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At least 73 records · Page 4Linked to original sources
PubMed2000

Three functionally diverged major structural proteins of white spot syndrome virus evolved by gene duplication.

White spot syndrome virus (WSSV) is an invertebrate virus causing considerable mortality in penaeid shrimp. The oval-to-bacilliform shaped virions, isolated from infected Penaeus monodon, contain four major proteins: VP28, VP26, VP24 and VP19 (28, 26, 24 and 19 kDa, respectively). VP26 and VP24 are associated with the nucleocapsid and the remaining two with the envelope. Forty-one N-terminal amino acids of VP24 were determined biochemically allowing the identification of its gene (vp24) in the WSSV genome. Computer-assisted analysis revealed a striking similarity between WSSV VP24, VP26 and VP28 at the amino acid and nucleotide sequence level. This strongly suggests that these structural protein genes may have evolved by gene duplication and subsequently diverged into proteins with different functions in the WSSV virion, i.e. envelope and nucleocapsid. None of these three structural WSSV proteins showed homology to proteins of other viruses including baculoviruses, underscoring the distinct taxonomic position of WSSV among invertebrate viruses.

Amino Acid Sequence↗
PubMed2004

Functional divergence in tandemly duplicated Arabidopsis thaliana trypsin inhibitor genes.

In multigene families, variation among loci and alleles can contribute to trait evolution. We explored patterns of functional and genetic variation in six duplicated Arabidopsis thaliana trypsin inhibitor (ATTI) loci. We demonstrate significant variation in constitutive and herbivore-induced transcription among ATTI loci that show, on average, 65% sequence divergence. Significant variation in ATTI expression was also found between two molecularly defined haplotype classes. Population genetic analyses for 17 accessions of A. thaliana showed that six ATTI loci arranged in tandem within 10 kb varied 10-fold in nucleotide diversity, from 0.0009 to 0.0110, and identified a minimum of six recombination events throughout the tandem array. We observed a significant peak in nucleotide and indel polymorphism spanning ATTI loci in the interior of the array, due primarily to divergence between the two haplotype classes. Significant deviation from the neutral equilibrium model for individual genes was interpreted within the context of intergene linkage disequilibrium and correlated patterns of functional differentiation. In contrast to the outcrosser Arabidopsis lyrata for which recombination is observed even within ATTI loci, our data suggest that response to selection was slowed in the inbreeding, annual A. thaliana because of interference among functionally divergent ATTI loci.

Amino Acid Sequence↗
PubMed2002

Functional divergence in the glutathione transferase superfamily in plants. Identification of two classes with putative functions in redox homeostasis in Arabidopsis thaliana.

Searches with the human Omega glutathione transferase (GST) identified two outlying groups of the GST superfamily in Arabidopsis thaliana which differed from all other plant GSTs by containing a cysteine in place of a serine at the active site. One group consisted of four genes, three of which encoded active glutathione-dependent dehydroascorbate reductases (DHARs). Two DHARs were predicted to be cytosolic, whereas the other contained a chloroplast targeting peptide. The DHARs were also active as thiol transferases but had no glutathione conjugating activity. Unlike most other GSTs, DHARs were monomeric. The other class of GST comprised two genes termed the Lambda GSTs (GSTLs). The recombinant GSTLs were also monomeric and had glutathione-dependent thiol transferase activity. One GSTL was cytosolic, whereas the other was chloroplast-targeted. When incubated with oxidized glutathione, the putative active site cysteine of the GSTLs and cytosolic DHARs formed mixed disulfides with glutathione, whereas the plastidic DHAR formed an intramolecular disulfide. DHAR S-glutathionylation was consistent with a proposed catalytic mechanism for dehydroascorbate reduction. Roles for the cytosolic DHARs and GSTLs as antioxidant enzymes were also inferred from the induction of the respective genes following exposure to chemicals and oxidative stress.

Amino Acid Sequence↗
PubMed2004

A maximum likelihood method for detecting functional divergence at individual codon sites, with application to gene family evolution.

