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PubMed2004

Population structure and evolutionary origins of Microsporum canis, M. ferrugineum and M. audouinii.

The recurrent evolutionary emergence of asexual lineages within sexual zoo- and anthropophilic dermatophyte species living in animal-frequented soil is likely to be triggered by changes in ecological niche, i.e., shifts of host animal. Subsequent adaptation to the new host species is noted. Sometimes geographic isolation or intrinsic host factors like human race may also play a role in speciation. In the present study, we elaborate concepts of speciation in dermatophytes using the Microsporum canis complex as an example. The group consists of a cluster of phylogenetically closely related anamorphs: the anthropophilic taxa Microsporum audouinii and M. ferrugineum, and the zoophilic taxon M. canis. The sexually reproducing species underlying this complex is Arthroderma otae. The study is done by an analysis of the population structure of about 200 isolates and using intergenic spacers, non-translated regions of genes as well as hypervariable microsatellite markers that are known to evolve at high mutation rates. The results suggest that sympatric speciation took place already during the period where mating ability was maintained and thus that strictly clonal fungal species emerged in Africa and led to genetically isolated clonal species elsewhere.

Alleles↗
PubMed2002

Analysis of CHK2 in patients with myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) comprise a group of clonal hemopoietic stem cell disorders characterized by ineffective hematopoiesis with an increased propensity to myeloid leukemic (AML) transformation. The underlying molecular basis for MDS and its leukemic evolution is unclear. Except for patients with 17p syndrome, loss of function of the p53 tumor suppressor gene accounts for <10% of MDS and AML cases. Recently, mutations of the checkpoint gene, CHK2, the human homologue of the yeast CDS1 and RAD53 genes, have been reported in patients with Li-Fraumeni syndrome who also have normal p53. As p53 mutations are rare in MDS and AML, we investigated the status of the CHK2 gene by reverse transcriptase-polymerase chain reaction (RT-PCR) in patients with MDS (n=10) and patients in whom MDS had transformed into AML (n=3). In the MDS group, we found one patient with a conserved mutation (Lys-->Arg) in the forked head-associated (FHA) domain of the CHK2 coding sequence. We also found a deletion in the CHK2 transcript in one patient from the MDS-->AML group, resulting in a truncated protein lacking the kinase domain. We conclude that alterations of CHK2 and possible involvement in the pathogenesis of MDS may be a rare event.

Bone Marrow↗
PubMed2006

Dermatophytes: recognizing species of clonal fungi.

Now that molecular data have forever changed our perspective on the anthropophilic and zoophilic dermatophyte species, the concepts of these species needs re-evaluation. In this paper, main concepts (morphological, biological (BSC), phylogenetic and genealogical concordance phylogenetic species recognition (GCPSR)) are compared. While in geophilic dermatophytes the application of the BSC works well for species distinction and is supported by molecular data, it is not applicable for the anthropophilic and zoophilic dermatophytes where the majority of species reproduce purely asexually. Also, the application of GCPSR (an operational method to define the limits of species using molecular, multi-locus data) is problematic. GCPSR can be applied in recombining fungi even when recombination is infrequent and fungi lack phenotypic sexuality. In truly clonal fungi, however, no incongruities in multi-locus data are found, and thus separation of species may be difficult. In fungi this problem is currently taken to be non-existent, since clonality is supposed to lead to extinction. In the medically relevant, host-associated dermatophytes, however, is reason to suggest that clonal dermatophyte lineages are able to maintain ongoing populations and to follow independent evolutionary trajectories. We distinguish seasonal, short-lived and long-lived clonal species. The final goal of a species concept, in the dermatophytes as well as in other fungi, is to provide a taxonomic system that reflects the evolution of the fungal species so that the underlying biological trends elucidated in this way may be brought forward to help to guide the clinician in applying optimal therapy and prophylaxis. The application of the different species concepts may have an enormous impact on the nomenclature of dermatophytes, directly affecting the quality of communications with care providers.

Arthrodermataceae↗
PubMed1991

Neutralization-resistant antigenic variants of caprine arthritis-encephalitis lentivirus associated with progressive arthritis.

