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PubMed1993

[Severe somatic complications of acute alcoholic intoxication].

Acute alcohol ingestion can affect life expectancy and is directly responsible for 3,500 deaths per year. Acute lung diseases are mainly caused by pneumococci, Gram negative bacilli and anaerobic germs, and are often due to multiple microbes. In this case, evolution toward abscess can be feared. Septicaemia and enterobacterial peritonitis are frequently observed in cirrhotic patients. Ethanol, hypokaliemia and hypophosphoraemia also lead to rhabdomyolysis. Rhabdomyolysis can be complicated with acute renal failure and hyperkaliaemia. Alcoholic ketoacidosis and the hypoglycaemia favored by prolonged inadequate nutrition, are corrected by infusion of glucose solutions. Hyponatraemia can be complicated by convulsions and central pontine myelinolysis. Minor forms of alcoholic hepatitis remiss after stopping alcohol intoxication. The major forms can evolve toward fatal encephalopathy; treatment with corticosteroids improves the prognosis in severe hepatitis. The cardiac failure with lactic acidosis in shoshin beriberi rapidly evolves to collapsus; treatment is based on emergency administration of vitamin B1. Management of patients in acute alcohol episodes requires great vigilance. Careful clinical examination and biological tests should eliminate severe somatic complications before concluding to simple alcoholic intoxication.

Alcoholic Intoxication↗
PubMed2001

Analysis of antibodies of known structure suggests a lack of correspondence between the residues in contact with the antigen and those modified by somatic hypermutation.

Forty unique murine antibody-antigen complexes determined at 2.5 A or less resolution are analyzed to determine whether the residues in direct contact with the antigen are modified by somatic hypermutation. This was done by taking advantage of the recent characterization of the pool of Vkappa germline genes of the mouse. The average number of residues in contact with the antigen in the V(L) gene, which contains the CDRL-1, CDRL-2, and all but one residue of CDRL-3, was six. The average number of somatic mutations was similar (around five). However, as many as 53% of the antibodies did not show somatic replacements of residues in contact with the antigen. Another 28% had only one. Overall, the frequency of antibodies with increasing number of somatic replacements in residues in contact with the antigen decreased exponentially. A possible explanation of this finding is that mutations in the contacting residues have an adverse effect on the antigen-antibody interaction. This implies that most of the observed mutations are those remaining after negative (purifying) selection. Therefore, efficient strategies of site-directed mutagenesis to improve the affinity of antibodies should be focused on residues other than those directly interacting with the antigen.

Animals↗
PubMed1989

[Study on molecular evolution for both variable segments of immunoglobulin heavy chain and T cell receptor].

In order to explain difference and similarity in producing antibody diversity between immunoglobulin (Ig) and T cell receptor (TCR), authors compared both codon substitution and concerted evolution rate between the variable segment of Ig heavy (Ig VH) and that of TCR (TCR V). The protein sequences of TCR V alpha (including 8 gene segments from mouse and 3 from human), TCR V beta (including 11 from mouse and one from human) and T cell V gamma (including 2 from mouse and 4 from human) were compiled, as well as the protein sequences of Ig VH (3 from human, 11 from mouse, 3 from caiman and one from shark) were collected. It is shown that: (1) the nucleotide substitution of TCR V segment is 2.4 times as large as that of Ig VH in coding region; (2) as for concerted evolution, gene duplicate rates in TCR V and Ig VH are 1.7 X 10(-8) and 1.6 X 10(-8)/gene/year, respectively. The number of TCR V(V alpha equals to 100 and V beta equals to 30) is less than the one of Ig VH (VH equals to 300), for TCR V is subject to negative selection of major histocompatibility complex according to the neutral theory. We discussed that is somatic mutation or DNA rearrangement the main force in producing antibody diversity and are there pseudogenes in TCR V or not.

Animals↗
PubMed2002

Human gene mutation in pathology and evolution.

Mutations in human gene pathology and evolution represent two sides of the same coin in that the same mechanisms that have frequently been implicated in disease-associated mutagenesis appear also to have been involved in potentiating evolutionary change. Indeed, the mutational spectra of germline mutations responsible for inherited disease, somatic mutations underlying tumorigenesis, polymorphisms (either neutral or functionally significant) and differences between orthologous gene sequences exhibit remarkable similarities, implying that they may have causal mechanisms in common. Since these different categories of mutation share multiple unifying characteristics, they should no longer be viewed as distinct entities but rather as portions of a continuum of genetic change that links population genetics and molecular medicine with molecular evolution.

Biological Evolution↗
PubMed2003

Natural selection and the evolution of genome imprinting.

