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PubMed2000

Consilience across evolving dysplasias affecting myeloid, cervical, esophageal, gastric and liver cells: common themes and emerging patterns.

In the present paper, an attempt is made to identify common biologic themes across dysplastic states affecting the marrow, gastro intestinal tissue, the cervix and liver as well as unifying patterns during disease evolution. The following algorithm appears generally applicable, although individual variations must necessarily be anticipated. It appears that there is an initial transforming event which in all dysplasias except that affecting the marrow has been found to be infectious. Increased cellular proliferation-increased apoptosis, telomere shortening, appearance of telomerase expression and clonal expansion follow the initial insult. Abnormalities in the cytokine environment are universally described and it is likely that the quintessential monoclonality aspect of dysplasia predisposes to accumulation of genetic mutations, and microsatellite instability leading to the appearance of evolved sub-clones. The conversion of a dysplastic phenotype to a malignant one reflects the success of one such sub-clone in developing a survival advantage over a large population of prematurely apoptotic neighbors. This state is usually acquired by silencing tumor suppressor genes through hypermethylation or actual loss or dysfunction. Thus, excessive apoptosis of cells resulting from a persistent infectious process predisposes the organ towards developing a cancerous phenotype. Evidence for the shared pathology is presented at length with the hope that these parallels between dysplastic states will be helpful in both biologic and therapeutic research.

Animals↗
PubMedDate not supplied

Altruism and social cheating in the social amoeba Dictyostelium discoideum.

The social amoeba, Dictyostelium discoideum, is widely used as a simple model organism for multicellular development, but its multicellular fruiting stage is really a society. Most of the time, D. discoideum lives as haploid, free-living, amoeboid cells that divide asexually. When starved, 10(4)-10(5) of these cells aggregate into a slug. The anterior 20% of the slug altruistically differentiates into a non-viable stalk, supporting the remaining cells, most of which become viable spores. If aggregating cells come from multiple clones, there should be selection for clones to exploit other clones by contributing less than their proportional share to the sterile stalk. Here we use microsatellite markers to show that different clones collected from a field population readily mix to form chimaeras. Half of the chimaeric mixtures show a clear cheater and victim. Thus, unlike the clonal and highly cooperative development of most multicellular organisms, the development of D. discoideum is partly competitive, with conflicts of interests among cells. These conflicts complicate the use of D. discoideum as a model for some aspects of development, but they make it highly attractive as a model system for social evolution.

Animals↗
PubMed2000

Clonal origin of the type 37 Streptococcus pneumoniae.

It has been recently reported that different type 37 clinical isolates of Streptococcus pneumoniae have an identical tts gene directing the formation of type 37 capsular polysaccharide. Here we show that type 37 S. pneumoniae strains isolated in two different continents (Europe and America) some 60 years apart frequently gave rise to nontypable variants upon in vitro cultivation. The tts gene from three independent nontypable mutants was PCR amplified and sequenced showing different classes of inactivating mutations. Furthermore, pulsed-field gel electrophoresis and multilocus sequence typing demonstrated that the type 37 pneumococcal isolates studied so far constitute a highly related strain cluster (a clonal complex), and strongly suggested that every type 37 pneumococcus has spread globally from a single, old clone.

Bacterial Typing Techniques↗
PubMed2001

Characterization of agglutinin-like sequence genes from non-albicans Candida and phylogenetic analysis of the ALS family.

The ALS (agglutinin-like sequence) gene family of Candida albicans encodes cell-surface glycoproteins implicated in adhesion of the organism to host surfaces. Southern blot analysis with ALS-specific probes suggested the presence of ALS gene families in C. dubliniensis and C. tropicalis; three partial ALS genes were isolated from each organism. Northern blot analysis demonstrated that mechanisms governing expression of ALS genes in C. albicans and C. dubliniensis are different. Western blots with an anti-Als serum showed that cross-reactive proteins are linked by beta 1,6-glucan in the cell wall of each non-albicans Candida, suggesting similar cell wall architecture and conserved processing of Als proteins in these organisms. Although an ALS family is present in each organism, phylogenetic analysis of the C. albicans, C. dubliniensis, and C. tropicalis ALS genes indicated that, within each species, sequence diversification is extensive and unique ALS sequences have arisen. Phylogenetic analysis of the ALS and SAP (secreted aspartyl proteinase) families show that the ALS family is younger than the SAP family. ALS genes in C. albicans, C. dubliniensis, and C. tropicalis tend to be located on chromosomes that also encode genes from the SAP family, yet the two families have unexpectedly different evolutionary histories. Homologous recombination between the tandem repeat sequences present in ALS genes could explain the different histories for co-localized genes in a predominantly clonal organism like C. albicans.

