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PubMed2001

Human chromosome 19 and related regions in mouse: conservative and lineage-specific evolution.

To illuminate the function and evolutionary history of both genomes, we sequenced mouse DNA related to human chromosome 19. Comparative sequence alignments yielded confirmatory evidence for hypothetical genes and identified exons, regulatory elements, and candidate genes that were missed by other predictive methods. Chromosome-wide comparisons revealed a difference between single-copy HSA19 genes, which are overwhelmingly conserved in mouse, and genes residing in tandem familial clusters, which differ extensively in number, coding capacity, and organization between the two species. Finally, we sequenced breakpoints of all 15 evolutionary rearrangements, providing a view of the forces that drive chromosome evolution in mammals.

Animals↗

PubMed2003

A comprehensive view on proteasomal sequences: implications for the evolution of the proteasome.

Proteasomes are large multimeric self-compartmentizing proteases, which play a crucial role in the clearance of misfolded proteins, breakdown of regulatory proteins, processing of proteins by specific partial proteolysis, cell cycle control as well as preparation of peptides for immune presentation. Two main types can be distinguished by their different tertiary structure: the 20S proteasome and the proteasome-like heat shock protein encoded by heat shock locus V, hslV. Usually, each biological kingdom is characterized by its specific type of proteasome. The 20S proteasomes occur in eukarya and archaea whereas hslV protease is prevalent in bacteria. To verify this rule we applied a genome-wide sequence search to identify proteasomal sequences in data of finished and yet unfinished genome projects. We found several exceptions to this paradigm: (1) Protista: in addition to the 20S proteasome, Leishmania, Trypanosoma and Plasmodium contained hslV, which may have been acquired from an alpha-proteobacterial progenitor of mitochondria. (2) Bacteria: for Magnetospirillum magnetotacticum and Enterococcus faecium we found that each contained two distinct hslVs due to gene duplication or horizontal transfer. Including unassembled data into the analyses we confirmed that a number of bacterial genomes do not contain any proteasomal sequence due to gene loss. (3) High G+C Gram-positives: we confirmed that high G+C Gram-positives possess 20S proteasomes rather than hslV proteases. The core of the 20S proteasome consists of two distinct main types of homologous monomers, alpha and beta, which differentiated into seven subtypes by further gene duplications. By looking at the genome of the intracellular pathogen Encephalitozoon cuniculi we were able to show that differentiation of beta-type subunits into different subtypes occurred earlier than that of alpha-subunits. Additionally, our search strategy had an important methodological consequence: a comprehensive sequence search for a particular protein should also include the raw sequence data when possible because proteins might be missed in the completed assembled genome. The structure-based multiple proteasomal alignment of 433 sequences from 143 organisms can be downloaded from the URL dagger and will be updated regularly.

Amino Acid Sequence↗

PubMed2004

Simulation study on effects of signaling network structure on the developmental increase in complexity.

The developmental increase in structural complexity in multicellular lifeforms depends on local, often non-periodic differences in gene expression. These, in turn, depend on a network of gene-gene interactions coded within the organismal genome. To see what architectural features of a network (size, connectivity, etc.) affect the likelihood of patterns with multiple cell types (i.e. patterns where cells express > or = 3 different combinations of genes), developmental pattern formation was simulated in virtual blastoderm embryos with small artificial genomes. Several basic properties of these genomic signaling networks, such as the number of genes, the distributions of positive (inductive) and negative (repressive) interactions, and the strengths of gene-gene interactions were tested. The results show that the frequencies of complex and/or stable patterns depended not only on the existence of negative interactions, but also on the distribution of regulatory interactions: for example, coregulation of signals and their intracellular effectors increased the likelihood of pattern formation compared to differential regulation of signaling pathway components. Interestingly, neither quantitative differences in strengths of signaling interactions nor multiple response thresholds to different levels of signal concentration (as in morphogen gradients) were essential for formation of multiple, spatially unique "cell types". However, those combinations of architectural features that greatly increased the likelihood for pattern complexity tended to decrease the likelihoods for pattern stability and developmental robustness. Nevertheless, elements of complex patterns (e.g. genes, cell type order within the pattern) could differ in their developmental robustness, which may be important for the evolution of complexity. The results show that depending on the network structure, the same set of genes can produce patterns of different complexity, robustness and stability. Because of this, the evolution of metazoan complexity with a combinatorial code of gene regulation may have depended at least as much on selection for favorable distribution of connections between existing developmental regulatory genes as on the simple increase in numbers of regulatory genes.

