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PubMed2005

Evolutionary conservation and diversification of Rh family genes and proteins.

Rhesus (Rh) proteins were first identified in human erythroid cells and recently in other tissues. Like ammonia transporter (Amt) proteins, their only homologues, Rh proteins have the 12 transmembrane-spanning segments characteristic of transporters. Many think Rh and Amt proteins transport the same substrate, NH(3)/NH(4)(+), whereas others think that Rh proteins transport CO(2) and Amt proteins NH(3). In the latter view, Rh and Amt are different biological gas channels. To reconstruct the phylogeny of the Rh family and study its coexistence with and relationship to Amt in depth, we analyzed 111 Rh genes and 260 Amt genes. Although Rh and Amt are found together in organisms as diverse as unicellular eukaryotes and sea squirts, Rh genes apparently arose later, because they are rare in prokaryotes. However, Rh genes are prominent in vertebrates, in which Amt genes disappear. In organisms with both types of genes, Rh had apparently diverged away from Amt rapidly and then evolved slowly over a long period. Functionally divergent amino acid sites are clustered in transmembrane segments and around the gas-conducting lumen recently identified in Escherichia coli AmtB, in agreement with Rh proteins having new substrate specificity. Despite gene duplications and mutations, the Rh paralogous groups all have apparently been subject to strong purifying selection indicating functional conservation. Genes encoding the classical Rh proteins in mammalian red cells show higher nucleotide substitution rates at nonsynonymous codon positions than other Rh genes, a finding that suggests a possible role for these proteins in red cell morphogenetic evolution.

Amino Acid Sequence↗
PubMed2004

The evolutionary repertoires of the eukaryotic-type ABC transporters in terms of the phylogeny of ATP-binding domains in eukaryotes and prokaryotes.

ABC (ATP-binding cassette) transporters play an important role in the communication of various substrates across cell membranes. They are ubiquitous in prokaryotes and eukaryotes, and eukaryotic types (EK-types) are distinguished from prokaryotic types (PK-types) in terms of their genes and domain organizations. The EK-types and PK-types mainly consist of exporters and importers, respectively. Prokaryotes have both the EK-types and the PK-types. The EK-types in prokaryotes are usually called "bacterial multidrug ABC transporters," but they are not well characterized in comparison with the multidrug ABC transporters in eukaryotes. Thus, an exhaustive search of the EK-types among diverse organisms and detailed sequence classification and analysis would elucidate the evolutionary history of EK-types. It would also help shed some light on the fundamental repertoires of the wide variety of substrates through which multidrug ABC transporters in eukaryotes communicate. In this work, we have identified the EK-type ABC transporters in 126 prokaryotes using the profiles of the ATP-binding domain (NBD) of the EK-type ABC transporters from 12 eukaryotes. As a result, 11 clusters were identified from 1,046 EK-types ABC transporters. In particular, two large novel clusters emerged, corresponding to the bacterial multidrug ABC transporters related to the ABCB and ABCC families in eukaryotes, respectively. In the genomic context, most of these genes are located alone or adjacent to genes from the same clusters. Additionally, to detect functional divergences in the NBDs, the Kullback-Leibler divergence was measured among these bacterial multidrug transporters. As a result, several putative functional regions were identified, some corresponding to the predicted secondary structures. We also analyzed a phylogeny of the EK-type ABC transporters in both prokaryotes and eukaryotes, which revealed that the EK-type ABC transporters in prokaryotes have certain repertoires corresponding to the conventional ABC protein groups in eukaryotes. On the basis of these findings, we propose an updated evolutionary hypothesis in which the EK-type ABC transporters in both eukaryotes and prokaryotes consisted of several kinds of ABC transporters in putative ancestor cells before the divergence of eukaryotic and prokaryotic cells.

ATP-Binding Cassette Transporters↗
PubMed2006

Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis.

