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PubMed2006

Cancer phenomics: RET and PTEN as illustrative models.

Cancer phenomics, the systematic acquisition and objective documentation of host and/or somatic cancer phenotypic data at many levels, is a young field compared with other molecular-based 'omics'. Two relatively advanced phenomic paradigms are associated with phosphatase and tensin homologue (PTEN) and rearranged during transfection (RET), genes that are associated with cancer predisposition syndromes in addition to developmental disorders. The phenomic characterization of PTEN and RET underscores the importance of incorporating robust phenomics into the host 'omic' profile, and shows that the evolution of phenomics will be crucial to the advancement of personalized medicine.

Evolution, Molecular↗
PubMed1990

Genotypic variation within asexual lineages of Taraxacum officinale.

Restriction site variation in DNA that encodes rRNA (rDNA) was surveyed among 714 offspring within 31 lineages (26 genotypes) of obligate asexually reproducing Taraxacum officinale (dandelions). Although clonal offspring are expected, plants with nonparental rDNA were produced from two parents that were themselves siblings (same genotype). The variation is best characterized by the loss of an EcoRI restriction site that maps to the spacer region in the parental rDNA and is most likely involved in amplification of rare or unique rDNA repeats. In one family, 41 surveyed offspring lacked the EcoRI site. In the other family, only 1 of 26 offspring lost the EcoRI site. Other classes of DNA surveyed, chloroplast DNA and the alcohol dehydrogenase 2 gene (Adh2), showed no variation. However, offspring with nonparental rDNA also had nonparental alcohol dehydrogenase 1 (Adh1) restriction fragments. Because somatic mutations in plants can be incorporated into reproductive tissue, we propose that somatic events affecting at least both multicopy rDNA and DNA homologous to the maize Adh1 gene occurred at different developmental times in the two families. An event early in development would result in all variant offspring; an event late in development would result in a single variant offspring. These results support the view that mutation (in the broad sense) influences the level of genotypic variation in asexual organisms, which may facilitate adaptive evolution of asexual species.

Alcohol Dehydrogenase↗
PubMed2000

Rearrangement of immunoglobulin genes in shark germ cells.

The variable (V), (diversity [D]), and joining (J) region recombinases (recombination activating genes [RAGs]) can perform like transposases and are thought to have initiated development of the adaptive immune system in early vertebrates by splitting archaic V genes with transposable elements. In cartilaginous fishes, the immunoglobulin (Ig) light chain genes are organized as multiple VJ-constant (C) clusters; some loci are capable of rearrangement while others contain fused VJ. The latter may be key to understanding the evolutionary role of RAG. Are they relics of the archaic genes, or are they results of rearrangement in germ cells? Our data suggest that some fused VJ genes are not only recently rearranged, but also resulted from RAG-like activity involving hairpin intermediates. Expression studies show that these, like some other germline-joined Ig sequences, are expressed at significant levels only early in ontogeny. We suggest that a rejoined Ig gene may not merely be a sequence restricting antibody diversity, but is potentially a novel receptor no longer tied to somatic RAG expression and rearrangement. From the combined data, we arrived at the unexpected conclusion that, in some vertebrates, RAG is still an active force in changing the genome.

Amino Acid Sequence↗
PubMed1980

The basic uniformity in structure of the neocortex.

The number of neuronal cell bodies has been counted in a narrow strip (30 micrometers) through the depth of the neocortex in several different functional areas (motor, somatic sensory, area 17, frontal, parietal and temporal and in many species (mouse, rat, cat, monkey and man). With the exception of area 17 of the visual cortex in a number of primates the same absolute number (congruent to 110) of neurons has been found in all areas and in all species. In the binocular part of area 17 of the primates there are approximately 2.5 times more neurons. Thus in mammalian evolution the area of the neocortex increases in larger brains but the number of neurons through the depth remains constant, except in area 17 of primates. From these and other findings it is suggested that the intrinsic structure of the neocortex is basically more uniform than has been thought and that differences in cytoarchitecture and function reflect differences in connections.

Adult↗
PubMed1976

The evolution of the cooperative group.

