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PubMed1997

Genetic drift can dominate short-term human immunodeficiency virus type 1 nef quasispecies evolution in vivo.

The evolution of human immunodeficiency virus (HIV) type 1 nef quasispecies in a patient clonally infected with a contaminated batch of blood clotting factor IX was monitored. nef sequences were derived at 11, 25, and 41 months postinfection from infected peripheral blood mononuclear cells after molecular cloning of PCR-amplified proviral DNA. The phylogenetic relationships among a total of 41 informative sequences were established by split decomposition analysis and used as a basis to establish a substitution matrix and to score synonymous (s) and nonsynonymous (ns) substitutions. The number of observed in-phase stop codons within the nef sequences was comparable to that expected on a random basis. Similarly, the numbers of observed s and ns substitutions did not differ significantly from expected values. No codon position was preferentially mutated. The maximum sequence divergence increased in a linear manner, with approximately 4.4 nucleotide and approximately 3.2 amino acid changes per year. It appears that stochastic processes strongly influence short-term HIV nef quasispecies evolution in vivo.

Amino Acid Sequence↗
PubMed2001

Chronic myelogenous leukemia in chronic phase.

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by genomic instability leading to its inevitable clinical evolution from an easily controlled chronic phase to a terminal blastic phase. The molecular abnormality responsible for this disease--BCR-ABL--and the critical biochemical aberrations resulting from it have been studied in depth. These discoveries have led to the development of a molecule, STI571, that specifically inhibits the abnormal kinase enzymatic activity exhibited by BCR-ABL. Early results of clinical trials using STI571 have shown responses even in blast crisis. There has also been striking hematologic and cytogenetic remission rates in patients with advanced chronic phase disease, with very little toxicity. It is our opinion that this molecule will revolutionize the treatment of CML. Furthermore, the path leading to its discovery will become a paradigm for cancer therapeutics. At the time of this writing, STI571 remains investigational (although it is widely believed that it will be approved for clinical use in the United States this year ). Although suggested therapy for a disease does not generally incorporate medications that are still investigational, in this case, the impact of a still investigational agent cannot be ignored. The current data suggest that STI571 will be the treatment of choice for patients with advanced or resistant chronic phase. To date, STI571 has not been studied adequately in untreated CML patients. Even so, it is our feeling that, based on its compelling success in patients with interferon-refractory and advanced disease and on its benign side effect profile, it will quickly become the front-line therapy for CML once it becomes available. Despite the ease of administration of STI571, patients should continue to be encouraged to participate in clinical studies so that several vital issues can be resolved: 1) the percentage of untreated CML patients who will eventually develop molecular remissions; 2) the proportion of patients in whom resistance to STI571 will emerge; 3) the optimum length of treatment; and 4) the impact on survival. Because interferon-alfa can also result in cytogenetic remissions, albeit in a small percent (less than 20%) of early chronic phase patients, it seems reasonable to suggest that patients who do not attain cytogenetic/molecular remissions with STI571 alone be treated with a combination of STI571 and interferon-alfa. Patients who are resistant to STI571 with or without interferon-alfa should undergo allogeneic hematopoietic cell transplant. Salvage therapy after transplant may include donor lymphocyte infusions, interferon-alfa, additional transplant, and perhaps STI571. Medications such as hydroxyurea appear destined to play a very limited role in CML. They may be used in the palliative treatment of older STI571-resistant patients or those without a transplant donor, although these patients may be best served by being considered for clinical trials of molecules, such as polyethylene glycol-interferon-alfa, on other novel agents.

Antineoplastic Agents↗
PubMed1992

Prognostic factors in the myelodysplastic syndromes.