Plasmacytoid dendritic cells (pDCs) represent a DC subtype that exerts divergent functions in innate and adoptive immunity including the immediate reaction to microbial factors and the induction of immunoregulatory responses. It is thought that different DC subtypes may be critically involved in the pathogenesis of multiple sclerosis (MS). In our study we assessed the phenotype, maturation and functional properties of peripheral blood pDCs from 35 clinically stable, untreated multiple sclerosis patients, 30 healthy controls and 9 patients with pneumonia, which was used as a non-specific inflammatory condition (NIC). Ex vivo expression of CD86 and 4-1BBL was significantly lower on pDCs from multiple sclerosis patients than from controls and patients with NIC (22 versus 47 versus 41% and 12 versus 35 versus 32%, respectively). When stimulated with IL-3 and CD40L, pDCs of multiple sclerosis patients showed inefficient maturation as demonstrated by significantly lower or delayed upregulation of CD86, 4-1BBL, CD40 and CD83. Additionally, in multiple sclerosis, stimulation of pDCs by unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODN) resulted in a significantly lower interferon (IFN) alpha secretion than in controls. In multiple sclerosis, but not in controls, pDCs failed to upregulate proliferative responses and IFN-gamma secretion of autologous peripheral blood mononuclear cells (PBMC) in a co-culture system. Moreover, depletion of pDCs in multiple sclerosis patients, but not in controls, had no effect on generation of CD4+Foxp3+ regulatory T cells. We also provide data showing that glatiramer acetate (GA) treatment partially restores phenotype and function of pDCs in multiple sclerosis patients. These findings suggest functional abnormalities of pDCs in these patients, which might be of importance in the understanding of the development of immune dysregulation in this disease.

Antigens, CD↗
PubMed1994

Functional importance of the A chain loop in relaxin and insulin.

Relaxin and insulin are disulfide homologues with divergent functions and antigenicity. We have synthesized human relaxin II and porcine insulin and several A chain loop variants of each and measured the effect of substitutions in vivo and in vitro. Substitution of IleA10 in insulin with glycine reduced the receptor binding ability by 2 orders of magnitude. Conversely, exchange of the glycine A14 residue in relaxin, which corresponds to the insulin position A10 for isoleucine, reduced the bio-activity and the receptor binding capacity of relaxin about 100-fold. Substitution of L-Ala in insulin as well as relaxin represented a compromise that allowed both hormones to recover about 30% of the native potency. X-ray analysis and computer-derived energy calculation confirm our receptor binding and biological potency studies, which suggest that the functional difference between derivatives and native hormones is based upon a structural change introduced into the A chain loop by substitution of the penultimate intrachain loop residue. In order to achieve a conformation that favors dynamic or passive interaction with the receptor, insulin and relaxin require a different A chain loop structure in spite of the striking overall similarity.

Animals↗
PubMed2006

Cross-species transcriptional profiles establish a functional portrait of embryonic stem cells.

An understanding of the regulatory mechanisms responsible for pluripotency in embryonic stem cells (ESCs) is critical for realizing their potential in medicine and science. Significant similarities exist among ESCs harvested from different species, yet major differences have also been observed. Here, by cross-species analysis of a large set of functional categories and all transcription factors and growth factors, we reveal conserved and divergent functional landscapes underlining fundamental and species-specific mechanisms that regulate ESC development. Global transcriptional trends derived from all expressed genes, instead of differentially expressed genes alone, were examined, allowing for a higher discriminating power in the functional portrait. We demonstrate that cross-species correlation of transcriptional changes that occur upon ESC differentiation is a powerful predictor of ESC-important biological pathways and functional cores within a pathway. Hundreds of functional modules, as defined by Gene Ontology, were associated with conserved expression patterns but bear no overt relationship to ESC development, suggestive of new mechanisms critical to ESC pluripotency. Yet other functional modules were not conserved; instead, they were significantly up-regulated in ESCs of either species, suggestive of species-specific regulation. The comparisons of ESCs across species and between human ESCs and embryonal carcinoma stem cells suggest that while pluripotency as an essential function in multicellular organisms is conserved throughout evolution, mechanisms primed for differentiation are less conserved and contribute substantially to the differences among stem cells derived from different tissues or species. Our findings establish a basis for defining the "stemness" properties of ESCs from the perspective of functional conservation and variation. The data and analyses resulting from this study provide a framework for new hypotheses and research directions and a public resource for functional genomics of ESCs.

