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PubMed2005

Characterisation of the marsupial-specific ATRY gene: implications for the evolution of male-specific function.

Many or most genes on the mammal Y chromosome evolved a testis-specific function after diverging from an X-borne copy with a general function in both sexes. In marsupial but not eutherian mammals, a testis-specific orthologue (ATRY) of the widely expressed X-borne ATRX gene lies on the Y chromosome. Since mutations in human ATRX cause sex reversal, it is possible that one function of ATRY in marsupials is testicular differentiation. We report here the isolation and sequencing of the tammar wallaby (Macropus eugenii) ATRY cDNA, and comparison of its sequence with that of tammar ATRX. The evolution of a testis-specific function for the ATRY protein distinct from the general role of ATRX in both sexes has been accompanied by sequence changes in many protein domains that would alter protein binding partners. A large open reading frame encodes a 1771 amino acid ATRY protein that has diverged extensively from ATRX. The conservation and loss of particular motifs identify those required for testicular function (ATRY) and function in other tissues (ATRX).

Amino Acid Sequence↗
PubMed2003

Different evolutionary patterns between young duplicate genes in the human genome.

BACKGROUND: Following gene duplication, two duplicate genes may experience relaxed functional constraints or acquire different mutations, and may also diverge in function. Whether the two copies will evolve in different patterns remains unclear, however, because previous studies have reached conflicting conclusions. In order to resolve this issue, by providing a general picture, we studied 250 independent pairs of young duplicate genes from the whole human genome. RESULTS: We showed that nearly 60% of the young duplicate gene pairs have evolved at the amino-acid level at significantly different rates from each other. More than 25% of these gene pairs also showed significantly different ratios of nonsynonymous to synonymous rates (Ka/Ks ratios). Moreover, duplicate pairs with different rates of amino-acid substitution also tend to differ in the Ka/Ks ratio, with the fast-evolving copy tending to have a slightly higher Ks than the slow-evolving one. Lastly, a substantial portion of fast-evolving copies have accumulated amino-acid substitutions evenly across the protein sequences, whereas most of the slow-evolving copies exhibit uneven substitution patterns. CONCLUSIONS: Our results suggest that duplicate genes tend to evolve in different patterns following the duplication event. One copy evolves faster than the other and accumulates amino-acid substitutions evenly across the sequence, whereas the other copy evolves more slowly and accumulates amino-acid substitutions unevenly across the sequence. Such different evolutionary patterns may be largely due to different functional constraints on the two copies.

Amino Acid Substitution↗
PubMed1996

Structural and functional diversity of cadherin superfamily: are new members of cadherin superfamily involved in signal transduction pathway?

A large number of cadherins and cadherin-related proteins are expressed in different tissues of a variety of multicellular organisms. These proteins share one property: their extracellular domains consist of multiple repeats of a cadherin-specific motif. A recent structure study has shown that the cadherin repeats roughly corresponding to the folding unit of the extracellular domains. The members of the cadherin superfamily are roughly classified into two groups, classical type cadherins proteins and protocadherin type according to their structural properties. These proteins appear to be derived from a common ancestor that might have cadherin repeats similar to those of the current protocadherins, and to have common functional properties. Among various cadherins, E-cadherin was the first to be identified as a Ca(2+)-dependent homophilic adhesion protein. Recent knockout mice experiments have proven its biological role, but there are still several puzzling unsolved properties of the cell adhesion activity. Other members of cadherin superfamily show divergent properties and many lack some of the expected properties of cell adhesion protein. Since recent studies of various adhesion proteins reveal that they are involved in different signal transduction pathways, the idea that the new members of cadherin superfamily may participate in more general cell-cell interaction processes including signal transduction is an intriguing hypothesis. The cadherin superfamily is structurally divergent and possibly functionally divergent as well.

Animals↗
PubMed2000

Using the CATH domain database to assign structures and functions to the genome sequences.

The CATH database of protein structures contains approximately 18000 domains organized according to their (C)lass, (A)rchitecture, (T)opology and (H)omologous superfamily. Relationships between evolutionary related structures (homologues) within the database have been used to test the sensitivity of various sequence search methods in order to identify relatives in Genbank and other sequence databases. Subsequent application of the most sensitive and efficient algorithms, gapped blast and the profile based method, Position Specific Iterated Basic Local Alignment Tool (PSI-BLAST), could be used to assign structural data to between 22 and 36 % of microbial genomes in order to improve functional annotation and enhance understanding of biological mechanism. However, on a cautionary note, an analysis of functional conservation within fold groups and homologous superfamilies in the CATH database, revealed that whilst function was conserved in nearly 55% of enzyme families, function had diverged considerably, in some highly populated families. In these families, functional properties should be inherited far more cautiously and the probable effects of substitutions in key functional residues carefully assessed.

