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PubMed2005

Detailed analysis of the genetic evolution of influenza virus during the course of an epidemic.

The genetic variability of influenza virus is usually studied with sequences selected over numerous years and countries, and rarely within a single season. Here we examined the viral evolution and the correlation between genetic and clinical features during an epidemic. From a French prospective household-based study in 1999-2000, 99 infected patients were randomly selected. The HA1 genomic domain was sequenced. Phylogenetic analysis showed the existence of two groups of A/H3N2 viruses. We found no distinct pattern of genomic evolution within either group according to time. A spatial correlation with the nucleotide distances was shown. The average nucleotide diversity was 3.4x10-3 nucleotides per site, and did not differ between the groups. A lower number of segregating sites was observed in patients who experienced influenza-like symptoms during the previous epidemic. These results suggest that the influenza virus undergoes regular HA1 nucleotide changes, but without clonal expansion of mutant strains within a single epidemic.

Adult↗
PubMed2005

Evolution of neuroendocrine mechanisms that regulate sexual behavior.

Whiptail lizards provide a unique system to study evolution of brain mechanisms because both ancestral (sexual) and descendant (parthenogenetic) species exist. Parthenogenetic whiptails enable us to avoid the two major confounds in sex differences research - males and females that differ both genetically and hormonally. Parthenogens are females that reproduce clonally, yet display alternately female-like and male-like pseudosexual behavior. Thus, the neural circuitry underlying male and female sexual behavior can be examined within the 'same' brain (same genome), enabling us to see how neuroendocrine mechanisms controlling mounting behavior change. In ancestral males, testicular androgens control sexual behavior, whereas male-like pseudocopulatory behavior is controlled by ovarian progesterone in parthenogens, revealing that progesterone is important in regulating sexual behavior in male vertebrates, including mammals.

Animals↗
PubMed1993

Evolution of complex chromosomal rearrangements in a case of biphenotypic pre-B/myeloid acute leukemia.

A case of acute biphenotypic leukemia, in which blast cells coexpress antigens of both lymphoid and myeloid lineages, was seen in a 24-year-old female. The clonal karyotype was complex but did not include any of the abnormalities previously found in biphenotypic leukemia. Chromosome abnormalities included breakpoints seen in both acute lymphoblastic and acute myeloid leukemias as well as a number of known fragile sites, namely the rare heritable fragile site at 10q24, and the common, aphidicolin-induced sites on chromosome 7.

Adult↗
PubMed1999

Where is typing going?

The basic premise in any bacterial typing scheme is that epidemiologically related isolates are derived from the clonal expansion of a single precursor. In simple terms this means that a certain characteristic is more useful than others on the basis that it is conserved within a strain but diverse with a species. Such a definition is appropriate when considering the spread of a species within a ward hospital or even a community. However, as we have developed more and more refined molecular techniques for analysis of the bacterial genome, such a definition has become stressed when considering the evolution that is occurring especially amongst drug-resistant bacteria whose genetic make-up is changing due to the selective pressure induced by drug usage in the hospital or community. Increased sophistication does not necessarily bring improved typing of bacterial strains which might only be variants of the same clonal type. Molecular epidemiology is perhaps too exacting to be practical in certain circumstances and one should be cautious in its interpretation and extrapolation. It is open to debate whether we shall see in the next century unanimity in the choice of pheno- or genotypic tests to be used for typing of bacterial strains.

Bacterial Typing Techniques↗
PubMed1990

Centromere splitting in bladder cancer.

Cytogenetic studies on a bladder carcinoma, carried out using short time cultures, showed centromere splitting (CS) mainly affecting chromosomes 22, 13, 14, 21, 15, 20, 12, 7, 17, and 18. Clonal trisomies and monosomies were also detected. Our case is the first description of CS in bladder tumor cells. Our results suggest that CS is an early phenomenon in the karyotypic evolution of this case; it can be considered a primary, yet unspecific, chromosome change related to aneuploidy in bladder cancer.

Aneuploidy↗
PubMed2001

Apoptotic mimicry by an obligate intracellular parasite downregulates macrophage microbicidal activity.

