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PubMed2004

Evolution of the core genome of Pseudomonas syringae, a highly clonal, endemic plant pathogen.

Pseudomonas syringae is a common foliar bacterium responsible for many important plant diseases. We studied the population structure and dynamics of the core genome of P. syringae via multilocus sequencing typing (MLST) of 60 strains, representing 21 pathovars and 2 nonpathogens, isolated from a variety of plant hosts. Seven housekeeping genes, dispersed around the P. syringae genome, were sequenced to obtain 400 to 500 nucleotides per gene. Forty unique sequence types were identified, with most strains falling into one of four major clades. Phylogenetic and maximum-likelihood analyses revealed a remarkable degree of congruence among the seven genes, indicating a common evolutionary history for the seven loci. MLST and population genetic analyses also found a very low level of recombination. Overall, mutation was found to be approximately four times more likely than recombination to change any single nucleotide. A skyline plot was used to study the demographic history of P. syringae. The species was found to have maintained a constant population size over time. Strains were also found to remain genetically homogeneous over many years, and when isolated from sites as widespread as the United States and Japan. An analysis of molecular variance found that host association explains only a small proportion of the total genetic variation in the sample. These analyses reveal that with respect to the core genome, P. syringae is a highly clonal and stable species that is endemic within plant populations, yet the genetic variation seen in these genes only weakly predicts host association.

Base Sequence↗

PubMed1997

Influence of the host microenvironment on the clonal selection of human colon carcinoma cells during primary tumor growth and metastasis.

The purpose of this study was to determine the subpopulation dynamics of human colon carcinoma (HCC) cells growing at orthotopic (cecum, liver) or ectopic (subcutis, kidney, spleen) sites in nude mice and to correlate any outgrowth of distinct clones with the differential expression of metastasis-related genes. Low metastatic KM12C HCC cells were genetically tagged with a retrovirus harboring the neomycin-resistance (Neo(R)) gene. Southern blot analyses demonstrated only minor resolution of the Neo(R) hybridization pattern in DNA isolated from primary tumors growing orthotopically or ectopically, suggesting a polyclonal outgrowth. In contrast, a major resolution of the Neo(R) hybridization pattern was observed in liver-specific metastases, demonstrating the outgrowth of single dominant clones. Expression of epidermal growth factor receptor (EGR-R) increased 20-60% in the liver metastases vs spleen tumors and the KM12C Neo(R) cells. Transforming growth factor alpha (TGF-alpha), amphiregulin (AR), and c-met showed only modest differences in mRNA expression. A 20-80% increase in type IV collagenase mRNA levels was also observed in all tumor specimens. Furthermore, expression of the multi-drug resistance gene PGY-1 and the carcinoembryonic antigen (CEA) gene were elevated in the liver metastases compared with the spleen tumors and cultured cells. Transcript levels of the angiogenic factors interleukin-8 and basic fibroblast growth factor did not correlate with clonal outgrowth. These data demonstrate a correlation between EGF-R, type IV collagenase, CEA, and PGY-1 gene expression and the production of liver metastases. Our results suggest that distinct HCC clones differentially expressing specific mRNA transcripts for metastasis-related genes are the forerunners of the experimental liver metastatic lesions.

Animals↗

PubMed2006

Identification and characterisation of human endometrial stem/progenitor cells.

The human endometrium is a dynamic, cyclically regenerating tissue. Because adult stem cells are present in other regenerative tissues, a clonal analysis of purified endometrial epithelial and stromal cells derived from hysterectomy tissue was undertaken, as a first attempt to identify and characterise endometrial stem/progenitor cells. Rare populations of epithelial and stromal cells were clonogenic. Only those cells initiating large clones, 0.09% of epithelial cells and 0.02% of stromal cells, are likely to be endometrial stem/progenitor cells.

Endometrium↗

PubMed2005

Evidence from the stop-EGFP mouse supports a niche-sharing model of epidermal proliferative units.

