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At least 1,279 records · Page 71Linked to original sources
PubMed2006

Evolution of hepatitis C virus quasispecies in children with chronic hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) circulates as a mixture of different but closely related genomes: this quasispecies nature could be essential for virus persistence and could induce resistance to interferon therapy. Since little is known on the behavior of HCV quasispecies in children and adolescents with chronic hepatitis C, we analyzed the virus population in six untreated children during a 5-year follow-up. METHODS: Six children aged 1-8 years, infected early in life with HCV, were included in the study. From each of them, 2 or 3 sequential serum samples obtained over a 5-year follow-up period were examined. The HCV quasispecies heterogeneity and diversity in the E2 hypervariable region-1 (HVR-1) were analyzed among samples by the heteroduplex mobility assay, and the distance between variants was estimated by the heteroduplex mobility ratio (HMR). RESULTS: The HCV population was initially highly homogeneous in all six children. During follow-up, diversification of HVR-1 leading to a more complex viral population occurred in all cases, and was particularly evident in the three older children (HMR: 0.82-0.54). Changes in the HVR-1 sequence occurred without relation to the profile of ALT and HCV-RNA levels. CONCLUSIONS: HCV quasispecies diversification is a common event during chronic hepatitis C in childhood. Host and environmental pressure could be major determinants. The increasing viral heterogeneity could impair the response to antiviral therapy, thus indicating a rationale for early antiviral treatment in children with chronic hepatitis C.

Child↗
PubMed1986

Myosin expression and specialization among the earliest muscle fibers of the developing avian limb.

Monoclonal antibodies specific to the light- and heavy-chain subunits of chicken skeletal muscle myosin have been used to identify fast and slow myosin-containing fibers in the thigh muscles of embryonic and adult chickens and to determine when in development diversification of muscle fiber types first occurs. Primary generation fibers which expressed different MLC and MHC types were evident within the dorsal and ventral premuscle masses and in the first muscles to form in the limb. These early embryonic muscle fiber types became distributed among and within the individual muscles of the thigh in a characteristic spatial pattern which served as a "blueprint" for guiding future muscle development and predicting the future fiber composition of the muscle. Despite the continuous addition of muscle fibers to the limb throughout development, the pattern remained unchanged. Neither the time of appearance, initial specialization, nor characteristic distribution of these primary fiber types within the limb was altered during the early embryonic period by chronic neuromuscular paralysis induced by D-tubocurarine. In contrast, muscles at later stages of embryonic development were markedly affected by such treatments and underwent atrophy and loss of differential staining characteristics. These results demonstrate that diversification of fibers in terms of myosin content is one of the earliest events in the formation of these muscles and suggest that the development of avian muscles be divided into two phases: an embryonic phase during which fibers of differing myosin content appear independently of innervation to become distributed in a specific topographic pattern within each muscle as it forms, followed by a fetal phase during which innervation becomes essential for maintaining this pattern and modulating the myosin content of its fibers.

Animals↗
PubMed1991

Myosin I: a new insight into the mechanism and cellular significance of actin-based motility.

From our work on brush border myosin I structure, activity, regulation, and function, we can begin to understand the significance of the diversification of myosin proteins. While myosin I and II proteins retain conserved elements of structure that may dictate their similar mechanisms of motility and actin-activated MgATPase activity, their unique structures may provide the basis for the distinct localization and regulation of the two myosin types. How does the tropomyosin-inhibited actin-binding site of myosin I differ from that of the tropomyosin-activated myosin II actin-binding site? What elements of the sites of interaction of the 110K-protein and calmodulin contribute to the conserved, light-chain dependent coupling of MgATPase activity to translocation and which confer the novel calcium regulation of dissociation in vitro? It seems that the evolutionary demand for diversification of cellular motility functions has been met, at least in the actin-based system, by the evolution of isoforms tailored in structure, activity, regulation, and localization to serve complementary needs.

Actins↗
PubMed1991

Somatic generation of diversity in a mammalian primary lymphoid organ: the sheep ileal Peyer's patches.

