Multimerization variants as potential drivers of neofunctionalization.
Ontology highlight
ABSTRACT:
SUBMITTER: Lee Y
PROVIDER: S-EPMC7997512 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Infectious diseases are economically detrimental to aquaculture, and with continued expansion and intensification of aquaculture, the importance of managing infectious diseases will likely increase in the future. Here, we use evolution of virulence theory, along with examples, to identify aquaculture practices that might lead to the evolution of increased pathogen virulence. We identify eight practices common in aquaculture that theory predicts may favor evolution toward higher pathogen virulence. Four are related to intensive aquaculture operations, and four others are related specifically to infectious disease control. Our intention is to make aquaculture managers aware of these risks, such that with increased vigilance, they might be able to detect and prevent the emergence and spread of increasingly troublesome pathogen strains in the future.
| S-EPMC4721074 | biostudies-other
Project description:ADIPOQ, encoding adiponectin, is a candidate gene for type 2 diabetes (T2D) identified by genome-wide linkage analyses with supporting evidence showing the protein function in sensitizing insulin actions. In an endeavor to characterize candidate genes causing T2D in Thai patients, we identified 10 novel ADIPOQ variations, several of which were non-synonymous variations observed only in the patients. To examine the impact of these non-synonymous variations on adiponectin structure and biochemical characteristics, we conducted a structural analysis of the wild-type and variant proteins by in silico modeling and further characterized biochemical properties of the variants with predicted structural abnormalities from the modeling by molecular and biochemical studies. The recombinant plasmids containing wild-type and variant ADIPOQ cDNAs derived from the variations identified by our study (R55H, R112H, and R131H) and previous work (G90S and R112C) were constructed and transiently expressed and co-expressed in cultured HEK293T cells to investigate their oligomerization, interaction, and secretion. We found that the novel R55H variant impaired protein multimerization but it did not exert the effect over the co-expressed wild-type protein while novel R131H variant impaired protein secretion and also affected the co-expressed wild-type protein in a dominant negative fashion. The R131H variant could traffic from the endoplasmic reticulum to the Golgi, trans-Golgi network, and early endosome but could not be secreted. The R131H variant was likely to be degraded through the lysosomal system and inhibition of its degradation rescued the variant protein from secretion defect. We have shown the possibility of using in silico modeling for predicting the effect of amino acid substitution on adiponectin oligomerization. This is also the first report that demonstrates a dominant negative effect of the R131H variant on protein secretion and the possibility of using protein degradation inhibitors as therapeutic agents in the patients carrying adiponectin variants with secretion defect.
| S-EPMC3202584 | biostudies-literature
Project description:RNA polymerase III (Pol III) occurs in two versions, one containing the POLR3G subunit and the other the closely related POLR3GL subunit. It is not clear whether these two Pol III forms have the same function, in particular whether they recognize the same target genes. We show that the POLR3G and POLR3GL genes arose from a DNA-based gene duplication, probably in a common ancestor of vertebrates. POLR3G- as well as POLR3GL-containing Pol III are present in cultured cell lines and in normal mouse liver, although the relative amounts of the two forms vary, with the POLR3G-containing Pol III relatively more abundant in dividing cells. Genome-wide chromatin immunoprecipitations followed by high-throughput sequencing (ChIP-seq) reveal that both forms of Pol III occupy the same target genes, in very constant proportions within one cell line, suggesting that the two forms of Pol III have a similar function with regard to specificity for target genes. In contrast, the POLR3G promoter--not the POLR3GL promoter--binds the transcription factor MYC, as do all other promoters of genes encoding Pol III subunits. Thus, the POLR3G/POLR3GL duplication did not lead to neo-functionalization of the gene product (at least with regard to target gene specificity) but rather to neo-functionalization of the transcription units, which acquired different mechanisms of regulation, thus likely affording greater regulation potential to the cell.
| S-EPMC3875860 | biostudies-other
Project description:Gene duplication provides much of the raw material from which functional diversity evolves. Two evolutionary mechanisms have been proposed that generate functional diversity: neofunctionalization, the de novo acquisition of function by one duplicate, and subfunctionalization, the partitioning of ancestral functions between gene duplicates. With protein interactions as a surrogate for protein functions, evidence of prodigious neofunctionalization and subfunctionalization has been identified in analyses of empirical protein interactions and evolutionary models of protein interactions. However, we have identified three phenomena that have contributed to neofunctionalization being erroneously identified as a significant factor in protein interaction network evolution. First, self-interacting proteins are underreported in interaction data due to biological artifacts and design limitations in the two most common high-throughput protein interaction assays. Second, evolutionary inferences have been drawn from paralog analysis without consideration for concurrent and subsequent duplication events. Third, the theoretical model of prodigious neofunctionalization is unable to reproduce empirical network clustering and relies on untenable parameter requirements. In light of these findings, we believe that protein interaction evolution is more persuasively characterized by subfunctionalization and self-interactions.
