[Somatic Darwinism "in vivo"].
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Animals↗
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Xist RNA is associated with the transcriptionally inactive XY body in mammalian male meiosis.
In eutherian mammals, X inactive-specific transcripts (Xist) are expressed in somatic cells possessing more than one X chromosome, and in germline cells of males, in which the single X chromosome is transcriptionally inactive. In early meiosis of males the sex chromosomes form an inactive XY nuclear compartment (XY body). We show by in situ reverse-transcribed polymerase chain reaction that Xist RNA is concentrated in the XY body. This fine localization suggests that Xist RNA is involved in inactivation of the male X chromosome, and that it has spreading capability, not only in cis but also in a quasi-cis mode, to juxtaposed non-X chromosomes. A hypothetical scheme links the evolution of heteromorphic sex chromosomes to the development of X condensation/inactivation in the male. The mechanism of X inactivation in somatic cells of mammalian females, resulting in male/female dosage compensation, has been recruited from the Xist-activated chromosome condensation machinery that developed in male meiosis earlier in evolution.
Animals↗
The evolution of ageing and longevity.
Ageing is not adaptive since it reduces reproductive potential, and the argument that it evolved to provide offspring with living space is hard to sustain for most species. An alternative theory is based on the recognition that the force of natural selection declines with age, since in most environments individuals die from predation, disease or starvation. Ageing could therefore be the combined result of late-expressed deleterious genes which are beyond the reach of effective negative selection. However, this argument is circular, since the concept of 'late expression' itself implies the prior existence of adult age-related physiological processes. Organisms that do not age are essentially in a steady state in which chronologically young and old individuals are physiologically the same. In this situation the synthesis of macromolecules must be sufficiently accurate to prevent error feedback and the development of lethal 'error catastrophes'. This involves the expenditure of energy, which is required for both kinetic proof-reading and other accuracy promoting devices. It may be selectively advantageous for higher organisms to adopt an energy saving strategy of reduced accuracy in somatic cells to accelerate development and reproduction, but the consequence will be eventual deterioration and death. This 'disposable soma' theory of the evolution of ageing also proposes that a high level of accuracy is maintained in immortal germ line cells, or alternatively, that any defective germ cells are eliminated. The evolution of an increase in longevity in mammals may be due to a concomitant reduction in the rates of growth and reproduction and an increase in the accuracy of synthesis of macromolecules. The theory can be tested by measuring accuracy in germ line and somatic cells and also by comparing somatic cells from mammals with different longevities.
Adaptation, Biological↗
Evolution of amitosis of the ciliate macronucleus: gain of the capacity to divide.
Ciliates exhibit nuclear dimorphism, i.e. they have a germline micronucleus and a somatic macronucleus. Macronuclei are differentiated from mitotic sisters of micronuclei. The macronuclei of "higher ciliates" are polyploid and divide acentromerically ("amitotically"); they differentiate once per life cycle. By contrast, Karyorelict (KR) ciliate macronuclei are nearly diploid and cannot divide; they must differentiate at every cell cycle. Diverse lines of evidence are presented to support the hypothesis that ancestral ciliate macronuclei were incapable of division (as in living karyorelict ciliates) and that higher ciliates gained, perhaps independently more than once, the ability to divide the macronucleus. Selective pressures that could have driven the evolution and macronuclear division and two plausible step-wise pathways for the evolution of macronuclear division are proposed. These hypotheses are relevant to our understanding of amitosis mechanisms, evolution of nuclear dimorphism, and phylogenetic classification of ciliates.
Animals↗
DNA sequence, genomic organization, and chromosomal localization of the mouse peripheral myelin protein zero gene: identification of polymorphic alleles.
We have cloned and characterized the mouse gene, P0, that encodes the predominant protein of peripheral myelin. Similar to the rat gene, the mouse P0 gene is encoded by six exons that span about 7 kb of DNA. The DNA sequence of the mouse gene is highly homologous with the rat gene, including the regions believed to be important in transcriptional control. Furthermore, the P0 protein appears well conserved throughout evolution. The gene was mapped to mouse chromosome 1 by Southern analysis of a Chinese hamster x mouse somatic cell hybrid panel. Several polymorphic restriction enzyme sites were identified within the P0 locus. Recombinant inbred strain mapping has linked the P0 gene to Ly-9/Ly/Sap in a region corresponding to band 1H3.
Alleles↗
The dual biological identity of human beings and the naturalization of morality.
