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PubMed2005

Variation in positive selection in termite GNBPs and Relish.

Social insects are model organisms for investigating molecular evolution in the innate immune system. Their diversity affords comparative analysis among closely related species, and group living is likely to contribute to the pathogen stress imposed on the immune system. We used different models of nucleotide substitution at nonsynonymous (amino acid altering) and synonymous (silent) sites to compare the different levels and type of selection among three immunity genes in 13 Australian termite species (Nasutitermes). The immunity genes include two encoding pathogen recognition proteins (gram-negative bacterial-binding proteins) that duplicated and diverged before or soon after the evolution of the termites and a transcription factor (Relish), which induces the production of antimicrobial peptides. A comparison of evolutionary models that assign four unrestricted classes of dN/dS (the ratio of the nonsynonymous to synonymous substitution rate) to different Nasutitermes lineages revealed that the occurrence of positive selection (dN/dS > 1) varies among lineages and the three genes. Positive selection appears to have driven the evolution of all three genes in an ancestral lineage of three subterranean termites. It had previously been suggested that there was a transition along this ancestral lineage to termite morphology and ecology associated with a diet of decayed wood, a diet that may expose termites to elevated levels of fungal and bacterial pathogens. Relish appears to have experienced the highest levels of selective pressure for change among all three genes. Positively selected sites in the molecule are located in regions that are important for its activation, which suggests that amino acid substitutions at these sites are a counter response to pathogen mechanisms that disrupt the activation of Relish.

Amino Acid Substitution↗

PubMed1994

Positive-selection vectors using the F plasmid ccdB killer gene.

Plasmids pKIL18/19 are positive-selection cloning vectors containing an active cytotoxic ccdB gene under the control of the lacP promoter. They are derivatives of high-copy-number pUC18/19 plasmids in which the ccdB killer gene has been fused in phase downstream from the lacP MCS18 and MCS19 multiple cloning sites. When an Escherichia coli wild-type gyrA+ strain is transformed by such vectors, the ccdB gene product blocks bacterial growth. However, if ccdB is inactivated by insertion of a foreign DNA fragment, this recombinant plasmid no longer interferes with host viability. The positive selection of recombinant clones is highly efficient and bench manipulations are simplified to the utmost: E. coli transformants are plated on rich medium and only cells containing recombinant plasmids give rise to colonies. The CcdB protein is a potent poison of gyrase and the gyrA462 mutation confers total resistance to CcdB [Bernard and Couturier, J. Mol. Biol. 226 (1992) 735-745]. Therefore, pKIL18/19 vectors can be amplified and prepared in large quantities in a gyrA462 host. Like pUC vectors, pKIL vectors are designed for general cloning/sequencing procedures.

Bacterial Proteins↗

PubMed1993

The role of peptide in the positive selection of CD8+ T cells in the thymus.

Recent experiments using fetal thymus organ culture (FTOC) systems derived from class I deficient mice have provided evidence supporting the view that specific recognition of class I MHC plus peptide complexes is required for the positive selection of CD8+ T cells. The addition of class I binding peptides to FTOC systems derived from beta 2-microglobulin and TAP 1 deficient mice induced the positive selection of CD8+ T cells in a peptide specific manner. The specific recognition of peptide during positive selection implies that the repertoire of specificity's exhibited by CD8+ T cells is at least in part determined by the repertoire of self-peptides presented by class I MHC in the thymus.

Animals↗

PubMed1996

The CD43 130-kD peripheral T-cell activation antigen is downregulated in thymic positive selection.

