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At least 937 records · Page 52Linked to original sources
PubMed1997

Intraclonal offspring expansion of gastric low-grade MALT-type lymphoma: evidence for the role of antigen-driven high-affinity mutation in lymphomagenesis.

Recent studies have shown that gastric mucosa-associated lymphoid tissue (MALT)-type lymphoma B cells are the malignant counterparts of hypermutated, postgerminal-center memory B cells. To further elucidate the role of antigen selection in the evolution of gastric low-grade MALT-type lymphoma, we analyzed intraclonal variations of the immunoglobulin heavy-chain variable region (Ig VH) genes expressed in three cases of lymphoma. The Ig VH genes expressed by tumor cells were amplified by PCR using primers for individual tumor-specific markers (complementarity-determining region 3 (CDR3)) and primers for six VH family leaders and then sequenced. The corresponding germ-line VH gene from these patients was also sequenced. The somatic mutations were highly concentrated in the CDR or framework region, with a clustering of replacement mutations in the CDR but only a few in the framework region. Each of the Ig VH genes of tumor cell clones of Cases 1 and 3 showed different mutations, whereas Case 2 showed no intraclonal variation. Although all three mutation pattern variants of Cases 1 and 3 occurred in postgerminal memory B cells, only one offspring from each case resulted in a dominant expansion. This finding suggests that antigen-driven high-affinity somatic mutation may play an important role in the expansion of intraclonal offspring from low-grade MALT-type lymphomas.

Base Sequence↗
PubMed1995

Genomic organization of a mouse glyceraldehyde 3-phosphate dehydrogenase gene (Gapd-s) expressed in post-meiotic spermatogenic cells.

The Gapd-s gene encodes an isoform of the glyceraldehyde 3-phosphate dehydrogenase enzyme expressed only in post-meiotic spermatogenic cells. Two clones containing the Gapd-s gene were isolated from a mouse genomic library. Sequencing and restriction enzyme analysis demonstrated that this single-copy gene contains 11 exons and spans 9596 base pairs. The locations of Gapd-s exons and introns are conserved when compared to the corresponding portions of the chicken and human somatic Gapd genes. The promoter region contains no TATA box, although there is a potential SP1 recognition site within exon 1. Like other TATA-less genes, primer extension analysis reveals some heterogeneity in the site of transcription initiation with Gapd-s transcripts initiating from three discrete sites. Northern analysis demonstrated that a 1.5-kb Gapd-s mRNA is expressed in the testis in at least three mammalian orders, indicating that the Gapd-s gene appeared early in mammalian evolution. Using GAPD-deficient bacteria, mouse GAPD-S was shown to be capable of functioning as a glycolytic enzyme. Since GAPD has been proposed to be a key enzyme regulating glycolysis in spermatogenic cells, GAPD-S may represent a potential target for toxicological or contraceptive agents affecting fertility by interfering with glycolysis.

Animals↗
PubMed1989

Isolation, chromosomal localization, and nucleotide sequence of the human HOX 1.4 homeobox.

We have isolated a 14-kb DNA sequence containing a single homeobox from a low-stringency screen of a human genomic phage library by using heterologous homeobox sequences as probes. Chromosomal mapping of this clone using in situ hybridization to metaphase chromosomes and a panel of mouse x human somatic cell hybrids localized it to human chromosome 7p13-p15 in the region of the HOX 1 locus. We have sequenced the homeobox and show it has 100% identity to the deduced amino acid sequence of the mouse Hox-1.4 homeobox. We detect no restriction fragment length polymorphisms with the 14-kb clone, which is devoid of any moderately repetitive DNA sequences. This implies an inability of this region to tolerate change in sequence, consistent with a function highly conserved throughout evolution. The regions in the human genome where homeobox-containing loci reside share patterns of organization and sequence and have other gene loci in common, implying evolutionary constraints over these regions and providing clues on how they may have evolved.

Animals↗
PubMed2003

Differentiation and diversification of the follicular cells in flies: insight from the studies of the lower brachycerans' ovaries.

Although all dipteran species have ovaries of the same meroistic-polytrophic type, the structure of individual ovarian follicles (egg chambers) as well as the course of oogenesis in major dipteran taxa are highly diversified and often significantly different from the widely known Drosophila model. In this report we present results of the morphological studies of the ovary structure in the representatives of three families of lower brachycerans (Orthorrhapha) and compare them with the present knowledge of the processes that lead to the formation of a mature egg cell in the model dipteran, the cyclorrhaphan fruit fly, Drosophila melanogaster. The most conspicuous and developmentally significant differences between Drosophila and lower brachycerans were found in the events that accompany the differentiation and diversification of somatic follicular cells. Our observations indicate that the directed migrations of some follicular cells within the egg chamber and the ability of border cells to invade the nurse cell compartment can be considered as evolutionary novelties that evolved in the ancestors of higher brachycerans.