Animals↗

PubMed2006

Does physiological beta cell turnover initiate autoimmune diabetes in the regional lymph nodes?

The initial immune process that triggers autoimmune beta cell destruction in type 1 diabetes is not fully understood. In early infancy there is an increased beta cell turnover. Recurrent exposure of tissue-specific antigens could lead to primary sensitization of immune cells in the draining lymph nodes of the pancreas. An initial immune injury to the beta cells can be inflicted by several cell types, primarily macrophages and T cells. Subsequently, infiltrating macrophages transfer antigens exposed by apoptotic beta cells to the draining lymph nodes, where antigen presenting cells process and amplify a secondary immune reaction. Antigen presenting cells evolve as dual players in the activation and suppression of the autoimmune reaction in the draining lymph nodes. We propose a scenario where destructive insulitis is caused by recurrent exposure of specific antigens due to the physiological turnover of beta cells. This sensitization initiates the evolution of reactive clones that remain silent in the regional lymph nodes, where they succeed to evade regulatory clonal deletion.

Animals↗

PubMed2006

The MPAC domain is a novel mitotically regulated domain, removed by apoptotic protease cleavage during cell death.

The apoptotic proteases, including caspases and granzyme B, have independent evolutionary origins, yet are both highly specific for cleavage after aspartic acid residues and cleave many of the same substrates at closely spaced sites. In addition, many of these substrates are also reversibly regulated during other processes such as the cell cycle. In these studies, we have identified a novel domain (the MPAC domain: Mitotically Phosphorylated, Apoptotically Cleaved) present at the N-terminus of Ufd2a, which is regulated both by cleavage during cell death, and by phosphorylation during mitosis. We have also identified a corresponding domain, at the C-terminus of polyA polymerase (PAP), which is similarly regulated by phosphorylation during mitosis and is delineated by an apoptotic protease cleavage site. The positioning of the apoptotic cleavage site suggests that it represents a novel connector between the regulatory domain and its functional partner(s), providing insights into the structure and function that guided the evolution of the apoptotic proteases.

Apoptosis↗

PubMed1999

Functional expression of human and Arabidopsis protein phosphatase 2A in Saccharomyces cerevisiae and isolation of dominant-defective mutants.

Protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine-specific protein phosphatase, comprises a catalytic subunit and two distinct regulatory subunits, A and B. The primary sequence of the catalytic (C) subunit is highly conserved in evolution, and its function has been shown to be essential in yeast, Drosophila and mice. In many eukaryotes, the C subunit is encoded by at least two nearly identical genes, impeding conventional loss-of-function genetic analysis. We report here the development of a functional complementation assay in S. cerevisiae that has allowed us to isolate dominant-defective alleles of human and Arabidopsis C subunit genes. Wild-type human and Arabidopsis C subunit genes can complement the lethal phenotype of S. cerevisiae PP2A-C mutations. Site-directed mutagenesis was used to create two distinct, catalytically impaired C subunit mutants of the human and Arabidopsis genes. In both cases, expression of the mutant subunit in yeast prevented growth, even in the presence of functional C subunit proteins. This dominant growth defect is consistent with a dominant-interfering mode of action. Thus, we have shown that S. cerevisiae provides a rapid system for the functional analysis of heterologous PP2A genes, and that two mutations that abrogate phosphatase activity exhibit dominant-defective phenotypes in S. cerevisiae.

Alleles↗

PubMed1995

Gating of thrombin in platelet aggregates by pO2-linked lowering of extracellular Ca2+ concentration.

