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PubMed1993

Recombination between separate MYC amplification structures in COLO320 cells.

Cytogenetically visible gene amplification structures can consist of arrays of amplicons presumably formed by secondary "rearrangements" following amplicon formation. The structural evolution of gene amplification sites in tumor cells suggests that complex secondary structures may have some selective advantage in the tumor cell environment. Although secondary amplicon rearrangements are a hallmark of the gene amplification process, little is known about the mechanics of this process. COLO320 neuroendocrine tumor cells carry two different types of amplified MYC oncogene sequences, one type with an intact MYC gene and the other with a rearranged "chimeric" MYC gene. We have studied various clonal subpopulations of COLO320 cells and identified regions within and downstream of the MYC locus that are unique to each amplicon type. Using double-label fluorescence in situ hybridization with DNA probes unique to each amplicon type, we have observed that both chromosomal and extrachromosomal MYC amplicon arrays in COLO320 cells frequently consist of heterogeneous mixtures of each MYC amplicon type. Our results suggest that the two MYC amplicon types of COLO320 cells were formed simultaneously but independently, and that double minute chromosomes observed in COLO320 cells were formed by intermolecular homologous recombination secondary to amplicon formation.

Adenocarcinoma↗
PubMedDate not supplied

Comparative cytogenetic and cytologic study in malignant lymphomas.

The possibility of a cytogenetic-cytologic correlation with implications in the diagnosis, evolutivity and prognosis of malignant lymphomas was studied. Cytogenetic investigations were carried out comparatively in the lymph node and spleen lymphoid cells from 25 patients with malignant lymphomas and in normal subjects or patients with malignant tumors. The dominant malignant cellular type was found to correspond genotypically to the abnormal clone. In lymphomas with more differentiated cells the chormosomal abnormalities were limited to a single chromosomal group, while in those with less differentiated cells there were many clonal chromozomal abnormalities. The pathogenic significance of an extra-chromosome in the C-group (observed in most of the cases) is discussed.

Chromosome Aberrations↗
PubMed1994

Molecular genetic studies of early breast cancer evolution.

In the past few years there has been an explosion in the number of patients diagnosed with hyperplastic breast disease and in situ breast cancer. Based on epidemiological data, these morphologically defined lesions may be categorized as those with little malignant potential (e.g. typical hyperplasia or proliferative disease without atypia [PDWA], those with significant malignant potential which may already be "initiated" (e.g. atypical ductal hyperplasia [ADH]), and early "transformed" lesions which are malignant but not yet invasive (e.g. ductal carcinoma in situ [DCIS]). They may represent sequential evolutionary stages in the ontogeny of invasive breast cancer, with each morphologically defined stage resulting from accumulating genetic changes culminating in a transformed clonal lineage capable of invasion and metastasis. Using loss-of-heterozygosity (LOH) analysis, we are studying the genetic changes associated with these lesions in archival tissue samples. 50% (6/12) of the proliferative lesions (PDWA and ADH) and 80% of the DCIS shared their LOH patterns with more advanced lesions from the same breast, strongly supporting a precursor/product relationship between these lesion and the cancers they accompany.

Breast Neoplasms↗
PubMed2003

A non-Darwinian role for mutagenesis in stem cell-derived cancers.

It is clear that mutations cause cancer. The implicated mechanism is Darwinism. That is, a stochastic series of mutations is purported to effect the cellular variability upon which natural selection acts to yield increasingly cancer-like intermediates leading ultimately to malignant clones. It is no wonder then that the neoplastic phenotype is considered "alien," having evolved via random unrehearsed events. Neoplasia, however, has also been depicted as something less than foreign, bordering on familiar. This is because cancer shares proliferative and invasive qualities with the native developmental processes of embryogenesis and adult tissue renewal/repair. A question then arises: If key features of malignancy already naturally exist within well-choreographed programs, why reinvent this phenotype via stochastic multistep schemes rather than reactivate it largely en bloc? Indeed, as will be shown, tissues do harbor a malignant potential capable of reactivation. Specifically, this capability is maintained by stem cells (having inherited such from embryonic precursors)-a phenotype controlled by a microenvironment favoring perpetual rearing by (quiescent) stem cells of proliferative progeny for orderly renewal over neoplasia. Accordingly, normally well-sequestered stem cells, when amid carcinogen/mutagen-induced disruption to local surroundings, produce progeny tending by default toward disorderliness (neoplasia) over renewal. Because such tumor-causing mutations act non-cell autonomously, this cancerous state is potentially reversible but subsequent cell-autonomous mutations can impair particular clonal progeny, already cancerous, from regressing. Thus, a scenario wherein mutations (1) de-repress malignancy non-cell autonomously and then (2) slow its reversion cell autonomously, commonly misinterpreted as Darwinian, may constitute a non-Darwinian mechanism for the genesis of cancers that are stem cell derived.