Ileal Peyer's patches (IPPs) in the sheep are composed of tightly packed follicles in which surface IgM-positive B cells proliferate and can be exported to the periphery. We report that the light chain rearrangement pattern in a single IPP follicle is much more restricted than in the entire tissue, which indicates that, as in the chicken bursa, ongoing rearrangement does not take place in this organ. Moreover, we show that B cells extensively diversify their antigen receptor while proliferating in IPP follicles. Sequencing of part of the V lambda locus indicates that this diversification is not achieved by gene conversion, but rather by untemplated somatic mutation and intense selective pressure. These results strongly imply that sheep IPPs behave as a bursa-equivalent, primary lymphoid organ of diversification and that somatic point hypermutation, which is known to proceed during secondary immune responses, can also generate an antibody repertoire.

Amino Acid Sequence↗
PubMed1993

Recombination activating genes-1 and -2 of the rabbit: cloning and characterization of germline and expressed genes.

The recombination activating genes RAG-1 and RAG-2 appear to be necessary components of the machinery needed for the Ig or TCR gene rearrangements that occur in developing B and T lymphocytes. In addition RAG-2 has been implicated in the process of V-gene diversification by somatic gene conversion in the chicken. Because gene conversion may be an important mechanism for V-gene diversification in the rabbit, we cloned the rabbit RAG locus and characterized the coding regions of the genomic RAG-1 and RAG-2. In addition, we sequenced cDNAs encompassing the RAG-2 coding region, part of the RAG-2 5' untranslated region and a 967 bp fragment of cDNA from the RAG-1 coding region. Northern analysis revealed a RAG-1 mRNA of 6.6 kb which is similar in size to the RAG-1 mRNA reported previously for other species, and a major species of RAG-2 mRNA of 4.4 kb, which is larger than that from the mouse (2.2 kb). Analysis of the genomic clones showed that, as in other species, the RAG-1 and RAG-2 genes are oriented so as to be convergently transcribed. The DNA sequence analysis showed that the rabbit RAG-1 coding region is 91, 85 and 72% identical to human, mouse and chicken, respectively. The deduced RAG-1 protein sequence for rabbit is 93, 90 and 78% identical to human, mouse and chicken. Comparison of the rabbit RAG-2 coding region revealed 90, 87 and 71% identity to human, mouse and chicken, respectively, at the nucleotide level, and 91, 90 and 72% at the protein level. Although there is considerable conservation of sequence between species, we obtained evidence for allelic forms of the rabbit RAG locus both by Southern analyses and by sequencing. A remarkable degree of polymorphism was found in our rabbit colonies, particularly in the region 3' of the rabbit RAG-2 coding region. A 5' cDNA probe hybridized with one or more additional fragments that are not detected with the coding region probes, suggesting that the 5' cDNA sequence results from splicing of one or more upstream exons.

Amino Acid Sequence↗
PubMed1996

Rearrangement/hypermutation/gene conversion: when, where and why?

Diversification strategies for immunoglobulins vary widely in different species. Here, Jean-Claude Weill and Claude-Agnès Reynaud argue that V(D)J recombination arose as a means for achieving allelic exclusion rather than diversity, and postulate that the choice of a diversification strategy is selected along with a specific site of B-cell differentiation. They propose that somatic mutation and gene conversion represent analogous molecular strategies occurring in specific chromatin accessibility contexts.

Animals↗
PubMed1995

Differences in peptide binding of DR11 and DR13 microvariants demonstrate the power of minor variation in generating DR functional diversity.

The influence of subtle HLA diversification on antigen binding was explored using murine L-cell transfectants expressing alleles in the DR11/DR13 family and a panel of peptides. The levels of binding among this family of DR microvariants were as diverse as the levels of binding among distantly related DR molecules. Even a single amino acid difference between allelic products had a profound effect on peptide binding. Specific amino acid substitutions, generated using site-directed mutagenesis to alter polymorphic residues at DR beta 32, 37, 57, 58, 67, 71, 86, demonstrated that a specific change within the context of a single DR molecule differed in its effect on the binding of specific peptides. In addition, a specific amino acid substitution had a differential effect on the binding level of a peptide to different DR molecules. Each polymorphic amino acid appeared to play a role in the binding of some peptide. Studies using the amino-terminal portion of the invariant chain CLIP peptide suggested that this peptide may offer varying degrees of competition in the binding of the cellular peptide pool in cells expressing different DR molecules. Finally, the results obtained with two strain-specific peptides from an immunodominant region of a malarial parasite show differential binding to two DR13 molecules, suggesting that immune pressure may promote parasite diversity. A dynamic interaction may exist between pathogens and the immune system shaping the HLA profile in a population. Thus even subtle diversification of the HLA molecules, possibly pathogen driven, can have a substantial effect on peptide binding and immune recognition.