Platelet accretion at sites of vascular injury yields a neo-tissue comprising packed platelets and having an interstitial space not supplied with blood. Within growing thrombi platelet masses become anoxic and depolarize to yield interstitial cation concentrations characteristic of the more voluminous platelet cytosol, with extracellular [Ca2+] falling below that adequate to support the plasma clotting system. The platelet-associated clotting system reactivates during disaggregation of the thrombi in vitro, which proceeds with high yield of apparently basal, functional platelets when specific anticoagulants are included in the disaggregating media. The capacity of regulatory demand to lower extracellular [Ca2+] in the microenvironment of platelet aggregates provides a physiological basis for evolution of the highly cooperative calcium interactions of the hemostasis system.

Adenosine Triphosphate↗

PubMed2006

Deciphering principles of transcription regulation in eukaryotic genomes.

Transcription regulation has been responsible for organismal complexity and diversity in the course of biological evolution and adaptation, and it is determined largely by the context-dependent behavior of cis-regulatory elements (CREs). Therefore, understanding principles underlying CRE behavior in regulating transcription constitutes a fundamental objective of quantitative biology, yet these remain poorly understood. Here we present a deterministic mathematical strategy, the motif expression decomposition (MED) method, for deriving principles of transcription regulation at the single-gene resolution level. MED operates on all genes in a genome without requiring any a priori knowledge of gene cluster membership, or manual tuning of parameters. Applying MED to Saccharomyces cerevisiae transcriptional networks, we identified four functions describing four different ways that CREs can quantitatively affect gene expression levels. These functions, three of which have extrema in different positions in the gene promoter (short-, mid-, and long-range) whereas the other depends on the motif orientation, are validated by expression data. We illustrate how nature could use these principles as an additional dimension to amplify the combinatorial power of a small set of CREs in regulating transcription.

Computational Biology↗

PubMed1984

Nucleotide sequence determination of guinea-pig casein B mRNA reveals homology with bovine and rat alpha s1 caseins and conservation of the non-coding regions of the mRNA.

Nucleotide sequence analysis of cloned guinea-pig casein B cDNA sequences has identified two casein B variants related to the bovine and rat alpha s1 caseins. Amino acid homology was largely confined to the known bovine or predicted rat phosphorylation sites and within the 'signal' precursor sequence. Comparison of the deduced nucleotide sequence of the guinea-pig and rat alpha s1 casein mRNA species showed greater sequence conservation in the non-coding than in the coding regions, suggesting a functional and possibly regulatory role for the non-coding regions of casein mRNA. The results provide insight into the evolution of the casein genes, and raise questions as to the role of conserved nucleotide sequences within the non-coding regions of mRNA species.

Amino Acid Sequence↗

PubMed2003

European experiences in the development of approaches for the successful control of workplace health risks.

In recent years, several approaches have been proposed for the application of control banding concepts to the assessment and management of various workplace health and safety risks. Whilst many of the earlier approaches have originated in the UK, several of the most recent examples have been developed in Europe. The European schemes have attempted to build upon the lessons learned from the earlier control banding schemes and to apply them to new areas of health and safety. This paper analyses the evolution of the earlier approaches and reviews the more recent European developments in the context of continuing regulatory and societal demands for the improved assessment and regulation of workplace chemical risks.

Europe↗

PubMed2001

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: suiting structure to need, in a family of tissue-specific enzymes.

The present review addresses recent advances in research into a family of bifunctional enzymes that are responsible for the twofold task of synthesizing and hydrolyzing fructose-2,6-bisphosphate (Fru-2,6-P2), which in turn regulates the rate of glycolysis in most cells. The structure of the synthetic kinase, conjoined at its carboxyl-terminus to the phosphatase, is very highly conserved throughout evolution and differentiation, with isotypic expression arising from highly variable amino-terminal and carboxyl-terminal regulatory domains. These domains, which frequently contain protein-kinase-catalyzed phosphorylation motifs, are responsible for the widely divergent kinetics observed in various tissues and species, and for the hormonal modulation that alters intracellular levels of Fru-2,6-P2. The present review discusses recent advances in relating structure to function, and the identification of new pathways of transcriptional regulation of this important family of regulatory enzymes.

