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PubMed2004

Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey.

Although jawless vertebrates are apparently capable of adaptive immune responses, they have not been found to possess the recombinatorial antigen receptors shared by all jawed vertebrates. Our search for the phylogenetic roots of adaptive immunity in the lamprey has instead identified a new type of variable lymphocyte receptors (VLRs) composed of highly diverse leucine-rich repeats (LRR) sandwiched between amino- and carboxy-terminal LRRs. An invariant stalk region tethers the VLRs to the cell surface by means of a glycosyl-phosphatidyl-inositol anchor. To generate rearranged VLR genes of the diversity necessary for an anticipatory immune system, the single lamprey VLR locus contains a large bank of diverse LRR cassettes, available for insertion into an incomplete germline VLR gene. Individual lymphocytes express a uniquely rearranged VLR gene in monoallelic fashion. Different evolutionary strategies were thus used to generate highly diverse lymphocyte receptors through rearrangement of LRR modules in agnathans (jawless fish) and of immunoglobulin gene segments in gnathostomes (jawed vertebrates).

Adaptation, Physiological↗
PubMed2004

Positive autoregulation of the Myocyte enhancer factor-2 myogenic control gene during somatic muscle development in Drosophila.

The myocyte enhancer factor-2 (MEF2) transcription factor plays a central role in the activation and maintenance of muscle gene expression in fruit flies and vertebrates. The mechanism of action and downstream target genes of MEF2 have been defined in considerable detail, but relatively little is known about the mechanisms that regulate MEF2 expression during muscle development. Here we demonstrate that MEF2 maintains its own expression in all differentiated muscle cell types during late embryonic and larval development in Drosophila by binding a conserved MEF2 site in a muscle-specific regulatory enhancer. Ectopic expression of Mef2 is sufficient to directly activate this enhancer in some, but not all, non-muscle cells. Furthermore, activation of the Mef2 enhancer normally in muscle cells and ectopically in non-muscle cells is dependent upon the integrity of the MEF2 binding site. These findings suggest an evolutionarily conserved mechanism whereby MEF2 can stabilize the muscle phenotype by sustaining its own expression through a myogenic autoregulatory loop.

Animals↗
PubMed1999

Enhanced evolvability in immunoglobulin V genes under somatic hypermutation.

Darwinian theory requires that mutations be produced in a nonanticipatory manner; it is nonetheless consistent to suggest that mutations that have repeatedly led to nonviable phenotypes would be introduced less frequently than others-if under appropriate genetic control. Immunoglobulins produced during infection acquire point mutations that are subsequently selected for improved binding to the eliciting antigen. We and others have speculated that an enhancement of mutability in the complementarity-determining regions (CDR; where mutations have a greater chance of being advantageous) and/or decrement of mutability in the framework regions (FR; where mutations are more likely to be lethal) may be accomplished by differential codon usage in concert with the known sequence specificity of the hypermutation mechanism. We have examined 115 nonproductively rearranged human Ig sequences. The mutation patterns in these unexpressed genes are unselected and therefore directly reflect inherent mutation biases. Using a chi2 test, we have shown that the number of mutations in the CDRs is significantly higher than the number of mutations found in the FRs, providing direct evidence for the hypothesis that mutations are preferentially targeted into the CDRs.

Arthritis↗
PubMed1998

Evolutionary conservation of a testes-specific proteasome subunit gene in Drosophila.