Programmed cell death by apoptosis of unnecessary or potentially harmful cells is clearly beneficial to multicellular organisms. Proper functioning of such a program demands that the removal of dying cells proceed without an inflammatory reaction. Phosphatidylserine (PS) is one of the ligands displayed by apoptotic cells that participates in their noninflammatory removal when recognized by neighboring phagocytes. PS ligation induces the release of transforming growth factor-beta (TGF-beta), an antiinflammatory cytokine that mediates the suppression of macrophage-mediated inflammation. In Hydra vulgaris, an organism that stands at the base of metazoan evolution, the selective advantage provided by apoptosis lies in the fact that Hydra can survive recycling apoptotic cells by phagocytosis. In unicellular organisms, it has been proposed that altruistic death benefits clonal populations of yeasts and trypanosomatids. Now we show that advantageous features of the apoptotic process can operate without death as the necessary outcome. Leishmania spp are able to evade the killing activity of phagocytes and establish themselves as obligate intracellular parasites. Amastigotes, responsible for disease propagation, similar to apoptotic cells, inhibit macrophage activity by exposing PS. Exposed PS participates in amastigote internalization. Recognition of this moiety by macrophages induces TGF-beta secretion and IL-10 synthesis, inhibits NO production, and increases susceptibility to intracellular leishmanial growth.

Animals↗
PubMed2000

Clonality and genetic divergence in multifocal low-grade superficial urothelial carcinoma as determined by chromosome 9 and p53 deletion analysis.

Multifocality and recurrence are clinically important features of urothelial carcinomas of the urinary bladder. Recent molecular genetic studies have suggested that multifocal urothelial carcinomas are monoclonally derived from an identical transformed progenitor cell. However, most of these studies investigated advanced and poorly differentiated tumors. The study presented focuses on early papillary tumors, including 52 superficial well-differentiated multifocal and recurrent bladder carcinomas from 10 patients. Microdissection separating urothelium from stromal cells was considered essential to obtain pure tumor cell populations. Genetic analysis was carried out by applying two different methods. Dual color fluorescence in situ hybridization (FISH) with centromeric probes for chromosomes 9 and 17 and gene-specific probes for chromosome loci 9q22, 9p21, and 17p13 was carried out in parallel to loss of heterozygosity (LOH) analyses applying 5 microsatellite markers on these chromosomes. Overall, deletions on chromosome 9p were found in 47 tumors (90%), at chromosome 9q in 36 tumors (69%) and at chromosome 17p in 3 tumors (6%). There was a very high correlation of the results between FISH and LOH analysis. Ten early superficial papillary tumors showed deletion of chromosome 9p without deletion of 9q, suggesting 9p deletions as a very early event in the development of papillary urothelial carcinoma. Although in four patients, all investigated tumors showed identical genetic alterations and one patient showed no genetic alterations at the loci investigated, in five patients, two or more clones with different deletions were found. In four of these patients, the results are compatible with clonal divergence and selection of different cell subpopulations derived from a common progenitor cell. However, in one patient different alleles in two markers at chromosome 9 were deleted, favoring an independent evolution of two recurring tumor cell clones. In summary, we could show that there is considerable genetic heterogeneity in early multifocal and recurring urothelial carcinoma and demonstrated the occurrence of two independent clones in at least one patient as an indicator of possible initial oligoclonality of bladder cancer.

Aged↗
PubMed2004

Multilocus sequence typing analysis of human and animal Clostridium difficile isolates of various toxigenic types.