Adrenal Cortex Hormones↗

PubMed1989

Androgen-regulated gene expression.

While a great deal of knowledge on the mechanisms of steroid hormone regulated gene expression now exists, specific information relating to androgens is lacking. A number of experimental systems have been developed and show promise as models for molecular studies of androgen regulation. Further development of these models must address the issue of whether or not the androgen receptor behaves similarly to other steroid receptors. This will require progress in the purification of the receptor itself or the cloning of its gene. Several features of androgen-regulated gene expression in the mouse kidney are applicable to a number of important biological problems. First, the presence of a variety of inducible mRNAs, whose responses to androgen are controlled at several genetic and molecular levels, should be valuable in obtaining basic information on mechanisms of gene regulation by hormones. Second, a genetic approach, for which the mouse is a convenient organism, will enable identification of novel regulatory elements that are responsible for variations in the hormonal activation of genes and that drive the evolution of species-specific gene expression phenotypes. Finally, the trophic effects of androgens in the mouse kidney afford opportunities to study a gene expression phenotype that is involved in cell growth; it will be of interest to determine how androgen induction of gene expression in kidney proximal tubule cells relates to the hormone-mediated growth of these cells.

Alcohol Dehydrogenase↗

PubMed1996

Genetic aspects of polydactyly.

The early limb development follows the similar pattern in all vertebrates since different species develop using the same regulatory genes in the formation of the body plan. Some of these genes remained well conserved during evolution and can be traced back as far as Drosophila--while some others changed their structure or developed new functions. This is why the limbs from different animals still look different from one another. However, all existing tetrapods have, like Homo Sapiens, limbs with five, or fewer digits. It has been argued that the interplay of the factors controlling the patterning and differentiation during the embryonal limb development can provide five distinct "genotypes" allowing development of only five different digits. This would imply that the Greek definition of polydactyly, namely "duplication of the finger or a part of it", is correct, not only in morphological but also in a genetical sense. Genes involved in the determination of the outline of the limb are candidates for disorders like polydactyly and syndactyly. Recently, we have localised the gene for triphalangeal thumb (TPT) on chromosome 7q. As almost 50% of our patient population also had rudimentary postaxial polydactyly and/or syndactyly, the interesting question arose whether the TPT gene also was responsible for isolated post-axial polydactyly. Our preliminary evidence suggests, however, that different gene(s) are involved in the pathomorphogenesis of postaxial polydactyly. Studies of human congenital hand malformations--combined with genetic studies in lower vertebrates--will help us to understand not only the molecular basis of these disorders, but also to get insight into the fascinating mechanisms involved in the normal development of the human hand.

Animals↗

PubMed2005

Co-evolution analysis on endocrine research: a methodological approach.

The rapid growth of different kinds of biological information allows a good opportunity to analyze the co-evolutionary characteristics in endocrine regulatory pathways. Data ranging from kinds of species' genome, gene sequence, protein structure, and expression profile of different organisms can reveal the inner co-evolutionary relationship of ligands, receptors, and other related molecules. In return, these co-evolutionary characteristics can help us determine uncharacterized ligands and receptors, annotate gene functions, highlight amino acid residues with biochemical significance, and identify regulated genes in the endocrine process. Encouraging examples in this field, although at their starting stage, have emerged. Here we focus on recent progress in endocrine-related co-evolution research from a methodological approach.

Endocrine System↗

PubMed2001

Domain fusion between SNF1-related kinase subunits during plant evolution.

Members of the conserved SNF1/AMP-activated protein kinase (AMPK) family regulate cellular responses to environmental and nutritional stress in eukaryotes. Yeast SNF1 and animal AMPKs form a complex with regulatory SNF4/AMPKgamma and SIP1/SIP2/GAL83/AMPKbeta subunits. The beta-subunits function as target selective adaptors that anchor the catalytic kinase and regulator SNF4/gamma-subunits to their kinase association (KIS) and association with the SNF1 complex (ASC) domains. Here we demonstrate that plant SNF1-related protein kinases (SnRKs) interact with an adaptor-regulator protein, AKINbetagamma, in which an N-terminal KIS domain characteristic of beta-subunits is fused with a C-terminal region related to the SNF4/AMPKgamma proteins. AKINbetagamma is constitutively expressed in plants, suppresses the yeast delta snf4 mutation, and shows glucose-regulated interaction with the Arabidopsis SnRK, AKIN11. Our results suggest that evolution of AKINbetagamma reflects a unique function of SNF1-related protein kinases in plant glucose and stress signalling.