Animals↗
PubMed2006

Functional diversification of B MADS-box homeotic regulators of flower development: Adaptive evolution in protein-protein interaction domains after major gene duplication events.

B-class MADS-box genes have been shown to be the key regulators of petal and stamen specification in several eudicot model species such as Arabidopsis thaliana, Antirrhinum majus, and Petunia hybrida. Orthologs of these genes have been found across angiosperms and gymnosperms, and it is thought that the basic regulatory function of B proteins is conserved in seed plant lineages. The evolution of B genes is characterized by numerous duplications that might represent key elements fostering the functional diversification of duplicates with a deep impact on their role in the evolution of the floral developmental program. To evaluate this, we performed a rigorous statistical analysis with B gene sequences. Using maximum likelihood and Bayesian methods, we estimated molecular substitution rates and determined the selective regimes operating at each residue of B proteins. We implemented tests that rely on phylogenetic hypotheses and codon substitution models to detect significant differences in substitution rates (DSRs) and sites under positive adaptive selection (PS) in specific lineages before and after duplication events. With these methods, we identified several protein residues fixed by PS shortly after the origin of PISTILLATA-like and APETALA3-like lineages in angiosperms and shortly after the origin of the euAP3-like lineage in core eudicots, the 2 main B gene duplications. The residues inferred to have been fixed by positive selection lie mostly within the K domain of the protein, which is key to promote heterodimerization. Additionally, we used a likelihood method that accommodates DSRs among lineages to estimate duplication dates for AP3-PI and euAP3-TM6, calibrating with data from the fossil record. The dates obtained are consistent with angiosperm origins and diversification of core eudicots. Our results strongly suggest that novel multimer formation with other MADS proteins could have been crucial for the functional divergence of B MADS-box genes. We thus propose a mechanism of functional diversification and persistence of gene duplicates by the appearance of novel multimerization capabilities after duplications. Multimer formation in different combinations of regulatory proteins can be a mechanistic basis for the origin of novel regulatory functions and a gene regulatory mechanism for the appearance of morphological innovations.

Amino Acid Sequence↗
PubMed2005

Comparative and evolutionary analysis of genes encoding small GTPases and their activating proteins in eukaryotic genomes.

Both small GTPase and its activating protein (GAP) superfamilies exist in various eukaryotes. The small GTPases regulate a wide variety of cellular processes by cycling between active GTP- and inactive GAP-bound conformations. The GAPs promote GTPase inactivation by stimulating the GTP hydrolysis. In this study, we identified 111 small GTPases and 85 GAPs in rice, 65 GAPs in Arabidopsis, 90 small GTPases in Drosophila melanogaster, and 35 GAPs in Saccharomyces cerevisiaeby genome-wide analysis. We then analyzed and compared a total of 498 small GTPases and 422 GAPs from these four eukaryotic and human genomes. Both animals and yeast genomes contained five families of small GTPases and their GAPs. However, plants had only four of these five families because of a lack of the Ras and RasGAP genes. Small GTPases were conserved with common motifs, but GAPs exhibited higher and much more rapid divergence. On the basis of phylogenetic analysis of all small GTPases and GAPs in five eukaryotic organisms, we estimated that their ancestors had small sizes of small GTPases and GAPs and their large-scale expansions occurred after the divergence from their ancestors. Further investigation showed that genome duplications represented the major mechanism for such expansions. Nonsynonymous substitutions per site (Ka) and synonymous substitutions per site (Ks) analyses showed that most of the divergence due to a positive selection occurred in common ancestors, suggesting a major functional divergence in an ancient era.

Amino Acid Motifs↗
PubMed2004

Molecular population genetics of redundant floral-regulatory genes in Arabidopsis thaliana.

