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At least 91 records · Page 5Linked to original sources
PubMed1991

Molecular evidence for multiple origins of hybridogenetic fish clones (Poeciliidae:Poeciliopsis).

Hybrid matings between the sexual species Poeciliopsis monacha and Poeciliopsis lucida produced a series of diploid all-female lineages of P. monacha-lucida that inhabit the Río Fuerte of northwestern Mexico. Restriction site analyses of mitochondrial DNA (mtDNA) clearly revealed that P. monacha was the maternal ancestor of these hybrids. The high level of mtDNA diversity in P. monacha was mirrored by similarly high levels in P. monacha-lucida; thus hybridizations giving rise to unisexual lineages have occurred many times. However, mtDNA variability among P. monacha-lucida lineages revealed a geographical component. Apparently the opportunity for the establishment of unisexual lineages varies among tributaries of the Río Fuerte. We hypothesize that a dynamic complex of sexual and clonal fishes appear to participate in a feedback process that maintains genetic diversity in both the sexual and asexual components.

Animals↗
PubMed2001

Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2.

The stage of progenitor maturation and factors that determine the fate and clonal acquisition of human natural killer (NK) cell receptors during development are unknown. To study human NK cell receptor ontogeny, umbilical cord blood CD34(+)/Lin(-)/CD38(-) cells were cultured with a murine fetal liver line (AFT024) and defined cytokines. In the absence of lymphocyte-stimulating cytokines or when contact with AFT024 was prohibited, NK cell progeny were killer immunoglobulinlike receptor (KIR) and CD94 lectin receptor negative. In contrast, efficient NK cell differentiation and receptor acquisition was dependent on direct contact of progenitors with AFT024 and the addition of interleukin-15 (IL-15) or IL-2 but not IL-7. To address the question of whether receptor acquisition was determined at the stem cell level, single CD34(+)/Lin(-)/CD38(-) progenitors were studied. More than 400 single cell progeny were analyzed from cultures containing IL-15 or IL-2 and NK cells were always polyclonal, suggesting that receptor fate is determined beyond an uncommitted progenitor and that receptor-negative NK cells acquire class I-recognizing receptors after lineage commitment. KIR2DL2/L3/S2 was expressed more than KIR2DL1/S1 or KIR3DL1, and NKG2A was the dominant CD94 receptor, independent of whether the stem cell source contained the respective major histocompatibility complex class I ligand, suggesting a nonrandom sequence of receptor acquisition. The conclusion is that NK receptor fate is determined after NK cell commitment, does not require stromal presentation of human class I alleles, and is clonally stable after expression but dynamic because new receptors are acquired over time. (Blood. 2001;98:705-713)

Animals↗
PubMed2006

Genetic instability and clonal expansion.

Inactivation of tumor suppressor genes can lead to clonal expansion. We study the evolutionary dynamics of this process and calculate the probability that inactivation of a tumor suppressor gene is preceded by mutations in genes that confer genetic instability. Unstable cells might have a slower rate of clonal expansion than stable cells because of an increased probability of generating lethal mutations or inducing apoptosis. We show that the different growth rates of genetically stable and unstable cells during clonal expansion represent, in general, only a small disadvantage for genetic instability. The intuitive reason for this conclusion is that robust clonal expansion, where cellular birth rates are significantly greater than death rates, occurs on a much faster time scale than waiting for those mutations that allow clonal expansion. Moreover, in special cases where clonal expansion is very slow, genetically unstable cells have a higher probability to accumulate additional mutations during clonal expansion that confer a selective advantage. Clonal expansion represents a major disadvantage for genetic instability only when inactivation of the tumor suppressor gene leads to a very small increase of the cellular reproductive rate that is cancelled by the increased mortality of unstable cells.

Animals↗
PubMed2006

Genetic variability and adaptive evolution in parthenogenetic root-knot nematodes.