A simple model, illustrating the transition from a population of free swimming, solitary cells (Chlamydomonas-type) to one consisting of small colonies (Gonium-type) serves as a basis to discuss the evolution of the cooperative group. The transition is the result of a mutation of the dynamics of cell division, delayed cell separation leads to colonies of four cells. With this mutation cooperative features appear, such as synchronised cell divisions within colonies and coordinated flagellar function which enables the colony to swim in definite directions. The selective advantages under given, environmental conditions are defined and the periods necessary for complete allelic replacement in small populations are calculated for asexual and sexual reproduction. The assumption of a steady-state population during allelic substitution is critically considered, particularly under conditions of competition. It is shown that density-dependent population control must operate in the process of selection, Sexual reproduction slows down the rate of selection even though all cells are haploid. This phenomenon can be explained in general terms of "organizational dominance', where individual units coordinate the function of their neighbours which may be of a different allelotype. Cooperativity is pointed out as an a priori systemic feature which resides in the sub-units of systems, group formation and coordination appears thus as an almost inevitable event. A particular type of system described as 'closed cycle of positive fitness interaction' is discussed in more detail. It has the remarkable feature that its members cannot compete with each other; selection takes place between whole cycles (in analogy to Eigen's 1971 model). Gonium has a wide spectrum of 'somatic plasticity' which enables it to assume various colonial configurations depending on physiological and environmental conditions. This feature can be explained as the result of dynamic flexibilities on the macro-molecular level. The particular relationship between the vast, molecular complexity and the relative simple dynamics of the cell cycle must lead eventually to the genetic fixation of an environmentally induced phenotype.

Animals↗
PubMedDate not supplied

[The evolution of the clinical course of infectious endocarditis].

As many as 188 records of IE patients were studied as were 67 autopsies of deceased persons. Significant changes in the clinical course of IE were disclosed over the past 10-15 years versus previous 15: more prominent role of staphylococcal and gram-negative flora in the etiology of the illness, with microbial associations-caused IE cases having become more common. Diagnostic value of hemoculture did not appear to show much promise. The following items were found to be important risk factors for IE: prior viral and bacterial infection, invasive interventions, and chronic somatic diseases. There prevailed those IE forms having appeared on the intact heart valves in elderly persons and those at a mature age. In the course of the illness there tended to be more toxic and allergic manifestations, thromboembolic complications, and extensive vascular pathology.

Adolescent↗
PubMed2001

Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma.

In this study, we analyzed the targeting of the somatic hypermutation (SHM) mechanism at specific hotspot sequence motifs in the V(H) and Vkappa genes of 10 follicular lymphoma (FL) cases and the Vkappa and Vlambda genes of 11 kappa- and six lamda-light chain expressing multiple myeloma (MM) cases. These sequences were analyzed for targeting of specific motifs, ie certain highly mutable trinucleotides (3-NTPs), the tetranucleotide (4-NTP) RGYW and its complementary, WRCY (where R = purine, Y = pyrimidine and W = A or T). Comparisons were carried out between mutation frequencies in RGYW vs WRCY and the incidence of mutations in complementarity determining region (CDR)-1 vs CDR2 vs CDR3. Statistically significant differences were obtained when comparing: (1) the ratio of mutations in 4-NTPs (RGYW, WRCY, RGYW+WRCY)/mutations in the whole V sequence in MM-Vkappa vs MM-Vlamda; (2) the total number of mutated 4-NTPs in MM-Vkappa vs FL-Vkappa; (3) the number of mutated RGYW 4-NTPs in MM-Vkappa vs FL-Vkappa and FL-V(H) vs FL-Vkappa; (4) the number of mutated WRCY 4-NTPs in MM-Vkappa vs FL-Vkappa (P= 0.006) and FL-V(H) vs FL-Vkappa; (5) the targeting of RGYW vs WRCY in the CDRs of FL-V(H) genes. Similar results (regarding statistical significance) were obtained when undertaking intergroup comparisons for 3-NTPs. These findings conform well with relevant data derived from normal peripheral B cells. The differences observed in favor of 4-NTP (RGYW and WRCY) targeting in FL-V(H) vs FL-Vkappa and MM-Vkappa vs FL-Vkappa may implicate differences in the evolution of SHM coupled with selection in different stages of B cell ontogeny. Several explanations can be offered for the fact that hotspot sequences were not always targeted by SHM in FL and MM: (1) other unrecognized motifs may be targets of SHM; (2) 'inappropriately' introduced mutations were fixed and propagated by the neoplastic process; (3) certain FL and MM cases might have lost their ability to correct mutations introduced in classic hotspots due to deficient mismatch-repair (MMR) mechanisms; conversely, in other cases with intact MMR function, the hotspot to non-hotspot targeting of somatic hypermutation is balanced.