Functional redundancy between duplicated genes is predicted to be transitory, as one gene either loses its function or gains a new function, or both genes accrue degenerative, yet complimentary mutations. Yet there are many examples where functional redundancy has been maintained between gene duplicates. To determine whether selection is acting on functionally redundant gene duplicates, we performed molecular evolution and population genetic analyses between two pairs of functionally redundant MADS-box genes from the model plant Arabidopsis thaliana: SEPALLATA1 (SEP1) and SEPALLATA2 (SEP2), involved in floral organ identity, and SHATTERPROOF1 (SHP1) and SHATTERPROOF2 (SHP2), involved in seed shattering. We found evidence for purifying selection acting to constrain functional divergence between paralogous genes. The protein evolution of both pairs of duplicate genes is functionally constrained, as evidenced by Ka/Ks ratios of 0.16 between paralogs. This functional constraint is stronger in the highly conserved DNA-binding and protein-binding MIK region than in the C-terminal region. We also assayed the evolutionary forces acting between orthologs of the SEP and SHP genes in A. thaliana and the closely related species, Arabidopsis lyrata. Heterogeneity analyses of the polymorphism-to-divergence ratio indicate selective sweeps have occurred within the transcriptional unit of SHP1 and the promoter of SHP2 in the A. thaliana lineage. Similar analyses identified a significant reduction in polymorphism within the SEP1 locus, spanning the 3' region of intron 1 to exon 3, that may represent an intragenic sweep within the SEP1 locus. We discuss whether the evolutionary forces acting on SEP1 and SEP2 versus SHP1 and SHP2 vary according to their position in the floral developmental pathway, as found with other floral-regulatory genes.

Arabidopsis↗
PubMed2006

Positive and negative selection in the beta-esterase gene cluster of the Drosophila melanogaster subgroup.

We examine the pattern of molecular evolution of the beta-esterase gene cluster, including the Est-6 and psiEst-6 genes, in eight species of the Drosophila melanogaster subgroup. Using maximum likelihood estimates of nonsynonymous/synonymous rate ratios, we show that the majority of Est-6 sites evolves under strong (48% of sites) or moderate (50% of sites) negative selection and a minority of sites (1.5%) is under significant positive selection. Est-6 sites likely to be under positive selection are associated with increased intraspecific variability. One positively selected site is responsible for the EST-6 F/S allozyme polymorphism; the same site is responsible for the EST-6 functional divergence between species of the melanogaster subgroup. For psiEst-6 83.7% sites evolve under negative selection, 16% sites evolve neutrally, and 0.3% sites are under positive selection. The positively selected sites of psiEst-6 are located at the beginning and at the end of the gene, where there is reduced divergence between D. melanogaster and D. simulans; these regions of psiEst-6 could be involved in regulation or some other function. Branch-site-specific analysis shows that the evolution of the melanogaster subgroup underwent episodic positive selection. Collating the present data with previous results for the beta-esterase genes, we propose that positive and negative selection are involved in a complex relationship that may be typical of the divergence of duplicate genes as one or both duplicates evolve a new function.

Animals↗
PubMed2002

Multiple tristetraprolin sequence domains required to induce apoptosis and modulate responses to TNFalpha through distinct pathways.

Expression of the immediate early protein tristetraprolin (TTP) is induced by numerous stimuli, including tumor necrosis factor-alpha (TNFalpha). Evidence indicates that TTP limits production of TNFalpha and other cytokines by directly binding and destabilizing their mRNAs. This effect seems to require only the conserved TTP zinc finger region, and is characteristic of the related proteins TIS11b and TIS11d. TTP, TIS11b, and TIS11d each also induce apoptosis through the mitochondrial pathway analogously to certain oncogenes, suggesting that they influence growth or survival signals. Among TTP/TIS11 proteins, TTP alone also promotes apoptosis synergistically with TNFalpha. Here we show that other regions of TTP along with the zinc fingers are required for TTP to induce apoptosis. We also demonstrate that TTP acts through an additional pathway to sensitize cells to the pro-apoptotic stimulus of TNFalpha. This modulation of TNFalpha responses specifically requires the TTP N-terminal region, which is not conserved in TIS11b or TIS11d. We conclude that the physiological functions of TTP depend upon multiple regions of the TTP protein, that TTP has diverged functionally from TIS11b and TIS11d, and that modulation of TNFalpha responses may be a unique and important aspect of TTP function.

