class I major histocompatibility complex molecule Kb and thymocytes expressing the antigen receptor from the cytolytic T lymphocyte 2C enhances maturation of T cells of the CD8 lineage in transgenic mice. By analyzing transgenic mice backcrossed to Kbm mutant strains of mice, we have identified five bm mutations of the Kb antigen-encoding gene that alter the positive selection of thymocytes induced by Kb antigen. Compared with Kb, Kbm10 and Kbm1 did not induce significant maturation of 2C T-cell receptor-bearing thymocytes, and Kbm8 antigen positively selected for transgenic thymocytes only weakly. Altering residue 77 of Kb molecule from aspartic acid to serine made Kbm3 and Kbm11 allogeneic targets for the 2C antigen receptor and caused deletion of transgenic thymocytes. This deletion spared T cells that expressed low levels of CD8, a result differing from the total deletion of CD8-bearing T cells seen in mice that expressed the original target alloantigen Ld. This evidence indicates that (i) self-peptides bound to thymic major histocompatibility complex molecules can influence the positive selection of thymocytes and (ii) thymocytes with apparently weak interaction with self-major histocompatibility complex antigens can escape clonal deletion.

Animals↗

PubMed2001

Evidence for positive selection in the capsid protein-coding region of the foot-and-mouth disease virus (FMDV) subjected to experimental passage regimens.

We present sequence data from two genomic regions of foot-and-mouth disease virus (FMDV) subjected to several experimental passage regimens. Maximum-likelihood estimates of the nonsynonymous-to-synonymous rate ratio parameter (d(N)/d(S)) suggested the action of positive selection on some antigenic sites of the FMDV capsid during some experimental passages. These antigenic sites showed an accumulation of convergent amino acid replacements during massive serial cytolytic passages and also in persistent infections of FMDV in cell culture. This accumulation was most significant at the antigenic site A (the G-H loop of capsid VP1), which includes an Arg-Gly-Asp (RGD) cellular recognition motif. Our analyses also identified a subregion of VP3, part of the fivefold axis of FMDV particles, that also appeared to be subjected to positive selection of amino acid replacements. From these results, we can conclude that under the restrictive conditions imposed either by the presence of the monoclonal antibodies, by the persistent infections, or by the competition processes established between different variants of the viral population, amino acid replacement in some capsid-coding regions can be positively selected toward an increase of those mutants with a higher capability to infect the cell.

Aphthovirus↗

PubMed2006

Recurrent positive selection at bgcn, a key determinant of germ line differentiation, does not appear to be driven by simple coevolution with its partner protein bam.

Surveys of nucleotide sequence polymorphism in Drosophila melanogaster and Drosophila simulans were performed at 2 interacting loci crucial for gametogenesis: bag-of-marbles (bam) and benign gonial cell neoplasm (bgcn). At the polymorphism level, both loci appear to be evolving under the expectations of the neutral theory. However, ratios of polymorphism and divergence for synonymous and nonsynonymous mutations depart significantly from neutral expectations for both loci consistent with a previous observation of positive selection at bam. The deviations suggest either an excess of synonymous polymorphisms or an excess of nonsynonymous fixations at both loci. Synonymous evolution appears to conform to neutrality at bam. At bgcn, there is evidence of positive selection affecting preferred synonymous mutations along the D. simulans lineage. However, there is also a significantly higher rate of nonsynonymous fixations at bgcn within D. simulans. Thus, the deviation from neutrality detected by the McDonald-Kreitman test at these 2 loci is likely due to the selective acceleration of nonsynonymous fixations. Differences in the pattern of amino acid fixations between these 2 interacting proteins suggest that the detected positive selection is not due to a simple model of coevolution.

Animals↗

PubMed1991

Kinetics of negative and positive selection in the thymus.

Recent experiments show that CD4+8+ thymocytes represent the critical stage in T cell development at which the specificity of randomly generated alpha beta T cell receptors is screened. These cells are deleted when the receptor binds to the MHC molecule plus specific peptide presented by bone marrow derived cells but are rescued from cell death and induced to mature if the receptor binds to the MHC molecule on thymic epithelium in the absence of the specific peptide. Different tolerogens delete CD4+8+ thymocytes earlier or later during their lifespan and negative selection can occur prior to positive selection. The specificity of the alpha beta T cell receptor for either class I or class II thymic MHC molecules determines the CD4-8+ and CD4+8- phenotype of mature T cells.

Animals↗

PubMed1990

Negative and positive selection of immature thymocytes: timing and the role of the ligand for alpha beta T cell receptor.

