Progress in understanding the mechanism and consequences of somatic hypermutation.
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Animals↗
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Equivalence hypothesis of mental and somatic processes. Theoretical considerations.
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Biological Evolution↗
[The epigenomic variability of somatic cells].
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Animals↗
A 30 kb region of the Epstein-Barr virus genome is colinear with the rearranged human immunoglobulin gene loci: implications for a "ping-pong evolution" model for persisting viruses and their hosts. A review.
The left part of the Epstein-Barr virus (EBV) genome exhibits a strong colinearity of structural and functional elements with the immunoglobulin (Ig) gene loci which is only partially reflected in nucleotide sequence homologies. We propose that this colinearity may be the result of an inter-dependent co-evolution of the immunoglobulin loci together with EBV. Our observation could help elucidating the mechanisms of somatic hypermutation, explaining the ability of EBV to accidentally cause tumors, and shedding more light on the general mechanisms of viral and organismal evolution. We suggest that persisting viruses served as a complement for the organismal germline like in a ping-pong game and outline The Ping-Pong Evolution Hypothesis.
Chromosome Mapping↗
The evolution of self-regulated transposition of transposable elements.
This paper examines the conditions under which self-regulated rates of transposition can evolve in populations of transposable elements infecting sexually reproducing hosts. Models of the evolution of both cis-acting regulation (transposition immunity) and trans-acting regulation (transposition repression) are analyzed. The potential selective advantage to regulation is assumed to be derived from the deleterious effects of mutations associated with the insertion of newly replicated elements. It is shown that both types of regulation can easily evolve in hosts with low rates of genetic recombination per generation, such as bacteria or bacterial plasmids. Conditions are much more restrictive in organisms with relatively free recombination. In haploids, the main selective force promoting regulation is the induction of lethal or sterile mutations by transposition; in diploids, a sufficiently high frequency of dominant lethal or sterile mutations associated with transpositions is required. Data from Drosophila and maize suggest that this requirement can sometimes be met. Coupling of regulatory effects across different families of elements would also aid the evolution of regulation. The selective advantages of restricting transposition to the germ line and of excising elements from somatic cells are discussed.
Animals↗
[Cancer and therapy for it--from gynecological standpoints].
Life phenomena have been studied scientifically for more than 160 years. Meanwhile many excellent technology and methodology which human race created have been used in the field of medicine. Analytical research for the constitution of life and impediments to life has remarkably advanced. Pathophysiology of many diseases has been clarified and reasonable and effective treatment for disorders has been organized. Many disorders which showed high mortality in the past are now listed as one of minor diseases in the textbook. However, the disease which cause is unclear and which deprives human race of life still exists. That is "CANCER". The society of medicine devotes the greatest energies to abolish the cancer. I am going to talk about the physiological characteristics of "the cancer in human race" from the gynecological standpoints and to present some facts of studies about the therapy for cancer in our department. I. Evolution of human and cancer 1. Life of species and life of individuals In the development from uni-nuclear cell creature to multicellular entity, to give new generation sexual reproduction was out-lasted for the adaptation to environment advantageously after the spread out of mutant gene in this entity. With this evolution, a living creature divided its cells into two types. One is somatic cells which would die in certain period and the other is germ cells which would not die on principle in good environment. In short well evolved living entity clearly established individual life span for the first time and its constituent, that is somatic cells demonstrated "AGEING" phenomena regulating life span.(ABSTRACT TRUNCATED AT 250 WORDS)
Adjuvants, Immunologic↗
Human longevity at the cost of reproductive success.
The disposable soma theory on the evolution of ageing states that longevity requires investments in somatic maintenance that reduce the resources available for reproduction. Experiments in Drosophila melanogaster indicate that trade-offs of this kind exist in non-human species. We have determined the interrelationship between longevity and reproductive success in Homo sapiens using a historical data set from the British aristocracy. The number of progeny was small when women died at an early age, increased with the age of death, reaching a plateau through the sixth, seventh and eighth decades of life, but decreased again in women who died at an age of 80 years or over. Age at first childbirth was lowest in women who died early and highest for women who died at the oldest ages. When account was taken only of women who had reached menopause, who were aged 60 years and over, female longevity was negatively correlated with number of progeny and positively correlated with age at first childbirth. The findings show that human life histories involve a trade-off between longevity and reproduction.