A multilocus sequence typing (MLST) scheme was developed to study the genetic relationships and population structure of 72 Clostridium difficile isolates from various hosts, geographic sources, PCR ribotypes, and toxigenic types (determined by PCR targeting tcdA and tcdB genes). MLST was performed by DNA sequence analysis of seven housekeeping genes (aroE, ddl, dutA, tpi, recA, gmk, and sodA). The number of alleles ranged from five (dutA and ddl) to eleven (recA). Allelic profiles allowed the definition of 34 different sequence types (STs). These STs lacked correlation with geographic source but were well correlated to toxigenic type. The dendrogram generated from a matrix of pairwise genetic distances showed that animal isolates did not constitute a distinct lineage from human isolates and that there was no hypervirulent lineage within the population of toxigenic human isolates (isolates recovered from pseudomembranous colitis and antibiotic-associated diarrhea did not cluster in distinct lineages). However, A(-) B(+) variant isolates shared the same ST that appeared as a divergent lineage in the population studied, indicating a single evolutionary origin. The population structure was further examined by analysis of allelic polymorphism. The dendrogram generated from composite sequence-based analysis revealed a homogeneous population associated with three divergent lineages, one of which was restricted to A(-) B(+) variant isolates. C. difficile exhibited a clonal population structure, as revealed by the estimation of linkage disequilibrium (Ia) between loci. The analysis of alleles within clonal complexes estimated that point mutation generated new alleles at a frequency eightfold higher than recombinational exchange, and the congruence of the dendrograms generated from separate housekeeping loci confirmed the mutational evolution of this species.

Alleles↗
PubMed2002

Myelodysplastic syndrome following therapy for brain tumor--two case reports.

A 3-month-old boy and a 29-year-old woman presented with myelodysplastic syndrome (MDS) following therapy for primary malignant brain tumor. Both received intensive alkylating agent doses for induction and maintenance chemotherapy combined with craniospinal or cranial radiation for medulloblastoma and anaplastic astrocytoma, respectively. They developed refractory anemia and pancytopenia. Approximately 9 years after the completion of induction chemoradiotherapy, chromosomal analysis of bone marrow cells resulted in the diagnosis of MDS. The boy died of leukemic evolution 15 months later, the woman died of hematopoietic failure 3 months later. The most common symptom of MDS is refractory anemia, either alone or as part of bi- or pancytopenia. Clonal proliferation with chromosomal analysis of bone marrow cells establishes the diagnosis of MDS. Patients with malignant brain tumors are at risk of the development of MDS as a late complication of chemotherapy based on high cumulative doses of alkylating agents.

Adult↗
PubMed1994

Granulomatous slack skin.

Granulomatous slack skin is a form of cutaneous lymphoma with an indolent but relentless course. It is characterized by circumscribed areas of pendulous lax skin that contain clonal infiltrates of helper T-cells, which infiltrate the epidermis in a manner similar to that of mycosis fungoides and attract a granulomatous component that mediates massive dermal elastolysis. The evolution of Hodgkin's disease occurs in some cases. There is no known curative treatment, but surgery, radiation therapy, systemic corticosteroids, and chemotherapy have slowed the progression of some lesions.

Diagnosis, Differential↗
PubMed2026

A guide to understanding tumour evolution through the lens of population genetics.

Every cancer carries the history of its own evolution, hidden in its genome. Modern DNA sequencing can catalogue millions of mutations and profile tumours across space and time, but sequencing alone struggles to answer the questions that matter most: when did key adaptations emerge, how strongly were they selected, why do some tumours relapse whereas others do not, and how will the cancer evolve next? The reason is fundamental: sequencing is a snapshot, whereas evolution is a dynamic process. Bridging this gap requires moving beyond descriptive cancer genomics towards quantitative evolutionary inference. In this Review, we argue that population genetics provides the mathematical framework needed to extract evolutionary dynamics from cancer genomes. We show how models of mutation, selection and drift transform allele frequencies from descriptive measurements into quantitative estimates of clonal fitness and evolutionary timings. We discuss how these principles extend to epigenetic inheritance, plasticity and ecological interactions within the tumour ecosystem, and examine the assumptions and limitations for their application to modern sequencing data. By reframing cancer genomes as quantitative records of evolutionary processes rather than catalogues of mutations, researchers have used population genetics to provide a foundation for understanding - and ultimately predicting - the trajectories of cancer evolution.

Journal Article↗
PubMed1991

Trypanosoma brucei rhodesiense: characterisation of stocks from Zambia, Kenya, and Uganda using repetitive DNA probes.