The classical model of epidermal proliferative units (EPUs) postulates that each EPU is composed of a single column of corneocytes plus epidermal cells directly below the column and is maintained by a single stem cell within the unit. Using the stop-enhanced green fluorescent protein (stop-EGFP) transgenic mouse system, we previously showed epidermal stem cell clonal lineages could produce multiple adjacent corneocytes (i.e. epidermal cells belonging to multiple adjacent EPUs), contradicting the classical EPU model. One possible problem with our earlier study was that N-ethyl-N-nitrosourea (ENU) was used to generate mutations for clonal analysis. This could alter the normal environment of the epidermal tissue and might lead to an artificial expansion of stem cell clonal lineages. In this study, we replicate our earlier findings using untreated stop-EGFP mice and relying on spontaneous mutations to generate clonal cell lineages. We propose an alternative to the classical EPU model to explain the dynamic nature of epidermal proliferation. Our niche-sharing model of EPUs allows epidermal cells to horizontally migrate among EPUs, so that multiple stem cells cooperatively maintain a larger proliferative compartment.

Animals↗

PubMed1997

Selective expansion of Vgamma2-Vdelta7 TCR gammadelta cells in C57BL/6 mice is postnatal and extrathymic.

Previous studies have shown that TCR-gammadelta cells expressing Vgamma2 region elements are selectively expanded in vivo in C57BL/6 (B6), but not DBA/2, mice. Genetic analysis demonstrated that the expansion of Vgamma2+ was linked to the TCR alphadelta loci, suggesting that a particular Vgamma-Vdelta pair may be necessary for the expansion. In the studies presented here, we find that the expanding TCR gammadelta cells in B6 mice express a Vgamma2+/Vdelta7+ TCR. The Vgamma2-Jgamma and Vdelta7-Ddelta-Jdelta junctional amino acid sequences of these cells display wide variation in length, suggesting that expansion is based on variable region usage and not junctional diversity. The kinetics and dynamics of Vgamma2+/Vdelta7+ T cell expression were studied to determine the biological basis of clonal expansion. Although expression of the Vgamma2+ cells in B6 and DBA/2 neonates was similar, Vgamma2+ cells in the B6 mice expanded fourfold by 4 wk of age, while the expression in DBA/2 mice remained constant. In addition, expansion of the Vgamma2+ cells occurred in athymic nude mice, suggesting that expansion was driven by extrathymic stimuli. Finally, B6 mice housed under germfree conditions expressed expanded levels of Vgamma2+ gammadelta T cells similar to their normally housed counterparts. Thus, expansion and diversification of Vgamma2+/Vdelta7+ T cells are postnatal extrathymic events that do not require microbial antigenic exposure.

Animals↗

PubMed1996

Time course analysis of alpha+ beta+ T cell clones during normal pregnancy.

During normal pregnancy, the fetus continues to mature inside the uterus without rejection. Inherited paternal antigens could be targeted by the maternal immune system. These reactions are believed to play a role in a number of habitual abortions. However, the precise maternal mechanisms preventing fetal tissue rejection are not well understood. Maternal T cells should recognize fetal antigens, so it is conceivable that antigen-specific T cell response to fetal antigens would occur by proliferation and accumulation of certain T cell clones in the pregnant mother. To elucidate the maternal immune response to the fetus we investigated the clonality of expanded T cells in peripheral blood lymphocytes in ten normal pregnant women. We employed reverse transcriptase-polymerase chain reaction for T cell receptor beta chain gene and subsequently analyzed the PCR product by single-strand conformation polymorphism analysis. A large number of distinctly expanded T cell clones were detected during pregnancy. These accumulations were observed as early as the ninth to tenth week post-conception and reached a maximum during the second trimester, suggesting the existence of dynamic antigen-specific T cell responses in the pregnant mother. However, after the 30th week of gestation, nearly all expanded T cell clones disappeared before parturition and the degree of clonality reached almost normal levels. Our results clearly indicate the existence of dynamic maternal T cell responses during pregnancy.

Adult↗

PubMed2003

Biofilm formation by Pseudomonas aeruginosa wild type, flagella and type IV pili mutants.

Biofilm formation by Gfp-tagged Pseudomonas aeruginosa PAO1 wild type, flagella and type IV pili mutants in flow chambers irrigated with citrate minimal medium was characterized by the use of confocal laser scanning microscopy and comstat image analysis. Flagella and type IV pili were not necessary for P. aeruginosa initial attachment or biofilm formation, but the cell appendages had roles in biofilm development, as wild type, flagella and type IV pili mutants formed biofilms with different structures. Dynamics and selection during biofilm formation were investigated by tagging the wild type and flagella/type IV mutants with Yfp and Cfp and performing time-lapse confocal laser scanning microscopy in mixed colour biofilms. The initial microcolony formation occurred by clonal growth, after which wild-type P. aeruginosa bacteria spread over the substratum by means of twitching motility. The wild-type biofilms were dynamic compositions with extensive motility, competition and selection occurring during development. Bacterial migration prevented the formation of larger microcolonial structures in the wild-type biofilms. The results are discussed in relation to the current model for P. aeruginosa biofilm development.