Biological Evolution↗
PubMed1992

Seronegative inflammatory arthritis in the myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a group of therapeutically refractory anemias resulting from a clonal stem cell disorder often associated with cytogenetic abnormalities. Immunologic abnormalities and occasionally vasculitis have been reported although no series has characterized an associated arthritis. All cases of MDS diagnosed in 1990 by bone marrow biopsy and followed up at the authors' institution were reviewed. Of the 28 consecutive patients, 8 had acute seronegative inflammatory arthritis temporally related to the initial discovery of cytopenia. Five patients had a symmetric polyarthritis resolving only with use of steroids or upon evolution to leukemia, and 3 had episodes of oligoarthritis with systemic features including fever, pleuritis, pericarditis, and hemolytic anemia. Arthrocenteses in 2 cases did not show crystals or infection. Serological studies were nondiagnostic. The arthritis and systemic features responded to steroids in all 5 treated patients. Inflammatory arthritis appears to be common in MDS. Most compelling is the apparent bone marrow response to steroids in 2 cases, possibly identifying a treatable subgroup.

Aged↗
PubMed1999

Evolutionary transition from single to multiple mating in fungus-growing ants.

Queens of leafcutter ants exhibit the highest known levels of multiple mating (up to 10 mates per queen) among ants. Multiple mating may have been selected to increase genetic diversity among nestmate workers, which is hypothesized to be critical in social systems with large, long-lived colonies under severe pressure of pathogens. Advanced fungus-growing (leafcutter) ants have large numbers (104-106 workers) and long-lived colonies, whereas basal genera in the attine tribe have small (< 200 workers) colonies with probably substantially shorter lifespans. Basal attines are therefore expected to have lower queen mating frequencies, similar to those found in most other ants. We tested this prediction by analysing queen mating frequency and colony kin structure in three basal attine species: Myrmicocrypta ednaella, Apterostigma collare and Cyphomyrmex longiscapus. Microsatellite marker analyses revealed that queens in all three species were single mated, and that worker-to-worker relatedness in these basal attine species is very close to 0.75, the value expected under exclusively single mating. Fungus growing per se has therefore not selected for multiple queen mating. Instead, the advanced and highly productive social structure of the higher attine ants, which is fully dependent on the rearing of an ancient clonal fungus, may have necessitated high genetic diversity among nestmate workers. This is not the case in the lower attines, which rear fungi that were more recently derived from free-living fungal populations.

Animals↗
PubMed2002

The structural nature of chromosomal instability in colon cancer cells.

Biological and genetic cell heterogeneity is a landmark of most colorectal cancers and provides a frame for tumor progression as an evolutional process. Classical models have hypothesized that increased genetic instability may contribute to modulating and shaping malignant transformation. This is true for the small subset of colorectal cancers displaying microsatellite instability. For the rest of colorectal tumors, numerical and/or structural chromosomal alterations are the most prominent outcome of genetic disruption. These observations have prompted some investigators to hypothesize about the presence of chromosomal instability in these cells. To characterize chromosomal instability in cancer cells, we have analyzed genetic clonal divergence in three colorectal cancer cell lines considered to be archetypes in cancer research (HCT116, LoVo, and SW480). A dynamic setting was designed to allow the calculation of mutation rates. Comprehensive analyses at the chromosomal level revealed distinctive patterns of genetic divergence. Aneuploid SW480 cells displayed high rates of structural alterations (>100-fold) as compared with near diploid LoVo cells. Numerical alterations also occurred more frequently in SW480 cells but at low rates as compared with rearrangements in the chromosomically unstable SW480 cells. These results strengthen the role of structural instability in the generation of genetic heterogeneity in colorectal cancer.

Chromosome Aberrations↗
PubMed2004

GroEL and the maintenance of bacterial endosymbiosis.

Many eukaryotic organisms have symbiotic associations with obligate intracellular bacteria. The clonal transmission of endosymbionts between host generations should lead to the irreversible fixation of slightly deleterious mutations in their non-recombinant genome by genetic drift. However, the stability of endosymbiosis indicates that some mechanism is involved in the amelioration of the effects of these mutations. We propose that the chaperone GroEL was involved in the acquisition of an endosymbiotic lifestyle not only by means of its over-production, as proposed by Moran, but also by its adaptive evolution mediated by positive selection to improve the interaction with the unstable endosymbiont proteome.