The tailoring of existing genetic systems to new uses is called genetic co-option. Mechanisms of genetic co-option have been difficult to study because of difficulties in identifying functionally important changes. One way to study genetic co-option in protein-coding genes is to identify those amino acid sites that have experienced changes in selective pressure following a genetic co-option event. In this paper we present a maximum likelihood method useful for measuring divergent selective pressures and identifying the amino acid sites affected by divergent selection. The method is based on a codon model of evolution and uses the nonsynonymous-to-synonymous rate ratio (omega) as a measure of selection on the protein, with omega = 1, < 1, and > 1 indicating neutral evolution, purifying selection, and positive selection, respectively. The model allows variation in omega among sites, with a fraction of sites evolving under divergent selective pressures. Divergent selection is indicated by different omega's between clades, such as between paralogous clades of a gene family. We applied the codon model to duplication followed by functional divergence of (i) the epsilon and gamma globin genes and (ii) the eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) genes. In both cases likelihood ratio tests suggested the presence of sites evolving under divergent selective pressures. Results of the epsilon and gamma globin analysis suggested that divergent selective pressures might be a consequence of a weakened relationship between fetal hemoglobin and 2,3-diphosphoglycerate. We suggest that empirical Bayesian identification of sites evolving under divergent selective pressures, combined with structural and functional information, can provide a valuable framework for identifying and studying mechanisms of genetic co-option. Limitations of the new method are discussed.

Amino Acids↗
PubMed2002

Predicting functional divergence in protein evolution by site-specific rate shifts.

Most modern tools that analyze protein evolution allow individual sites to mutate at constant rates over the history of the protein family. However, Walter Fitch observed in the 1970s that, if a protein changes its function, the mutability of individual sites might also change. This observation is captured in the "non-homogeneous gamma model", which extracts functional information from gene families by examining the different rates at which individual sites evolve. This model has recently been coupled with structural and molecular biology to identify sites that are likely to be involved in changing function within the gene family. Applying this to multiple gene families highlights the widespread divergence of functional behavior among proteins to generate paralogs and orthologs.

Amino Acid Sequence↗
PubMed2003

Functional divergence of two zebrafish midkine growth factors following fish-specific gene duplication.

In mammals, the unique midkine (mdk) gene encodes a secreted heparin-binding growth factor with neurotrophic activity. Here, we show the presence of two functional mdk genes named mdka and mdkb in zebrafish and rainbow trout. Both midkine proteins are clearly different from the related pleiotrophin, which was also identified in zebrafish and other fishes. Zebrafish mdka and mdkb genes map to linkage groups LG7 and LG25, respectively, both presenting synteny to human chromosome 11, in which the unique human ortholog mdk is located. At least four other genes unique in mammals are also present as duplicates on LG7 and LG25. Phylogenetic and divergence analyses suggested that LG7/LG25 paralogs including mdka and mdkb have been formed at approximately the same time, early during the evolution of the fish lineage. Hence, zebrafish and rainbow trout mdka and mdkb might have been generated by an ancient block duplication, and might be remnants of the proposed fish-specific whole-genome duplication. In contrast to the ubiquitous expression of their mammalian counterpart, zebrafish mdka and mdkb are expressed in spatially restricted, mostly nonoverlapping patterns during embryonic development and strongly in distinct domains in the adult brain. Ectopic ubiquitous expression of both mdk genes in early zebrafish embryos caused completely distinct effects on neural crest and floorplate development. These data indicate that mdka and mdkb underwent functional divergence after duplication. This provides an outstanding model to analyze the molecular mechanisms that lead to differences in pathways regulating the formation of homologous embryonic structures in different vertebrates.

Amino Acid Sequence↗
PubMed2003

Using evolutionary rates to investigate protein functional divergence and conservation. A case study of the carbonic anhydrases.

Functional constraints on proteins limit their evolutionary rates at specific sites. These constraints allow for the interpretation of conserved residues and sites with a rate change as those most likely underlying the functional similarities and differences among protein subfamilies, respectively. This study describes new likelihood-ratio tests (LRTs) that complement existing ones for the identification of both conserved and rate change sites. These identifications are validated by the recovery of residues that are known from existing biochemical and structural information to be critical for the functional similarities and differences among carbonic anhydrases (CAs). In combination with this other information, these LRTs also support a unique antioxidant defense role for the puzzling CA III. As illustrated by the CAs, these LRTs, in combination with other biological evidence, offer a powerful and cost-effective approach for testing hypotheses, making predictions, and designing experiments in protein functional studies.

Amino Acid Sequence↗
PubMed2003

Sequence divergence, functional constraint, and selection in protein evolution.