Specific glycoforms of CD43, the major O-glycosylated cell-surface protein on T lymphocytes, can affect cell adhesion according to the types of carbohydrate side chains carried. In the peripheral immune system, CD43 130 kD, which carries core 2 O-glycan structures on its surface, is an activation antigen expressed on both CD4 and CD8 single-positive (SP) T cells. We have previously shown that the 115-kD resting and 130-kD activation glycoforms of murine CD43 are differentially regulated on peripheral SP T cells. In this study, we used transgenic mice expressing T-cell receptors (TCRs) specific for antigens presented by class I and class II major histocompatibility complex (MHC) molecules to determine whether CD43 glycoforms are involved in thymocyte differentiation. Positive selection in these mice results in an increase in the production of CD8 and CD4 SP T cells, respectively, which express the transgenic TCR. Positive selection is also accompanied by the upregulation of TCR, CD69, and CD5. Using these markers to define stages of thymocyte maturation, we found that CD43 130 kD was downregulated in the positive selection of CD4 CD8 double-positive thymocytes expressing a class I but not class II MHC-restricted TCR. These data suggest that core 2 glycosyltransferase (C2GnT) modulated expression of CD43 glycoforms may be involved in thymic selection events.

Animals↗

PubMed1994

Positive selection by purified MHC class II+ thymic epithelial cells in vitro: costimulatory signals mediated by B7 are not involved.

We have investigated the possibility that the costimulatory signals required for activation of mature T cells also play a role in providing differentiation signals for positive selection during T-cell development. We show that purified MHC Class II+ thymic epithelial cells are able to support positive selection in vitro but lack both the functional capacity to deliver costimulatory signals and expression of the costimulatory ligand B7. Our results suggest that the additional signals provided by costimulatory ligands are not required for TCR-mediated positive selection, although other ancillary signals provided by thymic epithelial cells may be involved.

Animals↗

PubMed1987

Positive selection vectors based on xylose utilization suppression.

High levels of xylose isomerase activity in wild-type Escherichia coli strains results in a Xyl- phenotype. This phenomenon was exploited for the development of a versatile positive selection system. The xylA promoter was deleted with the exonuclease BAL 31 and the resulting structural gene was inserted into the SmaI site of pUC9, yielding the prototype vector, pLX100. In this construct xylA expression is placed under the transcriptional control of the lac promoter. Transformation of any wild-type E. coli strain with pLX100 results in high levels of xylose isomerase and a Xyl- phenotype. Decreasing the activity below a critical level (approx. 100 u) restores the Xyl+ phenotype. pLX100 contains contiguous restriction sites for HindIII, PstI, BamHI and XhoI, suitable for positive selection cloning experiments. E. coli transformants containing pLX100 cannot grow in minimal medium with xylose unless a DNA fragment is inserted into any one of the unique restriction sites. This makes the plasmid an ideal positive-selection cloning vector.

Aldose-Ketose Isomerases↗

PubMed2004

Identification of a locus under complex positive selection in Drosophila simulans by haplotype mapping and composite-likelihood estimation.

The recent action of positive selection is expected to influence patterns of intraspecific DNA sequence variation in chromosomal regions linked to the selected locus. These effects include decreased polymorphism, increased linkage disequilibrium, and an increased frequency of derived variants. These effects are all expected to dissipate with distance from the selected locus due to recombination. Therefore, in regions of high recombination, it should be possible to localize a target of selection to a relatively small interval. Previously described patterns of intraspecific variation in three tandemly arranged, testes-expressed genes (janusA, janusB, and ocnus) in Drosophila simulans included all three of these features. Here we expand the original sample and also survey nucleotide polymorphism at three neighboring loci. On the basis of recombination events between derived and ancestral alleles, we localize the target of selection to a 1.5-kb region surrounding janusB. A composite-likelihood-ratio test based on the spatial distribution and frequency of derived polymorphic variants corroborates this result and provides an estimate of the strength of selection. However, the data are difficult to reconcile with the simplest model of positive selection, whereas a new composite-likelihood method suggests that the data are better described by a model in which the selected allele has not yet gone to fixation.

Animals↗

PubMed1992

Positive selection of T-lymphocytes induced by intrathymic injection of a thymic epithelial cell line.