Sexual reproduction results from the fusion of gametes in which the chromatin configuration of maternal and paternal chromosomes is distinct at fertilization. Although many of the differences are erased during successive cellular divisions and chromatin modifications, some are retained in both somatic and germline cells. These epigenetic modifications can confer different characteristics on maternal and paternal chromosomes and such differences can be selected during any process that has the ability to distinguish between homologues. The end result of these selective forces are parental origin effects, writ large. The range of effects observed, including transcriptional imprinting and effects on chromosome segregation and heterochromatization, reflects the diversity of selective forces in operation. However, a closer look at these effects suggests that parental origin-dependent differences in chromatin structure might be subject to some common forces and that these forces may explain many of the "nontranscriptional" parental origin effects observed in mammals.

Animals↗
PubMed1987

Hemopexin is localized to human chromosome 11.

Hemopexin, a plasma protein that migrates during electrophoresis with the beta-globulins, transports free heme to sites of its catabolism in the liver. A hemopexin cDNA clone has been utilized for mapping the hemopexin (HPX) gene to human chromosome 11 in the region pter----p11 by somatic cell hybrid analysis.

Animals↗
PubMed2000

Chromatin diminution in the parasitic nematodes ascaris suum and parascaris univalens.

Chromatin diminution in Parascaris univalens and Ascaris suum undoubtedly represents an interesting case of developmentally programmed DNA rearrangement in higher eukaryotes. It is a complex mechanism involving chromosomal breakage, new telomere addition and DNA degradation, and occurs in all presomatic cells. The process is rather specific with respect to its developmental timing and the chromosomal regions that are eliminated. The functional significance of chromatin diminution still remains an enigma. The fact, however, that single-copy, protein-coding genes are contained in the eliminated DNA demonstrates that in P. univalens and A. suum, there is a qualitative difference between germ-line and somatic genomes, and suggests that chromatin diminution may be used as a "throw-away" approach to gene regulation. We present a hypothesis as to how, during evolution, a partial genome duplication might have been linked to the process of chromatin diminution, in order to provide a selective advantage to parasitic DNA-eliminating nematodes.

Animals↗
PubMed2000

The role of senescence and immortalization in carcinogenesis.

Normal somatic cells are able to divide only a limited number of times before they become senescent. The occurrence of intratumoral cell death and the need for clonal evolution mean that many more cell divisions are required for tumorigenesis than is possible unless cells breach the senescence proliferation barrier and become immortalized. Senescence may therefore be a major tumor suppressor mechanism. During the past decade the study of senescence and immortalization has entered the mainstream of cancer research. A major reason for the current interest in this subject is the observation that most cancers have an activated telomere maintenance mechanism, a marker of immortalization. It has also been found that some of the most common genetic changes known to occur in cancer have a key role in the immortalization process.

Animals↗
PubMed2000

Molecular characterisation of two paralogous SPO11 homologues in Arabidopsis thaliana.

The Spo11 protein of yeast has been found to be covalently bound to double-strand breaks in meiosis, demonstrating a unique role of the protein in the formation of these breaks. Homologues of the SPO11 gene have been found in various eukaryotes, indicating that the machinery involved in meiotic recombination is conserved in eukaryotes. Here we report on SPO11 homologues in plants. In contrast to what is known from other eukaryotes, Arabidopsis thaliana carries in its genome at least two SPO11 homologues, AtSPO11-1 and AtSPO11-2. Both genes are not more closely related to each other than to other eukaryotic SPO11 homologues, indicating that they did not arise via a recent duplication event during higher plant evolution. For both genes three different poly-adenylation sites were found. AtSPO11-1 is expressed not only in generative but also to a lesser extent in somatic tissues. We were able to detect in different organs various AtSPO11-1 cDNAs in which introns were differently spliced-a surprising phenomenon also reported for SPO11 homologues in mammals. In the case of AtSPO11-2 we found that the 3' end of the mRNA is overlapping with a mRNA produced by a gene located in inverse orientation next to it. This points to a possible antisense regulation mechanism. Our findings hint to the intriguing possibility that, at least for plants, Spo11-like proteins might have more and possibly other biological functions than originally anticipated for yeast.

Alternative Splicing↗
PubMedDate not supplied

Formation of nucleolar polymorphisms in trisomic chickens and subsequent microevolution of rRNA gene clusters in diploids.