We have previously described a system for characterising the relationships between trypanosome stocks of the T.brucei group based on Southern blotting with repetitive DNA probes followed by cluster analysis of resultant banding patterns (G. Hide et al. Molec. Bioch. Parasitol. 39, 213-226, 1990). In this study, we extend this analysis to examine the relationships between trypanosome stocks isolated from major sleeping sickness foci in Zambia, Kenya, and Uganda. We show that the trypanosome strains responsible for disease in Zambia are quite distinct from those sampled from the Kenya/Uganda foci. Furthermore, the human serum resistant stocks isolated from the Kenya/Uganda foci which were isolated from man (or from animals) were found to form a tight group in the cluster analysis, while stocks isolated from nonhuman sources in the same area or stocks from elsewhere were found in separate groups. Thus, the human infective trypanosome strains found in these foci may have common origins and have, perhaps, arisen by clonal selection from a common source.

Animals↗
PubMed2004

The accumulation of deleterious mutations within the frozen niche variation hypothesis.

The frozen niche variation hypothesis proposes that asexual clones exploit a fraction of a total resource niche available to the sexual population from which they arise. Differences in niche breadth may allow a period of coexistence between a sexual population and the faster reproducing asexual clones. Here, we model the longer term threat to the persistence of the sexual population from an accumulation of clonal diversity, balanced by the cost to the asexual population resulting from a faster rate of accumulation of deleterious mutations. We use Monte-Carlo simulations to quantify the interaction of niche breadth with accumulating deleterious mutations. These two mechanisms may act synergistically to prevent the extinction of the sexual population, given: (1) sufficient genetic variation, and consequently niche breadth, in the sexual population; (2) a relatively slow rate of accumulation of genetic diversity in the clonal population; (3) synergistic epistasis in the accumulation of deleterious mutations.

Biological Evolution↗
PubMed2000

Diminishing returns of population size in the rate of RNA virus adaptation.

Whenever an asexual viral population evolves by adapting to new environmental conditions, beneficial mutations, the ultimate cause of adaptation, are randomly produced and then fixed in the population. The larger the population size and the higher the mutation rate, the more beneficial mutations can be produced per unit time. With the usually high mutation rate of RNA viruses and in a large enough population, several beneficial mutations could arise at the same time but in different genetic backgrounds, and if the virus is asexual, they will never be brought together through recombination. Thus, the best of these genotypes must outcompete each other on their way to fixation. This competition among beneficial mutations has the effect of slowing the overall rate of adaptation. This phenomenon is known as clonal interference. Clonal interference predicts a speed limit for adaptation as the population size increases. In the present report, by varying the size of evolving vesicular stomatitis virus populations, we found evidence clearly demonstrating this speed limit and thus indicating that clonal interference might be an important factor modulating the rate of adaptation to an in vitro cell system. Several evolutionary and epidemiological implications of the clonal interference model applied to RNA viruses are discussed.

Adaptation, Physiological↗
PubMed1994

Molecular genetic demonstration of the diverse evolution of Richter's syndrome (chronic lymphocytic leukemia and subsequent large cell lymphoma).

