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PubMed1998

Increased telomere size in sperm cells of mammals with long terminal (TTAGGG)n arrays.

An increase in the length of telomeres in human sperm compared to somatic cells has long been noted and considered within a popular hypothesis involving telomere shortening and cell aging. In the present study we determined telomere length in two species with long terminal TTAGGG arrays--bovine and porcine. Using several independent methods we demonstrate that the telomeres in the sperm of human, porcine and bovine are elongated by 69%, 24%, and 14%, respectively, in comparison with somatic tissues. Therefore, increased sperm telomere length is a feature preserved throughout mammalian evolution. The biological role of this phenomenon is discussed in the context of telomere functions in meiosis and fertilization.

Animals↗

PubMed1992

Chromosome mapping of the owl monkey CSF1R and IL5 genes.

We mapped the owl monkey colony-stimulating factor 1 receptor (CSF1R) locus to the proximal region of chromosome 3q of karyotype VI(K-VI) and karyotype V(K-V) and the interleukin 5 (IL5) locus to the mid-region of chromosome 3q(K-VI) and 19q(K-IV) using a combination of Southern hybridization of somatic cells and in situ chromosomal hybridization methodologies. The findings support the proposed evolution of owl monkey chromosome 3(K-VI) from a fusion of two smaller structures, the homologs of chromosomes 6 and 19 (K-IV). The data also indicate genomic conservation of the HSA 5q23-q35 segment in the higher primates.

Animals↗

PubMed1999

Apaf1 and the apoptotic machinery.

The molecular characterization of the Caenorhabditis elegans cell death genes has been crucial in revealing some of the biochemical mechanisms underlying apoptosis in all animals. Four C. elegans genes, egl-1, ced-9, ced-4 and ced-3 are required for all somatic programmed cell death to occur. This genetic network is highly conserved during evolution. The pro-death gene egl-1 and the anti-death gene ced-9 have structural and functional similarities to the vertebrate Bcl2 gene family. The killer gene ced-3 encodes a cystein-aspartate protease (caspase), which is the archetype of a family of conserved proteins known as effectors of apoptosis in mammals. Zou and collaborators1 reported the biochemical identification of an apoptotic protease activating factor (Apaf1), a human homolog of C. elegans CED-4, providing important clues to how CED-4 and its potential relatives could work. A number of proteins have been shown to interact with Apaf1 or to be determinant for its activity as an apoptotic adapter. The aim of this review is to provide an overview of the recent progress made in the field of developmental apoptosis by means of the murine Apaf1 targeted mutations. The central role of Apaf1 in the cell death machinery (apoptosome) and its involvement in different apoptotic pathways will also be discussed.

Animals↗

PubMed2005

Exploiting nuclear duality of ciliates to analyse topological requirements for DNA replication and transcription.

Spatial and temporal replication patterns are used to describe higher-order chromatin organisation from nuclei of early metazoan to mammalian cells. Here we demonstrate evolutionary conserved similarities and differences in replication patterns of micronuclei and macronuclei in the spirotrichous ciliate Stylonychia lemnae. Since this organism possesses two kinds of morphologically and functionally different nuclei in one cell, it provides an excellent model system to analyse topological requirements for DNA replication and transcription. Replication in the heterochromatic micronucleus occurs in foci-like structures showing spatial and temporal patterns similar to nuclei of higher eukaryotes, demonstrating that these patterns are inherent features of nuclear architecture. The 'nanochromosomes' of the macronucleus are replicated in the propagating replication band. We show that it consists of hundreds of replication foci. Post-replicative macronuclear chromatin remains organised in foci. These foci are not randomly distributed throughout the macronucleus, indicating a higher-order organisation of macronuclear chromatin above the level of 'nanochromosomes'. Both telomerase and proliferating cell nuclear antigen (PCNA) occur as foci-like structures in the rear zone of the replication band, suggesting that a wave of chromatin modification driven by a short or continuous exogenous signal permits the assembly of replication factories at predicted sites. We further show that transcription occurs at discrete sites colocalised with putative nucleoli and dispersed chromatin. Common principles of functional nuclear architecture were conserved during eukaryotic evolution. Moreover nuclear duality inherent to ciliates with their germline micronucleus and their somatic macronucleus may eventually provide further insight into epigenetic regulation of transcription, replication and nuclear differentiation.