Root-knot nematodes (RKN) of the genus Meloidogyne are biotrophic plant parasites of major agricultural importance, which exhibit very variable modes of reproduction, from classical amphimixis to mitotic parthenogenesis. This review focuses on those RKN species that reproduce exclusively by mitotic parthenogenesis (apomixis), in contrast to those that have meiotic/amphimitic events in their life cycle. Although populations of clonal organisms are often represented as being ecologically isolated and evolutionary inert, a considerable volume of literature provides evidence that asexual RKN are neither: they are widely distributed, extremely polyphagous, and amenable to selection and adaptive variation. The ancestors of the genus are unknown, but it is assumed that the parthenogenetic RKN have evolved from amphimictic species through hybridization and subsequent aneuploidization and polyploidization events. Molecular studies have indeed confirmed that the phylogenetic divergence between meiotic and mitotic RKN lineages occurred early, and have revealed an unexpected level of clonal diversity among populations within apomictic species. Laboratory experiments have shown that asexual RKN can rapidly adapt to new environmental constraints (eg host resistance), although with some fitness costs. Lastly, the molecular and chromosomal mechanisms that could contribute to genome plasticity leading to persistent genetic variation and adaptive evolution in apomictic RKN are discussed. It is concluded that RKN provide an excellent model system in which to study the dynamic nature and adaptive potential of clonal genomes.

Adaptation, Physiological↗
PubMed2003

Shoot population dynamics of persisting clones of Miscanthus sinensis in the warm-temperate region of Japan.

The population dynamics of annual shoots in four clonal patches of Miscanthus sinensis was surveyed in terms of clone persistence. Over a study period of 3 years, a stable net shoot number was attained through a balanced replacement of old shoots by tillering 2-3 times a year. The birth rate was significantly correlated with the average monthly temperature. This suggests that a warm climate advances the date of tillerings, and shoots become taller as they emerge earlier. Five cohorts were identified, corresponding to shoots that were born in spring, early summer, summer, autumn and early winter. The autumn cohorts were more numerous and had a greater longevity than the other cohorts; they were thus were best suited for overwintering and, consequently, maintaining the population from one generation to the next. The shoots of earlier cohorts grew too tall to survive the cold of winter, which might cause freezing injury, while later cohorts' shoots excelled in overwintering because of their shortness. However, if the delayed shoots are very short, they will also have difficulty in surviving the early season of growth. Therefore, M. sinensis shoots have an optimum size for survival.

Climate↗
PubMed1997

Comparative analysis of alpha beta and gamma delta T cell activation by Mycobacterium tuberculosis and isopentenyl pyrophosphate.

Phosphorylated nonpeptide compounds have recently been identified as potent mycobacteria-derived ligands for human V gamma 9/V delta 2-expressing gamma delta T cells. Crude mycobacterial extracts also contain protein antigens which stimulate CD4 alpha beta T cells to produce growth factors that are used by gamma delta T cells for clonal expansion. We have investigated the dynamics in vitro of expansion of CD4 T cells and V gamma 9 cells in cultures of peripheral blood mononuclear cells stimulated with synthetic isopentenyl pyrophosphate (IPP) in the absence or presence of additional stimuli. The results indicated that following stimulation with IPP, gamma delta T cells express CD25 and CD69 antigens, but fail to proliferate unless growth factors are provided exogenously or endogenously through activation of CD4 T cells by additional stimuli such as tetanus toxoid, alloantigen, or superantigens. Furthermore, the presence of antigen presenting cells are required for expansion of gamma delta T cells. In response to IPP stimulation, purified CD4 T cells neither express CD25 or CD69, nor do they proliferate even in the presence of exogenous IL-2. Apart from IL-2, IL-15 and, less efficiently, IL-4, IL-7, and IL-12 can contribute to cellular expansion of IPP-reactive V gamma 9 cells. Together, the results demonstrate that peripheral blood gamma delta T cells proliferate in response to IPP only if CD4 T cells are simultaneously activated by an additional stimulus. This mechanism provides a tight control of the reactivity of gamma delta T cells towards phosphorylated nonpeptide antigens.

Antigen-Presenting Cells↗
PubMed1993

Cytogenetics and clinical correlations in breast cancer.

We describe an ongoing study examining the relevance of cytogenetic changes in primary and metastatic breast cancer. Tumors samples from breast cancer patients are karyotype using G-banding techniques, and all chromosomal findings, including the presence of structural and numeric clonal abnormalities, are documented in a dynamic patient data base. Information on essential clinical characteristics is collected, and patients are followed longitudinally for disease recurrence, progression, and survival. Statistical analyses will examine potential correlations between specific abnormalities and clinical features of the disease, and survival differences between patients will be examined as a function of karyotypic differences. We anticipate that this research will provide insights on the natural history of breast cancer and help direct the search for the underlying molecular mechanisms of tumor genesis and progression.

Adult↗
PubMed1993

The fate of genetically marked human oral keratinocytes in vitro.