Animals↗
PubMed1999

Cloning and characterization of the rat and human phosducin-like protein genes: structure, expression and chromosomal localization.

We isolated and characterized the rat gene encoding phosducin-like protein (PhLP), a putative heterotrimeric G protein modulator. The transcription start site was mapped by primer extension. The putative promoter region lacked a TATA sequence but contained a potential initiator element. Two splice variants were identified by RT-PCR of rat brain RNA, potentially generating either the full length or an amino-truncated protein. Only the full-length protein was immunodetected in all mouse tissues surveyed. Comparison of the conceptual translation product of the rat PhLP gene with those from human and Drosophila clones shows a striking conservation in the amino-terminal region of PhLP from these species. This contrasts with the relatively low degree of homology between PhLP and phosducin in this region, suggesting a functional role for this portion of the PhLP protein. Finally, we mapped the human PhLP gene by PCR analysis of somatic cell hybrids and the Stanford G3 radiation hybrid panel. The human PhLP gene (PDCL) is located on chromosome 9, linked to the polymorphic markers D9S1876 and D9S1674 (66-71 cM).

Amino Acid Sequence↗
PubMed1997

Selection on the protein-coding genes of the TBE1 family of transposable elements in the ciliates Oxytricha fallax and O. trifallax.

TBE1s are "cut-and-paste" transposable elements found in high copy number in the germline genomes of the ciliates Oxytricha fallax and O. trifallax. TBE1 "family" sequence (sequence of mixed polymerase chain reaction products generated using primers that match roughly half the TBE1s in host whole-cell DNA) was obtained from both host species. Although family sequence autoradiograms represent thousands of different elements, they are as legible as those representing corresponding sequences of a single TBE1, implying that ideal polymorphisms are rare within the genes examined. Nucleotide polymorphisms among TBE1s (indicated by ambiguities in family sequence) are far more common at third than at first or second positions of codons of genes, implying that selection has conserved the amino acid sequences of these genes in the majority of TBE1s. Portions of the transposase gene and another TBE1 gene have been sequenced from 10 individual TBE1s. None of these portions is interrupted by stop codons or frameshifts, and, for both genes, pairwise comparisons of these sequences show that nonsynonymous differences are significantly less common than synonymous differences, again implicating conservative selection Phylogenetic analysis shows that multiple divergent lineages of TBE1s have evolved under this selection within O. fallax. All these results are unexpected for cut-and-paste transposons in eukaryotic hosts: since transposase encoded by intact elements presumably acts in trans, it can duplicate mutant copies (those that do not encode functional transposase) found in the same genome, and thus no selection is expected to maintain the transposase gene. The selection demonstrated here could act at transposition (if functional TBE1s are preferentially transposed) or at the level of the host (if the host's fitness depends on functional TBE1 genes). TBE1-encoded proteins might be responsible for the precise excision of TBE1s that occurs during development of the host somatic nucleus; selection on hosts for uninterrupted somatic genes would then translate into selection for TBE1 protein-coding competence. We suggest a method for distinguishing between these two classes of explanations by finding and analyzing divergent alleles of ancestral transposable element insertions.

Animals↗
PubMed2006

Telomerase activity coevolves with body mass not lifespan.

In multicellular organisms, telomerase is required to maintain telomere length in the germline but is dispensable in the soma. Mice, for example, express telomerase in somatic and germline tissues, while humans express telomerase almost exclusively in the germline. As a result, when telomeres of human somatic cells reach a critical length the cells enter irreversible growth arrest called replicative senescence. Replicative senescence is believed to be an anticancer mechanism that limits cell proliferation. The difference between mice and humans led to the hypothesis that repression of telomerase in somatic cells has evolved as a tumor-suppressor adaptation in large, long-lived organisms. We tested whether regulation of telomerase activity coevolves with lifespan and body mass using comparative analysis of 15 rodent species with highly diverse lifespans and body masses. Here we show that telomerase activity does not coevolve with lifespan but instead coevolves with body mass: larger rodents repress telomerase activity in somatic cells. These results suggest that large body mass presents a greater risk of cancer than long lifespan, and large animals evolve repression of telomerase activity to mitigate that risk.