Proteasomes are large multisubunit particles that act as the proteolytic machinery for the ubiquitin-dependent proteolytic pathway. The core of this complex, the 20S proteasome, is made up of seven alpha-type and seven beta-type subunits, arranged in an (alpha1-alpha7)(beta1-beta7)(beta1-beta7)(alpha1-al pha7) configuration. Previous work had shown that there exist alternative isoforms of the Drosophila melanogaster alpha4-type subunit, encoded by two distinct genes, alpha4t1_dm and alpha4t2_dm, and that these are expressed exclusively in the germline of the testes. We sought to investigate the evolutionary conservation of this phenomenon by screening for orthologs of the alpha4-type gene family in the distantly related Drosophila species, D. virilis. We isolated the D. virilis orthologs of the somatically expressed gene, alpha4_dm, and the testes-specific gene, alpha4t2_dm. We failed to find an ortholog of the other testes-specific gene, alpha4t1_dm. The alpha4_dv gene maps to the X chromosome at 12A-C, its product shares 90% amino acid identity with alpha4_dm, and it is expressed at high levels in both males and females. The other gene, alpha4t_dv, encodes a protein most similar to the testes-specific alpha4t2_dm proteasome subunit (59% a.a. identity), and it maps to position 27 on chomosome 2. The expression of the alpha4t_dv gene is testes-specific, like that of alpha4t2_dm. The existence of testes-specific alpha4-type subunits in two widely diverged subgenera of Drosophila suggests that these subunit isoforms have important functional roles in spermatogenesis.

Amino Acid Sequence↗
PubMed2003

Conservation of a Pumilio-Nanos complex from Drosophila germ plasm to human germ cells.

Germ cells are the cells which ultimately give rise to mature sperm and eggs. In model organisms such as flies and worms, several genes that are required for formation and maintenance of germ cells have been identified and their interactions are rapidly being delineated. By contrast, little is known of the genes required for development of human germ cells and it is not clear whether findings from model organisms will translate into knowledge of human germ cell development, especially given observations that reproductive pathways may evolve more rapidly than somatic pathways. The Pumilio and Nanos genes have been especially well-characterized in model organisms and encode proteins that interact and are required for development of germ stem cells in one or both sexes. Here we report the first characterization of a mammalian Nanos homolog, human NANOS1 ( NOS1). We show that human NOS1 protein interacts with the human PUMILIO-2 (PUM2) protein via highly conserved domains to form a stable complex. We also show that in men, the NOS1 and PUM2 proteins are particularly abundant in germline stem cells. These observations mirror those in distant species and document for the first time a conserved protein-protein interaction in germ cells from flies to humans. These results suggest the possibility that the interaction of PUM2 and NOS1 may play a conserved role in germ cell development and maintenance in humans as in model organisms.

Animals↗
PubMed2004

Selection in modular organisms: is intraclonal variation in macroalgae evolutionarily important?

Theoretical and practical difficulties occur when defining the units of selection in modular organisms that grow by iteration of repeated parts (modules). Modules may become physically autonomous through fragmentation and may vary because of genetic variation arising in somatic cell lineages. Since cells destined for gamete production are not sequestered in early development, heritable variation and selection among asexual progeny are possible. We used the branching red macroalgae Delisea pulchra and Asparagopsis armata to test whether modules fulfill three fundamental criteria for units of selection: that they replicate, that they display heritable variation, and that selective agents distinguish among the variants. We detected significant phenotypic variation among modules for fitness-related traits (growth, secondary metabolite concentrations, and rates of tissue loss to herbivory) in each species and significant heritability estimates for secondary metabolite production and tissue loss to herbivory in D. pulchra. Variation in growth rate among A. armata modules was largely phenotypic with small but important estimates of genetic variation. Our results indicate that selection may indeed act on phenotypic variation among modules within individuals and that this process may effect evolutionary change within asexual lineages given sufficient genetic variation in the traits examined.

Animals↗
PubMed1998

Novel immunogenic antigen homologous to hyaluronidase in meningioma.