The fate of the progeny of human oral gingival keratinocytes was mapped in stratified epithelial tissues in vitro by following the expression of a marker gene in genetically related clones. Oral epithelial progenitor cells were genetically marked at high efficiency by transducing them with a retrovirus vector that carried the gene for a histochemically detectable product, Escherichia coli beta-galactosidase (beta-gal). These cells were then grown in submerged cultures and on collagen rafts at the air-liquid interface to demonstrate the distribution of genetically marked cells in a differentiating tissue in vitro. The dynamics of transduced cells showed that clonally related cells were arranged in discrete units of labelled cells and these clusters were defined as 'clonal proliferation units'. The size and configuration of these units were related to the proliferative potential and differentiating capacity of the cell that was initially transduced. This model demonstrates the relation between clonally related cells and tissue architecture for oral keratinocytes in vitro.

Cell Differentiation↗
PubMed2026

Liquid biopsy: a new window on the BRCA genes.

The Breast Cancer Susceptibility Gene (BRCA)-associated tumors represent a constantly evolving and intriguing scenario in oncology, in which the availability of novel systemic treatment, mainly including the poly (ADP-ribose) polymerase (PARP) inhibitors, has enabled an improved survival benefit in clinical subgroups. The expanding regulatory approvals of PARP inhibitors have inevitably reshaped the clinical indications for BRCA testing, moving the BRCA1/2 profiling from the traditional and preventive workflows to therapeutic paths. Despite advances in technology and treatment, substantial limitations remain in current genetic and genomic tools for the detection of deleterious BRCA1/2 variants. Germline and tumor tissue testing provide only a snapshot of a patient's disease, failing to capture the dynamic and longitudinal aspects of tumor clonal evolution. In this scenario, liquid biopsy (LB) profiling of BRCA1/2 genes, primarily as circulating tumor DNA, represents a highly active area of research potentially affecting many aspects of cancer screening, diagnosis, and monitoring in individuals who are carriers of BRCA1/2 deleterious variants. Beyond the attractive potential to surrogate the tumor tissue testing, to overcome the cancer spatial and temporal heterogeneity, and to monitor the tumor mutational profile over time, accurately detecting all clinically relevant BRCA genetic variants and epigenetic modifications using LB remains technically challenging.

BRCA1/2↗
PubMed2001

The role of selection in progressive neoplastic transformation.

Mathematical modeling indicates that selective growth of cells with biallelic mutations in tumor suppressor genes is the driving force in the development of most human tumors, and that increased mutation rate is not required. Spontaneous neoplastic transformation of cells in culture offers the opportunity for quantitative analysis of all stages of neoplastic progression, the cellular variation that underlies it, and the selective conditions that promote it. Most of the early work on spontaneous transformation was done in primary cultures of mouse embryo cells, but established mouse cell lines have been used more in recent years. The main criteria for transformation have been tumorigenesis in mice, increase in saturation density, and production of discrete, multilayered foci in confluent cell cultures. Spontaneous transformation in NIH 3T3 mouse fibroblasts is efficiently evoked by progressive selection under prolonged contact inhibition at high population density or during multiplication at low population density in suboptimal concentrations or types of serum. In general, it is a multistep process with some stages of progression occurring before there is any visible sign of transformed foci. There is a high degree of heritable heterogeneity in the original NIH 3T3 cell population for susceptibility to transformation. Isolation and expansion of minority susceptible clones from a relatively refractory population exhibit transformation long before the polyclonal parental population does because of the increased proportion of susceptible cells in these clones. There are indications that the selective conditions induce selectable variants. Tumor development in animals and man shares important characteristics with spontaneous transformation in culture, including a major role for selection, but the selective conditions for clonal expansion probably vary with the dynamics of differentiation in each tissue. These considerations support a role for an altered microenvironment (as in the aging process) in selective growth of rogue clones.

Animals↗
PubMed1989

Mutation and selection in bacterial populations: alternatives to the hypothesis of directed mutation.

Bacterial populations have served as model systems for studying evolutionary processes ever since the classic experiments of Luria and Delbrück, which demonstrated the occurrence of mutations prior to selection for the traits they conferred. However, several authors have recently presented experiments suggesting that bacteria may have mechanisms for directing which mutations occur, such that the rate of adaptive mutations is enhanced. Before the hypothesis of directed mutation is accepted, it is imperative to consider alternative hypotheses that might account for the same observations. To this end, we expand upon existing mathematical theory of the dynamics of mutation and selection in clonal populations for two cases of particular interest. The first case concerns selection against mutants before plating; this selection occurs as the result of differences in growth rate between mutants and nonmutants. We demonstrate that this selection model gives rise to distributions of mutants, obtained by plating from sister cultures, that are very similar to those expected when some mutations are induced by the selective environment. The second case concerns the sequential incorporation of two mutations as the result of selection for an intermediate genotype after plating. We demonstrate that this two-step mutation model also yields distributions that are similar to those expected when some mutations are induced by the selective environment. These two cases therefore provide alternatives to the hypothesis of directed mutation. We suggest experiments that might be used to examine our alternative hypotheses. We also contrast the hypothesis of directed mutation with the notion of inheritance of acquired characteristics.