Biofilms↗

PubMed2002

Antigen-driven T-cell turnover.

A mathematical model is developed to characterize the distribution of cell turnover rates within a population of T lymphocytes. Previous models of T-cell dynamics have assumed a constant uniform turnover rate; here we consider turnover in a cell pool subject to clonal proliferation in response to diverse and repeated antigenic stimulation. A basic framework is defined for T-cell proliferation in response to antigen, which explicitly describes the cell cycle during antigenic stimulation and subsequent cell division. The distribution of T-cell turnover rates is then calculated based on the history of random exposures to antigens. This distribution is found to be bimodal, with peaks in cell frequencies in the slow turnover (quiescent) and rapid turnover (activated) states. This distribution can be used to calculate the overall turnover for the cell pool, as well as individual contributions to turnover from quiescent and activated cells. The impact of heterogeneous turnover on the dynamics of CD4(+) T-cell infection by HIV is explored. We show that our model can resolve the paradox of high levels of viral replication occurring while only a small fraction of cells are infected.

Antigens, Viral↗

PubMed2000

Germ-line selection ensures embryonic autoreactivity and a positive discrimination of self mediated by supraclonal mechanisms.

It is necessary to clarify principles and mechanisms of natural tolerance to body tissues, in order to derive appropriate diagnostics, therapeutics and prognostics of autoimmune diseases (AID). I will argue that AIDs result from deficits in autoreactive regulatory T cell generation and/or function, and propose a model that explains why relatively few prototypes of AID exist, as well as their organ-specificity or systemic nature. The model suggests that natural tolerance is achieved through evolutionarily selected developmental genetic programs: (i) for patterns of V-region expression early in life that ensure auto(multi)reactivity at the outset of the system; (ii) for a cellular composition of thymic stroma that 'breeds' and activates regulatory (autoreactive) T cells in early development; (iii) for lymphocyte differentiation and population dynamics, that results in peripheral 'education' of regulatory tissue-specific cells, while allowing for 'unregulated' clonal responses to nonself. In the present model, S/NS discrimination is 'supraclonal' and 'dominant', related to other 'systemic' properties such as the regulation of total lymphocyte numbers, the 'open-endedness' of repertoires, and their differences in health and disease. Dominant tolerance models in general, also solve the paradox that pathogenic autoreactivity is rare, in spite of the extensive V-region degeneracy of lymphocyte recognition and the high frequency of cross-reactivity between S/NS; in short, it is astonishing that we are not autoimmune every time we get infected. As in other areas of biomedical science, time is perhaps ripe to move from component (clonal) analysis to system's biology, as some have proned for years.

Autoimmunity↗

PubMed2002

Sexual and vegetative reproduction of Hieracium pilosella L. under competition and disturbance: a grid-based simulation model.

We used a spatially explicit simulation model to examine the relative importance of vegetative and sexual reproduction in Hieracium pilosella L. Based on an understanding of the complex life cycle of this species and on data from in situ population dynamics in a calcareous grassland in NW Switzerland, we simulated growth and the relative contribution of clonal reproduction by stolons and reproduction by seeds across a gradient of increasing soil fertility. Competition by a clonal grass resulted in nearly complete exclusion of H. pilosella from the more fertile part of the simulation plot. Under low soil fertility, when grass could not survive, H. pilosella largely persisted by vegetatively produced rosettes. This pattern of a sharp separation of both species was shifted slightly in favour of H. pilosella by introducing random disturbances. Only by adding: (1) long-distance seed dispersal, and (2) facilitation of seedling establishment in the vicinity of grass tussocks in vegetation gaps was a more realistic representation of field observations realised, with rosettes of H. pilosella grown from seeds occasionally distributed within dense grass vegetation. Phenotypic plasticity of stolon length was a decisive factor for the maintenance of H. pilosella populations. We conclude that a mixed strategy of clonal growth and reproduction by seeds in H. pilosella is necessary to maintain populations of this species in the presence of high interspecific competition and a shortage of open space.

Algorithms↗

PubMed1998

Regulation and function of DNA methylation in vertebrates.