The last two centuries have been the centuries of the discovery of the cell evolution: in the XIX century of the germinal cells and in the XX century of two groups of somatic cells, namely those of the brain-mind and of the immune systems. Since most cells do not behave in this way, the evolutionary character of the brain-mind and of the immune systems renders human beings formed by t wo different groups of somatic cells, one with a deterministic and another with an indeterministic (say Darwinian) behavior. An inherent consequence is that of the generation, during ontogenesis, of a dual biological identity. The concept of the dual biological identity may be used to explain the Kantian concept of the two metaphysical worlds, namely of the causal necessity and of the free will (Azzone, 2001). Two concepts, namely those of complex adaptive systems (CAS) and of emergence (Holland, 2002), are useful tools for understanding the mechanisms of adaptation and of evolution. The concept of complex adaptive systems indicates that living organisms contain series of stratified components, denoted as building blocks, forming stratified layers of increasing complexity. The concept of emergence implies the use of repeating patterns and of building blocks for the generation of structures of increasing levels of complexity, structures capable of exchanging communications both in the top-down and in the bottom-up direction. Against the concept of emergence it has been argued that nothing can produce something which is really new and endowed of causal efficacy. The defence of the concept of emergence is based on two arguments. The first is the interpretation of the variation-selection mechanism as a process of generation of information and of optimization of free energy dissipation in accord with the second principle of thermodynamics. The second is the objective evidence of the cosmological evolution from the Big Bang to the human mind and its products. Darwin has defended the concept of the continuity of evolution. However evolution should be considered as continuous when there is no increase of information and as discontinuous when there is generation of new information. Examples of such generation of information are the acquisition of the innate structures for language and the transition from absence to presence of morality. There are several discontinuity thresholds during both phylogenesis and ontogenesis. Morality is a relational property dependent on the interactions of human beings with the environment. Piaget and Kohlberg have shown that the generation of morality during childhood occurs through several stages and is accompanied by reorganization of the child mental organization. The children respect the conventions in the first stage and gradually generate their autonomous morality. The transition from absence to presence of morality, a major adaptive process, then, not only has occurred during phylogenesis but it occurs again in every human being during ontogenesis. The religious faith does not provide a logical justification of the moral rules (Ayala, 1987) but rather a psychological and anthropological justification of two fundamental needs of human beings: that of rendering Nature an understandable entity, and that of increasing the cooperation among members of the human societies. The positive effects of the altruistic genes in the animal societies are in accord with the positive effects of morality for the survival and development of the human societies.
Adaptation, Biological↗
Chronic daily headache: risk factors and pathogenetic considerations.
Chronic daily headache (CDH) is a major clinical concern, although it is still plagued by difficulties with classification and definitions. CDH usually evolves from an episodic headache, mainly migraine. Drug overuse and other somatic or psychological traits are considered risk factors for CDH. The neurobiology underlying this clinical evolution is incompletely understood. There is evidence of a progressive dysfunction of central pain systems in some individuals probably genetically predisposed.
Chronic Disease↗
Evidence suggesting an evolutionary relationship between transposable elements and immune system recombination sequences.
Sequence similarity between the termini of invertebrate Tcl-like transposable sequences and the signal sequences of the vertebrate immunoglobulin somatic recombination pathway is described. These similarities suggest that the Tcl transposition pathway may share common sequence-specific binding factors with the immunoglobulin somatic recombination pathway.
Animals↗
Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification.
Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5(+) B lymphocyte that is thought not to undergo intraclonal diversification. Using V(H)DJ(H) cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1-35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their V(H)DJ(H) genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone.
Antibody Diversity↗
A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal.
Germ-line stem cells (GSCs) serve as the source for gametogenesis in diverse organisms. We cloned and characterized the Drosophila piwi gene and showed that it is required for the asymmetric division of GSCs to produce and maintain a daughter GSC but is not essential for the further differentiation of the committed daughter cell. Genetic mosaic and RNA in situ analyses suggest that piwi expression in adjacent somatic cells regulates GSC division. piwi encodes a highly basic novel protein, well conserved during evolution. We isolated piwi homologs in Caenorhabditis elegans and humans and also identified Arabidopsis piwi-like genes known to be required for meristem cell maintenance. Decreasing C. elegans piwi expression reduces the proliferation of GSC-equivalent cells. Thus, piwi represents a novel class of genes required for GSC division in diverse organisms.
Amino Acid Sequence↗
Immunocytogenetics. IV. Human autoantibodies to heterochromatin-associated proteins.