Base Sequence↗
PubMed2005

Unequal segregation of parental chromosomes in embryonic stem cell hybrids.

Chromosome segregation was studied in 14 intra- and 20 inter-specific hybrid clones generated by fusion of Mus musculus embryonic stem (ES) cells with fibroblasts or splenocytes of DD/c mice or Mus caroli. As a control for in vitro evolution of tetraploid karyotype we used a set of hybrid clones obtained by fusion of ES cells (D3) with ES cells (TgTP6.3). Identification of the parental chromosomes in the clones was performed by microsatellite analysis and in situ hybridization with labeled species-specific probes. Both analyses have revealed three types of clones: (i) stable tetraploid, observed only for ES x ES cell hybrids; (ii) bilateral loss of chromosomes of both ES and somatic partners; (iii) unilateral segregation of chromosomes of the somatic partner. Observed unilateral segregation was extensive in ES-splenocyte cell hybrids, but lower in ES-fibroblast hybrid clones. Developmental state of the somatic partner is presumably responsible for directional chromosome loss. Nonrandom segregation implies that initial differences in the parental homologous chromosomes were not immediately equalized implying at least transient persistence of the differentiated epigenotype.

Animals↗
PubMed2002

Group counseling psychotherapy for patients with functional gastrointestinal disorders: development of new measures for symptom severity and quality of life.

Functional gastrointestinal disorders (FGID) can benefit from various psychological interventions. The main objective here was to define the contribution of a new psychotherapeutic intervention, group counseling psychotherapy, for the management of FGID patients. Secondary aims included validation of new measures for gastrointestinal symptoms and quality of life in patients with FGID. Fifty patients seen in a tertiary care center were included in a program of 10 weekly sessions of 2 hr each. Gastrointestinal symptoms, quality of life, and psychological conditions were measured before and after treatment by quantitative indices and by qualitative self-analysis. Gastrointestinal index and quality-of-life index were significantly (P < 0.02) improved at the end of the psychotherapeutic intervention (from 77.5 +/- 4.0 to 63.2 +/- 4.3 and from 67.7 +/- 3.9 to 54.9 +/- 3.9, respectively). In a control group of patients observed for a comparable period of time while waiting for the psychotherapy program, gastrointestinal and quality of life indices remained unchanged. The severity of gastrointestinal symptoms and the quality of life deterioration were highly correlated factors (r = 0.8) at entry into the trial, and their improvement with psychotherapy was also correlated (r = 0.6; P < 0.001). Psychological abnormalities were frequent in these patients (anxiety in 31%, somatization in 29%, depression in 26% of the patients). However, no specific disorder could predict the results of the psychotherapeutic intervention. Over the long term (6-24 months after conclusion of treatment), gastrointestinal status, quality of life, and psychological condition were estimated as improved by 53%, 63%, and 67% of the patients, respectively. The gastrointestinal index and quality of life index we developed were validated to detect the disease and to follow its evolution in response to treatment. In conclusion, group counseling psychotherapy offered a significant contribution for the management, improving gastrointestinal symptoms and quality of life, of FGID patients. New measures for symptom severity and quality of life are available.

Adult↗
PubMed2025

Germline-restricted chromosome of songbirds has different centromere compared to regular chromosomes.

Centromeres are an important part of chromosomes which direct chromosome segregation during cell division. Their modifications can therefore explain the unusual mitotic and meiotic behaviour of certain chromosomes, such as the germline-restricted chromosome (GRC) of songbirds. This chromosome is eliminated from somatic cells during early embryogenesis and later also from male germ cells during spermatogenesis. Although the mechanism of elimination is not yet known, it is possible that it involves a modification of the centromeric sequence on the GRC, resulting in problems with the attachment of this chromosome to the mitotic or meiotic spindle and its lagging during anaphase, which eventually leads to its elimination from the nucleus. However, the repetitive nature and rapid evolution of centromeres make their identification and comparative analysis across species and chromosomes challenging. Here, we used a combination of cytogenetic and genomic approaches to identify the centromeric sequences of two closely related songbird species, the common nightingale (Luscinia megarhynchos) and the thrush nightingale (L. luscinia). We found a 436-bp satellite repeat present in the centromeric regions of all regular chromosomes (i.e., autosomes and sex chromosomes), making it a strong candidate for the centromeric repeat. This centromeric repeat was highly similar between the two nightingale species. Interestingly, hybridization of the probe to this satellite repeat on meiotic spreads suggested that this repeat is missing on the GRC. Our results indicate that the change of the centromeric sequence may underlie the unusual inheritance and programmed DNA elimination of the GRC in songbirds.