AMP-Activated Protein Kinases↗

PubMed2000

Stress and transposable elements: co-evolution or useful parasites?

The activity of transposable elements can be induced by environmental and population factors and in particular by stresses in various organisms. A consequence of the increase in transposable element mobility is the creation of new genetic variability that can be useful in the face of stressful conditions. In this review, results supporting this hypothesis are presented and discussed. The main question is how stress induces the activity of transposable elements. We discuss hypotheses based upon the existence of promoters or fixation sites of transcription activators in the untranslated regions of transposable elements, similar to those found in regulatory regions of host defence genes.

Biological Evolution↗

PubMed2002

Complete genomic sequence of SfV, a serotype-converting temperate bacteriophage of Shigella flexneri.

Bacteriophage SfV is a temperate serotype-converting phage of Shigella flexneri. SfV encodes the factors involved in type V O-antigen modification, and the serotype conversion and integration-excision modules of the phage have been isolated and characterized. We now report on the complete sequence of the SfV genome (37,074 bp). A total of 53 open reading frames were predicted from the nucleotide sequence, and analysis of the corresponding proteins was used to construct a functional map. The general organization of the genes in the SfV genome is similar to that of bacteriophage lambda, and numerous features of the sequence are described. The superinfection immunity system of SfV includes a lambda-like repression system and a P4-like transcription termination mechanism. Sequence analysis also suggests that SfV encodes multiple DNA methylases, and experiments confirmed that orf-41 encodes a Dam methylase. Studies conducted to determine if the phage-encoded methylase confers host DNA methylation showed that the two S. flexneri strains analyzed encode their own Dam methylase. Restriction mapping and sequence analysis revealed that the phage genome has cos sites at the termini. The tail assembly and structural genes of SfV show homology to those of phage Mu and Mu-like prophages in the genome of Escherichia coli O157:H7 and Haemophilus influenzae. Significant homology (30% of the genome in total) between sections of the early, regulatory, and structural regions of the SfV genome and the e14 and KpLE1 prophages in the E. coli K-12 genome were noted, suggesting that these three phages have common evolutionary origins.

Amino Acid Sequence↗

PubMed2006

On the origin and evolution of major morphological characters.

Although the mathematical principles underpinning population-level evolution are now well studied, the origin and evolution of morphological novelties has received far less attention. Here, a broad but general theory for how this sort of change takes place is outlined, relying on functional continuity, least-constrained components of morphology, redundancy and preadaptation. At least four distinct sorts of redundancy are identified: (i) redundancy arising through duplication (amplification); (ii) redundancy arising through regionalisation (parcellation); (iii) redundancy arising through functional convergence; and (iv) redundancy arising from shared function (functional degeneracy). Although organisms are here recognised to be functionally constrained ("burdened", in Riedl's terminology), these constraints can be overcome through the combination of the four principles given above. Contrary to its common treatment, functional constraint is neither an ever-increasing restriction on the scope of evolution, nor does it require drastic events to overcome or "break" it. Rather, it is an evolutionary quantity, subject to selection at some level. The rules that govern morphological evolution are the primary controls on what is allowed to happen in the evolution of the overall genotype-phenotype system, suggesting strong controls on the sorts of developmental changes that might be associated with macroevolution. This model, then, sees organism functionality as the primary control on evolvability, with exact genetic make-up being of secondary importance. It should prove possible to recast traditional notions of body-plan evolution into the formulations of complex system analysis, which in the future may prove a unifying discipline for fields as disparate as palaeontology and gene regulatory networks. In particular, understanding how morphology can evolve may provide the critical link between the ecological and morphological networks that are currently the intense focus of evolutionary investigations.

Adaptation, Physiological↗