Adult↗
On the evolution of X-chromosome inactivation in mammals and the clinical consequences to man--a hypothesis.
A clinical analysis of abnormal sex chromosome states in man suggests that Lyon's recent X-Y translocation hypothesis for the evolution of X-chromosome inactivation in mammals most likely would have lead to an evolutionary dead-end. Therefore, as an alternate I have hypothesized that: X-chromosome inactivation in somatic cells of mammals could have evolved by a complementary process of one by one heterozygous physical deletion in males and heterozygous inactivation in females of genes for "somatic" traits scattered throughout the genome whose effective output had become 50% excessive during prior evolution. However, this complementary process could occur safely only if the genes so deleted or inactivated first segregated by chance onto the evolving sex-chromosomes via a one by one reciprocal exchange for non-sex related genes already there. The complementary process thereby would allow slow evolution of the Y-chromosome in the male and X-chromosome inactivation in the female. Evolution of X-chromosome inactivation in this manner is compatible with Ohno's observation of "conservation" of the X-chromosome in mammals; and the occurrance of clinical "somatic" abnormalities in the abnormal X or Y chromosome states of man despite X-chromosome inactivation.
Aneuploidy↗
Human natural chimerism: an acquired character or a vestige of evolution?
Analysis on five common classes of human natural chimeras (cytomictical, whole body, fetal-maternal, germ cell, and tumor chimeras) reveals that (1) they initiate only during pregnancy, (2) the most common class are chimeras which contain maternal cells, and (3) the primary mechanisms that are involved in their formation and establishment are still elusive. These classes of natural chimerism, are involved only with maladaptive phenomena such as malignancy and autoimmune diseases and without any documented benefit. A recent review has challenged the accepted dogma that the evolution of immunity is pathogen-directed and asserted that preserving individuality from littering the soma and the germline by conspecific alien cells might have been the original function of the innate immunity. Following this tenet, I propose here that human natural chimerism is a by-product of the new role evolved from primitive components of immunity to "educate" the developing embryo with the armamentarium of effector mechanisms, dedicated to purge the individual from pervasive somatic and germline variants, and is not a vestige of evolution.
Animals↗
Limits to genetic intervention in humans: somatic and germline.
The promise of somatic cell gene therapy is likely to be limited to a narrow range of monogenic hereditary defects. This therapy raises few moral issues. However, extension to the 'improvement' of a normal trait might raise problems, similar to the use of hormones in sports. Another danger is uses that result, like heroic measures to save the premature newborn, in the prolongation of misery and in intolerable expense. The genetic alteration of germline cells, which can already be accomplished in animals, is in principle applicable to all monogenic diseases. Its use in humans is much less acceptable than somatic cell therapy. The objection that it tampers with human evolution is widely cited. However, more important may be the risk of producing a new defect, for risk is much less acceptable in a yet unborn person than in an already ill individual. In addition, the goal of germline therapy could almost always be accomplished more simply and safely by prenatal diagnosis and selective abortion. The highly polygenic nature of the most interesting traits, both behavioural and physical, makes it unlikely that we shall be able to modify them usefully in the foreseeable future by either somatic or germline intervention. Despite this delivery from temptation, public fear of future 'blueprinting' of humans no doubt contributes to a multi-faceted antiscience movement.
Ethics, Medical↗
[Delirium and hallucinations in depression: cultural aspects].
Study of depression in North-Africa and Sub-Saharan Africa has shown that, since the seventies, the clinical expression of depression is markedly different from that of depression in the West. Several authors have noted the rareness of guilt themes and the frequency of persecution themes and somatic complaints in depressed Africans, even those living in the West. More recent studies have shown an evolution in depressive symptoms in North-Africa with an increase in guilt and a decrease in persecution and somatic complaints. This shift in symptoms brings the expression of depression closer to that observed in the West. Our study addresses delusional depression: in 73 cases of delusional depression, delusions of guilt were present in 31% of cases, persecution in 48% and hallucinations in 31.5%. A comparison of the sub-groups consulting in 1991 and a second sub-group consulting in 1998 shows a marked increase in guilt (23.5 versus 39%).
Adult↗
Innate antibody catalysis.