Animals↗

PubMed1996

The role of telomeres and telomerase in human cancer.

Human cancers/malignant transformation of normal cells occur from multiple independent genetic changes/mutations that can subvert the normal growth controls of cells, leading to distinct phenotypic changes and immortalization. Normal human somatic cells have limited proliferative capacity both in vitro and in vivo and undergo senescence. Recent studies have implicated telomeres and telomerase in the regulation of lifespan of cells. Telomeres are the stretches of DNA consisting of tandem repeats of nucleotide sequences that cap chromosomes and prevent its degradation and play a role, both in normal control of cell proliferation and abnormal growth of cancers. They are highly conserved during evolution. Telomerase, the novel reverse transcriptase enzyme that synthesizes telomeric DNA is repressed in most human somatic cells, it results in telomere shortening with each cell division, leading to a process thought to contribute to senescence. Recent research proposes that activation of telomerase is important for cells to proliferate indefinitely and that all human cancer cells require activation of this enzyme to maintain telomeric DNA, to overcome cellular senescence and to attain immortality. Thus telomeres and telomerase offer potential for diagnostics, cancer therapy as well as for understanding the process of aging.

Humans↗

PubMed1996

The immunological evolution of catalysis.

The germline genes used by the mouse to generate the esterolytic antibody 48G7 were cloned and expressed in an effort to increase our understanding of the detailed molecular mechanisms by which the immune system evolves catalytic function. The nine replacement mutations that were fixed during affinity maturation increased affinity for the transition state analogue by a factor of 10(4), primarily the result of a decrease in the dissociation rate of the hapten-antibody complex. There was a corresponding increase in the rate of reaction of antibody with substrate, k(cat)/k(m), from 1.7 x 10(2)M(-1) min(-1) to 1.4 x 10(4)M(-1) min(-1). The three-dimensional crystal structure of the 48G7-transition state analogue complex at 2.0 angstroms resolution indicates that one of the nine residues in which somatic mutations have been fixed directly contact the hapten. Thus, in the case of 48G7, affinity maturation appears to play a conformational role, either in reorganizing the active site geometry of limiting side-chain and backbone flexibility of the germline antibody. The crystal structure and analysis of somatic and directed active site mutants underscore the role of transition state stabilization in the evolution of this catalytic antibody.

Amino Acid Sequence↗

PubMedDate not supplied

The origin of the cancer cell: oncogeny reverses phylogeny.

The formulation in 1874 of the biogenetic law by Ernst Haeckel as "ontogeny recapitulates phylogeny" emphasized the structural similarities detected in metazoans between their developmental and ancestral forms. More recently, many workers have independently commented on the similarities observed between the behaviours displayed by dedifferentiated cancer cells and their embryonic precursors. This review will explore a possible linkage between these disparate observations and will suggest that cancer cells behave in ways that are reminiscent of primitive eukaryotic cells. In particular, we suggest that the acquisition of a multicellular level of organization during early metazoan evolution required a critical and difficult change in growth strategy as germ line and somatic cells became distinct. Whereas unicellular free living eukaryotes follow a simple strategy of rapid division as long as conditions permit, the elaboration of powerful growth inhibitory pathways must have been necessary in primitive multicellular organisms to enable some but not all sister cells to stop dividing, even under conditions of nutrient abundance. This limitation on cellular growth would than have permitted the appearance of tissues and organs with differentiated characteristics, ultimately enabling the enhanced survival of the meiotic lineage. Cancer cells might therefore be considered to represent, with their loss of tumor suppressor inhibitory activity and elevation of oncogene stimulatory activity, a reversion to a more primitive evolutionary state capable of indeterminate growth at the expense of the host. By this analogy, the growth phenotypes displayed by cancer cells, embryonic cells, and free-living eukaryotes are fundamentally similar.