Alleles↗
PubMed1987

Chemical selection, diversity, teleonomy and the second law of thermodynamics. Reflections on Eigen's theory of self-organization of matter.

Two fundamental properties of animate matter, specific complexity and purposeful organization (teleonomy), are traced to their origin, applying Eigen's theory of self-organization of matter. Template-replicating copolymers possess the three dynamic properties that are essential for prebiotic evolution: autocatalysis, diversification and selection. By autocatalysis, even a single microscopic molecule replicates exponentially to macroscopic quantities. By diversification, it extends to a divergent distribution of such molecules. By selection, the distribution converges to a 'quasi-species' that possesses properties like 'survival' and 'adaptation' to its environment. These are teleonomic properties that evolved from a nonteleonomic distribution by selection. Alternating divergent and convergent courses of chemical evolution lead such distributions to ever-growing complexity, including mutual catalytic interactions between the template-replicating copolymers and their chemical environment. Thus, chemical evolution may have started from even a single step, a de novo synthesis of a template-replicating copolymer, and arrived at a primordial living cell, just as biological evolution has started from a primordial cell and arrived at the biological world of today.

DNA Replication↗
PubMed1992

An analysis of partial 28S ribosomal RNA sequences suggests early radiations of sponges.

Sequences from the 5' end terminal part of 28S ribosomal RNA were obtained and compared for 22 animals belonging to all diploblastic phyla and for a large number of representatives of triploblastic Metazoa and protists. Phylogenetic analyses undertaken using different methods showed deep radiations of phyla such as Ctenophora, Cnidaria and Placozoa but also for groups of Porifera of low taxonomic rank. Short internodes between these radiations suggested an early rapid diversification of diploblasts. A long internal branch preceding the diversification of all triploblasts analyzed could be explained either by a long period with a single ancestor or by the extinction of the earliest triploblastic radiations. Finally some unexpected relationships were revealed among Porifera.

Animals↗
PubMed2004

Composition and functional specificity of SWI2/SNF2 class chromatin remodeling complexes.

By regulating the structure of chromatin, ATP-dependent chromatin remodeling complexes (remodelers) perform critical functions in the maintenance, transmission and expression of the eukaryotic genome. Although all known chromatin-remodeling complexes contain an ATPase as a central motor subunit, a number of distinct classes have been recognized. Recent studies have emphasized a more extensive functional diversification among closely related chromatin remodeling complexes than previously anticipated. Here, we discuss recent insights in the functional differences between two evolutionary conserved subclasses of SWI/SNF-related chromatin remodeling factors. One subfamily comprises yeast SWI/SNF, fly BAP and mammalian BAF, whereas the other subfamily includes yeast RSC, fly PBAP and mammalian PBAF. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses of SWI/SNF remodelers. In particular, we will focus on the roles of specific subunits in developmental gene control and human diseases. Recent findings suggest that functional diversification among SWI/SNF complexes allows the eukaryotic cell to fine-tune and integrate the execution of diverse biological programs involving the expression, maintenance and duplication of its genome.

Actins↗
PubMed2026

Comparative genomic and proteomic analysis reveals orthogroup structured evolution of tick protease inhibitors.

Protease inhibitors (PIs) play central roles in regulating endogenous proteolysis and host-parasite interactions in ticks. However, the evolutionary architecture underlying their diversification across tick lineages remains insufficiently resolved. Here, we performed a genome-wide comparative analysis of predicted proteomes from 14 tick species to systematically characterize PI repertoires. In total, 4931 putative PIs were identified and grouped into 20 families using the MEROPS classification system. Further, PI families such as Antistasin, WAP-type, and Pacifastin, which have not previously been systematically reported in tick genomes, were classified. Orthogroup inference demonstrated that PI expansion is structured at the level of evolutionary lineages rather than uniformly across families. By stratifying orthogroups according to duplication burden and taxonomic conservation, we identified a broadly conserved single-copy core under strong purifying selection. Motif level analysis of serpin reactive center loops further revealed conservation of inhibitory specificity within single copy orthogroups and diversification of key functional residues in duplication-associated lineages. Integration of secretion prediction and tissue-resolved proteomics from Hyalomma anatolicum and Rhipicephalus microplus demonstrated that evolutionary stratification is reflected at the protein level. Together, these findings provide an orthogroup-resolved evolutionary framework linking duplication dynamics, molecular evolution, and tissue-level protein deployment. This integrative approach offers a systematic basis for prioritizing conserved and diversified PI lineages for future functional and anti-tick intervention studies.