| S-EPMC2597716 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM.
| S-EPMC8260873 | biostudies-literature
Project description:G-quadruplexes can multimerize under certain conditions, but the sequence requirements of such structures are not well understood. In this study, we investigated the ability of all possible variants of the central tetrad in a monomeric, parallel-strand G-quadruplex to form higher-order structures. Although most of these 256 variants existed primarily as monomers under the conditions of our screen, ?10% formed dimers or tetramers. These structures could form in a wide range of monovalent and divalent metal ions, and folding was highly cooperative in both KCl and MgCl2. As was previously shown for G-quadruplexes that bind GTP and promote peroxidase reactions, G-quadruplexes that form dimers and tetramers have distinct sequence requirements. Some mutants could also form heteromultimers, and a second screen was performed to characterize the sequence requirements of these structures. Taken together, these experiments provide new insights into the sequence requirements and structures of both homomultimeric and heteromultimeric G-quadruplexes.
| S-EPMC5587800 | biostudies-other
Project description:Gene duplication is a key source of genetic innovation that plays a role in the evolution of phenotypic complexity. Although several evolutionary processes can result in the long-term retention of duplicate genes, their relative contributions in nature are unknown. Here we develop a phylogenetic approach for comparing genome-wide expression profiles of closely related species to quantify the roles of conservation, neofunctionalization, subfunctionalization, and specialization in the preservation of duplicate genes. Application of our method to pairs of young duplicates in Drosophila shows that neofunctionalization, the gain of a novel function in one copy, accounts for the retention of almost two-thirds of duplicate genes. Surprisingly, novel functions nearly always originate in younger (child) copies, whereas older (parent) copies possess functions similar to those of ancestral genes. Further examination of such pairs reveals a strong bias toward RNA-mediated duplication events, implicating asymmetric duplication and positive selection in the evolution of new functions. Moreover, we show that young duplicate genes are expressed primarily in testes and that their expression breadth increases over evolutionary time. This finding supports the "out-of-testes" hypothesis, which posits that testes are a catalyst for the emergence of new genes that ultimately evolve functions in other tissues. Thus, our study highlights the importance of neofunctionalization and positive selection in the retention of young duplicates in Drosophila and illustrates how duplicates become incorporated into novel functional networks over evolutionary time.
| S-EPMC3808614 | biostudies-literature
Project description:Pediatric malignancies including Ewing sarcoma (EwS) feature a paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here, we demonstrate in EwS how cooperation of dominant oncogenes and regulatory germline variants determine tumor growth, patient survival and drug response. Binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls expression of the transcription factor MYBL2 mediating these phenotypes. Whole-genome and RNA sequencing reveals that variability at this locus is inherited via the germline and is associated with variable inter-tumoral MYBL2 expression. High MYBL2 levels sensitize EwS cells for inhibition of its upstream activating kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a putative biomarker for anti-CDK2-therapy. Collectively, we establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and highlight the importance of integrating the regulatory genome in precision medicine.
| S-EPMC6739408 | biostudies-literature
Project description:Protein-glutamine ?-glutamyltransferases (transglutaminases, Tgs) belong to the class of transferases. They catalyze the formation of an isopeptide bond between the acyl group at the end of the side chain of protein- or peptide-bound glutamine residues and the first order ?-amine groups of protein- or peptide-bound lysine. The Tgs are considered to be universal protein cross-linkers, and they play an essential role in a number of human diseases. In this review, we discuss mainly the bacterial Tgs in terms of the functionality of the enzymes and a potential role they may play in bacterial survival. Since microbial transglutaminases (mTgs) are functionally similar to the human homologs, they may be involved in the human disease provocation. We suggest here a potential involvement of Tgs in the pathologies such as autoimmune diseases. In this hypothesis, the endogenous mTgs that are secreted by the gut microbiota, especially in a dysbiotic configuration, are potential drivers of systemic autoimmunity, via the enzymatic posttranslational modification of peptides in the gut lumen. These mTg activities directed toward cross-linking of naïve proteins can potentially generate neo-epitopes that are not only immunogenic but may also activate some immune response cascades leading to the pathological autoimmune processes.
| S-EPMC5258703 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ?10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
| S-EPMC7161085 | biostudies-literature