Agglutinins↗
PubMed1996

Emerging foodborne pathogens: Escherichia coli O157:H7 as a model of entry of a new pathogen into the food supply of the developed world.

There would appear to be little argument that the large outbreaks of E. coli O157:H7 which have occurred since the early 1980s represent a distinct, new phenomenon. The number of reported cases have increased dramatically, starting from zero in 1981; however, it is also clear that this increase in reported cases is in part an artifact of improved surveillance and reporting. Available data suggest that E. coli O157:H7 infections were present prior to 1982, although numbers appear to have been small. At a molecular level, the organism shows evidence of clonal origin, but there is not the striking clonality, with virtually identical pulsed-field gel electrophoresis and ribotyping patterns, which has been seen in situations such as the emergence of Vibrio cholerae O139 Bengal in the Indian subcontinent in 1992 or the introduction of V. cholerae O1 into naïve populations in South America in 1991 (127-129). Findings are more consistent with the image of an organism which arose from a common ancestor, but which has had time to become distributed geographically and to show some evidence of genetic divergence. While this is an "emerging" infection, at least in terms of its distribution and public recognition, it is unlikely that it will be possible to identify the "first" O157:H7 case or to track the clonal spread of the organism through cattle or human populations.

Animals↗
PubMed1998

Proliferation and the monoclonal origins of atherosclerotic lesions.

Benditt's observation of the monoclonal origin of the atherosclerotic lesion has been controversial because it appeared to conflict with conventional wisdom. A new method based on a polymerase chain reaction amplification of the DNA of an X-inactivated gene from microdissected tissue confirms that Benditt was correct. However, this monoclonal expansion can also be found in nonatherosclerotic intima and media. These new data suggest that plaque clonality may represent expansion of preexisting patches of cells arising during development of the media. This developmental view does not conflict with other recent evidence that plaque expansion is associated with mutation or viral events. However, if plaques arise from patches, then early developmental mechanisms may be critical to the later evolution of the lesions.

Arteriosclerosis↗
PubMed2004

Drift increases the advantage of sex in RNA bacteriophage Phi6.

The pervasiveness of sex and recombination remains one of the most enigmatic problems in evolutionary biology. According to many theoretical models, recombination can increase the rate of adaptation by restoring genetic variation. However, the potential for genetic drift to generate conditions that produce this outcome has yet to be studied experimentally. We have designed and performed an experiment that reveals the effects of drift on existing genetic variation by minimizing the influence of variation on beneficial mutation rate. Our experiment was conducted in populations of RNA bacteriophage Phi6 initiated from a common source population at varying bottleneck sizes. The segmented genome of this virus results in genetic exchange between viruses that co-infect the same host cell. In response to selection for growth in a high-temperature environment, sexual lines outperformed their asexual counterparts on average. The advantage of sex attenuated with increasing effective population size, implying that the rate of adaptation was limited by clonal interference among segments caused by drift. This is the first empirical evidence that the advantage of sex during adaptation increases with the intensity of drift.

Bacteriophage phi 6↗
PubMed1993

Progression of essential thrombocythemia to blastic crisis via idiopathic myelofibrosis.

We report a 61-year-old man with essential thrombocythemia (ET) whose clinical course was followed for 12 years. The ET evolved into true idiopathic myelofibrosis (IM) 6 years after the initial diagnosis and progressed to myeloid blastic transformation 6 years later. The cytogenetic analysis showed a normal karyotype during the ET phase but subsequent analysis revealed an abnormal karyotype during the IM phase which evolved clonally at blastic crisis with constant involvement of chromosome 13q and chromosome 7. The close monitoring of essential events, using clinical, morphologic, immunologic and cytogenetic parameters, allowed us to carefully identify the transition from one chronic myeloproliferative disease (MPD) to another. This is only the second case reported showing a clinical evolution of this nature. The clinical and biological aspects of the disease are briefly discussed.