3T3 Cells↗
PubMed2006

Tracking the connection between evolutionary and functional shifts using the fungal lipase/feruloyl esterase A family.

BACKGROUND: There have been many claims of adaptive molecular evolution, but what role does positive selection play in functional divergence? The aim of this study was to test the relationship between evolutionary and functional shifts with special emphasis on the role of the environment. For this purpose, we studied the fungal lipase/feruloyl esterase A family, whose functional diversification makes it a very promising candidate. RESULTS: The results suggested functional shift following a duplication event where neofunctionalisation of feruloyl esterase A had occurred with conservation of the ancestral lipase function. Evolutionary shift was detected using the branch-site model for testing positive selection on individual codons along specific lineages. Positively selected amino acids were detected. Furthermore, biological data obtained from site-directed mutagenesis experiments clearly demonstrated that certain amino acids under positive selection were involved in the functional shift. We reassessed evolutionary history in terms of environmental response, and hypothesized that environmental changes such as colonisation by terrestrial plants might have driven adaptation by functional diversification in Euascomycetes (Aspergilli), thus conferring a selective advantage on this group. CONCLUSION: The results reported here illustrate a rare example of connection between fundamental events in molecular evolution. We demonstrated an unequivocal connection between evolutionary and functional shifts, which led us to conclude that these events were probably linked to environmental change.

Amino Acids↗
PubMed2006

Functionally redundant SHI family genes regulate Arabidopsis gynoecium development in a dose-dependent manner.

Gene duplication events, and the subsequent functional divergence of duplicates, are believed to be important evolutionary agents, driving morphological diversification. We have studied the structural and functional diversification of members of a plant-specific gene family in Arabidopsis thaliana by analysing mutant phenotypes, expression patterns and phylogeny. The SHI gene family comprises ten members that encode proteins with a RING finger-like zinc finger motif. We show that, despite being highly divergent in sequence, except in two conserved regions, many of the SHI-related genes are partially redundant in function and synergistically promote gynoecium, stamen and leaf development in Arabidopsis. Gynoecia of the loss-of-function sty1-1 mutant display subtle morphological defects, and, although mutations in the related STY2, SHI, SRS3, SRS4, SRS5, SRS7 and LRP1 genes have no apparent effect on gynoecium development, the sty1-1 mutant phenotype is gradually enhanced in double, triple, quadruple and quintuple mutant combinations, suggesting a remarkably extensive functional conservation within the family, which appears to be based on dosage dependency and protection against dominant negative mutations. In multiple mutant lines, all marginal tissues in the apical part of the gynoecium are dramatically reduced or missing, and our data indicate that SHI family members may promote formation of these tissues downstream of the transcriptional co-repressor LEUNIG (LUG).

Arabidopsis↗
PubMed2000

A case for evolutionary genomics and the comprehensive examination of sequence biodiversity.

Comparative analysis is one of the most powerful methods available for understanding the diverse and complex systems found in biology, but it is often limited by a lack of comprehensive taxonomic sampling. Despite the recent development of powerful genome technologies capable of producing sequence data in large quantities (witness the recently completed first draft of the human genome), there has been relatively little change in how evolutionary studies are conducted. The application of genomic methods to evolutionary biology is a challenge, in part because gene segments from different organisms are manipulated separately, requiring individual purification, cloning, and sequencing. We suggest that a feasible approach to collecting genome-scale data sets for evolutionary biology (i.e., evolutionary genomics) may consist of combination of DNA samples prior to cloning and sequencing, followed by computational reconstruction of the original sequences. This approach will allow the full benefit of automated protocols developed by genome projects to be realized; taxon sampling levels can easily increase to thousands for targeted genomes and genomic regions. Sequence diversity at this level will dramatically improve the quality and accuracy of phylogenetic inference, as well as the accuracy and resolution of comparative evolutionary studies. In particular, it will be possible to make accurate estimates of normal evolution in the context of constant structural and functional constraints (i.e., site-specific substitution probabilities), along with accurate estimates of changes in evolutionary patterns, including pairwise coevolution between sites, adaptive bursts, and changes in selective constraints. These estimates can then be used to understand and predict the effects of protein structure and function on sequence evolution and to predict unknown details of protein structure, function, and functional divergence. In order to demonstrate the practicality of these ideas and the potential benefit for functional genomic analysis, we describe a pilot project we are conducting to simultaneously sequence large numbers of vertebrate mitochondrial genomes.