We report here a novel class of human autoantibodies with immunological affinity for constitutive heterochromatin. Indirect immunofluorescence localized different proteinaceous antigens to the AT-rich paracentromeric heterochromatin of mouse chromosomes, the GC-rich heterochromatic regions of sheep chromosomes, and the large C-banded regions of human chromosomes 1, 9, and 16. Minor amounts of the heterochromatin-associated proteins were uniformly distributed on the chromosomes of all vertebrate species. Their antigenic determinants have been highly conserved during evolution. The chromosomal distribution of the heterochromatin-associated antigens is not altered in interspecific somatic cell hybrids but apparently reflects a stable structural property germane to each chromosome type. The antigenic proteins remain bound to their respective epitopes throughout the entire cell cycle and in meiosis. The heterochromatin-associated antigens represent a major nonhistone component of the mitotic chromosome scaffold and the interphase nuclear matrix. Immunoblotting performed with a human autoimmune serum to mouse heterochromatin revealed a characteristic pattern of polypeptides with molecular weights ranging from 35 to 120 kDal. Drugs that interfere in vivo with the higher-order chromatin structure had no effect on the expression and chromosomal distribution of the heterochromatin-associated antigens. However, the antibody binding sites in chromatin can be completely masked by treating fixed cell preparations with certain DNA-binding ligands.
Animals↗
Recombinant antibodies: a novel approach to cancer diagnosis and therapy.
Recombinant antibodies and their fragments currently represent over 30% of all biological proteins undergoing clinical trials for diagnosis and therapy. These reagents dominate the cancer-targeting field, as highlighted by the recent approval of the first engineered therapeutic antibodies by the Food and Drugs Administration (FDA). Last year, important advances have been made in the design, selection and production of recombinant antibodies. The natural immune repertoire and somatic cell affinity maturation has been superseded by large antibody display libraries and rapid molecular evolution strategies. These novel libraries and selection methods have enabled the rapid isolation of high-affinity cancer targeting and antiviral antibodies, the latter capable of redirecting viruses for gene therapy applications. In alternative strategies for cancer diagnosis and therapy, recombinant antibody fragments have been fused to radioisotopes, drugs, toxins, enzymes and biosensor surfaces. Antibody-directed cancer pre-targeting followed by prodrug activation (ADEPT) has proved a most promising therapeutic strategy. Multi-specific antibodies have been effective for cytotoxic T-cell recruitment and antibody-fusion proteins have delivered enhanced immunotherapeutic and vaccination strategies. The new millennium is indeed an exciting time for the design, selection and formulation of a range of new antibody-based products for cancer diagnosis and therapy.
Animals↗
Ecology and the Evolution of Biphasic Life Cycles.
Sexual eukaryotes undergo an alternation between haploid and diploid nuclear phases. In some organisms, both the haploid and diploid phases undergo somatic development and exist as independent entities. Despite recent attention, the mechanisms by which such biphasic life cycles evolve and persist remain obscure. One explanation that has received little theoretical attention is that haploid-diploid organisms may exploit their environments more efficiently through niche differentiation of the two ploidy phases. Even in isomorphic species, in which adults are morphologically similar, slight differences in the adult phase or among juveniles may play an important ecological role and help maintain haploid-diploidy. We develop a genetic model for the evolution of life cycles that incorporates density-dependent growth. We find that ecological differences between haploid and diploid phases can lead to the evolution and maintenance of biphasic life cycles under a broad range of conditions. Parameter estimates derived from demographic data on a population of Gracilaria gracilis, a haploid-diploid red alga with an isomorphic alternation of generations, are used to demonstrate that an ecological explanation for haploid-diploidy is plausible even when there are only slight morphological differences among adults.
Gracilaria↗
Structure of the human phosphoglycerate kinase gene and the intron-mediated evolution and dispersal of the nucleotide-binding domain.
The human X-linked phosphoglycerate kinase (PGK) gene, which is expressed in all somatic cells, was cloned and its structure was determined. The gene is interrupted by 10 introns and spans 23 kilobases. When projected on the three-dimensional structure of the PGK protein molecule, splice junctions are located between established peptide domains. In particular, an intron separates the two mononucleotide subdomains of the ATP-binding region, and additional introns divide each of these subdomains between their characteristic beta-strands. Similar correlations are found in the bipartite NAD-binding domains of alcohol dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. Furthermore, in each case the nucleotide-binding domain is separated from the catalytic domain by at least one intron. The homology of the exon organization in structurally similar regions of these three enzymes suggests that a nucleotide-binding domain evolved by gene duplication and was subsequently dispersed to different proteins through a process of intron-mediated recombination.
Amino Acid Sequence↗
Genomic homogeneity in fibrolamellar carcinomas.