Animals↗
PubMed2026

Distributed clonal deletion prevents autoimmune disease progression.

Self-reactive B cells arise during development and can increase pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that self-tolerance is enforced through temporally distinct mitochondrial outer membrane permeabilization (MOMP) checkpoints. Using conditional Bcl-2 expression to inhibit MOMP either from B cell development or activation, we find that early inhibition permits survival of autoreactive B cells after peripheral egress, expanding the pool available for activation and AID-dependent diversification. This results in broadened class-switched IgG autoreactivity, complement activation, kidney pathology, and drives lethal autoimmune disease. In contrast, post-activation MOMP inhibition promotes autoreactive cell accumulation and autoantibody production but causes limited tissue damage and normal survival. Together, these findings support a Distributed Clonal Deletion Model in which temporally distinct checkpoints cooperate to constrain autoimmune disease progression.

AID↗
PubMed2026

From colonization to infection: Genomic evolution of Clostridioides difficile pathogenesis.

Clostridioides difficile is a spore-forming, toxin-producing anaerobe that is a leading cause of healthcare-associated infections. Its success as a pathogen reflects a complex interplay between bacterial evolution, virulence regulation, ecological adaptation, environmental selection, and host susceptibility. Comparative genomics has revealed deep C. difficile lineage diversification, driven by mobile genetic elements and selective pressures from antibiotics and host environments. These events affect strain-specific virulence by shaping the organization and regulation of the pathogenicity toxin loci, metabolic adaptations for nutrient utilization, and enhanced spore resilience. This review integrates evolutionary and genomic perspectives to illustrate how adaptive diversification has sculpted C. difficile pathogenesis and epidemic success.

CP: microbiology↗
PubMed2006

Antibody repertoire development in the sheep.

The model of immunoglobulin (Ig) repertoire diversification in sheep has evolved dramatically in recent years. A process thought to involve the rearrangement of a very limited number of variable (V), diversity (D) and joining (J) segments followed by intense, antigen (Ag)-independent, somatic hypermutation is now known to be less recombinatorially restrictive and to involve fewer mutational events. Although mutation rates are now lower than previously thought, the somatic hypermutation process itself is no less critical to the development of the primary Ig repertoire in sheep. Recent studies have shown that those B cells that fail to mutate will die via apoptosis. Much of the V(D)J rearrangement is thought to occur in the fetal liver and spleen prior to development of the ileal Peyer's patch (PP) at approximately day 100 of gestation. Although de novo Ig rearrangement likely does not occur in the ileal PP, this tissue is a site of massive B-cell proliferation, selection and Ig diversification through somatic hypermutation.

Animals↗
PubMed2006

Antibodies, immunoglobulin genes and the bursa of Fabricius in chicken B cell development.

The bursa of Fabricius is critical for the normal development of B lymphocytes in birds. It is productively colonized during embryonic life by a limited number of B cell precursors that have undergone the immunoglobulin gene rearrangements required for expression of cell surface immunoglobulin. Immunoglobulin gene rearrangement occurs in the absence of terminal deoxynucleotidyl transferase and generates minimal antibody diversity. In addition, observations that immunoglobulin heavy and light chain variable gene rearrangement occur at the same time and that allelic exclusion of immunoglobulin expression is regulated at the level of variable region gene rearrangement provide a striking contrast to rodent and primate models of immunoglobulin gene assembly. Following productive colonization of the bursa, developing B cells undergo rapid proliferation and the immunoglobulin V region genes that generate the specificity of the B cell surface immunoglobulin receptor undergo diversification. Immunoglobulin diversity in birds is generated by somatic gene conversion events in which sequences derived from upstream families of pseudogenes replace homologous sequences in unique and functionally rearranged immunoglobulin heavy and light chain variable region genes. This mechanism is distinct from and much more efficient than mechanisms of antibody diversification seen in rodents and primates. While the bursal microenvironment is not required for immunoglobulin gene rearrangement and expression, it is essential for the generation of antibody diversity by gene conversion. Following hatch, gut derived antigens are taken up by the bursa. While bursal development prior to hatch occurs in the absence of exogenous antigen, chicken B cell development after hatch may therefore be influenced by the presence of environmental antigen. This review focuses on the differences between B cell development in the chicken as compared to rodent and primate models.