Animals↗
PubMed2001

Detection of mitochondrial DNA mutations in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear DNA mutations.

We sequenced the complete 16.5-kb mitochondrial genome (mtDNA) in 15 pancreatic cancer cell lines and xenografts. Homoplasmic mtDNA somatic mutations and novel variants were identified in nearly all samples. Southern blot analysis and direct sequencing of mutation sites showed that the intracellular mass of mtDNA was greatly (6-8-fold) increased in pancreatic cancer cells in relation to corresponding normal cells; this property accounted for and greatly facilitated the identification of these mutations among the dense desmoplastic host reaction characteristic of primary pancreatic cancers. Structural characteristics and mathematical modeling of the evolution of mtDNA mutations suggested that many of the mutations identified might represent a random evolution of homoplasmic variants, rather than necessarily being a product of selective pressures. Complete sequencing of the nuclear MnSOD gene, which protects cells from the mitogenic and toxic effects of oxygen radicals, did not reveal any mutations. Nevertheless, the nearly ubiquitous prevalence and high copy number of mtDNA mutations suggest that they be considered of promising clinical utility in diagnostic applications.

Adenocarcinoma↗
PubMed2003

Conservation of IGF2-H19 and IGF2R imprinting in sheep: effects of somatic cell nuclear transfer.

In different mammalian species, in vitro culture and manipulation can lead to aberrant fetal and peri-natal development. It has been postulated that these diverse abnormalities are caused by epigenetic alterations and that these could affect genes that are regulated by genomic imprinting. To explore this hypothesis relative to somatic cell nuclear transfer in sheep, we investigated whether the ovine H19-IGF2 and IGF2R loci are imprinted and analysed their DNA methylation status in cloned lambs. A comparison between parthenogenetic and control concepti established that imprinting at these two growth-related loci is evolutionarily conserved in sheep. As in humans and mice, IGF2R and H19 comprise differentially methylated regions (DMRs) that are methylated on one of the two parental alleles predominantly. In tongue tissue from 12 out of 13 cloned lambs analysed, the DMR in the second intron of IGF2R had strongly reduced levels of DNA methylation. The DMR located upstream of the ovine H19 gene was found to be similarly organised as in humans and mice, with multiple CTCF binding sites. At this DMR, however, aberrant methylation was observed in only one of the cloned lambs. Although the underlying mechanisms remain to be determined, our data indicate that somatic cell nuclear transfer procedures can lead to epigenetic deregulation at imprinted loci.

Alleles↗
PubMed2004

The evolutionary and structural 'logic' of antigen receptor diversity.

Most vertebrate species utilize antibody and T-cell receptor (TCR) genes to create a vast repertoire of antigen sensor molecules on their B and T lymphocytes, respectively. While the organization of these genes exhibits substantial variation between species, one common theme is that, in almost every case, there is at least one variable region with a highly diverse CDR3 region and often much less diversity elsewhere in the binding site. Whereas with alphabeta TCRs this skewing of diversity correlates well with the need to recognize diverse peptides bound to MHC molecules, this cannot explain why this same pattern is evident in immunoglobulins (Igs) or gammadelta TCRs. Instead we have postulated that in the primary repertoire, all or most antigen receptors have a bipartite binding site, in which diverse CDR3 loops act as a highly antigen specific 'core' whereas other CDRs bind in a largely opportunistic fashion. In the case of antibodies, somatic hypermutation then acts to improve the complementarity to a given antigen and increase antibody affinity. A test of this model in mice engineered to have a very limited V region repertoire shows that primary antibodies can be generated that are highly specific for distinct antigens, yet identical in sequence except for their V(H) CDR3. Furthermore, very high affinity antibodies can be raised by repeated immunizations, showing that somatic hypermutation can mold these low affinity antibodies into high affinity ones. Thus, the wide variations seen in V region repertoires amongst vertebrates is likely to be of lesser importance than the preservation of one or more diverse CDR3 regions.

Amino Acid Sequence↗
PubMed1995

Comparative mapping of the imprinted U2afbpL gene on mouse chromosome 11 and human chromosome 5.