By screening a meningioma expression library with autologous serum we identified four cDNA clones representing a novel gene with striking homology to Caenorhabditis elegans hyaluronidase as indicated by BLASTP analysis. In humans hyaluronidase has been implicated in cancer development and three human genes are known to encode proteins with hyaluronidase activity. None of the human genes, however, showed any homology at the nucleotide or amino acid sequence level to the newly isolated antigen we termed meningioma expressed antigen 5 (MGEA5). Somatic cell hybrid mapping and fluorescence in situ hybridization mapped the gene for MGEA5 to chromosomal band 10q24.1-q24.3. Reverse transcription (RT)-PCR and northern blot hybridization revealed expression of the gene encoding MGEA5 in several meningioma and additional human tissues. Expression analysis also indicated an alternative splicing event giving rise to a shorter and altered transcript termed MGEA5s. The expression of MGEA5 and MGEA5s as fusion proteins revealed an approximate molecular weight of 92 and 54 kDa, respectively. Using heterologous sera we found antibodies against MGEA5s in five out of 23 meningioma patients, whereas no immune reaction was detected in 12 control sera from healthy individuals. Confirmation of hyaluronidase activity was independently achieved by turbidometric analysis and a gel matrix assay. A model for involvement of the novel hyaluronidase gene in meningioma development is proposed.

Acetylglucosaminidase↗
PubMed2006

Systematic variation in mRNA 3'-processing signals during mouse spermatogenesis.

Gene expression and processing during mouse male germ cell maturation (spermatogenesis) is highly specialized. Previous reports have suggested that there is a high incidence of alternative 3'-processing in male germ cell mRNAs, including reduced usage of the canonical polyadenylation signal, AAUAAA. We used EST libraries generated from mouse testicular cells to identify 3'-processing sites used at various stages of spermatogenesis (spermatogonia, spermatocytes and round spermatids) and testicular somatic Sertoli cells. We assessed differences in 3'-processing characteristics in the testicular samples, compared to control sets of widely used 3'-processing sites. Using a new method for comparison of degenerate regulatory elements between sequence samples, we identified significant changes in the use of putative 3'-processing regulatory sequence elements in all spermatogenic cell types. In addition, we observed a trend towards truncated 3'-untranslated regions (3'-UTRs), with the most significant differences apparent in round spermatids. In contrast, Sertoli cells displayed a much smaller trend towards 3'-UTR truncation and no significant difference in 3'-processing regulatory sequences. Finally, we identified a number of genes encoding mRNAs that were specifically subject to alternative 3'-processing during meiosis and postmeiotic development. Our results highlight developmental differences in polyadenylation site choice and in the elements that likely control them during spermatogenesis.

3' Untranslated Regions↗
PubMed2000

Structure and function of the type 1 insulin-like growth factor receptor.

The type 1 insulin-like growth factor receptor (IGF-1R), a transmembrane tyrosine kinase, is widely expressed across many cell types in foetal and postnatal tissues. Activation of the receptor following binding of the secreted growth factor ligands IGF-1 and IGF-2 elicits a repertoire of cellular responses including proliferation, and the protection of cells from programmed cell death or apoptosis. As a result, signalling through the IGF-1R is the principal pathway responsible for somatic growth in foetal mammals, whereas somatic growth in postnatal animals is achieved through the synergistic interaction of growth hormone and the IGFs. Forced overexpression of the IGF-1R results in the malignant transformation of cultured cells: conversely, downregulation of IGF-1R levels can reverse the transformed phenotype of tumour cells, and may render them sensitive to apoptosis in vivo. Elevated levels of IGF-IR are observed in a variety of human tumour types, whereas epidemiological studies implicate the IGF-1 axis as a predisposing factor in the pathogenesis of human breast and prostate cancer. The IGF-1R has thus emerged as a therapeutic target for the development of antitumour agents. Recent progress towards the elucidation of the three-dimensional structure of the extracellular domain of the IGF-1R represents an opportunity for the rational assembly of small molecule antagonists of receptor function for clinical use.

Amino Acid Sequence↗
PubMed1992

Environmental effects of genotoxins (eco-genotoxicology).