T lymphocytes recognize antigens as peptide fragments associated with molecules encoded by the major histocompatibility complex (MHC) and expressed on the surface of antigen-presenting cells. In the thymus, T cells bearing alpha beta receptors that react with the MHC molecules expressed by radioresistant stromal elements are positively selected for maturation. In (A x B-->A) bone marrow chimaeras, T cells restricted to the MHC-A haplotype are positively selected, whereas MHC-B-reactive thymocytes are not. We investigated whether the introduction of particular thymic stromal elements bearing MHC-B molecules could alter the fate of B-reactive T cells in these (A x B-->A) chimaeras. Thymic epithelial cell (TEC) lines expressing H-2b were introduced by intrathymic injection into (H-2b/s-->H2s) bone marrow chimaeras and we measured their ability to generate H-2b-restricted cytotoxic T-lymphocytes (CTLs). We report here that one TEC line, 427.1, was able positively to select CTLs specific for influenza and vesicular stomatitis virus antigens in association with class I H-2b molecules. In addition, line 427.1 can process cytoplasmic proteins for presentation to H-2Kb- and H-2Db-restricted CTLs. Thus, a TEC line capable of normal class I MHC antigen processing and presentation in vitro can induce positive selection after intrathymic injection.

Animals↗

PubMed1996

Positive selection is not required for thymic maturation of transgenic gamma delta T cells.

Previously published reports describing thymic differentiation in two TCR gamma delta transgenic mouse models have suggested that gamma delta T cells require MHC-mediated positive selection to reach full maturity. Recent studies indicate that recognition of antigen by mature gamma delta T cells is not MHC restricted, raising the issue of why developing gamma delta T cells would even require MHC-driven positive selection. Therefore, we have reinvestigated the requirements for development and selection in G8 gamma delta T cell receptor (TCR) transgenic mice. Analyses of absolute cell numbers, phenotypic subsets, and functional competence of thymic and peripheral G8 gamma delta T cells indicate that these cells can fully mature in class I MHC-deficient mice. Moreover, mixed bone marrow chimeras demonstrate that gamma delta T cells of mutant B2-microglobulin (beta 2m zero) origin are partially deleted in the presence of H-2d-bearing thymocytes (previously believed to be the haplotype mediating positive selection). We conclude that there is no requirement for class I-like molecules for the maturation/development of these transgenic gamma delta T cells and that the differences in thymocyte phenotype and number observed are, instead, attributable to effects of clonal deletion.

Animals↗

PubMed1999

The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery.

Positive selection to self-MHC/peptide complexes has long been viewed as a device for skewing the T cell repertoire toward recognition of foreign peptides presented by self-MHC molecules. Here, we provide evidence for an alternative possibility, namely, that the self-peptides controlling positive selection in the thymus serve to maintain the longevity of mature T cells in the periphery. Surprisingly, when total T cell numbers are reduced, these self-ligands become overtly stimulatory and cause naive T cells to proliferate and undergo homeostatic expansion.

Animals↗

PubMed1983

An improved positive selection plasmid vector constructed by oligonucleotide mediated mutagenesis.

An Escherichia coli plasmid vector, pUN121, has been constructed which allows for positive selection of transformants harboring DNA inserts. The positive selection of transformants harboring DNA inserts. The vector is based on plasmid pTR262 (Roberts et al. Gene, 12, (1980), 123-127) in which the tetracycline resistance gene is under transcriptional control of the repressor protein coded by the phage lambda cI gene. This plasmid has been rearranged, using in vitro recombinant techniques including oligonucleotide mediated mutagenesis to yield a smaller plasmid (4.4 kb) with unique cloning sites for EcoRI, XmaI and SmaI in addition to the unique HindIII and BclI sites. The plasmid has a functional ampicillin resistance gene and the new restriction sites (EcoRI, XmaI and SmaI) when used for cloning, give rise to tetracycline resistant transformants.

Ampicillin↗

PubMed2002

Searching for evidence of positive selection in the human genome using patterns of microsatellite variability.