Animals↗
PubMed1980

The "one day at a time" syndrome in post-transplant evolution: the regressive megalomanic model versus the progressive hypomanic model.

After kidney transplantation patients experience an initial period of euphoria which is usually followed by a phase of disillusionment and depression. At this point the "one day at a time syndrome" appears as an attitude of adaptation and defense. It is proposed that there are two dynamically and prognostically different varieties of this syndrome: A first type represents a regressive megalomanic defense whereby depressive anxiety concerning the rejection of the part-self represented by the graft is conscious but depressive anxiety concerning the eventual death of the whole self is omnipotently denied. This variety of the syndrome is related to a more negative prognosis both psychologically and somatically. The second type of the "one day at a time syndrome" is a progressive hypomanic defense whereby depressive anxiety concerning the rejection of the part-self represented by the graft is present and conscious but relative and does not preclude the conscious depressive anxiety concerning the eventual death of the whole self, which once acknowledged can gradually be mastered, permitting the pursuit of as pleasurable a life as possible. This variety of the syndrome is prognostically more favourable both physically and psychologically.

Adaptation, Psychological↗
PubMed2004

hTERT expression and prognosis in B-chronic lymphocytic leukemia.

BACKGROUND: In B-chronic lymphocytic leukemia (B-CLL), there is a need for molecular markers to predict the evolution of this heterogeneous disease in individual patients. The level of expression of the human telomerase reverse transcriptase (hTERT) gene has been associated with disease aggressiveness in human cancers. The purpose of the present study was to examine the prognostic significance of hTERT expression in B-CLL. PATIENTS AND METHODS: We used real-time reverse transcription-PCR to quantitate the amount of hTERT transcripts in mononuclear blood cells from 90 B-CLL patients. In addition, samples were analyzed for somatic mutations in the immunoglobulin V (IgV) genes. RESULTS: The expression of hTERT gene was detected in 59% of patients. The level of expression increased with advancing B-CLL stage (P=0.0064). Patients expressing hTERT showed significantly shorter survival than hTERT-negative patients (P=0.000034), irrespective of the disease stage. On average, the level hTERT mRNA expression was seven-fold higher in the poor-prognosis B-CLL group with unmutated IgV than in the Ig-mutated group (P<10(-7)). The level of hTERT expression discriminated the Ig-unmutated from Ig-mutated B-CLL in 89% of cases. CONCLUSION: Our data indicate that hTERT expression in B-CLL may serve as a molecular prognostic marker.

Adult↗
PubMed1993

Unique hexokinase messenger ribonucleic acids lacking the porin-binding domain are developmentally expressed in mouse spermatogenic cells.

We have identified cDNAs representing three hexokinase mRNAs (Hk1-sa, Hk1-sb, Hk1-sc) by screening mouse spermatogenic cell cDNA libraries with a mouse hepatoma cell line hexokinase (Hk1) cDNA [Arora KK, Fanciulli M, Pederson PL. J Biol Chem 1990; 265:6481-6488]. Although all three cDNAs show 99% identity to the somatic Hk1 cDNA sequence throughout most of their coding region, they differ from this sequence at the 5' end. They contain a common spermatogenic cell-specific sequence and a sequence unique to each cDNA immediately 5' to the common domain. However, they lack the porin-binding domain (PBD) present in this region of Hk1, used for binding to a pore-forming protein in the outer mitochondrial membrane. These observations appear to support a model proposed by others for hexokinase gene evolution in mammals. In addition, we found that Hk1-sb has an internal sequence that is not present in Hk1, Hk1-sa, or Hk1-sc. Moreover, Hk1-sa and Hk1-sb transcripts are developmentally expressed in mouse spermatogenic cells. Hk1-sa mRNA is first expressed during meiosis and continues to be present in postmeiotic germ cells, while the more abundant Hk1-sb mRNA is detected only in postmeiotic germ cells. These and other findings suggest that enzymes encoded by Hk1-sa, Hk1-sb, and Hk1-sc are present only in spermatogenic cells.

Aging↗
PubMed2006

Targeted deletion of MKK4 in cancer cells: a detrimental phenotype manifests as decreased experimental metastasis and suggests a counterweight to the evolution of tumor-suppressor loss.