Animals↗

PubMed2002

[Psychosocial factors in chronic back pain].

The evolution of the industrial era into the information society brought with it a dramatic increase in back pain. Epidemiological data are at odds with the former concept of somatic overload and degeneration as the underlying causes of back trouble. Personality, as well as psychosocial and socio-economic factors all impact on the evolution from acute to chronic back pain. It is suggested that the model of external causes and linear responses to explain back pain will be replaced by the holistic, nondeterministic complexity concept, i.e. multifactorial etiopathogenesis, multidimensional interactions, nonlinear causal pathways.

Back Pain↗

PubMed1977

Evolution of ageing.

An evolutionary view of ageing suggests that mortality may be due to an energy-saving strategy of reduced error regulation in somatic cells. This supports Orgel's 'error catastrophe' hypothesis and offers a new basis for the study of normal and abnormal ageing syndromes and of apparently immortal transformed cell lines.

Aging↗

PubMed2000

Structural evolution of the germ line-limited chromosomes in Acricotopus.

The elimination of chromatin or whole chromosomes from the future somatic nuclei during germ line-soma differentiation in early embryogenesis is a genetic phenomenon found in a wide variety of animal species. Less is known about the origin, structure, and function of the germ line-limited chromosomes. In the chironomid Acricotopus lucidus fluorescence in situ hybridization (FISH) with labeled soma DNA to "Keimbahn" chromosomes (Ks) and soma chromosomes (Ss) of spermatogonial mitoses revealed that each of the nine different K types possesses large S-homologous sections, mostly in the distal parts of both chromosome arms. Painting probes of the three Ss and of each of their chromosome arms were generated by microdissection of polytene salivary gland chromosomes and subsequent amplification by the degenerate oligonucleotide-primed polymerase chain reaction. Multicolor FISH demonstrated that each of the Ks, with the exception of one K type, was painted by only one of the three S probes. Furthermore, in seven Ks, one chromosome arm was painted by the long-arm probe and the other by the short-arm probe of the S concerned. The hybridization pattern strongly suggests that each of these K types is derived from a specific S. One function of the S-homologous K sections is thought to be determination of the regular occurrence of crossover events, with the resulting chiasmata in these sections ensuring correct segregation of the K homologs during meiosis. Reverse chromosome painting on polytene S sets with a probe generated from metaphase Ks corroborates the above results and produces conclusive evidence for the hypothesis that during evolution the Ks have developed from the Ss by endopolyploidization and rearrangements followed by the accumulation of germ line-specific repetitive DNA sequences in the centromeric regions.

Animals↗

PubMed1979

Analysis of the constancy of DNA sequences during development and evolution of the nematode Caenorhabditis elegans.

In order to test for the occurrence of rearrangements in DNA during development and to assess the rate of DNA divergence during evolution, we have compared restriction fragments derived from DNA from four sources: sperm cells and somatic tissues of one strain of the nematode Caenorhabditis elegans, somatic tissues of a second strain of the same species, and whole animals of a closely related species. Restriction fragments were detected by hybridizing radioactive cloned fragments to restriction digests that had been fractionated by size on agarose gels and transferred to nitrocellulose sheets. In this way, approximately 50 BamHI restriction fragments were visualized and compared. Fragments from sperm and somatic DNAs were found to be identical; 15% differed in size between the two strains. Little cross homology was found between the two species. We conclude that, if rearrangements occur in C. elegans DNA during development, they must affect fewer than a few percent of the restriction fragments or restriction sites. The difference found between the two strains and the two species is surprisingly great.