Both natural selection and nonequilibrium population-level processes can lead to a skew in the frequency distribution of polymorphisms. Population-level processes are expected to affect all loci in a roughly equal fashion, whereas selection will affect only some regions of the genome. We conducted a sliding-window analysis of the frequency distribution of microsatellite polymorphisms across the human genome to identify regions that may be under positive selection. The analysis was based on a published data set of 5,257 mapped microsatellites in individuals of European ancestry. Observed and expected numbers of alleles were compared under a stepwise mutation model (SMM) using analytical formulae. Observed and expected heterozygosities were compared under a SMM using coalescent simulations. The two sets of analyses gave similar results. Approximately one-fourth of all loci showed a significant deficit of heterozygosity, consistent with a recent population expansion. Forty-three windows were identified with extreme skews in the frequency distribution of polymorphisms (in the direction of a deficit of heterozygosity, given the number of alleles). If these extreme windows are tracking selection at linked sites, theory predicts that they should be more common in regions of the genome with less recombination. We tested this prediction by comparing recombination rates in these extreme windows and in other regions of the genome and found that extreme windows had a significantly lower recombination rate than the genomic average. The proportion of extreme windows was significantly higher on the X chromosome than on the autosomes. Moreover, all the windows with extreme skews on the X chromosome were found in two clusters near the centromere; both these clusters exhibit markedly reduced recombination rates. These analyses point to regions of the genome that may recently have been subject to positive selection. These results also suggest that the effects of positive selection may be more pronounced on the X chromosome than on the autosomes in humans.

Alleles↗

PubMed1996

Large-scale search for genes on which positive selection may operate.

We conducted a systematic search for the candidate genes on which positive selection may operate, on the premise that for such genes the number of nonsynonymous substitution is expected to be larger than that of synonymous substitutions when the nucleotide sequences of genes under investigation are compared with each other. By obtaining 3,595 groups of homologous sequences from the DDBJ, EMBL, and GenBank DNA sequence databases, we found that 17 gene groups can be the candidates for the genes on which positive selection may operate. Thus, such genes are found to occupy only about 0.5% of the vast number of gene groups so far available. Interestingly enough 9 out of the 17 gene groups were the surface antigens of parasites or viruses.

Amino Acid Sequence↗

PubMed2002

Accuracy and power of bayes prediction of amino acid sites under positive selection.

Bayes prediction quantifies uncertainty by assigning posterior probabilities. It was used to identify amino acids in a protein under recurrent diversifying selection indicated by higher nonsynonymous (d(N)) than synonymous (d(S)) substitution rates or by omega = d(N)/d(S) > 1. Parameters were estimated by maximum likelihood under a codon substitution model that assumed several classes of sites with different omega ratios. The Bayes theorem was used to calculate the posterior probabilities of each site falling into these site classes. Here, we evaluate the performance of Bayes prediction of amino acids under positive selection by computer simulation. We measured the accuracy by the proportion of predicted sites that were truly under selection and the power by the proportion of true positively selected sites that were predicted by the method. The accuracy was slightly better for longer sequences, whereas the power was largely unaffected by the increase in sequence length. Both accuracy and power were higher for medium or highly diverged sequences than for similar sequences. We found that accuracy and power were unacceptably low when data contained only a few highly similar sequences. However, sampling a large number of lineages improved the performance substantially. Even for very similar sequences, accuracy and power can be high if over 100 taxa are used in the analysis. We make the following recommendations: (1) prediction of positive selection sites is not feasible for a few closely related sequences; (2) using a large number of lineages is the best way to improve the accuracy and power of the prediction; and (3) multiple models of heterogeneous selective pressures among sites should be applied in real data analysis.

Amino Acid Substitution↗

PubMed1993

[Positive selection of hematopoietic CD 34 stem cells for autograft].

The CD 34 antigen is a glycoprotein found on the surface of hematopoietic stem cells and early committed progenitors. The CE 34 stem cells from 14 samples of bone marrow, cord blood or leucapheresis were isolated using a positive selection procedure involving an anti CD 34 biotinylated monoclonal antibody and an avidin immunoabsorption device. Results showed that in 60 percent of samples, the positively-selected fractions contained more than 70 percent CD 34 cells. Concentration in CFU-GM and BFU-E progenitors increased 15 and 26 fold respectively in the CE 34 enriched samples. Long-term culture of two samples demonstrated that nearly all of the most immature progenitors were recovered in the procedure. These preliminary results showed that the positive selection technique of CD 34 hematopoietic stem cells is now available for use in autologous or allogeneic hematopoietic stem cell transplantation.