Variations in nucleolar size are common in animals and man, yet the basis and significance of this variation are not well understood. In this report, we describe the generation de novo of individuals that express nucleolar size variations (polymorphisms) and the underlying basis for this phenotype in a vertebrate animal system (Gallus domesticus). Individuals that express nucleolar size polymorphisms were produced from mating chickens trisomic for the nucleolar organizer (NO) chromosome; 10%-18% of progeny demonstrated nucleolar polymorphisms. These progeny were incorporated into a diploid genetic line in which the polymorphic trait was observed to segregate in Mendelian fashion. An even more dramatic nucleolar size polymorphism (one macro- plus one micronucleolus) evolved in one diploid family over the course of only two generations. These individuals were used to ascertain that the polymorphic-nucleoli phenotype was expressed in tissues derived from the three primary embryonic cell layers in embryos and neonates. Image analysis was conducted on cells of these birds to quantitate the size differences between macro- and micronucleoli (5 mu2 versus 1 mu2, respectively). Finally, these birds were studied with the technique of in situ hybridization, which showed that gene number differences between homologous NO chromosomes (i.e., heterozygosity for rRNA gene copy number), underlies the polymorphic-nucleoli phenotype. Thus, the chicken emerges as an experimental system through which heterozygosity for the rRNA gene copy number can be induced, easily identified, transmitted, and expressed in all somatic tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Environmental calcium modifies induced defences in snails.

Inducible defences are adaptive phenotypes that arise in response to predation threats. Such plasticity incurs costs to individuals, but there has been little interest in how such induced traits in animals may be constrained by environmental factors. Here, we demonstrate that calcium availability interacts with predation cues to modify snail shell growth and form. Small snails increased their growth and were heavier when exposed to fish chemical cues, but this response was calcium limited. There was also an interactive effect of fish cues and calcium on the shell growth of larger snails, but shell strength and aperture narrowness were affected by calcium alone. For small snails, behavioural avoidance was greatest for snails exhibiting least morphological plasticity, suggesting a trade-off. There was no trade-off of somatic growth with plasticity. We suggest that the expression of defensive traits in molluscs can be constrained by calcium availability, which has implications for molluscan ecology and evolution.

Analysis of Variance↗
PubMed1984

Immunoglobulin variable region genes.

The picture that emerges of a V gene locus, albeit still sketchy, is one of a continuously evolving region, subject on occasion to quite dramatic flux due to the operation of gene conversion, transposing elements, recombination and unequal crossing over. The V genes are separated by surprisingly large tracts of DNA of unknown function which are 'littered' by a number of simple-sequence and moderately repetitive elements. The diversity of immunoglobulins is in part accounted for by selection operating on multiple germline genes: 100-300 for mouse VK and VH, but probably less for human VK and VH. Somatic recombinational and mutational mechanisms play a substantial role in increasing the diversity still further.

Animals↗
PubMed2004

The molecular chaperones and the phenomena of cellular immortalization and apoptosis in vitro.

The molecular chaperones are housekeeping molecules that assist in the folding and prevention of the aggregation of proteins and nucleotides, as well as participating in the elimination of ubiquitinated molecules. Evidence is reviewed to suggest that the Werner protein is a DNA chaperone and also that an increase in the expression of the molecular chaperones is the common denominator in the extension of cellular and species longevity as well as in the process of cellular immortalization, the inherent immortality of germ cells, and the inhibition of cellular apoptosis. It is possible that the immortalization of normal somatic cells is caused by an accidental reprogramming of the genome, recreating the chaperone expression of the germ cells. It is suggested that the molecular chaperones are evolution facilitators determining the life span of individual cells as the evolution of longevity in species.

Aging↗
PubMed2005

p53 gain-of-function: tumor biology and bioinformatics come together.

p53 is typically viewed as a tumor suppressor. However, many missense somatic and germline mutations in the p53 gene cause gain-of-function whereby p53 acquires novel biochemical activities, such as the ability to transactivate transcription of new genes or to mediate new regulatory protein-protein interactions. Several recent studies show that at least some gain-of-function mutations of p53 are biologically relevant leading to a change in the tumor phenotype. Independent bioinformatic analysis of somatic mutation spectra of the p53 gene yields three lines of evidence supporting the notion that gain-of-function could be the prevalent mode of p53 evolution in tumors. (1) The hotspots in the p53 gene show signs of intensive positive selection. (2) The hotspots are located primarily in functionally important motifs of the DNA-binding domain of p53 which are highly conserved in interspecies evolution. (3) The spectra of hotspots significantly differ among various tumor types and the germline (Li-Fraumeni syndrome); in addition to the hotspots shared by the germline and some of the tumors, many are tumor-specific. The latter observation suggests an unexpected level of complexity of p53 evolution in tumors, with distinct novel function gained in different tumors.

Animals↗
PubMed1996

Control of precancer cell transformation into cancer cells: its relevance to cancer prevention.