Bacterial Physiological Phenomena↗
PubMed2004

Do collision tumors of the gastroesophageal junction exist? A molecular analysis.

Collision tumors are thought to arise from the accidental meeting of two independent tumors. Here we present five gastroesophageal junction tumors consisting of two collision tumors and three composite tumors (characterized by two divergent lineages originating from the same neoplastic clonal proliferation), as diagnosed on histology. In an attempt to prove this distinction at a genetic level, we performed TP53 sequence analysis and p53 immunohistochemistry. In addition, loss of heterozygosity (LOH) analysis using 10 microsatellite markers was carried out. An identical TP53 mutation and a similar pattern of retention and LOH were found in both neoplastic components of the presumed collision tumors, suggesting that both components are derived from a single precursor cell that undergoes divergent differentiation in the evolution of the tumor. In the composite group, 1 case had a genetic basis for the possible diagnosis of a collision tumor, with a TP53 mutation in the adenocarcinoma component only, and a different pattern of retention and loss of heterozygosity. These findings imply that it is not possible to recognize true collision tumors from immunohistologic appearance alone and suggest that the long-standing histologic criteria for the diagnosis of these neoplasms have no molecular basis.

Adenocarcinoma↗
PubMed2006

Immune pathogenesis of paroxysmal nocturnal hemoglobinuria.

Somatic mutation in the PIG-A gene is the initial event in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), but the pathophysiologic mechanisms leading to clonal expansion remain unclear. The intricate association of PNH with immune-mediated bone marrow failure syndromes, including aplastic anemia (AA), suggests an immunologic selection process for the glycosylphosphatidyl-inositol (GPI)-deficient hematopoietic clone. The mechanism for the growth advantage of PNH cells may be related to the nature of the antigens targeted by the immune response or to the function of immunomodulatory GPI-anchored proteins on the surface of the hematopoietic target cells. Alternative theories of PNH evolution may include intrinsic properties of the mutated cells, but the experimental evidence is largely lacking. Elucidation of the pathogenesis of PNH may provide key information about the causes of idiopathic AA and help understand the regulation of the hematopoietic stem cell compartment.

Anemia, Aplastic↗
PubMed2000

Intrachromosomal homologous recombination in Arabidopsis induced by a maize transposon.

In plants, the frequency of spontaneous intrachromosomal homologous recombination is low. Here, we show that a maize transposable element greatly stimulates intrachromosomal homologous recombination between direct repeat sequences in Arabidopsis. Plants were transformed with a construct (GU-Ds-US) containing a Ds (Dissociation) transposable element inserted between two partially deleted GUS reporter gene segments. Homologous recombination between the overlapping GUS fragments generates clonal sectors visible upon staining for GUS activity. Plants containing the GU-Ds-US construct and a source of Ac (Activator) transposase showed an over 1000-fold increase in the incidence of recombination relative to plants containing the same construct but lacking transposase. Transposon-induced recombination was observed in vegetative and floral organs, and several germinally transmitted events were recovered. Transposon-induced recombination appears to be a general phenomenon in plants, and thus may have contributed to genome evolution by inducing deletions between repeated sequences.

Arabidopsis↗
PubMed2006

Comparative gene expression by WC1+ gammadelta and CD4+ alphabeta T lymphocytes, which respond to Anaplasma marginale, demonstrates higher expression of chemokines and other myeloid cell-associated genes by WC1+ gammadelta T cells.

The functions of gammadelta T cells are enigmatic, and these cells are often considered as evolutionary remnants of well-characterized alphabeta T cells. However, their conservation throughout evolution suggests that gammadelta T cells are biologically unique. In ruminants, gammadelta T cells expressing the workshop cluster 1 (WC1) scavenger receptor comprise a large proportion of circulating lymphocytes, suggesting these cells are biologically relevant and functionally different from alphabeta T cells. In fact, bovine WC1(+) gammadelta T cells can act as APC for alphabeta T cells, indicating they may express genes encoding proteins associated with innate immunity. The present study was designed to compare immune function gene expression profiles of clonal populations of WC1(+) gammadelta and CD4(+) alphabeta T cells derived from the same animal, which respond to major surface protein 2 (MSP2) of the intraerythrocytic rickettsial pathogen of cattle, Anaplasma marginale. Gene expression profiles of activated T cell clones were compared using a microarray format, and differential gene expression was confirmed by real-time RT-PCR and protein analyses. We demonstrate that although MSP2-specific alphabeta and gammadelta T cell clones express many of the same genes, gammadelta T cell clones express high levels of genes associated with myeloid cells, including chemokines CCL2, CXCL1, CXCL2, CXCL6, and surface receptors CD68, CD11b, macrophage scavenger receptor 1, macrophage mannose receptor, and galectin-3. It is important that many of these genes were also expressed at higher levels in polyclonal WC1(+) gammadelta T cells when compared with CD4(+) alphabeta T cells selected from peripheral blood.