Fifteen newborn Saanen goats were orally infected with a biologically cloned isolate of caprine arthritis-encephalitis virus (CAEV-63). At 33.5 months after infection, 8 of 12 seropositive goats had CAEV-63-specific neutralizing antibody. Five neutralization-positive goats developed clinically apparent arthritis of carpal joints, three of which had periarticular swelling indicating severe synovitis. Arthritis was not evident in age-matched controls or infected goats without neutralizing antibody. Multiple viral isolates were obtained from synovial fluid or synovial fluid cells of arthritic joints between 36.4 and 44.9 months after infection, and successive isolates from individual joints were defined as antigenic variants expressing type-specific neutralization epitopes. Thus, the evolution of neutralizing antibody does not arrest viral replication or development of progressive inflammatory lesions. Rather, some antigenic variants produced in the presence of neutralizing antibody are clonally expanded within carpal joints, and severe joint inflammation is specifically associated with these variants.

Animals↗
PubMed2006

Evolutionary history of Salmonella typhi.

For microbial pathogens, phylogeographic differentiation seems to be relatively common. However, the neutral population structure of Salmonella enterica serovar Typhi reflects the continued existence of ubiquitous haplotypes over millennia. In contrast, clinical use of fluoroquinolones has yielded at least 15 independent gyrA mutations within a decade and stimulated clonal expansion of haplotype H58 in Asia and Africa. Yet, antibiotic-sensitive strains and haplotypes other than H58 still persist despite selection for antibiotic resistance. Neutral evolution in Typhi appears to reflect the asymptomatic carrier state, and adaptive evolution depends on the rapid transmission of phenotypic changes through acute infections.

Adaptation, Physiological↗
PubMed2004

Comprehensive scanning of somatic mitochondrial DNA alterations in acute leukemia developing from myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by ineffective hematopoiesis resulting in refractory cytopenias. Transformation resulting in acute myeloblastic leukemia is the final stage in the multistep process of MDS evolution. Functional relevant mutations of mitochondrial DNA (mtDNA) have been related to sideroblastic anemia and MDS. To investigate the role of mtDNA in malignant transformation to acute leukemia, we used high-resolution techniques such as single-strand conformational polymorphism and fluorescence sequencing for investigation of the whole mitochondrial genome from blood cells of 10 patients with MDS. Functionally relevant point mutations in mitochondrial RNA and polypeptide-encoding genes were detected in 50% of patients with MDS. Their increasing mutation load connects MDS and the developing acute myeloid leukemias. Several point mutations of mtDNA, including secondary point mutations for Leber's hereditary optic neuropathy, occur in one bone marrow and may synergically affect bone marrow stem cells by an apoptotic pathway.

Acute Disease↗
PubMed2002

Gametocyte sex ratio of a malaria parasite: experimental test of heritability.

The gametocyte sex ratio of Plasmodium mexicanum, a malaria parasite of western fence lizards, was studied in a modified garden experiment. Each of 6 naturally infected lizards was used to initiate 20 replicate-infections in naive western fence lizards. A significant donor effect was observed for the sex ratios of recipient infections at their maximal parasitemia, and this effect was associated with the sex ratio of the donor infection. In 20 infections in which sex ratio was followed during the course of the infection, 9 revealed constant sex ratios and 11 showed an increase in proportion of males over time. Recipient sex ratio was correlated with another life-history trait, a composite of rate of asexual replication and peak parasitemia, such that higher Rate-Peak scores were associated with infections with less female-biased sex ratios. These results are placed into the context of sex ratio theory that concludes that the degree of selfing of parasite genotypes (number of parasite clones) within the vector will influence the evolution of gametocyte sex ratio. The theory predicts that the sex ratio should be under some genetic control and thus be heritable as observed in the experiment. Clonal diversity should also influence the life-history trait, Rate-Peak, which was found to be correlated with sex ratio.

Animals↗
PubMed1993

Chromosome study of 249 patients examined for a bone tumor.

The authors have performed cytogenetic studies of bone tumors since 1987, and this article, based on previous work, summarizes their experiences in this field. Altogether 304 samples from 249 consecutive patients examined for a possible bone tumor at the Helsinki University Central Hospital, between October 1987 and April 1992, have been analyzed. The series consisted of 86 nonneoplastic disorders, 108 benign and 78 malignant primary bone tumors, and 32 other bone malignancies. In the group of nonneoplastic disorders, one sample from an infectious lesion demonstrated a simple clonal chromosome aberration. Simple clonal aberrations were seen in six of 75 successfully cultured benign tumors. Complex clonal aberrations occurred in 21 of 54 successfully cultured malignant primary bone tumors and in eight of 21 secondary bone malignancies. The complexity of clonal aberrations correlated with the grade of malignancy as the osteosarcomas and chondrosarcomas of high grade demonstrated chaotic abnormalities. The chaotic nature of the aberrations implicates the evolution of several different clones and thus advanced malignant transformation. Six of eight successfully cultured Ewing's sarcomas demonstrated the diagnostic t(11;22)(q24;q12); this translocation was also seen in one primitive neuroectodermal tumor. Cytogenetic study provides increasing knowledge of the biology of bone tumors and is a valuable adjunct in their evaluation.