Genotoxic chemicals can damage the genetic material of humans as well as that of organisms living in the environment. With respect to adverse effects, alterations induced in the germ line, leading to alterations in the genetic make-up of populations, are of primary concern in ecosystems, because somatic changes, even if they lead to a loss of individuals, will not be critical in populations with a large reproductive surplus. This is different in human toxicology where genetic alterations in germ cells as well as in somatic cells of any individual are of concern. Increased frequencies of mutations and related genetic alterations in the gene pools of individual species or populations in ecosystems have to be judged against the background of spontaneous mutations that have enabled species to survive and adapt in changing environments since the beginning of life on our planet, and which have played an important role as the substrate for evolutionary developments. Examples of the selection of altered phenotypes (and genotypes) in response to environmental pollution and environmental stress are melanism in moth populations, metal resistance in plants, insecticide resistance in insects and malaria resistance in humans. Pollution, in general, can represent a stress factor selectively leading to a change in genetic make-up. In addition, environmental genotoxins can directly alter gene pools. A change in the genetic constitution may be advantageous for certain populations living in stressful conditions, but may present a disadvantage for others, including man.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Phylogenetic conservation of chromosome numbers in Actinopterygiian fishes.

The genomes of ray-finned fishes (Actinopterygii) are well known for their evolutionary dynamism as reflected by drastic alterations in DNA content often via regional and whole-genome duplications, differential patterns of gene silencing or loss, shifts in the insertion-to-deletion ratios of genomic segments, and major re-patternings of chromosomes via non-homologous recombination. In sharp contrast, chromosome numbers in somatic karyotypes have been highly conserved over vast evolutionary timescales - a histogram of available counts is strongly leptokurtic with more than 50% of surveyed species displaying either 48 or 50 chromosomes. Here we employ comparative phylogenetic analyses to examine the evolutionary history of alterations in fish chromosome numbers. The most parsimonious ancestral state for major actinopterygiian clades is 48 chromosomes. When interpreted in a phylogenetic context, chromosome numbers evidence many recent instances of polyploidization in various lineages but there is no clear indication of a singular polyploidization event that has been hypothesized to have immediately preceded the teleost radiation. After factoring out evident polyploidizations, a correlation between chromosome numbers and genome sizes across the Actinopterygii is marginally statistically significant (p = 0.012) but exceedingly weak (R (2) = 0.0096). Overall, our phylogenetic analysis indicates a mosaic evolutionary pattern in which the forces that govern labile features of fish genomes must operate largely independently of those that operate to conserve chromosome numbers.

Amphibians↗
PubMed2004

Ontogenic changes of the GABAergic system in the embryonic mouse spinal cord.

Numerous studies have demonstrated an excitatory action of GABA early in development, which is likely to play a neurotrophic role. In order to better understand the role of GABA in the mouse spinal cord, we followed the evolution of GABAergic neurons over the course of development. We investigated, in the present study, the ontogeny of GABA immunoreactive (GABA-ir) cell bodies and fibers in the embryonic mouse spinal cord at brachial and lumbar levels. GABA-ir somata were first detected at embryonic day 11.5 (E11.5) exclusively at brachial level in the marginal zone. By E13.5, the number of GABAergic neurons sharply increased throughout the extent of the ventral horn both at brachial and lumbar level. Stained perikarya first appeared in the future dorsal horn at E15.5 and progressively invaded this area while they decreased in number in the presumed ventral gray matter. At E12.5, E13.5 and E15.5, we checked the possibility that ventral GABA-ir cells could belong to the motoneuronal population. Using a GABA/Islet-1/2 double labeling, we did not detect any double-stained neurons indicating that spinal motoneurons do not synthesize GABA during the course of development. GABA-ir fibers also appeared at the E11.5 stage in the presumptive lateral white matter at brachial level. At E12.5 and E13.5, GABA-ir fibers progressively invaded the ventral marginal zone and by E15.5 reached the dorsal marginal zone. At E17.5 and postnatal day 0 (P0), the number of GABA-ir fibers declined in the white matter. Finally, by P0, GABA immunoreactivity that delineated somata was mainly restricted to the dorsal gray matter and declined in intensity and extent. The ventral gray matter exhibited very few GABA-ir cell bodies at this neonatal stage of development. The significance of the migration of somatic GABA immunoreactivity from ventral to the dorsal gray matter is discussed.