Paired samples of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and the subsequent diffuse large cell lymphoma (DLL) of six cases of Richter's syndrome were investigated to establish the clonal relationship between the CLL/SLL and the DLL components and to define the oncogene and/or tumor-suppressor gene alterations involved in the morphologic transformation of CLL/SLL. Southern blot hybridization analysis showed identical clonal immunoglobulin (Ig) gene-rearrangement patterns in the CLL/SLL and DLL components in four cases and different Ig gene-rearrangement patterns in two cases. Polymerase chain reaction (PCR) amplification, cloning, and DNA sequencing of complementary determinant region 3 (CDR3) of the Ig-heavy chain gene of one of the two cases in which the Ig gene-rearrangement patterns were different showed nonidentical sequences in the CLL/SLL and DLL components. In the other case, monomorphic Epstein-Barr virus (EBV) genome integration was detected in the DLL but not in the CLL, suggesting that the CLL and DLL components in this case of Richter's syndrome also represent unrelated clones. Single-strand conformation polymorphism (SSCP) analysis and sequencing of exons 5 through 9 of the p53 tumor-suppressor gene showed a mutation in codon 176 of the DLL but not in the CLL/SLL component in one case where the CLL/SLL and DLL represented different clones. The p53 mutation probably played a role in the development of the lymphoma rather than morphologic transformation of the CLL/SLL in this case. SSCP analysis and sequencing also showed identical mutations in codon 282 in both the CLL/SLL and DLL components in a case where the CLL and DLL represented identical clones. Thus, this p53 gene mutation was present both before and after morphologic transformation, and therefore, probably did not play a primary role in this process. Southern blot hybridization analysis failed to show evidence of bcl-1, bcl-2, c-myc proto-oncogene or retinoblastoma (Rb) tumor-suppressor gene rearrangements in these six cases of Richter's syndrome. In conclusion, the original CLL/SLL and the subsequent DLL in Richter's syndrome may or may not be derived from identical clones, and the well-known proto-oncogenes and tumor-suppressor genes do not appear to play an obvious and consistent role in the morphologic transformation of CLL/SLL to DLL.

Adult↗
PubMed1993

Population biology of Toxoplasma: clonality, virulence, and speciation (or not).

The population biology of Toxoplasma gondii is reviewed in the context of how its complex life cycle might be responsible for the current picture and how a knowledge of the population structure may have an impact on the thinking of both clinician and researcher. Published results already clearly indicate that the population can be divided into two distinct groups that are genetically and biologically distinct. The more virulent group, as defined by their LD50 in mice, is apparently a single, clonal line. The biological and clinical implications of the existence of such a group are discussed.

Animals↗
PubMed1996

Random important alterations in HIV-1 viral quasispecies after antiviral treatment.

The evolution of HIV-1 viral populations was studied in a set of MT-2-co-cultured viruses isolated from five patients at the beginning of treatment with zidovudine and after 11-36 months of drug therapy. We first characterized the HIV-1 pol gene to detect the zidovudine-resistance mutations at codons 215 and 219. To analyse the effect that the selective pressure of zidovudine on pol exerted on other genomic regions, we also studied the env gene. The env gene sequence of virus isolated from one individual was unchanged, whereas three other sample pairs had minor alterations in env. In one individual, we detected a significant change in the env gene sequence, and so performed a clonal analysis on viruses isolated before and after treatment. In this individual, the zidovudine-resistant variant that became predominant in the resistant virus population was an undetected minority variant of the viral population before treatment was initiated. These results indicate that the evolution of quasispecies produced by selective pressure on the pol gene from zidovudine treatment could select, in a random process, important changes in other genomic regions; in particular, we describe alterations in the env gene.

Anti-HIV Agents↗
PubMedDate not supplied

HOX genes in human cancers.

Knowledge about transcription factors is crucial for understanding the molecular basis of neoplasia. Homeobox-containing genes are a family of transcription factors mostly involved in normal development. Class I human homeobox-containing genes (HOX genes) are organized in four clusters on different chromosomes. The order of the genes within each cluster is highly conserved throughout evolution suggesting that the physical organization of HOX genes may be (1) essential for their expression and (2) responsible for major biological functions. We have studied HOX gene expression in several human tissues and organs as well as in their neoplastic counterparts. We have observed (a) characteristic patterns of HOX gene expression for each normal solid organ analyzed, (b) altered HOX gene expression in kidney and colon cancer, (c) a correlation between HOX gene expression and different histological types of primary small cell lung cancer (SCLC) and (d) marked alterations of HOX gene expression among primary and metastatic SCLC variant types. Furthermore, we have shown that differential patterns of HOX gene expression correlate with the adhesion profile (VLA-2, VLA-5, VLA-6 and ICAM-1) and N-RAS mutation in clonal melanoma populations isolated from a single human melanoma metastasis. This suggests that HOX genes act as a network of transcriptional regulators involved in the process of cell to cell communication during normal morphogenesis, the alteration of which may contribute to the evolution of cancer.

Adult↗