Bone Neoplasms↗
PubMed1997

Evolutionary variants of the human immunodeficiency virus type 1 V3 region characterized by using a heteroduplex tracking assay.

Syncytium-inducing (SI) variants of human immunodeficiency virus type 1 (HIV-1) are evolutionary variants that are associated with rapid CD4+ cell loss and rapid disease progression. The heteroduplex tracking assay (HTA) was used to detect evolutionary V3 variants by amplifying the V3 sequences from viral RNA derived from 50 samples of patient plasma. For this V3-specific HTA (V3-HTA), heteroduplexes were formed between the patient V3 sequences and a probe with the subtype B consensus V3 sequence. Evolution was then measured by divergence from the consensus. The presence of evolutionary variants was correlated with SI detection data on the same samples from the MT-2 cell culture assay. Evolutionary variants were correlated with the SI phenotype in 88% of the samples, and 96% of the SI samples contained evolutionary variants. In most cases the evolutionary V3 variants represented discrete clonal outgrowths of virus. Sequence analysis of the six discordant samples that did not show this correlation indicated that three non-syncytium-inducing (NSI) samples had V3 sequences that had evolved away from the consensus sequence but not toward an SI genotype. A fourth sample showed little evolution away from the consensus but was SI, which indicates that not all SI variants require basic substitutions in V3. The other two samples had SI-like genotypes and NSI phenotypes, suggesting that V3-HTA was able to detect SI emergence in these samples in the absence of their detection in vitro. V3-HTA was also used to confirm SI variant selection in MT-2 cells and to examine the possibility of variant selection during virus culture in peripheral blood cells.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Evolution of Wolbachia cytoplasmic incompatibility types.

The success of obligate endosymbiotic Wolbachia infections in insects is due in part to cytoplasmic incompatibility (CI), whereby Wolbachia bacteria manipulate host reproduction to promote their invasion and persistence within insect populations. The observed diversity of CI types raises the question of what the evolutionary pathways are by which a new CI type can evolve from an ancestral type. Prior evolutionary models assume that Wolbachia exists within a host individual as a clonal infection. While endosymbiotic theory predicts a general trend toward clonality, Wolbachia provides an exception in which there is selection to maintain diversity. Here, evolutionary trajectories are discussed that assume that a novel Wolbachia variant will co-exist with the original infection type within a host individual as a superinfection. Relative to prior models, this assumption relaxes requirements and allows additional pathways for the evolution of novel CI types. In addition to describing changes in the Wolbachia infection frequency associated with the hypothesized evolutionary events, the predicted impact of novel CI variants on the host population is also described. This impact, resulting from discordant evolutionary interests of symbiont and host, is discussed as a possible cause of Wolbachia loss from the host population or host population extinction. The latter is also discussed as the basis for an applied strategy for the suppression of insect pest populations. Model predictions are discussed relative to a recently published Wolbachia genome sequence and prior characterization of CI in naturally and artificially infected insects.

Animals↗
PubMed2000

Evolution of chloramphenicol resistance, with emergence of cross-resistance to florfenicol, in bovine Salmonella Typhimurium strains implicates definitive phage type (DT) 104.

The prevalence of resistance to florfenicol, a phenicol drug newly introduced in veterinary therapy, was determined in 86 chloramphenicol-resistant Salmonella Typhimurium isolates from cattle collected during 1985-1995. All were highly resistant to chloramphenicol (MICs > or = 128 mg/L) and 38 were simultaneously resistant to florfenicol (MICs >16 mg/L) and to beta-lactam agents, spectinomycin, streptomycin, sulphonamides and tetracyclines. The isolates susceptible to florfenicol harboured the chloramphenicol acetyl transferase gene, cat of type I. All the florfenicol-resistant isolates harboured the floR resistance gene and the characteristic multiple resistance genetic locus, previously characterised in a S. Typhimurium DT104 strain and identified by a multiplex PCR. Plasmid profiles and ribotype patterns were determined for all the isolates. The florfenicol-resistant isolates were grouped into the same ribotyping pattern and presented similar plasmid profiles, whereas the florfenicol-susceptible isolates showed a wider genetic diversity that is usual for S. Typhimurium. Thus, the florfenicol-resistant isolates could represent a clonal cluster, closely related to, if not of DT104 phage type, which appeared in 1989 and is now predominant within chloramphenicol-resistant S. Typhimurium. The multiplex PCR provided a useful tool to survey further evolution of multiresistant S. Typhimurium strains.