Algorithms↗
PubMed1978

Experimental evolution of a new enzymatic function. II. Evolution of multiple functions for ebg enzyme in E. coli.

The evolution of ebgo enzyme of Escherichia coli, an enzyme which is unable to hydrolyze lactose, lactulose, lactobionate, or galactose-arabinoside effectively, has been directed in successive steps so that the evolved enzyme is able to hydrolyze these galactosides effectively. I show that in order for a strain of E. coli with a lacZ deletion to evolve the ability to use lactobionate as a carbon source, a series of mutations must occur in the ebg genes, and that these mutations must be selected in a particular order. The ordered series of mutations constitutes an obligatory evolutionary pathway for the acquisition of a new function for ebgo enzyme. A comparison of newly evolved strains with parental strains shows that when ebg enzyme acquires a new function, its old functions often suffer; but that in several cases old functions are either unaffected or are improved. I conclude that divergence of functions catalyzed by an enzyme need not require gene duplication.

Biological Evolution↗
PubMed2005

Alternative splicing removes an Ets interaction domain from Lozenge during Drosophila eye development.

Physical and functional characteristics of the RUNX family of transcription factors are conserved between vertebrates and the Drosophila protein Lozenge. The runt-homology domain responsible for DNA binding and also the C-terminus are both nearly identical between the two proteins. The mammalian and fly proteins heterodimerize with a non-DNA binding partner protein to form a core binding factor essential for gene regulation during cell differentiation. The mammalian protein RUNX1 (AML1/PEBP2alphaB) interacts with the transcription factor Ets-1 to increase DNA binding and transactivation potential. Alternative splicing of the mammalian RUNX1 removes a domain required for this cooperative transactivation. In this work we determine the structure of the lozenge transcription unit and map 21 mutations. We show that the lozenge transcript is alternatively spliced during eye development to remove an Ets interaction domain. Emphasis is placed on Pointed the Drosophila homolog of the vertebrate Ets-1 protein; both Lozenge and Pointed proteins are needed for the activation of prospero expression. We use site-directed mutagenesis and yeast two-hybrid analysis to show that conserved amino acids within the alternate Lozenge exon are important for interaction with Pointed. Furthermore, the ectopic expression of Lozenge is sufficient to rescue Prospero expression in the presence of the Pointed competitor, Yan(ACT). We show that both lozenge isoforms are expressed during eye development and that the relative ratio of the transcripts for the two isoforms is sensitive to changes in Ras activity. We suggest that during eye development, Lozenge isoforms function in divergent roles, either interacting with Pointed on downstream targets or by functioning independently to establish distinct cell fates.

Alternative Splicing↗
PubMed1984

Saccharomyces cerevisiae GAL1-GAL10 divergent promoter region: location and function of the upstream activating sequence UASG.

The GAL1 and GAL10 genes, separated by 680 base pairs and divergently transcribed on chromosome 2 of Saccharomyces cerevisiae, were separately fused to the lacZ gene of Escherichia coli so that beta-galactosidase synthesis in S. cerevisiae reflected GAL1 and GAL10 promoter function. Analysis of two sets of deletions defined a 75-base-pair sequence, located ca. midway between the transcription initiation regions of GAL1 and GAL10, that mediates GAL4-dependent induction of both genes. Deletion of various parts of this sequence (called the GAL upstream activating sequence or UASG) reduced GAL1 and GAL10 induction about equally. Sequences in the GAL10-proximal half of UASG in some sequence contexts functioned independently of sequences in the GAL1-proximal half of UASG. A 33-base-pair deletion of the GAL10-proximal half of UASG drastically reduced induction. Deletions between UASG and the GAL1 TATA box caused beta-galactosidase to be synthesized at an unexpectedly high basal level, that is, in the absence of galactose and GAL4 product. Some of these mutations also reduced the repression caused by glucose.

Base Sequence↗
PubMed1996

Relative reactivity of platelets from thrombopoietin- and interleukin-6-treated dogs.