The genetic map location of the recently discovered imprinted gene U2afbpL has been verified and refined in several mouse crosses. RI strain analysis had previously shown that the gene is located on mouse chromosome 11. This assignment has been verified using interspecific backcrosses. Moreover, the location of the gene relative to a fixed order of markers in the proximal region of mouse chromosome 11 has been established. The location of the gene on mouse chromosome 11 corresponds to a homologous linkage group that is conserved on human chromosome 5q. The location of the human homologue has been determined using both somatic cell hybrid genetic analysis and fluorescence in situ hybridization. These analyses have mapped the human locus U2AFBPL to human chromosome 5q23-->q31.

Animals↗
PubMed2002

Psychobiological and evolutionary perspectives on coping and health characteristics following loss: a twin study.

An analysis of coping, grief and health characteristics is reported for a bereaved monozygotic (MZ) and dizygotic (DZ) same-sex twin sample. The data were examined with reference to psychobiological and evolutionary perspectives on behavior. A Coping Scale, included as part of a comprehensive Twin Loss Survey (TLS), assessed coping with daily responsibilities and activities 1-2 months before the co-twin's death, 1-2 months following the co-twin's death and currently. A Grief Intensity Scale obtained judgments of grief 1-2 months following the loss, and currently. Information on physical symptoms was available from the Somatization Scale of the Grief Experience Inventory. Psychobiological and evolutionary perspectives specified hypotheses for two twin groups: one model was specified to reflect bereavement experiences immediately following loss of the co-twin (retrospective twin group); a second model represented present bereavement response (current twin group). Consistent with psychobiological theory, twins' social closeness showed a positive association with grief intensity which, in turn, affected somatic symptoms and coping efficacy in predicted directions. With respect to evolutionary psychological theory, the effect of zygosity on current grief implicated correlates of genetic relatedness as factors in the bereavement process.

Activities of Daily Living↗
PubMed2001

Temporal control of DNA replication and the adaptive value of chromatin diminution in copepods.

Chromatin diminution is a precisely controlled, highly repeatable, genome-wide deletion of noncoding heterochromatic segments from the presomatic line. The somatic line is reduced in size and reorganized; the germ line remains unaltered. Little is understood about its mechanistic underpinnings and adaptive significance in the nematodes, copepods, and hagfish in which it occurs. Here, we propose that microcrustacean copepods, whose cytology, development, and evolutionary ecology are well understood from an adaptationist point of view, provide the vehicle to test how chromatin diminution might orchestrate certain cell cycle dynamics, with the consequence of influencing the evolution of nuclear DNA contents, organismal development rates, and body size.

Adaptation, Physiological↗
PubMed2006

Depression in neurological disorders: an update.

PURPOSE OF REVIEW: Depressions are a heterogeneous group of conditions that contribute significantly to impairments in quality of life, independent of the severity of neurological illness. Depression may predate neurological signs and symptoms in the evolution of neurodegenerative disorders, and there is some evidence that depressive illness itself may be a risk factor in the aetiology of some dementias. This review aims to summarize the relevant current literature on diagnosis, aetiology and treatment of depression in neurology. RECENT FINDINGS: Diagnosing depression in neurological conditions can be particularly difficult because of communication difficulties and changes in emotional expression as a result of the underlying neurological disease. Rating scales loaded towards somatic symptoms can show poor validity for screening or rating of severity in this setting. The evidence for the treatment of depression in neurological disease is scant, and often the treatment advice is based on consensus views of clinicians. Nevertheless, there have been some clinical trials, which are reported. SUMMARY: Depression is common in neurology. It is underrecognized and undertreated. Recent research has allowed us to define depression more clearly in this setting. Trials of treatment are urgently needed, especially as depression is a significant factor in quality of life and may affect prognosis.

Brain Injuries↗
PubMed1994

[Epidemiologic approach to the evolution by age and sex of childhood and adolescent depression].

Review of the literature on the epidemiology of depression in children and young adolescents taking into account the age and sex evolution of 1/its frequency, 2) its symptoms, 3) the risk factors and 4) prognostic factors, shows the following: age evolution of depressive conditions (self-perceived depression and clinical disturbances) is different according to sex and type of disturbances. In early adolescence there is an increase in frequency of depressive feelings, specially in girls. Clinical depression also differs according to sex: boys seem to present more severe depressions and at a younger age, more frequently associated with behavior problems and have a worse prognosis. Symptomatic expression of depressive disturbances: 1) differ with age (somatic complaints and relational isolation in younger children, loss of self-esteem in adolescents) and 2) are different according to sex in adolescents (somatic preoccupations in girls, social problems in boys).

Adolescent↗