Animals↗
PubMed2002

Bacillus anthracis evolution and epidemiology.

Bacillus anthracis is a pathogen that is widely distributed around the globe. However, this great distribution is not accompanied by great genetic diversity. Although subtle morphological and biochemical differences exist, the underlying genetic basis for this plasticity is not known. Indeed, very few single nucleotide differences have been detected among isolates and the only documented high variable sequences are associated with variable number tandem repeated (VNTR) sequences. The differences among the VNTRs has been used to suggest phylogenetic relationships among the worldwide isolates. There is one major clonal split in B. anthracis (A and B), with two minor clusters established within the B branch and four or more minor branches within the A group. The A branch is the most common worldwide, though the B branch is locally important in certain areas. The ecology and the evolution of B. anthracis have been greatly influenced by the spore phase of the lifecycle.

Animals↗
PubMed2001

Molecular evolution of catalytic antibodies in autoimmune mice.

Catalytic Abs (catAbs) preferentially evolved in autoimmune MRL/MPJ-lpr/lpr (MRL/lpr) mice upon immunization with the phosphonate transition-state analogue (TSA), but this did not happen in normal BALB/c mice. The majority of the catAbs from MRL/lpr mice were from several independent clones of the same family. Most of them had a lysine at position 95 in the heavy chain (H95), which is at the junctional region. This residue, which interacts with the phosphonate moiety of the TSA and presumably is involved in the catalytic activity, was not changed even after expansive evolution following multiple mutations. By contrast, the majority that arose from BALB/c mice were the non-catAbs, which were quite different in the sequence from the catAbs from MRL/lpr mice, but they were clonally related to one another, so most of them were originated from a single clone. In the MRL/lpr mice, the catalytic subsets that existed in the initial repertoire were effectively captured by the phosphonyl oxygens in the TSA by interacting with the lysine at H95. In the BALB/c mice, however, another noncatalytic subset with only the binding capability directed to a moiety other than the phosphonate moiety was alternatively evolved, because of the lowest abundance or elimination of the catalytic subsets.

Amino Acid Sequence↗
PubMed2004

The evolution of a pleiotropic fitness tradeoff in Pseudomonas fluorescens.

The evolution of ecological specialization is expected to carry a cost, due to either antagonistic pleiotropy or mutation accumulation. In general, it has been difficult to distinguish between these two possibilities. Here, we demonstrate that the experimental evolution of niche-specialist genotypes of the bacterium Pseudomonas fluorescens that colonize the air-broth interface of spatially structured microcosms is accompanied by pleiotropic fitness costs in terms of reduced carbon catabolism. Prolonged selection in spatially structured microcosms caused the cost of specialization to decline without loss of the benefits associated with specialization. The decline in the cost of specialization can be explained by either compensatory adaptation within specialist lineages or clonal competition among specialist lineages. These results provide a possible explanation of conflicting accounts for the cost of specialization.

Adaptation, Physiological↗
PubMed2000

Malignant hematopoietic cell lines: in vitro models for the study of myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by bone marrow cell dysplasia and ineffective hematopoiesis leading to peripheral refractory cytopenias. The course of the disease ranges from a chronic status with progressively impaired hematopoiesis to rapid evolution to acute myeloid leukemia (AML). A panel of continuous malignant hematopoietic cell lines has been established from the whole spectrum of MDS variants and also from the different stages of the diseases, namely from the MDS phase or the overt leukemia post-MDS phase. Ten cell lines were derived from the various MDS subtypes; 17 cell lines were established from patients with leukemia (mainly AML) post-MDS. While most cell lines display myelocytic, monocytic or erythroid features, some cell lines carry lymphoid characteristics (precursor B-cell, B-cell, or T-cell), With regard to these lymphoid MDS-derived cell lines, more detailed authentication (prove of derivation from the assumed patient) and verification (prove of the malignant nature of the cell line and derivation from the assumed neoplastic cells) are required to validate the cell lines as true in vitro representatives of MDS and to exclude any cross-contamination with other cells or immortalization of normal bystander cells. On the other hand, lymphoid MDS-derived cell lines may attest to the clonal nature of MDS which may afflict progenitor cells giving rise to lymphoid or myelomonocytoid cells. Many of the MDS-derived cell lines carry cytogenetic and molecular genetic abnormalities typically associated with MDS: gain or loss of all or parts of chromosomes 5, 7, 8 and 20 (-5/5q-, -7/7q-, + 8, 20q-); alterations of oncogenes and tumor suppressor genes (IRF-1, p15, p16, p53, RAS, RB). In summary, the present panel of cell lines provides continuously growing cells and thus unlimited cell material for use as in vitro paradigms covering the whole spectrum of MDS-related hematopoetic malignancies. Properly authenticated and verified MDS-derived cell lines which should be made freely available will represent important research tools for the study of MDS biology.