Previous reports have shown that interleukin-6 (IL-6) enhances the responsiveness of platelets to thrombin stimulation and has modest thrombocytopoietic effects in vivo. Thrombopoietin (TPO; mpl ligand) has been shown to have dramatic thrombocytopoietic effect in vivo, but little is known of its capacity to alter platelet function. In this study, a direct comparison of the effects of IL-6 and TPO on platelet function in dogs has been performed, with modest doses of TPO (1 microgram/kg/d) chosen to match or moderately exceed the platelet counts achieved with IL-6 (40 micrograms/kg/d) for 10 days. Platelet responsiveness to thrombin stimulation was assessed in TPO-treated, IL-6-treated, and control dogs by flow cytometric measurement of P-selectin expression. On day 5, the dose of thrombin promoting half maximal stimulation (EC50) of platelets was not significantly changed in TPO-treated dogs, whereas in IL-6-treated dogs the EC50 decreased to 73.1% +/- 6.1% (mean +/- 1 SD; n = 5) of control values (P < 0.01). These experiments were performed on both gel-filtered platelets and washed whole blood, indicating that the observed changes in EC50 were caused by cytokine-mediated alteration of platelets rather than plasma components. Because it has been shown that thiazole orange specifically labels a subpopulation of dog platelets that is less than 24 hours old, the thrombin responsiveness of these young, newly synthesized platelets was determined. The EC50 of thiazole orange-positive platelets from IL-6-treated dogs decreased dramatically by day 5 to 46.5% +/- 13.1% (n = 4) of control values (P < 0.001), whereas TPO-treated dogs did not significantly change. When TPO was directly incubated with platelets ex vivo, no effects on either thrombin-mediated P-selectin expression or adenosine diphosphate-induced fibrinogen binding were observed. These data show that IL-6 alters platelet function, as measured by reactivity to thrombin, whereas TPO does not. This divergence in function is observed even though TPO is equally, or more, effective at promoting platelet production under these experimental conditions.

Adenosine Diphosphate↗
PubMed1995

Evolution of neuroblast identity: seven-up and prospero expression reveal homologous and divergent neuroblast fates in Drosophila and Schistocerca.

In the Drosophila CNS, early neuroblast formation and fate are controlled by the pair-rule class of segmentation genes. The distantly related Schistocerca (grasshopper) embryo has a similar arrangement of neuroblasts, despite lack of known pair-rule gene function. Does divergent pair-rule gene function lead to different neuroblast identities, or can different patterning mechanisms produce homologous neuroblasts? We use four molecular markers to compare Drosophila and Schistocerca neuroblast identity: seven-up, prospero, engrailed, and fushi-tarazu/Dax. In both insects some early-forming neuroblasts share key features of neuroblast identity (position, time of formation, and temporally accurate gene expression); thus, different patterning mechanisms can generate similar neuroblast fates. In contrast, several later-forming neuroblasts show species-specific differences in position and/or gene expression; these neuroblast identities seem to have diverged, suggesting that evolution of the insect central nervous system can occur through changes in embryonic neuroblast identity.

Amino Acid Sequence↗
PubMed2004

Polymicrobial sepsis induces divergent effects on splenic and peritoneal dendritic cell function in mice.

Dendritic cells (DCs) are professional antigen-presenting cells that act as sentinels in the cell-mediated response against invading pathogens associated with septic challenge. The purpose of the present study was to determine whether there is a loss of dendritic cells and/or changes in function of these cells in septic mice. Here we report that the number of DCs, in both spleen and peritoneum, decreased over 24 h postsepsis [cecal ligation and puncture (CLP)] when compared with sham. The most dramatic change was seen in the peritoneal cavity. This decrease appeared to be caused mainly by the depletion of immature DCs rather than mature DCs. This change was LPS independent and minimally affected by FasL; however, overexpression of human Bcl-2 gene provides protection of the septic peritoneal DCs. Moreover, although the level of IL-12 release decreased significantly in splenic DCs obtained from CLP mice, IL-12 secretion was markedly elevated by peritoneal DCs as well as in both plasma and peritoneal fluid at 24 h post-CLP. In peritoneal cells, the expression of CD40, CD80, and CD86 was unchanged, but their respective ligands CD40L, CD28, and CD152 all increased in mice 24 h after CLP, although no such change was observed in splenocytes. Regardless of the presence or absence of antigen, peritoneal DCs from CLP mice showed higher capacity to stimulate T-cell proliferation than those cells from the sham control. However, splenic DCs from CLP mice only showed augmented capacity to induce antigen-dependent stimulation of T-cell proliferation. Together, these data indicate that sepsis produces divergent functional changes in splenic and peritoneal DC populations.

Animals↗
PubMed1996

The cloning and sequencing of a ribosomal L18 protein from an evolutionary divergent eukaryote, Trypanosoma brucei.