Anaplasma marginale↗
PubMed2006

Molecular-genetic biodiversity in a natural population of the yeast Saccharomyces cerevisiae from "Evolution Canyon": microsatellite polymorphism, ploidy and controversial sexual status.

The yeast S. cerevisiae is a central model organism in eukaryotic cell studies and a major component in many food and biotechnological industrial processes. However, the wide knowledge regarding genetics and molecular biology of S. cerevisiae is based on an extremely narrow range of strains. Studies of natural populations of S. cerevisiae, not associated with human activities or industrial fermentation environments, are very few. We isolated a panel of S. cerevisiae strains from a natural microsite, "Evolution Canyon" at Mount Carmel, Israel, and studied their genomic biodiversity. Analysis of 19 microsatellite loci revealed high allelic diversity and variation in ploidy level across the panel, from diploids to tetraploids, confirmed by flow cytometry. No significant differences were found in the level of microsatellite variation between strains derived from the major localities or microniches, whereas strains of different ploidy showed low similarity in allele content. Maximum genetic diversity was observed among diploids and minimum among triploids. Phylogenetic analysis revealed clonal, rather than sexual, structure of the triploid and tetraploid subpopulations. Viability tests in tetrad analysis also suggest that clonal reproduction may predominate in the polyploid subpopulations.

Alleles↗
PubMed1996

Analysis of the kappa light chain variable region in multiple myeloma.

The study of immunoglobulin heavy chain gene rearrangements in multiple myeloma has revealed extensive divergence from the germline sequences, but no intraclonal diversity with disease evolution. Our study investigated the state of the rearranged kappa light chain variable region (V kappa) gene segments as well as abortive V kappa family gene usage in cases of multiple myeloma expressing lambda light chain. We studied 11 cases of kappa and five cases of lambda light chain-expressing multiple myeloma. Total cellular RNA was extracted from the bone marrow of patients with overt disease and subjected to reverse transcription-polymerase chain reaction (RT-PCR) analysis to amplify clonally rearranged variable region sequences. Direct nucleotide sequencing by the dideoxy-chain termination method was performed on the RT-PCR products. We did not observe preferential usage of certain V kappa gene families. Mutation frequencies of the V kappa segments varied in number. In the majority of cases, extensive somatic mutations occurred within the complementarity determining regions (CDRs) of V kappa, whereas only a limited degree of divergence from the germline was observed in others. In all cases studied. replacement mutations tended to cluster in the CDRs, a finding compatible with an antigen-driven somatic hypermutation process. In 3/5 cases of lambda light-chain expressing multiple myeloma, abortively rearranged V kappa gene segments were amplified from genomic DNA; in two cases a non-templated nucleotide insertion rendering the V kappa sequences out-of-frame was observed, and in the third a stop codon was identified in the open reading frame of the V kappa sequence. Somatic mutations were observed in all cases of abortive V kappa genes studied; however, their distribution does not suggest selection by antigen. We conclude that somatic mutations observed in the V kappa regions of myeloma cells are of variable extent and suggest operation of the antigen selection process. Lack of or minimal somatic hypermutation in a few cases may be in some way implicated in the biological heterogeneity of the disease.

Amino Acid Sequence↗
PubMed1999

Evolutionary genetics of Trypanosoma and Leishmania.

We review recent advances in the study of population structure and phylogenetic diversity of parasites belonging to the genera Trypanosoma and Leishmania. In all species properly analyzed, these parasites exhibit a basically clonal population structure, with occasional bouts of genetic exchange or hybridization, and a strong structuration of their populations into discrete evolutionary lineages. On an evolutionary scale, the impact of sex appears to be greater in African than in American trypanosomes. The taxonomic status of some Leishmania 'species' is questionable.

Animals↗
PubMed2005

Isolation and characterization of the mating-type locus of the barley pathogen Pyrenophora teres and frequencies of mating-type idiomorphs within and among fungal populations collected from barley landraces.