Blast Crisis↗
PubMed1986

The molecular evolution of the immune response: idiotope-specific suppression indicates that B cells express germ-line-encoded V genes prior to antigenic stimulation.

Antibodies expressed by the immune B cell population are characterized by variable region amino acid substitutions resulting from somatic nucleotide replacement (somatic mutation). This is not true of antibodies expressed by the "naive" B cell population. It is at present unclear whether this discrepancy is due to the preferential clonal selection of a pre-existing subpopulation of naive B cells that express variable regions altered via nucleotide replacement, or whether the process of nucleotide replacement occurs only during the antigen-dependent stages of B cell differentiation. To address this question we have used anti-idiotypic suppression to functionally delete B cells that express particular variable-region structures from the antigen-responsive repertoire. Suppression of the major cross-reactive idiotype (IdCR) expressed in strain A mice in response to p-azophenylarsonate (Ars) was induced using the monoclonal anti-IdCR antibody AD8. The idiotope recognized by AD8 is easily destroyed by alteration of IdCR variable-region structure via nucleotide replacement. The IdCR anti-Ars immune repertoire is characterized by antibodies that lack the AD8-cognate idiotope due to nucleotide replacement. However, complete suppression of the IdCR could reproducibly be achieved by administration of AD8 prior to Ars immunization. This result indicates that all IdCR-expressing B cells also express the AD8-cognate idiotope prior to immunization. Thus, somatic nucleotide replacement must occur exclusively during the antigen-dependent stages of B cell differentiation in this system.

Animals↗
PubMed1999

Sequence diversity of flagellin (fliC) alleles in pathogenic Escherichia coli.

To study the molecular evolution of flagellin, the protein subunit specifying flagellar (H) antigens, the fliC genes from 15 pathogenic strains of Escherichia coli were amplified by PCR and sequenced. Comparison of fliC sequences of H6 and H7 strains revealed that alleles have a mosaic structure indicating the occurrence of past horizontal transfer of DNA segments between strains. The close similarity of H7 sequences also indicates the exchange of an entire fliC H7 allele between distant clonal lineages. In addition, the ratio of silent substitutions to amino acid replacements suggests that a short segment in the central region of fliC has been under positive selection in the divergence of H6 and H7 alleles. Phylogenetic analysis demonstrates that the fliC sequences of O157:H7 and O55:H7 serotypes are nearly identical and highly divergent from those of E. coli strains expressing H6 and H2 flagellar antigens. A nonmotile clone of sorbitol-fermenting O157 has rapidly accumulated multiple mutations in fliC, presumably as a result of the silencing of flagellin expression.

Alleles↗
PubMed2006

Evolution of the uniquely adaptable lentiviral envelope in a natural reservoir host.

BACKGROUND: The ability of emerging pathogens to infect new species is likely related to the diversity of pathogen variants present in existing reservoirs and their degree of genomic plasticity, which determines their ability to adapt to new environments. Certain simian immunodeficiency viruses (SIVcpz, SIVsm) have demonstrated tremendous success in infecting new species, including humans, resulting in the HIV-1 and HIV-2 epidemics. Although SIV diversification has been studied on a population level, the essential substrates for cross-species transmission, namely SIV sequence diversity and the types and extent of viral diversification present in individual reservoir animals have not been elucidated. To characterize this intra-host SIV diversity, we performed sequence analyses of clonal viral envelope (env) V1V2 and gag p27 variants present in individual SIVsm-infected sooty mangabeys over time. RESULTS: SIVsm demonstrated extensive intra-animal V1V2 length variation and amino acid diversity (le38%), and continual variation in V1V2 N-linked glycosylation consensus sequence frequency and location. Positive selection was the predominant evolutionary force. Temporal sequence shifts suggested continual selection, likely due to evolving antibody responses. In contrast, gag p27 was predominantly under purifying selection. SIVsm V1V2 sequence diversification is at least as great as that in HIV-1 infected humans, indicating that extensive viral diversification in and of itself does not inevitably lead to AIDS. CONCLUSION: Positive diversifying selection in this natural reservoir host is the engine that has driven the evolution of the uniquely adaptable SIV/HIV envelope protein. These studies emphasize the importance of retroviral diversification within individual host reservoir animals as a critical substrate in facilitating cross-species transmission.