Eukaryotic ribosomal proteins are highly conserved across widely divergent species, suggesting that strong functional constraints prevent divergence of important amino acid motifs. Using this as a basis, an evolutionary approach could be used to identify putative functional motifs. We obtained the DNA sequence of the ribosomal protein L18 from the evolutionary divergent protozoan parasite, Trypanosoma brucei. Analysis of this sequence showed that it had 46% and 43% identity with the human and yeast sequences, respectively, and 30% of amino acid residues were identical across all the species analysed. Using these data, amino acids essential to the structure and function of ribosomal protein L18 can be inferred and could provide valuable information for molecular modelling and mutational studies.

Amino Acid Sequence↗
PubMed1988

A gene encoding the major beta tubulin of the mitotic spindle in Physarum polycephalum plasmodia.

The multinucleate plasmodium of Physarum polycephalum is unusual among eucaryotic cells in that it uses tubulins only in mitotic-spindle microtubules; cytoskeletal, flagellar, and centriolar microtubules are absent in this cell type. We have identified a beta-tubulin cDNA clone, beta 105, which is shown to correspond to the transcript of the betC beta-tubulin locus and to encode beta 2 tubulin, the beta tubulin expressed specifically in the plasmodium and used exclusively in the mitotic spindle. Physarum amoebae utilize tubulins in the cytoskeleton, centrioles, and flagella, in addition to the mitotic spindle. Sequence analysis shows that beta 2 tubulin is only 83% identical to the two beta tubulins expressed in amoebae. This compares with 70 to 83% identity between Physarum beta 2 tubulin and the beta tubulins of yeasts, fungi, alga, trypanosome, fruit fly, chicken, and mouse. On the other hand, Physarum beta 2 tubulin is no more similar to, for example, Aspergillus beta tubulins than it is to those of Drosophila melanogaster or mammals. Several eucaryotes express at least one widely diverged beta tubulin as well as one or more beta tubulins that conform more closely to a consensus beta-tubulin sequence. We suggest that beta-tubulins diverge more when their expression pattern is restricted, especially when this restriction results in their use in fewer functions. This divergence among beta tubulins could have resulted through neutral drift. For example, exclusive use of Physarum beta 2 tubulin in the spindle may have allowed more amino acid substitutions than would be functionally tolerable in the beta tubulins that are utilized in multiple microtubular organelles. Alternatively, restricted use of beta tubulins may allow positive selection to operate more freely to refine beta-tubulin function.

Animals↗
PubMedDate not supplied

Measuring genetic distances between breeds: use of some distances in various short term evolution models.

Many works demonstrate the benefits of using highly polymorphic markers such as microsatellites in order to measure the genetic diversity between closely related breeds. But it is sometimes difficult to decide which genetic distance should be used. In this paper we review the behaviour of the main distances encountered in the literature in various divergence models. In the first part, we consider that breeds are populations in which the assumption of equilibrium between drift and mutation is verified. In this case some interesting distances can be expressed as a function of divergence time, t, and therefore can be used to construct phylogenies. Distances based on allele size distribution (such as (deltamu)(2)and derived distances), taking a mutation model of microsatellites, the Stepwise Mutation Model, specifically into account, exhibit large variance and therefore should not be used to accurately infer phylogeny of closely related breeds. In the last section, we will consider that breeds are small populations and that the divergence times between them are too small to consider that the observed diversity is due to mutations: divergence is mainly due to genetic drift. Expectation and variance of distances were calculated as a function of the Wright-Malécot inbreeding coefficient, F. Computer simulations performed under this divergence model show that the Reynolds distance [57]is the best method for very closely related breeds.

Breeding↗
PubMed1995

Structural similarity between two-layer alpha/beta and beta-proteins.

This paper demonstrates that overall folds of two-layer alpha/beta-proteins and beta-proteins with aligned beta-sheet packings have a number of common features. First of all, there are similar recurrent folding units, the so-called abcd-units, in proteins of both the classes. There are also some larger commonly occurring structures in many representatives of these classes. The fact that these proteins belong to different structural classes and have different functions supports the idea that some physical principles governing the polypeptide chain folding rather than the evolutionary divergence or functional convergence of proteins are the basis of such similarities. The analysis reported here shows that practically all the known protein structures of these classes can be obtained by stepwise addition of secondary structure element to the abcd-units taking into account three simple rules: (1) crossing of connection regions is prohibited; (2) alpha-helices should be packed into the alpha-layer and beta-strands in to the beta-layer of the growing structure; (3) beta alpha beta-units should be folded into right-handed superhelices; three consecutive beta-strands can be folded into the similar right-handed beta beta beta-superhelix if there is at least one additional beta-strand in the layer between the first and third ones. A possible selection of a conformation of a polypeptide chain segment by its protein environment is also discussed.