Animals↗
PubMed2006

Antibody repertoire development in swine.

Swine belong to the Order Artiodactyla and like mice and humans, express IgM, IgD, IgG, IgE and IgA antibodies but a larger number of IgG subclasses. Like rabbits and chickens, expressed V(H) genes belong to the ancestral V(H)3 family and only 5 comprise >80% of the pre-immune repertoire. Since they use primarily two D(H) segments and have a single J(H) like chickens, junctional diversity plays a relatively greater role in repertoire formation than in humans and mice. Proportional light chain usage surprisingly resembles that in humans and is therefore distinctly different from the predominant kappa chain usage (>90%) of lab rodents and predominant lambda chain usage in other ungulates (>90%). The pre-immune V(kappa) repertoire also appears restricted since >95% of V(kappa)J(kappa) rearrangements use only a few members of the IGKV2 family and only J(kappa)2. Two V(lambda) families (IGLV3 and IGLV8) are used in forming the pre-immune repertoire. Antibodies that do not utilize light chains as in camelids, or the lengthy CDR3 regions seen in cattle that use V(H)4 family genes, have not been reported in swine. B cell lymphogenesis first occurs in the yolk sac but early VDJ rearrangements differ from mice and humans in that nearly 100% are in-frame and N-region additions are already present. Swine possess ileal Peyers patches like sheep which may be important for antigen-independent B cell repertoire diversification. The presence of pro B-like cells in interlobular areas of thymus and mature B cells in the thymic medulla that have switched to especially IgA in early gestation, is so far unique among mammals. The offspring of swine are believed to receive no passive immunity in utero and are precosial. Thus, they are a useful model for studies on fetal-neonatal immunological development. The model has already shown that: (a) colonization of the gut is required for responsiveness to TD and TI-2 antigens, (b) responsiveness due to colonization depends on bacterial PAMPs and (c) some viral pathogens can interfere with the establishment of immune homeostasis in neonates. Studies on swine reinforce concerns that caution be used when paradigms arising from studies in one mammal are extrapolated to other mammals, even when similarities are predicted by taxonomy and phylogeny. Swine exemplify a situation in which evolutionary diversification of the immune system is not characteristic of an entire order or even of other related systems in the same species.

Animals↗
PubMed2006

Co-expression of antibody fab heavy and light chain genes from separate evolved compatible replicons in E. coli.

Antibody molecules bind to antigen with six complementary determining region (CDR) loops, three of which are located on each variable heavy (V(H)) and light (V(L)) chains. Discovery and optimization of antibodies that bind antigen using in vitro techniques require diversification of one or more of these CDRs. Since antibodies are dimeric, simultaneous diversification of heavy and light chains on separate genetic elements would allow "chain shuffling" to occur simply and efficiently. Efficient expression of antibody V(H) and V(L) requires that the two separate replicons be compatible with one another, but also have similar properties, such as copy number in E. coli. Standard plasmids that are compatible with one another in E. coli exist at widely variable copy numbers. Recently we described the isolation of ColE1 mutants that have similar copy numbers but different incompatibility characteristics. Thus, new compatibility groups in the ColE1 family were established. Herein we describe the E. coli expression of V(H) and V(L) genes to form a functional Fab. The ability to express antibody heavy and light chains from separate but compatible high copy plasmids should allow new opportunities in antibody engineering, such as rapid chain shuffling and generation of more complex antibody libraries.

Biological Evolution↗
PubMed2004

Can extinction rates be estimated without fossils?

There is considerable interest in the possibility of using molecular phylogenies to estimate extinction rates. The present study aims at assessing the statistical performance of the birth-death model fitting approach to estimate speciation and extinction rates by comparison to the approach considering fossil data. A simulation-based approach was used. The diversification of a large number of lineages was simulated under a wide range of speciation and extinction rate values. The estimators obtained with fossils performed better than those without fossils. In the absence of fossils (e.g. with a molecular phylogeny), the speciation rate was correctly estimated in a wide range of situations; the bias of the corresponding estimator was close to zero for the largest trees. However, this estimator was substantially biased when the simulated extinction rate was high. On the other hand the estimator of extinction rate was biased in a wide range of situations. Surprisingly, this bias was lesser with medium-sized trees. Some recommendations for interpreting results from a diversification analysis are given.

Animals↗