Animals↗
PubMed1991

Blast crisis in a murine model of chronic myelogenous leukemia.

The P210bcr/abl protein is produced in cells from patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Retroviral transfer of the gene encoding P210bcr/abl into murine bone marrow induces a granulocytic leukemia that models the chronic phase of human CML. We have transferred the leukemic clone to syngeneic animals, albeit with surprising inefficiency, and have observed CML and clonally related acute leukemias of lymphoid or myeloid phenotype in some transplant recipients. These data show that murine CML can result from retroviral transfer of the bcr/abl gene into pluripotent hematopoietic stem cells, that infected clones repopulate poorly after adoptive transfer, and that these clones can give rise to acute leukemia, reflecting evolution to a phase resembling blast crisis in the human disease.

Animals↗
PubMedDate not supplied

Characterization of the mycoplasma genome.

Recent advances on the properties of the mycoplasma genome, including size, base composition, replication, extrachromosomal DNA, and transfer of genetic material are briefly reviewed, with emphasis on their phylogenetic implications. The use of cleavage patterns of the mycoplasma genome by restriction endonucleases as "finger-prints" indicating genetic relatedness among strains is discussed. The data support the notion that strains of mycoplasma species of strict host and tissue specificity exhibit marked genetic homogeneity, suggesting a clonal origin for some species. The regions of the mycoplasma genome carrying the ribosomal RNA (rRNA) genes have been studied using restriction endonucleases, cloning, and hybridization procedures. The mycoplasmal rRNA cistrons cross-hybridized among themselves, and with the seven rRNA cistrons of Escherichia coli, demonstrating the marked conservation of structure during evolution of this part of the procaryotic genome. In most of the mollicutes tested so far the number of rRNA cistrons is two, but a few species appear to carry only one rRNA cistron in their genome.

Acholeplasma↗
PubMed2002

Application of molecular genetics to the diagnosis of lymphoid-rich effusions: study of 95 cases with concomitant immunophenotyping.

The cytological differentiation between reactive lymphocytosis and malignant lymphoma in serous effusions is often difficult. The present study was designed to evaluate the potential contribution of molecular genetic clonality analysis to a solution to this problem. We examined the cytological specimens of 95 consecutive patients collected during a 4-yr period, including 74 pleural, 20 peritoneal, and one pericardial fluids. Cytological diagnosis in the 95 lymphocyte-rich effusions was positive for lymphoma in 20 cases, suspicious for lymphoma in 26 cases, and negative in 49 cases. The analysis by ICC was not carried out, inconclusive, or noninterpretable in 25 cases. In five cases molecular genetic analysis was hampered by technical problems. By immunocytochemistry, eight additional cases of lymphoma were detected and lineage classification was achieved in 15 of the 20 cytologically positive effusions. PCR and Southern blot analysis were used to assess B- and T-cell clonality. Monoclonality was found in 40 (42%) of the 95 effusions analyzed. One-third of the effusions with a monoclonal B-cell gene rearrangement were detected by Southern blot analysis but not by the PCR performed in parallel. The results of molecular genetic analysis were corroborated by histological findings and/or clinical evolution in 15 cases. Our results indicate that molecular genetic analysis is a useful tool in the analysis of lymphocyte-rich serous effusions.

Adolescent↗
PubMed1984

Cytogenetic studies on acute nonlymphocytic leukemias following polycythemia vera.

Chromosome studies were performed on 15 patients suffering from acute nonlymphocytic leukemia (ANLL) and in one patient in a preleukemic state following polycythemia vera (PV). Clonal chromosome abnormalities that were present in all cases were clearly nonrandom and involved chromosomes #1, #5, #7, #8, #9, #11, and #21. A subdivision of ANLL into two categories occurring in the course of PV is proposed from the clinical, hematologic, and cytogenetic data: one resembling de novo ANLL with rapid initial evolution, easy classification into one group of the FAB nomenclature, and simple chromosome abnormalities; the other resembling induced leukemia, often with more progressive initial evolution, difficulty or impossibility of classification into one group of the FAB nomenclature, and complex chromosome abnormalities. The consequences for the commitment level of progenitor cell from which the leukemic clones originate are discussed.

Acute Disease↗
PubMed1995

The quantitation of altered hepatic foci during multistage hepatocarcinogenesis in the rat: transforming growth factor alpha expression as a marker for the stage of progression.