Animals↗
PubMed2004

Novel human testis-specific histone H2B encoded by the interrupted gene on the X chromosome.

Testis-specific histones are synthesized and accumulated at specific stages of mammalian spermatogenesis. Their proposed functions range from facilitation of the replacement of somatic histones by protamines to epigenetic control of gene transcription. Several testis histone variants were characterized in mouse and rat; however, few are known in humans. Here we report the identification and characterization of a novel human histone 2B gene (TH2B-175) located at Xq22.2, which encodes a highly divergent H2B variant. The TH2B-175 gene contains two introns and is transcribed exclusively in testis, where the spliced polyadenylated mRNA was detected. Genomic PCR, Southern blot analysis, and BLAST-based searches indicate that TH2B-175 evolved in the primate lineage or has been lost in rodents. In transfected Chinese hamster cells, GFP-tagged TH2B-175 targeted to large fluorescent bodies that partially colocalize with the interstitial telomeric blocks. Therefore, TH2B-175 may have telomere-associated functions and participate in the telomere-binding complex in the human sperm [1].

Alternative Splicing↗
PubMed2006

Redundancy and recombination in the Echinococcus AgB multigene family: is there any similarity with protozoan contingency genes?

Numerous genetic variants of the Echinococcus antigen B (AgB) are encountered within a single metacestode. This could be a reflection of gene redundancy or the result of a somatic hypermutation process. We evaluate the complexity of the AgB multigene family by characterizing the upstream promoter regions of the 4 already known genes (EgAgB1-EgAgB4) and evaluating their redundancy in the genome of 3 Echinococcus species (E. granulosus, E. ortleppi and E. multilocularis) using PCR-based approaches. We have ascertained that the number of AgB gene copies is quite variable, both within and between species. The most repetitive gene seems to be AgB3, of which there are more than 110 copies in E. ortleppi. For E. granulosus, we have cloned and characterized 10 distinct upstream promoter regions of AgB3 from a single metacestode. Our sequences suggest that AgB1 and AgB3 are involved in gene conversion. These results are discussed in light of the role of gene redundancy and recombination in parasite evasion mechanisms of host immunity, which at present are known for protozoan organisms, but virtually unknown for multicellular parasites.

Alleles↗
PubMed1993

Phylogenetic diversification of immunoglobulin genes and the antibody repertoire.

Immunoglobulins are encoded by a large multigene system that undergoes somatic rearrangement and additional genetic change during the development of immunoglobulin-producing cells. Inducible antibody and antibody-like responses are found in all vertebrates. However, immunoglobulin possessing disulfide-bonded heavy and light chains and domain-type organization has been described only in representatives of the jawed vertebrates. High degrees of nucleotide and predicted amino acid sequence identity are evident when the segmental elements that constitute the immunoglobulin gene loci in phylogenetically divergent vertebrates are compared. However, the organization of gene loci and the manner in which the independent elements recombine (and diversify) vary markedly among different taxa. One striking pattern of gene organization is the "cluster type" that appears to be restricted to the chondrichthyes (cartilaginous fishes) and limits segmental rearrangement to closely linked elements. This type of gene organization is associated with both heavy- and light-chain gene loci. In some cases, the clusters are "joined" or "partially joined" in the germ line, in effect predetermining or partially predetermining, respectively, the encoded specificities (the assumption being that these are expressed) of the individual loci. By relating the sequences of transcribed gene products to their respective germ-line genes, it is evident that, in some cases, joined-type genes are expressed. This raises a question about the existence and/or nature of allelic exclusion in these species. The extensive variation in gene organization found throughout the vertebrate species may relate directly to the role of intersegmental (V<==>D<==>J) distances in the commitment of the individual antibody-producing cell to a particular genetic specificity. Thus, the evolution of this locus, perhaps more so than that of others, may reflect the interrelationships between genetic organization and function.