The myelodysplastic syndromes are acquired clonal hematologic malignancies characterized by progressive cytopenia and an increased risk of evolution to acute myeloid leukemia. It mainly affects elderly people, but may also be found in younger patients and children. MDS represents a heterogeneous group of disorders. Some patients will experience prolonged survival, whereas a substantial number of patients will die within the first year after diagnosis. Treatment of patients should be based on life expectancy. Patients with pancytopenia, excess of bone marrow blasts, complex chromosome abnormalities, abnormal chromosome 7, older age and secondary MDS have a poor prognosis. Several simple scoring systems are available, based on peripheral counts, percent of bone marrow blasts and age, that provide significant prognostic information about life expectancy in patients with MDS. The most widely used is the Bournemouth scoring system. The prognostic factors and the scoring systems are reviewed.

Blast Crisis↗
PubMedDate not supplied

Genetic and transcriptional analysis of spindle checkpoint genes in bone marrow failure patients.

The evolution of bone marrow failure syndromes such as aplastic anemia (AA) to clonal hematologic diseases such as myelodysplastic syndrome is well recognized. Cytogenetic abnormalities are commonly seen late events, particularly aneuploidy of chromosomes 7 and 8. A proportion of bone marrow failure patients may also develop aneuploidy that is detectable by fluorescence in situ hybridization but not by standard cytogenetic analysis. The molecular basis for aneuploidy in this setting is currently unknown but may include abnormalities in the mitotic spindle checkpoint. For this reason, we searched for mutations in the mitotic spindle checkpoint genes hBUB1 and hMAD2, and also examined the expression of hBUB1 in cells of bone marrow failure patients. No pathogenic mutations were found in 59 patients. Of 170 bone marrow failure patients, less than one-third expressed hBUB1 transcript. Gene expression profiling confirmed a significant down-regulation of hBUB1 message in patients. We conclude that mutations in mitotic spindle checkpoint genes do not account for aneuploidy in marrow failure states. However, we cannot exclude epigenetic inactivation of hBUB1 as a potential mechanism in some patients.

Aneuploidy↗
PubMed2004

Hypermutable Haemophilus influenzae with mutations in mutS are found in cystic fibrosis sputum.

Hypermutable bacterial pathogens exist at surprisingly high prevalence and benefit bacterial populations by promoting adaptation to selective environments, including resistance to antibiotics. Five hundred Haemophilus influenzae isolates were screened for an increased frequency of mutation to resistance to rifampicin, nalidixic acid and spectinomycin: of the 14 hypermutable isolates identified, 12 were isolated from cystic fibrosis (CF) sputum. Analysis by enterobacterial repetitive intergenic consensus (ERIC)-PCR and ribotyping identified eight distinct genetic fingerprints. The hypermutable phenotype of seven of the eight unique isolates was associated with polymorphisms in conserved sites of mutS. Four of the mutant mutS alleles were cloned and failed to complement the mutator phenotype of a mutS : : TSTE mutant of H. influenzae strain Rd KW20. Antibiotic susceptibility testing of the hypermutators identified one beta-lactamase-negative ampicillin-resistant (BLNAR) isolate with two isolates producing beta-lactamase. Six isolates from the same patient with CF, with the same genetic fingerprint, were clonal by multilocus sequence typing (MLST). In this clone, there was an evolution to higher MIC values for the antibiotics administered to the patient during the period in which the strains were isolated. Hypermutable H. influenzae with mutations in mutS are prevalent, particularly in the CF lung environment, and may be selected for and maintained by antibiotic pressure.

Adenosine Triphosphatases↗
PubMed1975

Incorporation of C-Photosynthate into Protein during Leaf Development in Young Populus Plants.

Gas exchange and protein metabolism were studied in expanding, mature, and near-senescent leaves of young clonal Populus x euramericana cv. Wisconsin-5 plants. Dark respiration, CO(2) evolution in the light, and CO(2) compensation concentrations were highest in unexpanded leaves but declined markedly as leaves matured and aged. Net photosynthesis was highest in nearly mature leaves. Fresh weight continued to increase after leaf expansion was complete, whereas soluble protein levels declined. Changes in the distribution of photosynthetically incorporated (14)C indicated that a high level of protein synthesis and rapid formation of structural components occurred only in expanding leaves. Protein turnover was slight in expanding leaves but was substantial after leaves were mature. Expanding leaves synthesized predominantly fraction I protein (ribulose diphosphate carboxylase). However, formation of this protein from photosynthate was slight once leaves matured.