The genome sequences of multiple species has enabled functional inferences from comparative genomics. A primary objective is to infer biological functions from the conservation of homologous DNA sequences between species. A second, more difficult, objective is to understand what functional DNA sequences have changed over time and are responsible for species' phenotypic differences. The neutral theory of molecular evolution provides a theoretical framework in which both objectives can be explicitly tested. Development of statistical tests within this framework has provided insight into the evolutionary forces that constrain and in some cases change DNA sequences and the resulting patterns that emerge. In this article, we review recent work on how functional constraint and changes in protein function are inferred from protein polymorphism and divergence data. We relate these studies to our understanding of the neutral theory and adaptive evolution.

DNA↗
PubMed2003

The soluble and membrane-bound transhydrogenases UdhA and PntAB have divergent functions in NADPH metabolism of Escherichia coli.

Pentose phosphate pathway and isocitrate dehydrogenase are generally considered to be the major sources of the anabolic reductant NADPH. As one of very few microbes, Escherichia coli contains two transhydrogenase isoforms with unknown physiological function that could potentially transfer electrons directly from NADH to NADP+ and vice versa. Using defined mutants and metabolic flux analysis, we identified the proton-translocating transhydrogenase PntAB as a major source of NADPH in E. coli. During standard aerobic batch growth on glucose, 35-45% of the NADPH that is required for biosynthesis was produced via PntAB, whereas pentose phosphate pathway and isocitrate dehydrogenase contributed 35-45% and 20-25%, respectively. The energy-independent transhydrogenase UdhA, in contrast, was essential for growth under metabolic conditions with excess NADPH formation, i.e. growth on acetate or in a phosphoglucose isomerase mutant that catabolized glucose through the pentose phosphate pathway. Thus, both isoforms have divergent physiological functions: energy-dependent reduction of NADP+ with NADH by PntAB and reoxidation of NADPH by UdhA. Expression appeared to be modulated by the redox state of cellular metabolism, because genetic and environmental manipulations that increased or decreased NADPH formation down-regulated pntA or udhA transcription, respectively. The two transhydrogenase isoforms provide E. coli primary metabolism with an extraordinary flexibility to cope with varying catabolic and anabolic demands, which raises two general questions: why do only a few bacteria contain both isoforms, and how do other organisms manage NADPH metabolism?

Down-Regulation↗
PubMed1999

Evolutionary trace analysis of the Kunitz/BPTI family of proteins: functional divergence may have been based on conformational adjustment.

The structural and functional evolution of the Kunitz/bovine pancreatic trypsin inhibitor (BPTI) family of proteins, which includes serine proteinase inhibitors and potassium channel blockers, was analysed with the evolutionary trace method. This method highlights sites in aligned primary sequences whose side-chain variation can be strongly linked with the past development of different functional classes or subgroups within the family. A total of 16 such "class-specific" positions distributed throughout the molecular fold were identified. On average, the side-chain chemistry at these positions had been more conserved and made greater contribution to molecular stability than the side-chain chemistry at remaining sites of variation. It was possible to use these 16 positions to describe the division of the Kunitz/BPTI family into general functional classes. According to known complexes of inhibitor variants with serine proteinases, only two of the 16 class-specific positions appear to be directly involved in intermolecular recognition via the "antiproteinase site". Instead, from various critical locations in the fold, the remainder seem to have been associated with various degrees of intramolecular conformational adjustment to the underlying framework of the antiproteinase site. It is, therefore, implied that functional diversification in this family has been founded upon both sustained evolutionary selection and conformational adjustment. The findings are important for protein engineers wishing to alter the binding selectivity of these molecules, because it appears that the issue of target recognition is dependent on the conformation of the chain segment to which the interactive side-chains are attached. To retarget members of this family towards potentially novel peptide binding sites, substitutions at certain structurally significant class-specific positions could be a good starting point.

Amino Acid Sequence↗
PubMed2003

Gene duplications: the gradual evolution of functional divergence.

Budding yeast provides a useful resource for studies of gene function. A new analysis of the fitness effects of deletion mutations in budding yeast reveals that genes that have duplicates create lower fitness losses when inactivated than do genes that are singletons.

Animals↗
PubMed2004

Genetic analysis of the neuronal and ubiquitous AP-3 adaptor complexes reveals divergent functions in brain.