Recent experiments show that CD4+8+ thymocytes represent the critical stage in T cell development at which the specificity of randomly generated ab T cell receptors is screened. These cells are deleted when the receptor binds to the MHC molecule plus specific peptide presented by bone marrow derived cells but are rescued from cell death and induced to mature if the receptor binds to the MHC molecule on thymic epithelium in the absence of the specific peptide. Different tolerogens delete CD4+8+ thymocytes earlier or later during their lifespan and negative selection can occur prior to positive selection. The specificity of the ab T cell receptor for either class I or class II thymic MHC molecules determines the CD4-8+ and CD4+8- phenotype of mature T cells.

Animals↗

PubMed2025

Positive selection and relaxed purifying selection contribute to rapid evolution of sex-biased genes in green seaweed Ulva.

BACKGROUND: The evolution of differences in gamete size and number between sexes is a cornerstone of sexual selection theories. The green macroalga Ulva, with incipient anisogamy and parthenogenetic gametes, provides a unique system to investigate theoretical predictions regarding the evolutionary pressures that drive the transition from isogamy to anisogamy, particularly in relation to gamete size differentiation and sexual selection. Its minimal gamete dimorphism and facultative parthenogenesis enable a rare window into early evolutionary steps toward anisogamy. RESULTS: By analyzing the expression profiles of sex-biased genes (SBGs) during gametogenesis, we found that SBGs evolve faster than unbiased genes, driven by higher rates of non-synonymous substitution (dN), indicating that SBGs are under stronger selective pressures. Mating type minus-biased genes (mt-BGs) exhibit higher dN/dS values than mating type plus-biased genes (mt+BGs), suggesting stronger selective pressures on mt-BGs, although this difference was not statistically significant (P = 0.08). Using branch-site and RELAX models, we found positive selection and relaxed purifying selection acting on a significant proportion of SBGs, particularly those associated with flagella function. CONCLUSIONS: This study highlights the selective pressures shaping anisogamy and provides insights into the molecular mechanisms underlying its evolution. The faster evolution of SBGs, particularly mt-BGs, and the positive selection on genes associated with motility, such as those related to flagella function, suggest the importance of enhanced gamete motility in the transition to anisogamy. These findings contribute to our understanding of sexual selection and the evolutionary forces that drive the differentiation of gamete size and number between sexes.

Selection, Genetic↗

PubMed1989

Positive selection of CD4-CD8+ T cells in the thymus of normal mice.

The diversification of the repertoire of T-cell antigen receptor (TCR) specificities is influenced by at least two selection processes which occur in the thymus. One of these, termed 'negative selection', is required to install a state of tolerance to self-antigens in the T-cell repertoire and is often achieved by clonal deletion. The second type of selection operating in the thymus results in preferential differentiation of T cells that have restriction specificity for thymic major histocompatibility complex glycoproteins, but the mechanisms leading to this selective process are not yet clear. One model used to describe this 'positive selection' proposes that only those T cells with sufficient avidity for the MHC glycoproteins expressed in the thymus are allowed to acquire functional competence. Here we directly investigate the generation of TCR specificities by following the fate of developing V beta 17+ CD4-CD8+ T cells under conditions where one of the main class I-MHC molecules, either H-2K or H-2D, was specifically blocked by in vitro monoclonal antibody treatment. The results show that development of V beta 17+ CD4-CD8+ T cells in the SJL H-2s mouse strain is selectively abrogated by blocking class I-Ks molecules but is unaffected by blocking class I-Ds molecules. These data directly demonstrate that generation of CD4-CD8+ T cells expressing a particular TCR V beta segment can be correlated with the expression of a particular class I-MHC molecule, thereby providing evidence for positive selection.

Animals↗

PubMed2006

Domain-specific positive selection contributes to the evolution of Arabidopsis leucine-rich repeat receptor-like kinase (LRR RLK) genes.

Leucine-rich repeat receptor-like kinases (LRR RLKs) comprise the largest group within the plant receptor-like kinase (RLK) superfamily, and the Arabidopsis genome alone contains over 200 LRR RLK genes. Although there is clear evidence for diverse roles played by individual LRR RLK genes in Arabidopsis growth and development, the evolutionary mechanism for this functional diversification is currently unclear. In this study, we focused on the LRRII RLK subfamily to investigate the molecular mechanisms that might have led to the functional differentiation of Arabidopsis LRR RLK genes. Phylogenetic analysis of 14 genes in this subfamily revealed three well-supported groups (I, II, and III). RT-PCR analysis did not find many qualitative differences in expression among these 14 genes in various Arabidopsis tissues, suggesting that evolution of regulatory sequences did not play a major role in their functional divergence. We analyzed substitution patterns in the predicted ligand-binding regions of these genes to examine if positive selection has acted to produce novel ligand-binding specificities, using the nonsynonymous/synonymous rate ratio (d (N)/d (S)) as an indicator of selective pressure. Estimates of d (N)/d (S) ratios from multiple methods indicate that nonsynonymous substitutions accumulated during divergence of the three lineages. Positive selection is likely to have occurred along the lineages ancestral to groups II and III. We suggest that positive selection on the ligand-binding sites of LRRII RLKs promoted diversification of ligand-binding specificities and thus contributed to the functional differentiation of Arabidopsis LRRII RLK genes during evolution.