Journal Article↗
PubMed2001

A community of ants, fungi, and bacteria: a multilateral approach to studying symbiosis.

The ancient and highly evolved mutualism between fungus-growing ants and their fungi is a textbook example of symbiosis. The ants carefully tend the fungus, which serves as their main food source, and traditionally are believed to be so successful at fungal cultivation that they are able to maintain the fungus free of microbial pathogens. This assumption is surprising in light of theories on the evolution of parasitism, especially for those species of ants that have been clonally propagating their cultivars for millions of years. Recent work has established that, as theoretically predicted, the gardens of fungus-growing ants are host to a specialized, virulent, and highly evolved fungal pathogen in the genus Escovopsis. In addition, the ants have evolved a mutualistic association with filamentous bacteria (actinomycetes) that produce antibiotics that suppress the growth of Escovopsis. Thus, the attine symbiosis appears to be a coevolutionary "arms race" between the garden parasite Escovopsis on the one hand and the ant-fungus-actinomycete tripartite mutualism on the other. These recent findings indicate that microbes may be key components in the regulation of other symbiotic associations between higher organisms.

Actinomycetales↗
PubMed2000

Leukemia relapse reconsidered from the molecular aspect.

Relapse, a major obstacle in the treatment of acute leukemia, is essentially caused by re-growth of residual leukemia cells, frequently accompanied by resistance to chemotherapy. Comparative studies of clones both at initial diagnosis and at subsequent relapse have indicated that phenotype and karyotype are frequently changed at relapse. This can be recognized as the result of negative selection by chemotherapy in a heterogeneous population. Furthermore, complex molecular alterations that include the loss of as well as the acquisition of mutations are noticed by comparing multiple genes associated with leukemia, suggesting a continuous genetic evolution. Studies on leukemia relapse have thus served as a model of clonal progression, which can be serially observed, including selection by chemotherapy, induction of resistant phenotype, and genetic alteration.

Antineoplastic Agents↗
PubMed2005

Speciation through competition: a critical review.

We examined causes of speciation in asexual populations in both sympatry and parapatry, providing an alternative explanation for the speciation patterns reported by Dieckmann and Doebeli (1999) and Doebeli and Dieckmann (2003). Both in sympatry and parapatry, they find that speciation occurs relatively easily. We reveal that in the sympatric clonal model, the equilibrium distribution is continuous and the disruptive selection driving evolution of discrete clusters is only transient. Hence, if discrete phenotypes are to remain stable in the sympatric sexual model, there should be some source of nontransient disruptive selection that will drive evolution of assortment. We analyze sexually reproducing populations using the Bulmer's infinitesimal model and show that cost-free assortment alone leads to speciation and disruptive selection only arises when the optimal distribution cannot be matched--in this example, because the phenotypic range is limited. In addition, Doebeli and Dieckmann's analyses assumed a high genetic variance and a high mutation rate. Thus, these theoretical models do not support the conclusion that sympatric speciation is a likely outcome of competition for resources. In their parapatric model (Doebeli and Dieckmann 2003), clustering into distinct phenotypes is driven by edge effects, rather than by frequency-dependent competition.