Neurons express adaptor (AP)-3 complexes assembled with either ubiquitous (beta3A) or neuronal-specific (beta3B) beta3 isoforms. However, it is unknown whether these complexes indeed perform distinct functions in neuronal tissue. Here, we explore this hypothesis by using genetically engineered mouse models lacking either beta3A- or beta3B-containing AP-3 complexes. Somatic and neurological phenotypes were specifically associated with the ubiquitous and neuronal adaptor deficiencies, respectively. At the cellular level, AP-3 isoforms were localized to distinct neuronal domains. beta3B-containing AP-3 complexes were preferentially targeted to neuronal processes. Consistently, beta3B deficiency compromised synaptic zinc stores assessed by Timm's staining and the synaptic vesicle targeting of membrane proteins involved in zinc uptake (ZnT3 and ClC-3). Surprisingly, despite the lack of neurological symptoms, beta3A-deficient mouse brain possessed significantly increased synaptic zinc stores and synaptic vesicle content of ZnT3 and ClC-3. These observations indicate that the functions of beta3A- and beta3B-containing complexes are distinct and divergent. Our results suggest that concerted nonredundant functions of neuronal and ubiquitous AP-3 provide a mechanism to control the levels of selected membrane proteins in synaptic vesicles.

Adaptor Protein Complex 3↗
PubMed2003

Functional divergence within the APETALA3/PISTILLATA floral homeotic gene lineages.

Changes in homeotic gene expression patterns or in the functions of the encoded proteins are thought to play a prominent role in the evolution of new morphologies. The floral homeotic APETALA3 (AP3) and PISTILLATA (PI) genes encode MADS domain-containing transcription factors required to specify petal and stamen identities in Arabidopsis. We have previously shown that perianth expression of AP3 and PI homologs varies in different groups of angiosperms with diverse floral structures, suggesting that changes in expression may contribute to changing morphology. We have investigated the possibility that changes in the functions of the encoded gene products may also have played a role in the evolution of different floral morphologies. AP3 and PI are members of paralogous gene lineages and share extensive similarity along the length of the protein products. Genes within these lineages encode products with characteristic C-terminal motifs that we show are critical for functional specificity. In particular, the C terminus of AP3 is sufficient to confer AP3 functionality on the heterologous PI protein. Furthermore, we have shown that the evolution of the divergent AP3 C-terminal domain in the core eudicots is correlated with the acquisition of a role in specifying perianth structures. These results suggest that divergence in these sequence motifs has contributed to the evolution of distinct functions for these floral homeotic gene products.

Amino Acid Sequence↗
PubMed2004

Evolution of neural precursor selection: functional divergence of proneural proteins.

How conserved pathways are differentially regulated to produce diverse outcomes is a fundamental question of developmental and evolutionary biology. The conserved process of neural precursor cell (NPC) selection by basic helix-loop-helix (bHLH) proneural transcription factors in the peripheral nervous system (PNS) by atonal related proteins (ARPs) presents an excellent model in which to address this issue. Proneural ARPs belong to two highly related groups: the ATONAL (ATO) group and the NEUROGENIN (NGN) group. We used a cross-species approach to demonstrate that the genetic and molecular mechanisms by which ATO proteins and NGN proteins select NPCs are different. Specifically, ATO group genes efficiently induce neurogenesis in Drosophila but very weakly in Xenopus, while the reverse is true for NGN group proteins. This divergence in proneural activity is encoded by three residues in the basic domain of ATO proteins. In NGN proteins, proneural capacity is encoded by the equivalent three residues in the basic domain and a novel motif in the second Helix (H2) domain. Differential interactions with different types of zinc (Zn)-finger proteins mediate the divergence of ATO and NGN activities: Senseless is required for ATO group activity, whereas MyT1 is required for NGN group function. These data suggest an evolutionary divergence in the mechanisms of NPC selection between protostomes and deuterostomes.

Animals↗
PubMed2004

Conservation of structure and functional divergence of duplicated Wnt8s in pufferfish.