Animals↗

PubMed2002

Minisatellite instability at the Adh locus reveals somatic polymorphism in amphioxus.

Amphioxus (subphylum Cephalochordata) is the closest living relative to vertebrates and widely used for phylogenetic analyses of vertebrate gene evolution. Amphioxus genes are highly polymorphic, but the origin and nature of this variability is unknown. We have analyzed the alcohol dehydrogenase locus (Adh3) in two amphioxus species (Branchiostoma lanceolatum and Branchiostoma floridae) and found that genetic variation is related to repetitive DNA sequences, mainly minisatellites. Small pool-PCR assays indicated that allelic variants are generated by minisatellite instability. We conclude that the generation of new forms was not preferentially linked to germline processes but rather to somatic events leading to mosaic adult animals. Furthermore, most Adh minisatellites belong to a novel class, which we have named mirages. Their distinctive feature is that the repeat subunit spans the exon-intron boundaries and generates potential duplications of the splice sites. However, splicing may not be compromised as no aberrant mRNA variants were detected.

Alcohol Dehydrogenase↗

PubMed2006

IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia.

Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented V(H)DJ(H) clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one V(L)J(L) rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s).

Aged↗

PubMed2003

Extrasalivary lymphoma development in Sjögren's syndrome: clonal evolution from parotid gland lymphoproliferation and role of local triggering.

OBJECTIVE: To characterize Sjögren's syndrome (SS)-related B cell lymphoproliferation at the premalignant stage and during the evolution to B cell lymphoma, and to better understand the pathobiologic mechanisms associated with clonal expansion and the possible influence of different microenvironments on neoplastic transformation. METHODS: We analyzed sequential parotid and lung biopsy specimens that were obtained from a single patient with SS at multiple time points over a 7-year period. Polymerase chain reaction DNA amplification, cloning, and sequencing of the immunoglobulin heavy chain variable region showed clonality, somatic mutations, intraclonal heterogeneity, and genealogic relationships of the B cell clones in the different biopsy specimens. RESULTS: The evolution of a nonmalignant B cell clone that was present in the parotid gland and evolved into a B cell lymphoma was documented. During such a process, one subclone was selected that accumulated somatic mutations in a pattern consistent with the preservation of antigen receptor functionality, possibly attributable to continued hypermutation and selection. Intraclonal diversity indicated the presence of local triggers in both the parotid and lung microenvironments. CONCLUSION: Molecular followup of B cell lymphoproliferation in SS, from nonmalignant stage to overt B cell lymphoma, indicated a role for B cell receptor engagement in clonal survival. The outgrowth of one subclone, with malignant transformation in the lung, a target organ different from the initial site of the lymphoproliferative process (the parotid gland), indicates that resident stimuli in different microenvironments may locally sustain ongoing lymphoproliferation and B cell transformation.

Adult↗

PubMed2002

[Aging as a metagenetic process].

Genomes of eukaryotic cells are so complicated that spontaneous processes lead inevitably to a continuous formation of egoistic genetic elements from the normal ones. These elements convert the intracellular Cosmos into Chaos and therefore they can be named chaonogenes. They behave as endogenous genetic parasites and are able to evaluate. The rate of their evolution is very rapid, which unevitably results in senescence and death of not only cells and multicellular organisms but also of populations and species, because chaonogens are transmitted from somatic cells to gametes. Populations of chaonogenes are very sensitive to environmental changes, and different sets of intracellular or extracellular changes are commonly used in nature to put obstracles in deleterious evolution of chaonogenes or to stop their evolution. These changes can be moderate (as at mitosis) or crude (as at meiosis), or they can be predicted (as programmed biochemical changes in the course of mitosis, meiosis and gametogenesis) or unpredicred (mutations, somatic crossingover, random association of gamets), but in all the cases they lead eventually to some degree of rejuvenation. In somatic cell populations, the process of senescence in slowed down by means of epigenetically determined changes and mitotic divisions, at which both kinds of changes (programmed and accidental) are moderate, and for this reason only a small part of dividing cells dies. At meiosis both kinds of changes are so acute that the majority of cells die, but the formation of gametes and zygotes becomes almost completely rejuvenated. Only mutations leading to very acute changes in intracellular conditions (whose products act on chaonogenes similarly as new antibiotics on bacteria) can save aging populations of multicellular organisms from death (as do L. N. Gumilev's "mutations of passionarity"), and only accidentally appearing "catastrophic" macromutations can give rise to new (and, of the same time, young) species. It is concluded that the induction of acute temporal biochemical changes in the inner environment is to slow down processes of human senescence and to lead to rejuvenation.