Biological Evolution↗
PubMed1999

Microevolution, low clonal diversity and genetic affinities of parthenogenetic sitobion aphids in new zealand

In sharp contrast to their southeast Asian and European counterparts, Sitobion miscanthi and S. near fragariae aphids in Australia exhibit a complete absence of sexual reproduction. This demands an explanation within the context of the evolution and maintenance of sex and parthenogenesis. Accordingly, we executed a genetic analysis of the two species in neighbouring New Zealand. Microsatellites and single-stranded conformation polymorphism/sequence analysis of the nuclear gene elongation factor 1alpha were used to identify aphid clones and confirm species identification, respectively. Karyotypic variation was also investigated. The New Zealand fauna showed few (nonrecombining) genotypes and appears to have received migrants from both Australia and Asia. Other genotypes have apparently arisen in situ in New Zealand, exhibiting stepwise mutation of microsatellite alleles and also karyotypic change. Thus, these data represent rare evidence of evolution within wild-living parthenogenetic lineages. Karyotypic changes appear to occur at a rate even greater than that of microsatellite evolution. Strong geographical partitioning of genotypes/karyotypes was found, with certain ones predominating over large areas. These data suggest that clonal selection could be important in the distribution and patterning of genetic variation. We present a model to explain the genetic patterns, with particular reference to the absence of sexual reproduction in Sitobion aphids in New Zealand and Australia.

Journal Article↗
PubMed2006

Evolution: vertebrate reproductive strategies get mixed up.

The mangrove killifish is the only vertebrate known to have a mixed-mating strategy, where hermaphrodites reproduce by either self-fertilisation or cross-breeding. New molecular evidence from this species reveals that occasional cross-breeding between common hermaphroditic individuals and rare pure males results in an injection of genetic variation into otherwise highly homozygous 'clonal' lineages.

Animals↗
PubMed2002

Identifying the transition between single and multiple mating of queens in fungus-growing ants.

Obligate mating of females (queens) with multiple males has evolved only rarely in social Hymenoptera (ants, social bees, social wasps) and for reasons that are fundamentally different from those underlying multiple mating in other animals. The monophyletic tribe of ('attine') fungus-growing ants is known to include evolutionarily derived genera with obligate multiple mating (the Acromyrmex and Atta leafcutter ants) as well as phylogenetically basal genera with exclusively single mating (e.g. Apterostigma, Cyphomyrmex, Myrmicocrypta). All attine genera share the unique characteristic of obligate dependence on symbiotic fungus gardens for food, but the sophistication of this symbiosis differs considerably across genera. The lower attine genera generally have small, short-lived colonies and relatively non-specialized fungal symbionts (capable of living independently of their ant hosts), whereas the four evolutionarily derived higher attine genera have highly specialized, long-term clonal symbionts. In this paper, we investigate whether the transition from single to multiple mating occurred relatively recently in the evolution of the attine ants, in conjunction with the novel herbivorous 'leafcutter' niche acquired by the common ancestor of Acromyrmex and Atta, or earlier, at the transition to rearing specialized long-term clonal fungi in the common ancestor of the larger group of higher attines that also includes the genera Trachymyrmex and Sericomyrmex. We use DNA microsatellite analysis to provide unambiguous evidence for a single, late and abrupt evolutionary transition from exclusively single to obligatory multiple mating. This transition is historically correlated with other evolutionary innovations, including the extensive use of fresh vegetation as substrate for the fungus garden, a massive increase in mature colony size and morphological differentiation of the worker caste.

Animals↗
PubMed1992

Multiple chromosomal changes and karyotypic evolution in a patient with myelofibrosis.

Several subclones were identified in unstimulated peripheral blood cells from a patient with chronic myeloproliferative disease, which was classified as myelofibrosis by morphologic terms. These subclones were characterized by an unusual number of different karyotype anomalies. Some of the more complex chromosomal rearrangements could be clearly defined by fluorescence in situ hybridization. Chromosome arms involved in clonal aberrations were 1q, 3p, 6p, 7q, 11q, 13q, 15q, 17q, 18p, and 20q. Reconstruction of karyotype evolution was attempted by karyotypic analysis of 100 metaphase spreads each in two separate investigations.

Aged↗
PubMed1989

Extreme heterogeneity in populations of vesicular stomatitis virus.