Tumor-suppressors have commanded attention due to the selection for their inactivating mutations in human tumors. However, relatively little is understood about the inverse, namely, that tumors do not select for a large proportion of seemingly favorable mutations in tumor-suppressor genes. This could be explained by a detrimental phenotype accruing in a cell type-specific manner to most cells experiencing a biallelic loss. For example, MKK4, a tumor suppressor gene distinguished by a remarkably consistent mutational rate across diverse tumor types and an unusually high rate of loss of heterozygosity, has the surprisingly low rate of genetic inactivation of only approximately 5%. To explore this incongruity, we engineered a somatic gene knockout of MKK4 in human cancer cells. Although the null cells resembled the wild-type cells regarding in vitro viability and proliferation in plastic dishes, there was a marked difference in a more relevant in vivo model of experimental metastasis and tumorigenesis. MKK4(-/-) clones injected i.v. produced fewer lung metastases than syngeneic MKK4-competent cells (P = 0.0034). These findings show how cell type-specific detrimental phenotypes can offer a paradoxical and yet key counterweight to the selective advantage attained by cells as they experiment with genetic null states during tumorigenesis, the resultant balance then determining the observed biallelic mutation rate for a given tumor-suppressor gene.

Animals↗
PubMed2002

Protamine 1: protamine 2 stoichiometry in the sperm of eutherian mammals.

We have compared the relative proportion of protamine 1 (P1) and protamine 2 (P2) bound to DNA in the sperm of a variety of eutherian mammals to obtain insight into how these two proteins interact in sperm chromatin. Gel electrophoresis (combined with microdensitometry) and high performance liquid chromatography (HPLC) were used to determine the content of the two protamines, and the identity of each protein was confirmed by amino-terminal sequencing or amino acid analysis. The sperm of all species examined contained P1, but P2 was found to be present only in certain species. Unlike the fixed ratio of core histones that package DNA into nucleosomes in all somatic cells, the proportion of P2 present in mature sperm was found to be continuously variable from 0 to nearly 80%. These results show that P1 and P2 do not interact with each other or DNA to form a discrete complex or subunit structure that is dependent upon particular P1/P2 stoichiometries. Data obtained from a number of closely and distantly related species also indicate that while the P2 content of sperm chromatin is allowed to vary over a wide range during the course of evolution, the relative proportion of P1 and P2 are tightly regulated within a genus.

Animals↗
PubMed2001

Expression profiles and intergenic structure of head-to-head oriented Brca1 and Nbr1 genes.

Mouse and human Brca1/BRCA1 and Nbr1/NBR2 genes lie head-to-head, being transcribed from the opposite strands. The normal function of Brca1 is associated with DNA damage-related responses and the maintenance of genome integrity. Mutations of this gene are major risk factors for developing breast and ovarian cancers. The function of Nbr1 is unknown. Here we analyzed expression profiles of Brca1 and a newly identified, evolutionary conserved isoform of Nbr1(1a) transcript. In adult testis, the Nbr1(1a) mRNA showed an 18-fold higher steady-state level than the ubiquitous Nbr1(1b) form and its expression was confined mainly to spermatids. The expression profile of Brca1 paralleled that of Nbr1(1b). The Nbr1(1a) mRNA was not significantly expressed in normal somatic tissues, but was found on a list of cDNA clones from a human myeloblast cell line. The newly defined intergenic region (289 bp) between Nbr1 and Brca1 in the mouse and rat corresponds well to that of human BRCA1-NBR2 region.

Animals↗
PubMed1998

Expression of ribozymes in gene transfer systems to modulate target RNA levels.

The possibility of designing ribozymes to cleave any specific target RNA has rendered them valuable tools in both basic research and therapeutic applications. In the therapeutics area, they have been exploited to target viral RNAs in infectious diseases, dominant oncogenes in cancers and specific somatic mutations in genetic disorders. Most notably, several ribozyme gene therapy protocols for HIV patients are already in Phase 1 trials. More recently, ribozymes have been used for transgenic animal research, gene target validation and pathway elucidation.

Animals↗
PubMed1996

The factor IX gene as a model for analysis of human germline mutations: an update.

The variation generated by germline mutation is essential for evolution, but individuals pay a steep price in the form of Mendelian disease and genetic predisposition to complex disease. Indeed, the health of a species is determined ultimately by the rate of germline mutation. Analysis of the factor IX gene in patients with hemophilia B has provided insights into the human germline mutational process. Herein, seven topics will be reviewed with emphasis on recent advances: (i) proposed mechanisms of deletions, inversions, and insertions; (ii) discordant sex ratios of mutation and associated age effects; (iii) somatic mosaicism; (iv) founder effects; (v) mutation rates; (vi) the factor IX gene as a germline mutagen test; and (vii) cancer as a possible mechanism for maintaining a constant rate of germline mutation.