Amino Acid Sequence↗

PubMed2004

Evidence for positive selection on Mycobacterium tuberculosis within patients.

BACKGROUND: While the pathogenesis and epidemiology of tuberculosis are well studied, relatively little is known about the evolution of the infectious agent Mycobacterium tuberculosis, especially at the within-host level. The insertion sequence IS6110 is a genetic marker that is widely used to track the transmission of tuberculosis between individuals. This and other markers may also facilitate our understanding of the disease within patients. RESULTS: This article presents three lines of evidence supporting the action of positive selection on M. tuberculosis within patients. The arguments are based on a comparison between empirical findings from molecular epidemiology, and population genetic models of evolution. Under the hypothesis of neutrality of genotypes, 1) the mutation rate of the marker IS6110 is unusually high, 2) the time it takes for substitutions to occur within patients is too short, and 3) the amount of polymorphism within patients is too low. CONCLUSIONS: Empirical observations are explained by the action of positive selection during infection, or alternatively by very low effective population sizes. I discuss the possible roles of antibiotic treatment, the host immune system and extrapulmonary dissemination in creating opportunities for positive selection.

DNA, Bacterial↗

PubMed1993

Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture.

We have used an in vitro system to study the effects of major histocompatibility complex class I binding peptides on thymic development. Fetal thymus lobes from mice deficient in the class I light chain (beta 2 microglobulin or beta 2 M-/-) were cultured for 10 d in vitro, during which time T cell precursors develop into mature T cells. In these organ cultures, as in the adult or neonatal beta 2 M-/- thymus, CD8+ mature T cells did not develop, demonstrating that the mature T cells seen during early murine thymic development are the result of the positive selection process. To these cultures we added various class I binding peptides with or without a source of exogenous beta 2M. CD8+ T cells developed to various degrees only in the presence of beta 2M and peptides. Using peptide mixtures of differing complexity, we showed that the efficiency of this process is dependent more on peptide complexity than on peptide concentration. These data argue for a specific role for peptides in the process of positive selection. Furthermore, this culture system should be useful in identifying peptides that can promote positive selection of cells expressing a specific T cell receptor (TCR) in TCR transgenic mice.

Amino Acid Sequence↗

PubMed1992

Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression.

We have examined the expression of the recombination activating gene RAG-1 by in situ hybridization to thymi from mice bearing transgenes for the T-cell receptor (TCR) alpha chain, TCR beta chain, or both TCR alpha and beta chains. RAG-1 transcription was found in the thymic cortex of transgenic mice carrying a single TCR alpha- or TCR beta-chain transgene, comparable to normal mice. However, RAG-1 transcription was strikingly reduced in the thymic cortex from transgenic mice carrying both TCR alpha- and beta-chain genes and expressing major histocompatibility complex (MHC) class I (H-2b) molecules necessary for positive selection of the transgenic TCR. In contrast, thymi of transgenic mice also carrying both TCR alpha- and beta-chain genes but expressing MHC molecules (H-2d) that did not positively select the transgenic TCR displayed high levels of RAG-1 transcription. The low thymic RAG-1 expression coincided with high transgenic TCR alpha-chain surface expression and with inhibition of endogenous TCR alpha-chain rearrangement. Our findings suggest that binding of the TCR to self MHC molecules during positive selection down-regulates RAG-1 transcription in cortical thymocytes and thereby prevents further TCR alpha-chain rearrangements.

Animals↗

PubMed2001

Marked reduction in the incidence of hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation with CD34(+) positive selection.

Veno-occlusive disease of the liver (VOD) is a common and severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). To determine the incidence of, and the risk factors for the development of VOD, we performed a retrospective analysis of a series of 178 patients, who underwent allogeneic HSCT at our institution between 1990 and 1999. Busulfan and cyclophosphamide constituted the conditioning regimen most frequently administered. Bone marrow was the source of stem cells in 129 patients (73%), and peripheral blood (PBSC) in 49 patients (27%). Thirty-one patients of the PBSC group received CD34(+) positively selected grafts. Most patients were given cyclosporin A and methotrexate (MTX) as graft-versus-host disease (GVHD) prophylaxis. Overall, 30 patients (17%) developed VOD. In univariate analyses, the incidence of VOD was significantly higher in recipients of unmanipulated grafts (20% vs 0%; P = 0.01), in patients with active malignant disease at transplantation (24% vs 9%; P = 0.03), in recipients of marrow from unrelated donors (33% vs 15%; P = 0.03), in patients grafted with bone marrow (21% vs 6%; P = 0.03), and in those receiving MTX as GVHD prophylaxis (21% vs 6%; P = 0.05). Under multivariate analysis, only CD34(+) positive selection (P = 0.0004) and the status of the disease at transplant (P = 0.03) were statistically significant variables for the development of VOD. We conclude that CD34(+) positively selected PBSC transplantation could result in a marked reduction in the incidence of VOD after allogeneic HSCT.