Adult↗
PubMed2004

Genetic evidence for recombination in Candida albicans based on haplotype analysis.

The possibility of sexual reproduction in the human pathogenic fungus Candida albicans is a question of great interest in medical mycology. Not only is it a fundamental biological issue, but it is also a potential mechanism for contributing to the phenotypic plasticity (and hence the virulence) of the organism. Molecular genotyping methods such as multi-locus sequence typing (MLST) are generating data that can shed light on this question. In the present study we have used MLST information to generate haplotypes that identify many different homologues of a chromosome within a collection of strains. Particular combinations of these haplotypes provide evidence for chromosomal segregation and intra-chromosome recombination. All of our observations of haplotype diversity could also be explained by other mechanisms, such as gene conversion or mitotic recombination, and the resolution of these issues will require a denser map of accurately localised markers. A common event observed in strain evolution is loss of heterozygosity at a particular marker. Our results contribute to the emerging picture of C. albicans as an organism whose primary means of reproduction is clonal, but with a small but important contribution from sexual reproduction, occurring in nature but not under commonly used laboratory conditions.

Alleles↗
PubMed1997

Dependence of the adaptive immune response on innate immunity: some questions answered but new paradoxes emerge.

Recently a new model of vertebrate immunity has been gaining popularity. In this new model it is hypothesized that activation of innate immunity is a prerequisite for an adaptive immune response to an antigen. Following activation the innate system induces key costimulator molecules on APC, which are essential for antigen-driven clonal expansion of T and B cells. The model largely explains the need for adjuvants in the induction of adaptive immunity, provides a possible mechanism for the immune system to perceive the biological nature of a pathogen and thereby produce the most effective immune response, and transfers much of the onus of self-non-self discrimination from the adaptive to the innate immune system. In the present article we highlight two paradoxes raised by the new model. First, by linking adaptive immunity to innate recognition the immune system is unable to take full advantage of the genetic diversity of T and B cell antigen receptors. Thus, the ability of the immune system to combat a pathogen is totally dependent on the efficiency of recognition by the innate system and, therefore, the germ-line mutation rate of the genes involved in the innate response. Second, if signals from the innate system induce costimulatory molecules on APC, then one would expect the accidental clonal expansion of many autoreactive T and B cells. We suggest that one means of resolving the first paradox is to propose that the major reason for the evolution of adaptive immunity was to provide, via immunological memory, resistance to reinfection, rather than simply to combat the primary infection by the pathogen. In the case of autoreactivity we suggest that autodestruction is prevented by immune responses being tightly regulated at the effector T cell level. Finally, we argue that the two paradoxes, rather than undermining the new model of immunity, highlight our lack of understanding of key elements of the vertebrate immune system.

Adaptation, Physiological↗
PubMed1991

DNA Fingerprinting with a Dispersed Repeated Sequence Resolves Pathotype Diversity in the Rice Blast Fungus.

The poor definition of pathotype variation in the rice blast fungus has historically handicapped strategies for reducing blast disease damage to the world's rice crop. We have employed a probe for a dispersed repeated DNA sequence called MGR [Hamer et al. (1989). Proc. Natl. Acad. Sci. USA 86, 9981-9985] to construct genotype-specific, EcoRl restriction fragment length profiles (MGR-DNA fingerprints) from United States field isolates of this fungus. By using a blind-test design, we demonstrated that MGR-DNA fingerprints distinguished the major pathotypes in the United States, accurately identified the pathotypes of isolates collected over a 30-year period, and defined the organization of clonal lineages within and among pathotype groups. These results resolved a lingering controversy regarding rice blast pathotype stability and illustrated new opportunities for tracking the population dynamics and evolution of this important crop pathogen.

Journal Article↗