The experimental three-stage hepatocarcinogenesis protocol of initiation, promotion, and progression, coupled with the analytical technique of stereology, permits quantitative analysis of the carcinogenic process, including the derivation of biologically based risk assessment models. The aberrant expression of the placental isozyme of glutathione S-transferase (PGST) is an efficient marker for initiated, preneoplastic, and neoplastic hepatocytes. Putatively initiated cells and their clonal progeny can be identified, enumerated, and their growth characteristics determined on the basis of their aberrant expression of this protein. A lack of suitable markers has made the identification and quantitation of hepatocytes in the early stage of progression more difficult. One characteristic of cells in the stage of progression is the evolution of relatively autonomous growth. The alteration of growth factor signalling pathways may provide one mechanism for this observation. The expression of transforming growth factor alpha (TGF alpha) is seen in many malignancies. The initiation-promotion-progression protocol has been used to induce progression in the rat liver. The focal expression of TGF alpha was found to correlate with areas of progression in rats subjected to this protocol. The ability to identify and quantitate cells in the stage of progression should facilitate application of the Moolgavkar-Venzon-Knudson model for assessing human risk from carcinogens active at each of these three stages. Validation of this model will require determination of the number and growth characteristics of hepatocytes in the stage of progression.

Animals↗
PubMed2023

Utilizing evolutionary conservation to detect deleterious mutations and improve genomic prediction in cassava.

INTRODUCTION: Cassava (Manihot esculenta) is an annual root crop which provides the major source of calories for over half a billion people around the world. Since its domestication ~10,000 years ago, cassava has been largely clonally propagated through stem cuttings. Minimal sexual recombination has led to an accumulation of deleterious mutations made evident by heavy inbreeding depression. METHODS: To locate and characterize these deleterious mutations, and to measure selection pressure across the cassava genome, we aligned 52 related Euphorbiaceae and other related species representing millions of years of evolution. With single base-pair resolution of genetic conservation, we used protein structure models, amino acid impact, and evolutionary conservation across the Euphorbiaceae to estimate evolutionary constraint. With known deleterious mutations, we aimed to improve genomic evaluations of plant performance through genomic prediction. We first tested this hypothesis through simulation utilizing multi-kernel GBLUP to predict simulated phenotypes across separate populations of cassava. RESULTS: Simulations showed a sizable increase of prediction accuracy when incorporating functional variants in the model when the trait was determined by<100 quantitative trait loci (QTL). Utilizing deleterious mutations and functional weights informed through evolutionary conservation, we saw improvements in genomic prediction accuracy that were dependent on trait and prediction. CONCLUSION: We showed the potential for using evolutionary information to track functional variation across the genome, in order to improve whole genome trait prediction. We anticipate that continued work to improve genotype accuracy and deleterious mutation assessment will lead to improved genomic assessments of cassava clones.

cassava (Manihot esculenta)↗
PubMed1993

Adult T-cell leukemia/lymphoma revealed by a surgically cured cardiac valve lymphomatous involvement in an Iranian woman: clinical, immunopathological and viromolecular studies.

A 60-year-old woman from the town of Mashhad in northeastern Iran developed cardiac failure due to aortic and mitral regurgitations which needed cardiac valve replacement. Histopathological study of the valves revealed a T-cell non-Hodgkin's lymphoma. Blood examination showed leukemic features with 32% of abnormal white blood cells. Human T-cell leukemia/lymphoma virus type I (HTLV-I) antibodies were present in the serum and the specific env HTLV-I sequences were detected in the DNA extracted from the valves and peripheral blood mononuclear cells (PBMC) using polymerase chain reaction technique. Clonal integration of two HTLV-I copies was found in both the valves and PBMC DNA, thus the diagnosis of adult T-cell leukemia/lymphoma (ATL) was established. In contrast to the acute life-threatening cardiac localization, our case met the diagnostic criteria of chronic ATL, this was confirmed by favorable evolution without chemotherapy during the 24 months after diagnosis. According to our knowledge, this is the first report of an isolated lymphomatous cardiac valve involvement, without other cardiac abnormalities. It seems important to underline that the patient originated from Iran where endemicity of HTLV-I has only recently been discovered.

Aortic Valve↗