Antigens, CD↗

PubMed2003

Positive selection of anti-thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development.

A natural serum autoantibody specific for the Thy-1 glycoprotein (anti-Thy-1 autoantibody [ATA]) is produced by B-1 cells that are positively selected by self-antigen. Here, using ATA micro kappa transgenic mice we show that cells with this B cell receptor are negatively selected during bone marrow (BM) development. In a Thy-1 null environment, BM ATA B cells progress to a normal follicular stage in spleen. However, in a self-antigen-positive environment, development is arrested at an immature stage in the spleen, concomitant with induction of CD5. Such cells are tolerant and short-lived, different from B-1. Nonetheless, ATA-positive selection was evident by self-antigen-dependent high serum ATA production, comprising approximately 90% of serum immunoglobulin M in ATA micro kappa mice. Splenectomy did not eliminate ATA production and transfer of tolerant splenic B cells did not induce it. These findings demonstrate that B-1 positive selection, resulting in the production of natural serum ATA, arises independently from the major pathway of BM B cell development and selection.

Animals↗

PubMed2004

Positive selection at sites of multiple amino acid replacements since rat-mouse divergence.

New alleles become fixed owing to random drift of nearly neutral mutations or to positive selection of substantially advantageous mutations. After decades of debate, the fraction of fixations driven by selection remains uncertain. Within 9,390 genes, we analysed 28,196 codons at which rat and mouse differ from each other at two nucleotide sites and 1,982 codons with three differences. At codons where rat-mouse divergence involved two non-synonymous substitutions, both of them occurred in the same lineage, either rat or mouse, in 64% of cases; however, independent substitutions would occur in the same lineage with a probability of only 50%. All three non-synonymous substitutions occurred in the same lineage for 46% of codons, instead of the 25% expected. Furthermore, comparison of 12 pairs of prokaryotic genomes also shows clumping of multiple non-synonymous substitutions in the same lineage. This pattern cannot be explained by correlated mutation or episodes of relaxed negative selection, but instead indicates that positive selection acts at many sites of rapid, successive amino acid replacement.

Alleles↗

PubMed2005

Positive selection drives the evolution of rhino, a member of the heterochromatin protein 1 family in Drosophila.

Heterochromatin comprises a significant component of many eukaryotic genomes. In comparison to euchromatin, heterochromatin is gene poor, transposon rich, and late replicating. It serves many important biological roles, from gene silencing to accurate chromosome segregation, yet little is known about the evolutionary constraints that shape heterochromatin. A complementary approach to the traditional one of directly studying heterochromatic DNA sequence is to study the evolution of proteins that bind and define heterochromatin. One of the best markers for heterochromatin is the heterochromatin protein 1 (HP1), which is an essential, nonhistone chromosomal protein. Here we investigate the molecular evolution of five HP1 paralogs present in Drosophila melanogaster. Three of these paralogs have ubiquitous expression patterns in adult Drosophila tissues, whereas HP1D/rhino and HP1E are expressed predominantly in ovaries and testes respectively. The HP1 paralogs also have distinct localization preferences in Drosophila cells. Thus, Rhino localizes to the heterochromatic compartment in Drosophila tissue culture cells, but in a pattern distinct from HP1A and lysine-9 dimethylated H3. Using molecular evolution and population genetic analyses, we find that rhino has been subject to positive selection in all three domains of the protein: the N-terminal chromo domain, the C-terminal chromo-shadow domain, and the hinge region that connects these two modules. Maximum likelihood analysis of rhino sequences from 20 species of Drosophila reveals that a small number of residues of the chromo and shadow domains have been subject to repeated positive selection. The rapid and positive selection of rhino is highly unusual for a gene encoding a chromosomal protein and suggests that rhino is involved in a genetic conflict that affects the germline, belying the notion that heterochromatin is simply a passive recipient of "junk DNA" in eukaryotic genomes.

Journal Article↗