In vertebrates, genomic DNA is often methylated at the 5th position of cytosine in the sequence of CpG, and this is the only chemical modification that genomic DNA of vertebrates allows under physiological conditions. During evolution, vertebrates acquired CpG methylation as a new tool for controlling gene expression in addition to the varieties of transcription factors. In mammals, the methylation pattern of genomic DNA is erased and reset in germ line and at the early stage of embryogenesis. Maintenance-type methylation activity ensures clonal transmission of the lineage-specific methylation pattern in somatic cells. The methylation pattern is dynamic and changes during cell differentiation. Prior to the expression of tissue-specific genes, specific sites of the promoters are demethylated. In general, the methylation of a gene suppresses its expression. However, not much is known about the mechanisms that regulate the methylation state and the gene expression by DNA methylation.

Amino Acid Sequence↗

PubMed2000

Dominant role of host selective pressure in driving hepatitis C virus evolution in perinatal infection.

The dynamics of the genetic diversification of hepatitis C virus (HCV) populations was addressed in perinatal infection. Clonal sequences of hypervariable region 1 of the putative E2 envelope protein of HCV were obtained from four HCV-infected newborns (sequential samples spanning a period of 6 to 13 months after birth) and from their mothers (all samples collected at delivery). The data show that the variants detected between birth and the third month of life in samples from the four newborns were present in the HCV populations of their mothers at delivery. In the newborns, a unique viral variant (or a small group of closely related variants) remained stable for weeks despite active viral replication. Diversification of the intrahost HCV population was observed 6 to 13 months after birth and was substantially higher in two of the four subjects, as documented by the intersample genetic distance (GD) (P = 0.007). Importantly, a significant correlation between increasing GD and high values for the intersample K(a)/K(s) ratio (the ratio between anoffymous and synonymous substitutions; an index of the action of selective forces) was observed, as documented by the increase of both parameters over time (P = 0.01). These data argue for a dominant role of positive selection for amino acid changes in driving the pattern of genetic diversification of HCV populations, indicate that the intrahost evolution of HCV populations is compatible with a Darwinian model system, and may have implications in the designing of future antiviral strategies.

Amino Acid Sequence↗

PubMed2005

The rapid isolation and growth dynamics of the tsetse symbiont Sodalis glossinidius.

Sodalis glossinidius is known exclusively in endosymbiosis with tsetse flies (Genus: Glossina) and is one of the few insect bacterial symbionts that have been successfully cultured in vitro. This study details improved isolation and solid culture protocols that allow for a standardised and rapid preparation/maintenance of clonal material from individual flies. The isolation and culture of S. glossinidius was confirmed by partial sequencing of the 16S rDNA gene and specific PCR. In addition, the growth dynamics and changes in cell viability during liquid culture are described. The potential for culture of other endosymbiont taxa is discussed.

Aedes↗

PubMed1999

Red queen dynamics, competition and critical points in a model of RNA virus quasispecies.

RNA viruses offer a unique opportunity for the study of evolution at the molecular level. Recent experiments involving clonal populations of RNA viruses have shown that competition among virus strains of approximately equal relative fitness can result in the eventual competitive exclusion of one of the species. As competition proceeds in time, both the winners and the losers exhibited absolute gains in fitness, consistent with the "Red Queen" hypothesis of evolution. Further experiments involving closely related evolving quasispecies revealed a highly predictable nonlinear behavior suggesting a deterministic component in the underlying quasispecies dynamics. This is apparently in contradiction with the standard view of RNA virus evolution as a highly unpredictable process. In this paper we present a simple model which allows previous hypothesis to be tested and provides an interpretation for the observed experimental results.

Cloning, Molecular↗

PubMed2001

T cell expansions in lymph nodes and peripheral blood in HIV-1-infected individuals: effect of antiretroviral therapy.