Age Factors↗
PubMed2003

[Priorities in fundamental research in gerontology: Russia contribution].

Current state-of-art and tendencies in the world gerontology and most important results of Russian researchers in the field are presented in the analytical review. Among the top achievements of the gerontology are: the identification of longevity genes in some animal species; Werner's progeria gene cloning; studies on genetic determinants of human longevity; discovery on evolution origin of species life span and the trade off with the reproduction; the theory of marginotomy and identification of the role of telomere and telomerase in cellular senescence; significant increase in the replicative life span of transfected with hTERT cells in vitro; the development of the free radical theory of aging; the evidence of the role of reactive oxygen species in DNA damage; the evidence of life span extension in genetically modified (transgenic, knockout or mutant) animals; the studies on the role of somatic mutations and DNA repair in mechanisms of aging, apoptosis and malignant transformation; the evidence of the life span extension by the exposure to calorie restriction diet from worms to primates and discovery of key mechanisms of the phenomena; the studies on the role of the pineal gland in the aging and the evidence of geroprotective activity of pineal peptides and melatonin. The prospects of the development of basic research on aging in Russia are reviewed as well.

Aged↗
PubMed2002

A neutral theory predicts multigenic aging and increased concentrations of deleterious mutations on the mitochondrial and Y chromosomes.

Population genetic forces have molded the constitution of the human genome over evolutionary time, and some of the most important parameters are the initial frequency of the allele, p, the effective population size, Ne, and the selection coefficient, s. There is considerable agreement among evolutionary gerontologists that the amplitude of -s is small for alleles that are Deleterious In Late Life (DILL), and thus DILL traits are effectively neutral and should be fixed in the human population in relationship to Ne and p. Even higher rates of fixation of deleterious mutations are predicted to occur in the two nonrecombinant genomes in humans, i.e., the Y chromosome and the mitochondrial genome, as a consequence of their lower Ne than autosomes, and the predicted higher rate of fixation of deleterious alleles on the Y may explain the reduced average life span of males vs. females. The high probability of fixation of neutral and mildly deleterious mutations in the mitochondrial genome explains in part its fast rate of evolution, the high observed frequency of mitochondrial disease in relationship to this genome's small size, and may be the underlying reason for the transfer of mitochondrial genes over evolutionary time to the nucleus. The predicted higher concentration of deleterious mutations on the mitochondrial genome could have some leverage to cause more dysfunction than that predicted by mitochondrial gene number alone, because of the essential role of mitochondrial gene function in multisubunit complexes, the coupling of mitochondrial functions, the observation that some mtDNA sequences facilitate somatic mutation, and the likelihood of deleterious mutations either increasing the production of or the sensitivity to mitochondrial ROS.

Aging↗
PubMed2004

The mouse juvenile spermatogonial depletion (jsd) phenotype is due to a mutation in the X-derived retrogene, mUtp14b.

The recessive juvenile spermatogonial depletion (jsd) mutation results in a single wave of spermatogenesis, followed by failure of type A spermatogonia to differentiate, resulting in adult male sterility. We have identified a jsd-specific rearrangement in the mouse homologue of the Saccharomyces cerevisiae gene UTP14, termed mUtp14b. Confirmation that mUtp14b underlies the jsd phenotype was obtained by transgenic bacterial artificial chromosome (BAC) rescue. We also identified a homologous gene on the Mus musculus X chromosome (MMUX) (mUtp14a) that is the strict homologue of the yeast gene, from which the intronless mUtp14b has been derived by retrotransposition. Expression analysis showed that mUtp14b is predominantly expressed in the germ line of the testis from zygotene through round spermatids, whereas mUtp14a, although well expressed in all somatic tissues, could be detected only in the germ line in round spermatids. In yeast, depletion of the UTP proteins impedes production of 18S rRNA, leading to cell death. We propose that the retroposed autosomal copy mUtp14b, having acquired a testis-specific expression pattern, could have provided a mechanism for increasing the efficiency and/or numbers of germ cells produced by meeting the need for more 18S rRNA and protein. Such a mechanism would be of obvious reproductive advantage and be strongly selected for in evolution. Consistent with this hypothesis is the finding of a similar X-autosome retroposition of UTP14 in human which seems to have arisen independently of that in rodents. In jsd homozygotes, which lack a functional copy of Utp14b, insufficient production of rRNA quickly leads to a cessation of spermatogenesis.

Animals↗