Cellular Senescence↗

PubMed1998

Developmental stability and signalling among cells.

The production of stable phenotypes depends from the earliest stages of development upon high levels of somatic cellular selection amongst cells or cell lineages. The signals exchanged amongst cells can reveal important aspects of a cell's phenotype, and might thereby be used in darwinian processes of developmental selection. Based upon an optimality model, we suggest that stable phenotypes require a substantial investment in two mechanisms of inter-cellular selection: "quality-selection" mechanisms regulate the average phenotype of a group of cells; "stability-selection" mechanisms regulate the variance in cell phenotypes. Variance in cell phenotypes may arise from developmental-error or other stochastic processes, or be generated as is true of the immune system, as part of a developmental strategy. The model shows that stability-selection mechanisms may exert the stronger effect on overall organ or body performance. Selection based upon reliable inter-cellular signalling of phenotypic properties may be the key way that bodies anticipate and then constrain variance in cell phenotypes around the optimal cellular attributes, and suggests an advantage of developmentally-selected systems over instructional ones. High levels of investments in stability mechanisms also ensure homogeneous collections of cells that can translate "upwards" into developmentally stable organ systems and phenotypes. Environmental and genetic factors, as well as the prevalent mode of selection, may all affect developmental stability and thereby give rise to varying of somatic selection.

Animals↗

PubMed2004

Evolution of isotype switching.

This review discusses evolution of the process of Ig heavy chain class switching, relating it to the first appearance of somatic hypermutation (SHM) of variable region genes. First, we discuss recent findings on the mechanism of class switch recombination (CSR) in mice and humans, and then review the mechanisms of expression of Ig heavy chain isotypes from fishes to mammals. Importantly, activation-induced cytidine deaminase (AID), which is essential for CSR and somatic hypermutation, is found in fishes. Although at least some fishes are likely to undergo SHM, CSR is highly unlikely to occur in this group. We discuss the first appearance of CSR in amphibians and how it differs in birds and mammals.

Animals↗

PubMed1991

On the evolution of the karyorelict ciliate life cycle: heterophasic ciliates and the origin of ciliate binary fission.

Karyorelict ciliates have near diploid somatic nuclei (macronuclei) incapable of division. If selective pressure favors nuclear division, how could such macronuclei have evolved? I propose that they initially evolved in the context of a diplophase stage that consisted entirely of a non-dividing trophont that was terminated by the induction of meiosis. The diploid macronucleus then differentiated, functioned and was destroyed in the absence of cell division. Such a life cycle would necessarily be heterophasic, i.e. with alternating haploid and diploid generations. I call these ancestors heterophasic ciliates. I further propose that the ability of this diploid trophont to undergo binary fission arose de novo. Ciliate binary fission would then be a derived characteristic, which possibly evolved indepedently in more than one heterophasic ciliate lineage. A progression of steps, leading to the reduction of the haplophase and the generation of the karyorelict life cycle, is proposed. The shared possession of nuclear dimorphism with non-dividing macronuclei, conjugation, and a putative heterophasic ancestry invites further investigation of the phylogenetic relationship between heterokaryotic foraminifera and karyorelict ciliates.

Animals↗