Models, Molecular↗
PubMed1999

Protein folds, functions and evolution.

The evolution of proteins and their functions is reviewed from a structural perspective in the light of the current database. Protein domain families segregate unequally between the three major classes, the 32 different architectures and almost 700 folds observed to date. We find that the number of new topologies is still increasing, although 25 new structures are now determined for each new topology. The corresponding analysis and classification of function is only just beginning, fuelled by the genome data. The structural data revealed unexpected conservations and divergence of function both within and between families. The next five years will see the compilation of a definitive dictionary of protein families and their related functions, based on structural data which reveals relationships hidden at the sequence level. Such information will provide the foundation to build a better understanding of the molecular basis of biological complexity and hopefully to facilitate rational molecular design.

Animals↗
PubMed2003

Functions of propeptide parts in cysteine proteases.

Regulation of proteolytic enzyme activity is an essential requirement for cells and tissues because proteolysis at the wrong time and location may be lethal. Two principal mechanisms to control the activity of proteases have been developed during evolution. The first is the co-evolution of endogenous inhibitors, typically occurring in cellular compartments separated from those containing active enzymes. The second is the fact that proteases are synthesized as inactive or less active precursor molecules. They are activated, in some cases, upon an appropriate signal like acidification, Ca(++) -binding or, in other cases, by limited intra- or intermolecular proteolysis cleaving off an inhibitory peptide. These regulatory proenzyme regions have attracted much attention during the last decade, since it became obvious that they harbour much more information than just triggering activation. In this review we summarize experimental data concerning three functions of propeptides of clan CA family C1 cysteine peptidases (papain family), namely the selectivity of their inhibitory potency, the participation in correct intracellular targeting and assistance in folding of the mature enzyme. Cysteine peptidases of the CA-C1 family include members from the plant kingdom like papain as well as from the animal kingdom like the lysosomal cathepsins L and B. As it will be shown, the functions are determined by certain structural motifs conserved over millions of years after the evolutionary trails have diverged. The function of propeptides of two other important classes of cysteine peptidases - the calpains, clan CA family C4, and the caspases, clan CD family C 14 - are not considered in this review.

Amino Acid Sequence↗
PubMed2002

The crystal structure of catechol oxidase: new insight into the function of type-3 copper proteins.

The crystal structure of catechol oxidase reveals new insight into the functional properties of the type-3 copper proteins. This class of proteins includes the closely related and better-known tyrosinase as well as hemocyanin, an oxygen transport protein. All these proteins have a dinuclear copper center, have similar spectroscopic behaviors, and show close evolutionary and functional relationships. Comparison between the 3D structures of catechol oxidase and hemocyanins reveals the structural reasons for the divergence in function.

Amino Acid Sequence↗
PubMed2000

ARIP3 (androgen receptor-interacting protein 3) and other PIAS (protein inhibitor of activated STAT) proteins differ in their ability to modulate steroid receptor-dependent transcriptional activation.

Steroid receptors mediate their actions by using various coregulatory proteins. We have recently characterized ARIP3/PIASx alpha as an androgen receptor (AR)-interacting protein (ARIP) that belongs to the PIAS [protein inhibitor of activated STAT (signal transducer and activator of transcription)] protein family implicated in the inhibition of cytokine signaling. We have analyzed herein the roles that four different PIAS proteins (ARIP3/PIASx alpha, Miz1/PIASx beta, GBP/PIAS1, and PIAS3) play in the regulation of steroid receptor- or STAT-mediated transcriptional activation. All PIAS proteins are able to coactivate steroid receptor-dependent transcription but to a differential degree, depending on the receptor, the promoter, and the cell type. Miz1 and PIAS1 are more potent than ARIP3 in activating AR function on minimal promoters. With the natural probasin promoter, PIAS proteins influence AR function more divergently, in that ARIP3 represses, but Miz1 and PIAS1 activate it. Miz1 and PIAS1 possess inherent transcription activating function, whereas ARIP3 and PIAS3 are devoid of this feature. ARIP3 enhances glucocorticoid receptor-dependent transcription more efficiently than Miz1 or PIAS1, and all PIAS proteins also activate estrogen receptor- and progesterone receptor-dependent transcription but to a dissimilar degree. The same amounts of PIAS proteins that modulate steroid receptor-dependent transcription influence only marginally transactivation mediated by various STAT proteins. It remains to be established whether the PIAS proteins play a more significant physiological role in steroid receptor than in cytokine signaling.

Amino Acid Sequence↗