Vesicular stomatitis virus (VSV) sequence evolution and population heterogeneity were examined by T1 oligonucleotide mapping. Individual clones isolated from clonal pools of wild-type Indiana serotype VSV displayed identical T1 maps. This was observed even after one passage at high concentrations of the potent viral mutagen 5-fluorouracil. Under low-multiplicity passage conditions, the consensus T1 fingerprint of this virus remained unchanged after 523 passages. Interestingly, however, individual clones from this population (passage 523) differed significantly from each other and from consensus sequence. When virus population equilibria were disrupted by high-multiplicity passage (in which defective interfering particle interference is maximized) or passage in the presence of mutagenic levels of 5-fluorouracil, rapid consensus sequence evolution occurred and extreme population heterogeneity was observed (with some members of these population differing from others at hundreds of genome positions). A limited sampling of clones at one stage during high-multiplicity passages suggested the presence of at least several distinct master sequences, the related subpopulations of which exhibit at least transient competitive fitness within the total virus population (M. Eigen and C.K. Biebricher, p. 211-245, in E. Domingo, J.J. Holland, P. Ahlquist, ed., RNA Genetics, vol. 3, 1988). These studies further demonstrate the important role of selective pressure in determining the genetic composition of RNA virus populations. This is true under equilibrium conditions in which little consensus sequence evolution is observed owing to stabilizing selection as well as under conditions in which selective pressure is driving rapid RNA virus genome evolution.

Animals↗
PubMed2006

Evolutionary clues from comparative analysis of Mycobacterium tuberculosis variable-number tandem repeat sequences within genetic families.

Mycobacterium tuberculosis is one of the most successful bacterial pathogens in the history of mankind, and the study of the evolutionary and genetic behaviour of this organism is ongoing. The potential of variable-number tandem repeat (VNTR) regions to provide insight into the evolutionary past of this organism has yet to be evaluated. The aim of this study was to investigate diversity occurring within VNTR loci within established evolutionary lineages. Mycobacterial interspersed repetitive unit (MIRU) 4 and 26 nucleotide sequencing was undertaken revealing significant differences in VNTR discriminatory power and distribution of allelic types within defined sub-lineages, within a moderately discriminant and a highly discriminant locus, respectively. These findings indicate potential allele bias at these loci within the defined groups dependent on the genotype of their progenitor strain, and the patterns of distribution suggest that a step-wise contraction/expansion process is responsible for VNTR repeat evolution. The results also identified a possible incidence of genetic drift within major genetic group 2 (MGG2), which has a point mutation at locus MIRU26 in a clonal subgroup.

Amino Acid Sequence↗
PubMed2001

Significant correlation between the breakpoints of rare clonal aberrations in benign solid tumors and the assignment of HMGIY retropseudogenes.

Recently, we described a mechanism by which a retropseudogene, during evolution, becomes an exon of a pre-existing active gene. Similar mechanisms may account for the activation of processed genes by chromosomal rearrangements in neoplasms. Because genes of the high-mobility group protein family HMGI(Y) are known to be involved in the development of a variety of benign solid tumors, it was the aim of the present study to analyze breakpoints of clonal chromosome abnormalities in that group of benign tumors for a possible correlation with retropseudogenes of the HMGIY gene. Whereas the HMGIYL1 retrospeudogene has recently been mapped to Xp22.1, we assigned a further retropseudogene by FISH to 4q13, and database research allowed us to assign a third retropseudogene to 12q24.1. Sequence analyses of these retropseudogenes revealed high-identity indices to the HMGIY gene and no frame-shift divergences. Breakpoint information was obtained from cytogenetic aberrations in uterine leiomyomas, lipomas, pleomorphic adenomas, and pulmonary chondroid hamartomas because, in all of these tumor entities, cytogenetic subgroups involving genes of the HMGI(Y) family exist. Chromosomal bands harboring HMGIY retropseudogenes were affected with a significantly higher frequency than expected under the assumption of purely randomly occurring breakages. These results support our hypothesis that HMGIY-related retropseudogenes can be affected by chromosomal rearrangements in benign human tumors.

Base Sequence↗