The zebrafish wnt8 locus differs from its tetrapod counterparts in that it produces two functionally overlapping but distinct Wnt8 proteins. Studies of zebrafish wnt8 have suggested that the two major Wnt8 proteins produced are functionally similar yet may behave differently depending on the assay context. To determine whether the bicistronic wnt8 and its accompanying unique protein activities found in zebrafish are more widespread (and perhaps universal) among teleosts, we have extended our studies to the pufferfish Takifugu rubripes. We have found that Takifugu wnt8 is also bicistronic, indicating that the wnt8 duplication occurred before the divergence of these teleosts approximately 150 million years ago. Furthermore, overexpression assays in zebrafish embryos show that functional differences between the zebrafish Wnt8.1 and Wnt8.2 proteins are conserved in their Takifugu orthologs. Thus, despite the fact that Wnt8.1 and Wnt8.2 proteins are as similar to each other as each is to Xenopus Xwnt-8, Wnt8 family members can behave quite differently in the context of zebrafish embryos. This finding suggests that zebrafish (and possibly teleost in general) Wnt8 receptors are able to discriminate between highly related ligands.

Amino Acid Sequence↗
PubMed2026

Divergent PXR function in seals: Endocrine adaptation or functional loss?

Seals accumulate xenobiotics through dietary biomagnification and exposure to polluted marine environments, with contaminants concentrating in their blubber. Biotransformation mitigates xenobiotic toxicity by converting lipophilic compounds into excretable hydrophilic metabolites, a process coordinated by nuclear receptors including the Pregnane X Receptor (PXR), whose plastic ligand-binding domain enables broad xenobiotic sensing. By examining PXR in pinnipeds, we investigated the evolutionary conservation and functional characterization of PXR using genomic sequence analysis, protein structural prediction, and transactivation assays, revealing broadly conserved structural features alongside species-specific functional divergence in receptor responsiveness to environmental stressors. Specifically, the obtained results highlight divergent gene and functional landscapes with ORF-disrupting mutations identified in Monachus monachus and Neomonachus schauinslandi that abolish receptor activation toward known PXR ligands. In contrast, Leptonychotes weddelli retained an intact PXR ORF but showed reduced receptor activity, revealing functional divergence in PXR among pinnipeds.

Biotransformation↗
PubMed2004

Functional divergence of duplicated genes formed by polyploidy during Arabidopsis evolution.

To study the evolutionary effects of polyploidy on plant gene functions, we analyzed functional genomics data for a large number of duplicated gene pairs formed by ancient polyploidy events in Arabidopsis thaliana. Genes retained in duplicate are not distributed evenly among Gene Ontology or Munich Information Center for Protein Sequences functional categories, which indicates a nonrandom process of gene loss. Genes involved in signal transduction and transcription have been preferentially retained, and those involved in DNA repair have been preferentially lost. Although the two members of each gene pair must originally have had identical transcription profiles, less than half of the pairs formed by the most recent polyploidy event still retain significantly correlated profiles. We identified several cases where groups of duplicated gene pairs have diverged in concert, forming two parallel networks, each containing one member of each gene pair. In these cases, the expression of each gene is strongly correlated with the other nonhomologous genes in its network but poorly correlated with its paralog in the other network. We also find that the rate of protein sequence evolution has been significantly asymmetric in >20% of duplicate pairs. Together, these results suggest that functional diversification of the surviving duplicated genes is a major feature of the long-term evolution of polyploids.

Arabidopsis↗
PubMed2000

Structural and functional divergence of a nuclear receptor of the RXR family from the trematode parasite Schistosoma mansoni.

We describe the cloning and functional characterization of Schistosoma mansoni retinoid-X-receptor (SmRXR; NR2B4-B), a novel member of the nuclear receptor superfamily from S. mansoni, a homologue of vertebrate retinoid-X-receptor. The DNA-binding C domain of SmRXR shows 80% sequence identity to both human RXRalpha and Drosophila ultraspiracle (USP), but a much lower level of conservation of the ligand-binding E domain (22-25% identity). Phylogenetic analysis places SmRXR within the RXR group as an early offshoot of this clade. SmRXR mRNA is expressed at all life-cycle stages but at higher levels in the free-living larval stages. However, the SmRXR protein is expressed at markedly different levels, being almost absent from eggs while present at the highest concentration in schistosomula. Recombinant SmRXR fails to bind to the consensus direct repeat response elements, either alone, or as a heterodimer with mouse retinoic acid receptor alpha or the Drosophila ecdysone receptor. However, the use of chimaeric constructions shows that the C domain of SmRXR will bind to conventional response elements as a heterodimer, and that its specificity is modified by the presence of the D and E domains. In accordance with these results, native SmRXR failed to transactivate the transcription of a reporter gene after cotransfection of mammalian cell lines.

Alternative Splicing↗