Adolescent↗

PubMed2003

Improvement in 5'-position-selective glucosylation of pyridoxine by Verticillium dahliae TPU 4900.

Optimization of culture and reaction conditions for 5'-position-selective transglucosylation to pyridoxine by Verticillium dahliae TPU 4900 was investigated. V. dahliae TPU 4900 had high transglucosylation activity when grown with soluble starch as a carbon source and organic nitrogens such as Esusan meat as a nitrogen source at 15-20 degrees C. Both the yield of pyridoxine 5'-alpha-D-glucoside (PN-5'-alpha-G) and the 5'-position-selectivity reached a maximum when an intact-cell reaction was done at 50-60 degrees C and pH 7 with additions of dextrin. The transglucosylation activity in culture broth was 71 times with the optimization of culture conditions that under the conditions used for screening. The productivity of PN-5'-alpha-G synthesis was 6.9 times that under the initial conditions when the reaction conditions of intact cells were optimized. From 1000 mM (206 g/L) pyridoxine hydrochloride, PN-5'-alpha-G was synthesized to the concentration of 300 mM (98.4 g/L as PN-5'-alpha-G) with 5'-selectivity of 85% in 53 h by intact cells of V. dahliae TPU 4900.

Carbon↗

PubMed1995

Positive selection of T cells.

In the past year, significant technical developments have provided the opportunity to investigate the more mechanistic features of positive selection. Major progress has been made in determining the structure and function of the early pre-T cell receptor, in defining cell types that mediate positive selection, and in analyzing the contribution of MHC and co-receptors to CD4/CD8 lineage commitment. The most revealing studies have been those addressing the role of peptides in thymic selection.

Animals↗

PubMed1990

Molecular analysis of the influences of positive selection, tolerance induction, and antigen presentation on the T cell receptor repertoire.

Immunization of both B10.A and B10.S(9R) mice with pigeon cytochrome c (pcc) elicits T cells capable of proliferating to pcc presented on I-E major histocompatibility complex (MHC) molecules. The T cell receptor (TCR) repertoire used by pcc-specific T cells from these two strains is markedly different, even for T cells recognizing very similar antigen/MHC complexes. Our current studies have been directed toward explaining this differential expression between MHC congenic strains of TCR gene elements capable of recognizing similar ligands. Analysis of the TCR repertoire of pcc-specific T cells from F1[B10.A x B10.S (9R)]----parent radiation chimeras has demonstrated that much of this difference is a result of the positive selection of T cells for MHC restriction specificity. Further analysis of T cell lines from F1 mice and from radiation chimeras stimulated in vitro with pcc on both B10.A and B10.S(9R) antigen-presenting cells has provided clear-cut examples of the influence of positive selection, tolerance induction and of both in vivo and in vitro antigen presentation on the shaping of the TCR repertoire for a protein antigen. This is the first molecular analysis of how positive selection, tolerance induction, and antigen presentation can combine to mold the TCR repertoire.

Animals↗

PubMed2005

Positive selection of primate TRIM5alpha identifies a critical species-specific retroviral restriction domain.

Primate genomes encode a variety of innate immune strategies to defend themselves against retroviruses. One of these, TRIM5alpha, can restrict diverse retroviruses in a species-specific manner. Thus, whereas rhesus TRIM5alpha can strongly restrict HIV-1, human TRIM5alpha only has weak HIV-1 restriction. The biology of TRIM5alpha restriction suggests that it is locked in an antagonistic conflict with the proteins encoding the viral capsid. Such antagonistic interactions frequently result in rapid amino acid replacements at the protein-protein interface, as each genetic entity vies for evolutionary dominance. By analyzing its evolutionary history, we find strong evidence for ancient positive selection in the primate TRIM5alpha gene. This selection is strikingly variable with some of the strongest selection occurring in the human lineage. This history suggests that TRIM5alpha evolution has been driven by antagonistic interactions with a wide variety of viruses and endogenous retroviruses that predate the origin of primate lentiviruses. A 13-aa "patch" in the SPRY protein domain bears a dense concentration of positively selected residues, potentially implicating it as an antiviral interface. By using functional studies of chimeric TRIM5alpha genes, we show that this patch is generally essential for retroviral restriction and is responsible for most of the species-specific antiretroviral restriction activity. Our study highlights the power of evolutionary analyses, in which positive selection identifies not only the age of genetic conflict but also the interaction interface where this conflict plays out.

Amino Acid Sequence↗