OBJECTIVE: To evaluate dynamics in CD8 T cell expansions during highly active antiretroviral therapy (HAART). DESIGN: Various T cell subsets were isolated from blood and lymph nodes and analysed for T cell receptor (TCR) diversity. METHODS: TCR complementarity determining region 3 (CDR3) spectratyping and single-strand conformation polymorphism (SSCP) analyses were performed in combination with sequencing to assess clonality of the subsets. RESULTS: Strongly skewed CDR3 patterns in total CD8 cells and the CD8 subsets CD45RO+CD27+ and CD45RO-CD27+ showed substantial dynamics in dominant CDR3 sizes, resulting in relative improvement of CDR3 size diversity in the first months of therapy. During sustained treatment, TCR diversity changed only moderately. SSCP profiles confirmed oligoclonality of TCR CDR3 perturbations. Various dominant CDR3 sizes for CD4 and CD8 T cells present in lymph nodes, but not in peripheral blood mononuclear cells, before the start of therapy emerged in peripheral blood early during therapy. CONCLUSIONS: HAART induces substantial changes in CD8 TCR diversity, eventually resulting in improvement of the repertoire. Clonal expansions observed in lymph nodes before therapy were observed in peripheral blood after therapy, suggesting that recirculation of CD4 and CD8 T cells from lymph nodes contributes to the early T cell repopulation. Decreased immune activation and possibly naive T cell regeneration subsequently decreased clonal expansions and perturbations in the CD8 TCR repertoire.

Antiretroviral Therapy, Highly Active↗

PubMed1995

Engrafted maternal T cells in a severe combined immunodeficiency patient express T-cell receptor variable beta segments characterized by a restricted V-D-J junctional diversity.

To better understand the peculiar functional behavior of engrafted maternal T cells in a severe combined immunodeficiency (SCID) patient, we characterized, at the molecular level, the T-cell repertoire of a SCID child with a high number of engrafted, mature, activated lymphocytes. We found that, although these transplacentally acquired T cells express a random set of T-cell receptor variable beta (TCRBV) segments, the TCRBV transcripts are characterized by an extremely restricted V-D-J junctional diversity. Only a few cDNA clones were dominant among the TCRBV4+, TCRBV6+, and TCRBV20+ populations in engrafted cells, whereas the same TCRBV chains expressed by the mother's lymphocytes had the expected junctional hetero-geneity. Highly diverse and polyclonal junctions were also expressed by maternal cells activated in mixed lymphocyte reaction by Epstein-Barr virus (EBV)-transformed B lymphocytes from the patient, indicating that the strong clonal selection that characterizes the engrafted cells repertoire is probably not due to allorecognition. Furthermore, we report that the repertoire of the transplacentally acquired lymphocytes is dynamic over time and is characterized by waves of expression and contraction of selected clones, expressing different TCRBV segments. These results help to explain some of the abnormal functional behaviors of engrafted maternal cells and raise new questions regarding the mechanisms responsible for the restricted clonal diversity.

Amino Acid Sequence↗

PubMed2004

Mutational effects on the clonal interference phenomenon.

We study the process of fixation of beneficial mutations in an asexual population by means of a theoretical model. Particularly, we wish to investigate how the supply of deleterious and beneficial mutations influences the dynamics of the adaptive process of an evolving population. It is well known that the deleterious mutations drastically affect the fate of beneficial mutations. In addition, an increasing supply of favorable mutations, to compensate the decay of the fitness due to the accumulation of deleterious mutations, produces the clonal interference phenomenon where advantageous mutations in distinct lineages compete to reach fixation. This competition imposes a limit to the speed of adaptation of the population. Intuitively, we would expect that the interplay of the two mechanisms would conspire to ensure fixation of only large-effect beneficial mutations. Our results, however, show that beneficial mutations of small effect have an increased probability of fixation when both beneficial and deleterious mutations rates are increased.

Adaptation, Biological↗

PubMed2006

Temporal analysis of French Bordetella pertussis isolates by comparative whole-genome hybridization.

Bordetella pertussis, a gram-negative beta-proteobacterium, is the agent of whooping cough in humans. Whooping cough remains a public health problem worldwide, despite well-implemented infant/child vaccination programs. It continues to be endemic and is observed cyclically in vaccinated populations. Classical molecular subtyping methods indicate that genome diversity among B. pertussis isolates is limited. Although the whole bacterial genome has been studied by pulsed-field gel electrophoresis, the genes implicated in the diversity have not been identified. We developed a B. pertussis whole-genome DNA microarray representing over 91% of the predicted coding sequences of the sequenced strain Tohama I. Genomic DNA from clinical isolates with various pulsed-field gel electrophoresis profile patterns was competitively hybridized with the DNA microarray and coding sequences were classified as present, absent or duplicated. Our data strongly suggest that the B. pertussis population is dynamic. In France, with highly vaccinated population, the genetic diversity is low and decreasing with time, and clonal expansion correlates with cycles of the disease. This decrease in diversity is essentially due to loss of genes and pseudogenes. The genes deleted are most of the time flanked by insertion sequences.

Bordetella pertussis↗