Animals↗
PubMed2004

Functional conservation and divergence of intersex, a gene required for female differentiation in Drosophila melanogaster.

In Drosophila melanogaster, somatic sexual differentiation is regulated by a well characterized genetic hierarchy, by which the ratio of X chromosomes to autosomes (X:A) ultimately directs the deployment of sex-specific transcription factors encoded by doublesex (dsx) and fruitless (fru). In other dipterans, the X:A ratio is not the primary sex-determination signal. Correspondingly, the Drosophila hierarchy is not fully conserved. In all non-drosophilid fly species examined, Sex-lethal (Sxl), the master switch at the top of the Drosophila hierarchy, does not control somatic sex. This rapid divergence contrasts with the apparently deep conservation of dsx, which in Drosophila controls virtually all aspects of somatic sex except for male courtship behavior (which is controlled by fru). Sex-specific dsx mRNAs have been reported in Diptera, Lepidoptera and Hymenoptera, and dsx homologs in nematodes and mammals are required for aspects of male differentiation. Thus, it seems that the bottom of the hierarchy is rather ancient, especially compared with the top. To test this, we cloned insect and vertebrate homologs of the Drosophila gene intersex (ix), which functions together with dsx at the bottom of the hierarchy in females. When expressed in D. melanogaster females mutant at the endogenous ix gene, dipteran and lepidopteran ix homologs restore proper sexual differentiation, substantiating the hypothesis that ix, like dsx, is broadly conserved. When the mouse homolog is expressed it produces a dominant-negative phenotype suggesting partial functional divergence. Our results raise the possibility that a functional association between ix- and dsx-related gene products existed before the origin of the bifunctional dsx gene used in insect sex determination.

Amino Acid Sequence↗
PubMed2004

To age or not to age.

According to the antagonistic pleiotropy theory of ageing, natural selection has favoured genes conferring short-term benefits to the organism at the cost of deterioration in later life. The 'disposable soma' theory expresses this as a life-history strategy in which somatic maintenance is below the level required to prevent ageing, thus enabling higher immediate fertility. It has been argued that a non-ageing strategy will always be bettered by a low but non-zero rate of ageing, because the costs of such ageing will be felt only in the distant future when they are of negligible importance. Here, we examine this argument critically. We find that a non-ageing strategy will be locally optimal if, in the presence of ageing, the onset of deterioration is sufficiently rapid or early. Conversely, ageing will be optimal if deterioration is sufficiently slow or late. As the temporal profile of ageing changes from one of steady deterioration to one involving a sudden loss of vitality after a period of little or no decline, the conditions for a non-ageing strategy to be locally optimal become progressively more stringent. But for all forms of profile considered, conditions can be found for which a strategy involving no ageing is locally optimal.

Aging↗
PubMed1992

Evolutionary conservation of a germ cell-specific lamin persisting through mammalian spermiogenesis.

We had identified earlier a germ cell-specific lamin of 60 kDa in rat which is related to somatic lamin B. This polypeptide was shown to be the only major component organizing the lamina structure of round spermatids. In the present study, we find that this 60-kDa polypeptide persists in the testicular and epididymal sperms of rat. We also show, by indirect immunofluorescence studies, that the 60-kDa protein is antigenically conserved in the germ cells of grasshopper, rooster, and frog and in plant meiocytes. The distribution of fluorescence among the various germ cell populations shows that the antigen is located around the nuclear cortex of pre- and postmeiotic germ cells, while it is distributed all over the pachytene nuclei. The anti-60-kDa polyclonal antibodies also reacted with a 60-kDa polypeptide in the Western blot analysis of nuclear matrix proteins of grasshopper germ cells. The similar fluorescent localization pattern of the antigen observed in various eukaryotic species strongly suggests that this germ cell-specific lamin may play a very crucial role during meiotic prophase, particularly during homologous chromosome pairing and recombination.

Animals↗