Catalysis by antibodies is often assumed to require immunization with artificial haptens, which are proposed to stimulate adaptive immune processes and enable the development of catalytic sites with the ability to bind the transition state. Contrary to this assumption, we describe here a serine protease-like catalytic triad in an antibody light chain raised by immunization with vasoactive intestinal peptide (VIP), the structure and function of which is inherited via a germline V(L) gene. The serine protease mechanism was evident from loss of the catalytic activity by site directed mutagenesis at a framework region residue Asp1 (present study) and at two complementarity determining region residues Ser27a and His 93 (Gao, Q-S., Sun, M., Rees, A., Paul, S., 1995. Site-directed mutagenesis of proteolytic antibody light chain. J. Mol. Biol. 253, 658-664). All three catalytic residues (Ser27a, His93, Asp1) are also present in the germline counterpart of the mature V(L) gene, but the mature and germline sequences differ by four amino acids remote from the catalytic site. Reversion mutations were introduced at these amino acids in the mature light chain (His27 d:Asp, Thr28e:Ser, Ile34:Asn, Gln96:Trp; Kabat numbering, germline encoded residues shown second), generating the germline configuration of the protein. The germline light chain expressed peptidase activity, determined by assaying the cleavage of VIP and a synthetic protease substrate, Pro-Phe-Arg-Methylcoumarinamide. Differences between the kinetic constants for the mature and germline light chains were marginal. Diisopropylfluorophosphate, a serine protease inhibitor, blocked the peptidase activity of the germline light chain, suggesting the presence of the catalytic triad in a functional state. Like the mature light chain, the germline protein preferentially cleaves peptide bonds on the C-terminal side of basic residues. We conclude that the catalytic activity of certain antibodies is an innate function, originating over the course of phylogenetic evolution of the V(L) genes, as opposed to somatic processes.
Amino Acid Sequence↗
Evolutionary immunology. A boost to immunity from nurse sharks.
A study of the nurse shark has revealed a type of rearranging gene that has yet to be seen in mammals; it encodes a secreted 'new antigen receptor' which, unlike shark immunoglobulin, revels in somatic hypermutation.
Animals↗
Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma.
Loss of genes at specific chromosomal loci is a characteristic of retinoblastoma, Wilms' tumour, transitional cell carcinoma of the bladder, embryonal tumours and small cell carcinoma of the lung. The significance of nonrandom gene loss in these neoplasms is that gene loss on one chromosome may uncover null mutations at corresponding loci of the homologous chromosome. Loss of specific gene products from somatic cells may be critical in the origin or evolution of certain human tumours. Clues to identification of new loci of gene loss in common adult solid tumours may be found in literature that describes chromosomal abnormalities in rare heritable cancers. Karyotypes of tumours in two families with hereditary renal carcinoma showed translocations involving the short arm of chromosome 3 (refs 10 and 11). We have examined tumours from 18 patients with non-hereditary renal cell carcinomas and found loss of alleles at loci on the short arm of chromosome 3 in all eleven of the patients who could be evaluated.
Adult↗
The phosphocreatine shuttle of sea urchin sperm: flagellar creatine kinase resulted from a gene triplication.
TCK, the creatine kinase (ATP:creatine N-phosphotransferase) from sperm flagella of the sea urchin Strongylocentrotus purpuratus, is a Mr 145,000 axonemal protein that is employed in energy transport. Its amino acid sequence was obtained by analysis of fragments from cyanogen bromide digestion and by sequencing cDNA clones from two sea urchin testis libraries. TCK contains three complete but nonidentical creatine kinase segments joined by regions of sequence that are not creatine kinase-like and flanked by unique amino and carboxyl termini. Each creatine kinase segment is homologous to vertebrate creatine kinases of both muscle and brain types, and all three repeats contain the essential active-site cysteine. The sequence differences among repeats suggest an ancient gene triplication, around the time of the chordate-echinoderm divergence. The echinoderm, with a unique creatine kinase in sperm, arginine kinase in eggs, and both phosphagen kinases in somatic cells, may represent a preserved branch point in evolution, and TCK may be a relic of this event.
Amino Acid Sequence↗
Isotype switch variants reveal clonally related subpopulations in diffuse large B-cell lymphoma.