It is well known that following the action of various carcinogens (chemical, physical, biological) on normal cells, a long period (latency) of several months to years (approximately 10 months approximately 30 years) in humans or one-half to two-thirds of the life span of laboratory animals occurs between development of precancer cells and their transformation into cancer cells. However, the molecular and biological events that take place within the precancer cells during this quiescent stage are not yet fully understood. The main purpose of this review is to evaluate the data from literature as well as my own findings regarding the preneoplastic cells and their progression into neoplastic cells. Recent studies reveal that preneoplastic cell development and transformation into cancer cells is determined initially by genetic (oncogenes, antioncogenes), with sequential multiple somatic mutations, and later by epigenetic or environmental cell factors such as hormones, growth factors (GFs), cytokines, vitamins, and prostaglandins (PGs). These factors can markedly change the evolution of preneoplastic cells by enhancing, retarding, or inhibiting their transformation into cancer cells, or even reversing them to a normal phenotype. These agents act on DNA, RNA, and protein synthesis, as well as on cell replication, cell cycles, cell surfaces, and intercellular communications. DNA, oncogenes, ultrastructural cell surface, and antigenic determination used as biomarkers are essential for early detection of preneoplastic cells and premalignant lesions. Further investigations regarding the precancer cell biology and metabolism will have a paramount significance for designing effective strategies for cancer prevention and treatment.

Animals↗
PubMed2001

Characterization of the three HERV-H proviruses with an open envelope reading frame encompassing the immunosuppressive domain and evolutionary history in primates.

The HERV-H family is one of the largest human endogenous retrovirus families, with approximately 1000 elements. Using a direct coupled in vitro transcription/translation approach (PTT for protein truncation test) and an extended series of primers on human genomic DNA, on monochromosomal hybrids and on a BAC library, we could demonstrate that there are only three envelopes with a large open reading frame encompassing the immunosuppressive (ISU) domain, corresponding to 62-, 60-, and 59-kDa potential translational products. The associated proviruses, HERV-H/env62, HERV-H/env60, and HERV-H/env59 were sequenced together with their flanking DNA and mapped by FISH, and their entry times within the primate lineage were determined. Analysis of the LTR sequences revealed numerous recombinational and/or homogenization events in the course of evolution, with divergences between 5' and 3' LTRs higher than expected for a simple time-dependent genetic drift. PTT analyses further revealed that the three large envelopes in humans are prematurely stopped in the majority of primates, and sequencing of the largest envelope gene, from HERV-H/env62, in five human individuals revealed two polymorphic sites. The results are consistent with the absence of a strong selective pressure for the conservation of a functional envelope gene of possible benefit for the host, but do not exclude somatic effects possibly associated with the immunosuppressive domain carried by these genes.

Animals↗
PubMed2003

Patterns of somatic mutations in VH genes reveal pathways of clonal transformation from MGUS to multiple myeloma.

Monoclonal gammopathy of undetermined significance (MGUS) can transform to multiple myeloma (MM). In myeloma, mutated V(H) genes with sequence homogeneity reveal a postfollicular origin. Previously, some MGUS cases showed mutated V(H) genes with intraclonal variation, indicating an earlier stage of arrest. We investigated progression from 2 of 2 MGUS to MM, in which V(H) genes confirmed clonal evolution. In one MGUS case, intraclonal heterogeneity was evident, and transformation to myeloma occurred rapidly with apparent homogeneity in the emergent clone. However, residual MGUS-derived sequences were detectable at this time. Heterogeneity in MGUS does not associate with benign disease, but it indicates an origin from a tumorigenic cell, most likely surface immunoglobulin(+), undergoing somatic mutation. The remaining case displayed intraclonal homogeneity at the MGUS stage, conceivably resulting from a self-cloning outgrowth from MGUS with heterogeneity. Transformation can occur at either MGUS stage, but it involves a single cell in which somatic mutation is then silent.

Bone Marrow Cells↗
PubMed1998

Evolution and the inevitability of human cancer.

Natural selection, which is absolutely dependent on genetic differences between individuals, is the process by which life has evolved on this planet. Genetic variability is ultimately depended on the occurrence of new mutations in the germ-line of species. The rate at which this occurs appears not to be arbitrary or dependent on chance external events. Rather the available evidence suggests that it is highly controlled and determined by endogenous processes. However, the body does not have separate mechanisms for controlling mutation frequency in the germinal and somatic lineages and the selective process described inevitably has also led to somatic cells being subject to mutation accumulation. Indeed, since mutation frequency increases exponentially with time, the human somatic mutation frequency at approximately 80 years of age in epithelial tissues appears to be more than 10-fold higher than in the human germline. This normal but highly elevated somatic mutation frequency is sufficient to account for the complex multi-step process of human tumorigenesis even in the absence of the effects of major external mutagens or rare transitions to even more elevated mutation frequencies. Thus, scrutiny of the apparently disparate biological phenomena of evolution and tumorigenesis leads to the postulate that they are in fact two interdependent manifestations of the same underlying process and that given an evolutionary process dependent on mutation accumulation then cancer in long lived organisms is an inevitable consequence.

Biological Evolution↗