Bacteria↗
PubMed2004

Growth competition of macrolide-resistant and -susceptible Helicobacter pylori strains.

We examined population dynamics in a mixed culture of clonally related macrolide-resistant and -susceptible Helicobacter pylori strains isolated from a single patient. The resistant strain had a macrolide resistance-conferring A2143G mutation in the 23S rRNA gene. The growth rate of these two strains did not apparently differ when cultured separately. On the other hand, by conducting sequential passage of a mixed culture of the resistant and the susceptible strains, the ratio of the resistant strain to the susceptible strain in the culture typically decreased per passage, indicating that the resistance imposed a significant disadvantage on bacterial fitness in the population.

Anti-Infective Agents↗
PubMed2005

Visualizing the onset and evolution of an autoantibody response in systemic autoimmunity.

The onset of systemic autoimmunity is variable, making it difficult to identify early events. In this study, we show in rheumatoid factor (RF) Ig-transgenic autoimmune-prone mice that the appearance of RF B cells in blood signifies the onset of RF B cell activation in spleen, providing a novel window into the initiation of an autoantibody response. This allowed us to study the early and late phases of spontaneous induction of the B cell autoimmune response. Using this approach we showed that extensive Ab-forming cell generation in spleen, accompanied by somatic hypermutation, occurred despite the lack of an early germinal center response. The onset of the RF response correlated with the levels of IgG2a-containing immune complexes but not total IgG2a. By identifying the time of onset in individual mice, we were able to track progression of disease. We found remissions of RF Ab-forming cell production in some mice, suggesting that at the clonal level, chronic autoantibody responses are dynamic and episodic, much like acute pathogen responses. Surprisingly, there was little accumulation of long-lived plasma cells in bone marrow of mice with long-standing RF responses in spleen. These studies are among the first to define the early events of a spontaneous B cell autoimmune response.

Animals↗
PubMed2002

The dynamics of germinal centre selection as measured by graph-theoretical analysis of mutational lineage trees.

We have developed a rigorous graph-theoretical algorithm for quantifying the shape properties of mutational lineage trees. We show that information about the dynamics of hypermutation and antigen-driven clonal selection during the humoral immune response is contained in the shape of mutational lineage trees deduced from the responding clones. Age and tissue related differences in the selection process can be studied using this method. Thus, tree shape analysis can be used as a means of elucidating humoral immune response dynamics in various situations.

Algorithms↗
PubMed2006

Population dynamics of the ectomycorrhizal fungal species Tricholoma populinum and Tricholoma scalpturatum associated with black poplar under differing environmental conditions.

Fungi combine sexual reproduction and clonal propagation. The balance between these two reproductive modes affects establishment dynamics, and ultimately the evolutionary potential of populations. The pattern of colonization was studied in two species of ectomycorrhizal fungi: Tricholoma populinum and Tricholoma scalpturatum. The former is considered to be a host specialist whereas T. scalpturatum is a generalist taxon. Fruit bodies of both basidiomycete species were mapped and collected over several years from a black poplar (Populus nigra) stand, at two different sites. Multilocus genotypes (= genets) were identified based on the analysis of random amplified polymorphic DNA (RAPD) patterns, inter-simple sequence repeat (ISSR) patterns and restriction fragment length polymorphisms (RFLPs) in the ribosomal DNA intergenic spacer (rDNA IGS). The genetic analyses revealed differences in local population dynamics between the two species. Tricholoma scalpturatum tended to capture new space through sexual spores whereas T. populinum did this by clonal growth, suggesting trade-offs in allocation of resources at the genet level. Genet numbers and sizes strongly differ between the two study sites, perhaps as a result of abiotic disturbance on mycelial establishment and genet behaviour.

Agaricales↗
PubMed2004

Clonal persistence of oral Fusobacterium nucleatum in infancy.