Pyrenophora teres f. sp. teres mating-type genes (MAT-1: 1190 bp; MAT-2: 1055 bp) have been identified. Their predicted proteins, measuring 379 and 333 amino acids, respectively, are similar to those of other Pleosporales, such as Pleospora sp., Cochliobolus sp., Alternaria alternata, Leptosphaeria maculans, and Phaeosphaeria nodorum. The structure of the MAT locus is discussed in comparison with those of other fungi. A mating-type PCR assay has also been developed; with this assay we have analyzed 150 isolates that were collected from 6 Sardinian barley landrace populations. Of these, 68 were P. teres f. sp. teres (net form; NF) and 82 were P. teres f. sp. maculata (spot form; SF). Within each mating type, the NF and SF amplification products were of the same length and were highly similar in sequence. The 2 mating types were present in both the NF and the SF populations at the field level, indicating that they have all maintained the potential for sexual reproduction. Despite the 2 forms being sympatric in 5 fields, no intermediate isolates were detected with amplified fragment length polymorphism (AFLP) analysis. These results suggest that the 2 forms are genetically isolated under the field conditions. In all of the samples of P. teres, the ratio of the 2 mating types was consistently in accord with the 1:1 null hypothesis. This ratio is expected when segregation distortion and clonal selection among mating types are absent or asexual reproduction is rare. Overall, sexual reproduction appears to be the major process that equalizes the frequencies of the 2 mating types within populations.

Amino Acid Sequence↗
PubMed1998

Stability and diversity of T cell receptor repertoire usage during lymphocytic choriomeningitis virus infection of mice.

Numerous studies have examined T cell receptor (TCR) usage of selected virus-specific T cell clones, yet little information is available regarding the stability and diversity of TCR repertoire usage during viral infections. Here, we analyzed the Vbeta8.1 TCR repertoire directly ex vivo by complementarity-determining region 3 (CDR3) length spectratyping throughout the acute lymphocytic choriomeningitis virus (LCMV) infection, into memory, and under conditions of T cell clonal exhaustion. The Vbeta8 population represented 30-35% of the LCMV-induced CD8(+) T cells and included T cells recognizing several LCMV-encoded peptides, allowing for a comprehensive study of a multiclonal T cell response against a complex antigen. Genetically identical mice generated remarkably different T cell responses, as reflected by different spectratypes and different TCR sequences in same sized spectratype bands; however, a conserved CDR3 motif was found within some same sized bands. This indicated that meaningful studies on the evolution of the T cell repertoire required longitudinal studies within individual mice. Such longitudinal studies with peripheral blood lymphocyte samples showed that (a) the virus-induced T cell repertoire changes little during the apoptosis period after clearance of the viral antigens; (b) the LCMV infection dramatically skews the host T cell repertoire in the memory state; and (c) continuous selection of the T cell repertoire occurs under conditions of persistent infections.

Animals↗
PubMed2003

Life-history differentiation and the maintenance of monoecy and dioecy in Sagittaria latifolia (Alismataceae).

The existence of monoecious and dioecious populations within plant species is rare. This limits opportunities to investigate the ecological mechanisms responsible for the evolution and maintenance of these contrasting sexual systems. In Sagittaria latifolia, an aquatic flowering plant, monoecious and dioecious populations exist in close geographic proximity but occupy distinct wetland habitats differing in the relative importance of disturbance and competition, respectively. Life-history theory predicts contrasting evolutionary responses to these environmental conditions. We propose that the maintenance of monoecy and dioecy in S. latifolia is governed by ecological selection of divergent life-history strategies in contrasting habitats. Here we evaluate this hypothesis by comparing components of growth and reproduction between monoecious and dioecious populations under four conditions: natural populations, a uniform glasshouse environment, a common garden in which monoecious and dioecious populations and their F1 progeny were compared, and a transplant experiment using shaded and unshaded plots in a freshwater marsh. Plants from dioecious populations were larger in size and produced heavier corms in comparison with monoecious populations. Monoecious populations flowered earlier and produced more flowers, clonal ramets, and corms than dioecious populations. The life-history differences between the sexual systems were shown to have a quantitative genetic basis, with F1 progeny generally exhibiting intermediate trait values. Survival was highest for each sexual system in field plots that most closely resembled the habitats in which monoecious (unshaded) and dioecious (shaded) populations grow. These results demonstrate that monoecious and dioecious populations exhibit contrasting patterns of investment in traits involved with growth and reproduction. Selection for divergent life histories between monoecious and dioecious populations of S. latifolia appears to be the principal mechanism maintaining the integrity of the two sexual systems in areas of geographic overlap.

Adaptation, Physiological↗