Animals↗
PubMed2002

Advances in our understanding of peroxiredoxin, a multifunctional, mammalian redox protein.

Organisms living under aerobic conditions have developed various anti-oxidative mechanisms to protect them from damage by reactive oxygen species (ROS). A novel family of anti-oxidative proteins, designated as peroxiredoxin (Prx), has been identified in the past two decades and currently comprises six members in mammals. They share a common reactive Cys residue in the N-terminal region, and are capable of serving as a peroxidase and involve thioredoxin and/or glutathione as the electron donor. Prx1 to Prx4 have an additional Cys residue in the conserved C-terminal region, and are cross members as judged by the amino acid sequence similarity. Prx5 also contains an additional Cys in its C-terminal region which is less conserved. On the other hand, Prx6 has only one unique Cys. These Prx family members are distributed in the cytosol, mitochondria, peroxisome and plasma, all of which are potential sites of ROS production. In addition to their role as a peroxidase, however, a body of evidence has accumulated to suggest that individual members also serve divergent functions which are associated with various biological processes such as the detoxification of oxidants, cell proliferation, differentiation and gene expression. It would be expected that these functions might not necessarily depend on peroxidase activity and, therefore, it seems likely that the divergence is due to unique molecular characteristics intrinsic to each member. A comparative study of the divergence would lead to a better understanding of the biological significance of the Prx family.

Animals↗
PubMed2003

Analysis of synergy between divergent simple retrovirus posttranscriptional control elements.

Mason-Pfizer monkey virus (MPMV) and spleen necrosis virus (SNV) are simple retroviruses that encode functionally divergent cis-acting RNA elements that use cellular proteins to facilitate nuclear export and translation of unspliced viral RNA. We tested the hypothesis that a combination of MPMV constitutive transport element (CTE) and SNV or MPMV RU5 translational enhancer on unspliced HIV-1 gag-pol reporter RNA synergistically augments Gag production. Results of transient transfection assays validate the hypothesis of synergistic augmentation in COS cells, but not 293 cells. RNA targeting experiments verified comparable responsiveness to CTE-interactive proteins tethered by RRE and RevM10Tap in COS and 293 cells. Exogeneous expression of Tap and NXT1 was necessary and sufficient to rescue Gag augmentation in 293 cells. Overexpression experiments established that CTE, but not RU5, confers the responsiveness to Tap and NXT1 and that CTE in conjunction with Tap and NXT1 conferred a 30-fold increase in translational utilization of the cytoplasmic RNA. Our results uncovered a previously unidentified role of CTE in conjunction with Tap and NXT1 in commitment to efficient cytoplasmic RNA utilization.

5' Untranslated Regions↗
PubMed2005

A small family of sushi-class retrotransposon-derived genes in mammals and their relation to genomic imprinting.