Once established, early-colonizing bacterial species tend to persist in the mouth. To obtain detailed information on the population dynamics of early-colonizing oral anaerobes, we examined the clonal diversity and persistence of clones among oral Fusobacterium nucleatum populations during the first 2 yrs of life. Consecutive salivary samples from 12 infants, collected at 2, 6, 12, 18, and 24 mos of age, yielded a total of 546 F. nucleatum isolates for clonal typing with arbitrarily primed PCR (AP-PCR). Up to 7 AP-PCR types were simultaneously detected in each sample. In 11 out of the 12 infants examined, AP-PCR types persisted for up to 1 yr. Strain turnover rate was high during the first year of life, but then the occurrence of persistent clones increased. This study indicates a wide genetic diversity within the species and provides evidence for the increasing persistence of F. nucleatum clones in the oral cavity with age.

Chi-Square Distribution↗
PubMed2002

Distinct clonal Ig diversification patterns in young appendix compared to antigen-specific splenic clones.

The young rabbit appendix is a dynamic site for primary B cell repertoire development. To study diversification patterns during clonal expansion, we collected single appendix B cells from 3- to 9-wk-old rabbits and sequenced rearranged H and L chain genes. Single cells obtained by hydraulic micromanipulation or laser capture microdissection were lysed, PCR amplified, and products directly sequenced. Gene conversion-like changes occurred in rearranged H and L chain sequences by 3-4 wk of age. Somatic mutations were found in the D regions that lack known conversion donors and probably also occurred in the V genes. A few small sets of clonally related appendix B cells were found at 3-5 wk; by 5.5 wk, some larger clones were recovered. The diversification patterns in the clones from appendix were strikingly different from those found previously in splenic germinal centers where an immunizing Ag was driving the expansion and selection process toward high affinity. Clonally related appendix B cells developed different amino acid sequences in each complementarity-determining region (CDR) including CDR3, whereas dominant clones from spleen underwent few changes in CDR3. The variety of combining sites generated by diversification within individual clones suggests that at least some clonal expansion and selection, known to require normal gut flora, may be driven through indirect effects of microbial components rather than solely by their recognition as specific foreign Ags. This diversity of combining sites within B cell clones supports the proposed role of appendix in generating the preimmune repertoire.

Amino Acid Sequence↗
PubMed1992

Mucosal immunity: implications for vaccine development.

The mucosal surfaces in e.g. the gastrointestinal, respiratory and urogenital tracts represent a very large exposure area to exogenous agents including microorganisms. Not surprising, therefore, those mucosal tissues are defended by a local immune system with properties and functions that in many respects are separate from the systemic immune system. The intestine is the largest immunological organ in the body. It comprises 70-80% of all immunoglobulin-producing cells and produces more secretory IgA (SIgA) (50-100 mg/kg body weight/day) than the total production of IgG in the body (ca. 30 mg/kg/day). The local immune system of the gut has two main functions: to protect against enteric infections, and to protect against uptake of and/or harmful immune response to undergraded food antigens. The best known entity providing specific immune protection for the gut is the SIgA system. The resistance of SIgA against normal intestinal proteases makes antibodies of this isotype uniquely well suited to protect the intestinal mucosal surface. The main protective function of SIgA antibodies is the "immune exclusion" of bacterial and viral pathogens, bacterial toxins and other potentially harmful molecules. SIgA has also been described to mediate antibody-dependent T cell-mediated cytotoxicity (ADCC), and to interfere with the utilization of necessary growth factors for bacterial pathogens in the intestinal environment, such as iron. It is now almost axiomatic that in order to be efficacious, vaccines against enteric infection must be able to stimulate the local gut mucosal immune system, and that this goal is usually better achieved by administering the vaccines by the oral route rather than parenterally. Based on the concept of a common mucosal immune system through which activated lymphocytes from the gut can disseminate immunity also to other mucosal and glandular tissues there is currently also much interest in the possibility to develop oral vaccines against e.g. infections in the respiratory and urogenital tracts. It has previously been widely assumed that only live vaccines would efficiently stimulate a gut mucosal immune response. However, an oral cholera vaccine, composed of the nontoxic B subunit of cholera toxin in combination with killed whole cell (WC) cholera vibrios has been shown to stimulate a strong intestinal SIgA antibody response associated with long-lasting protection against cholera. We have used this new cholera subunit vaccine and developed ELISPOT methods for examining at the clonal B and T cell level the dynamics of intestinal and extra-intestinal immune responses in humans after enteric immunizations.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