Primary diffuse large B-cell lymphomas (DLBCLs) are aggressive tumors accounting for approximately 40% of B-cell malignancies. The immunoglobulin (Ig) variable region genes have undergone rearrangement and are commonly somatically mutated. The majority show intraclonal variation which indicates that somatic mutation has continued after transformation. Typically, cells of DLBCLs express Ig of a single isotype, but there may be accompanying cells that express alternative isotypes. To probe the status of the isotype switch process in DLBCL, 4 cases of tumor-derived constant region transcripts of all isotypes were investigated. Following the identification of the VDJ sequences, the presence of the major isotype expected from immunohistochemical analysis was confirmed at the RNA level. Another 3-4 alternative isotypes were revealed in all cases, some of which could also be detected by immunohistochemistry. All cases were somatically mutated with an intraclonal variation. In 2 cases there were clearly distinct patterns of somatic mutation between isotypes, which was consistent with independent evolution of the tumor subpopulations. There was apparent clustering of mutational patterns into either an IgMD/IgG3/IgA set or an IgG1/IgA set, indicating that the switch to IgA can occur by different routes. Alternative isotype expression is evident in DLBCL at both the RNA and protein levels. The pattern of mutation indicates that switching is occurring in subpopulations of the tumor after malignant transformation. The findings support the concept that isotype switch events may be a feature of DLBCL.
Adult↗
[Paradoxical sleep: is it the guardian of psychological individualism].
The brain is the sole organ of homeotherms that do not undergo cell division. We thus have to explain how certain aspects of psychological heredity (found in homozygotes twins raised in different surroundings) may persist for a whole life (psychological individuation). A definitive genetic programming during development (by neurogenesis) is unlikely due to the plasticity of the nervous system. That's why we have to consider the possibility of an iterative genetic programming. The internal mechanisms (synchronous) of paradoxical sleep (SP) are particularly adapted to such programming. This would activate an endogenous system of stimulation that would stimulate and stabilize receptors genetically programmed by DNA in some neuronal circuits. The excitation of these neurons during SP leads to oniric behaviours that could be experimentally revealed--the lists of these behaviours are specific to each individual and indirect data suggest a genetic component of this programming. Amongst the mechanisms allowing the iterative programming of SP, sleep is particularly important. Security--and hence the inhibition of the arousal system--is a sine qua non condition for genetic programming to take place. In that sense, sleep could very well be the guardian of dreaming. On the other hand, sleep seems to be necessary for the accumulation of energetic resources used by the cholinergic mechanisms of SP. The temporal modalities of SP (diachronic organization) are also discussed in relation to phylogenesis. Thus, the absence of SP in poikilotherms is explained by a continual neurogenesis in the adult. During ontogenesis in mammals, a stage of programming by neurogenesis (seismic sleep) precedes the appearance of SP so long as the programming system isn't functional. The presence, or absence, of rebound after SP deprivation is interpreted in terms of the existence, or non existence, of stress during SP suppression. An explanation is proposed to account for the absence of specific effects of SP deprivation in humans. In the same way somatic intraspecific variability is one of the conditions of evolution, it is proposed that one of the functions of SP is to maintain psychological variability in a given population.
Animals↗
Variable heavy chain gene analysis of follicular lymphomas: correlation between heavy chain isotype expression and somatic mutation load.
The expansion of follicular lymphomas (FLs) resembles, both morphologically and functionally, normal germinal center B-cell growth. The tumor cells proliferate in networks of follicular dendritic cells and are believed to be capable of somatic hypermutation and isotype switching. To investigate the relation between somatic mutation and heavy chain isotype expression, we analyzed the variable heavy (V(H)) chain genes of 30 FL samples of different isotypes. The V(H) genes of the FLs were heavily mutated (29.3 mutations on average). In addition, isotype-switched lymphomas contained more somatic mutations than immunoglobulin M-positive lymphomas (33.8 mutations per V(H) gene versus 23.0, respectively). In all but one of the FLs, the ratios of replacement versus silent mutations in the framework regions were low, independent of the absolute number of somatic mutations and the level of intraclonal variation. Analysis of relapse samples of 4 FLs showed no obvious increase in somatic mutation load in most FLs and a decrease in intraclonal variation in time. In 3 of 4 cases, we obtained evidence for selection of certain subclones, rather than clonal evolution. Our findings question if intraclonal variation is always a reflection of ongoing somatic hypermutation. This may have implications for the concept of antigen-driven lymphomagenesis. (Blood. 2000;95:2922-2929)
Adult↗