BACKGROUND: Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC) with distinctive clinical and histological features. To date there have been few studies on the genotypic aspects of FLC and no previous attempts have been made to use the arbitrarily primed-polymerase chain reaction (AP-PCR) technique to detect genetic alterations in this disease. AIM: The aim of this study was to assess the degree of genomic heterogeneity of FLC using the AP-PCR technique. METHODS: A total of 50 tissue samples of primary and metastatic FLCs from seven patients were microdissected. AP-PCR amplification of each genomic DNA sample was carried out using two arbitrary primers. RESULTS: DNA fingerprints of the primary FLCs and all their metastatic lesions (both synchronous and metachronous disease) were identical in an individual patient. The fingerprints were different between tumours of different patients. No evidence of intratumour heterogeneity was observed. CONCLUSIONS: Such genomic homogeneity in FLCs may explain their indolent growth. The absence of clonal evolution, which is present in other tumours (particularly HCCs), may explain the distinct behaviour in this tumour. The tumorigenic pathway and degree of somatic genomic changes in this disease may be less complex than in HCC.
Carcinoma, Hepatocellular↗
Organization of rDNA spacer fragment variants among human acrocentric chromosomes in somatic cell hybrids.
Although the human rDNA gene family is organized in clusters of tandem repeats on five pairs of acrocentric chromosomes, all rDNA genes have undergone a "concerted" evolution resulting in a homogeneous population of genes. Two steps are necessary for a variant to spread to all rDNA genes: dissemination of the variant to all genes in a cluster; and exchange of rDNA genes between nonhomologous chromosomes. To study the organization of rDNA genes, a restriction fragment length polymorphism in the spacer region adjacent to the 28S gene was examined in somatic cell hybrids in which individual human acrocentric chromosomes could be isolated. Human DNA cut with BamHI and analyzed by Southern hybridization yields two to four major bands that hybridize to a 32P-labeled cloned fragment of the 28S gene. Hybrids containing single human acrocentric chromosomes do not recapitulate the parental patterns, but frequently have only one of the parental bands. The data suggest that the quantitative distribution of spacer length variants differs among the human acrocentric chromosomes in hybrids. The frequently observed homogeneity of the rDNA variants on individual acrocentric chromosomes in hybrid cells may reflect the individual rDNA clusters in the parental cell or may be a result of unequal crossing over in the hybrid cell.
Animals↗
Stroke-in-evolution: infarct-inherent mechanisms versus systemic causes.
BACKGROUND: It is uncertain whether deterioration after acute ischemic stroke is neurological and/or systemic (somatic) in origin. METHODS: 442 consecutive patients admitted with first-ever ischemic stroke (FIS) were assessed by the Unified Neurological Stroke Scale (UNSS) at admission, on hospitalization days 1, 2 and 3 and before discharge. RESULTS: Among 71/442 (16.1%) patients deteriorated during hospitalization, the worsening from stroke onset was early (<or=72 h) in 67 (94.4%) of them. The majority (57/71, 80.3%) had CT-confirmed cerebral causes and 14/71 (19.7%) had systemic causes. The causes of late deterioration were exclusively systemic. In the logistic regression analysis the initial mean UNSS score was the only significant independent predictor of stroke deterioration (p < 0.0001). CONCLUSIONS: Early clinical deterioration in FIS patients results from infarct-inherent mechanisms while late stroke deterioration is due primarily to systemic factors. An initially severe neurological deficit might predict further decline.
Aged↗
The structure and complete nucleotide sequence of the human cyclophilin 40 (PPID) gene.
Cyclophilin 40 is a recently identified member of the cyclophilin family that is found in an unactivated steroid hormone receptor complex. Cyclophilin 40 possesses a region homologous to FKBP59, a member of the FK506-binding protein family that is also a component of the receptor complex. We report the isolation and sequencing of the entire human cyclophilin 40 (hCyP40) gene (human gene symbol PPID). The gene contains 10 exons (43 to 698 bp) and 9 introns encompassing 14.2 kb. The exon organization of the cyclophilin-like region is not similar to that of the human cyclophilin A gene (PPIA), suggesting their early divergence in evolution. Determination of the sequence of the 5' end of the hCyP40 mRNA by an "anchor-ligation PCR" procedure showed that transcription is initiated from a cluster of sites about 80 bp upstream from the first in-frame ATG. The immediate 5'-flanking region of the gene lacks typical TATA and CAAT boxes, but is GC-rich and contains Sp1 sites, features characteristic of promoters associated with housekeeping genes. The hCyP40 gene was mapped to chromosome 4 by PCR with genomic DNA from somatic cell hybrids. As shown by "Zoo blot" analysis, the cyclophilin 40 gene appears to be highly conserved throughout evolution.
Amino Acid Isomerases↗