Ty3/gypsy retrotransposons are rare in mammalian genomes despite their abundance in invertebrate and other vertebrate classes. Here we identify a family of nine conserved mammalian genes with homology to Ty3/gypsy retrotransposons but which have lost their ability to autonomously retrotranspose. Of these, five map to the X chromosome while the remaining four are autosomal. Comparative phylogenetic analyses show them to have strongest homology to the sushi-ichi element from Fugu rubripes. Two of the autosomal gene members, Peg10 and Rtl1, are known to be imprinted, being expressed from the paternally inherited chromosome homologue. This suggests, consistent with the host-parasite response theory of the evolution of the imprinting mechanism, that parental-origin specific epigenetic control may be mediated by genomic "parasitic" elements such as these. Alternatively, these elements may preferentially integrate into regions that are differentially modified on the two homologous chromosomes such as imprinted domains and the X chromosome and acquire monoallelic expression. We assess the imprinting status of the remaining autosomal members of this family and show them to be biallelically expressed in embryo and placenta. Furthermore, the methylation status of Rtl1 was assayed throughout development and was found to resemble that of actively, silenced repetitive elements rather than imprinted sequences. This indicates that the ability to undergo genomic imprinting is not an inherent property of all members of this family of retroelements. Nonetheless, the conservation but functional divergence between the different members suggests that they have undergone positive selection and acquired distinct endogenous functions within their mammalian hosts.

Amino Acid Sequence↗
PubMed2003

Convergent neofunctionalization by positive Darwinian selection after ancient recurrent duplications of the xanthine dehydrogenase gene.

Gene duplication is a primary source of molecular substrate for the emergence of evolutionary novelties. The chances for redundant gene sequences to evolve new functions are small compared with the probability that the copies become disabled by deleterious mutations. Functional divergence after gene duplication can result in two alternative evolutionary fates: one copy acquires a novel function (neofunctionalization), or each copy adopts part of the tasks of their parental gene (subfunctionalization). The relative prevalence of each outcome is unknown. Similarly unknown is the relative importance of positive selection versus random fixation of neutral mutations. Aldehyde oxidase (Ao) and xanthine dehydrogenase (Xdh) genes encode two complex members of the xanthine oxidase family of molybdo-flavoenzymes that carry different functions. Ao is known to have originated from a duplicate of an Xdh gene in eukaryotes, before the origin of multicellularity. We show that (i) Ao evolved independently twice from two different Xdh paralogs, the second time in the chordates, before the diversification of vertebrates; (ii) after each duplication, the Ao duplicate underwent a period of rapid evolution during which identical sites across the two molecules, involving the flavin adenine dinucleotide and substrate-binding pockets, were subjected to intense positive Darwinian selection; and (iii) the second Ao gene likely endured two periods of redundancy, initially as a duplicate of Xdh and later as a functional equivalent of the old Ao, which is currently absent from the vertebrate genome. Caution is appropriate in structural genomics when using sequence similarity for assigning protein function.

Aldehyde Oxidase↗
PubMed2004

The cation/Ca(2+) exchanger superfamily: phylogenetic analysis and structural implications.

Cation/Ca(2+) exchangers are an essential component of Ca(2+) signaling pathways and function to transport cytosolic Ca(2+) across membranes against its electrochemical gradient by utilizing the downhill gradients of other cation species such as H(+), Na(+), or K(+). The cation/Ca(2+) exchanger superfamily is composed of H(+)/Ca(2+) exchangers and Na(+)/Ca(2+) exchangers, which have been investigated extensively in both plant cells and animal cells. Recently, information from completely sequenced genomes of bacteria, archaea, and eukaryotes has revealed the presence of genes that encode homologues of cation/Ca(2+) exchangers in many organisms in which the role of these exchangers has not been clearly demonstrated. In this study, we report a comprehensive sequence alignment and the first phylogenetic analysis of the cation/Ca(2+) exchanger superfamily of 147 sequences. The results present a framework for structure-function relationships of cation/Ca(2+) exchangers, suggesting unique signature motifs of conserved residues that may underlie divergent functional properties. Construction of a phylogenetic tree with inclusion of cation/Ca(2+) exchangers with known functional properties defines five protein families and the evolutionary relationships between the members. Based on this analysis, the cation/Ca(2+) exchanger superfamily is classified into the YRBG, CAX, NCX, and NCKX families and a newly recognized family, designated CCX. These findings will provide guides for future studies concerning structures, functions, and evolutionary origins of the cation/Ca(2+) exchangers.

Amino Acid Sequence↗