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Systematic characterization of the zinc-finger-containing proteins in the mouse transcriptome.

Zinc-finger-containing proteins can be classified into evolutionary and functionally divergent protein families that share one or more domains in which a zinc ion is tetrahedrally coordinated by cysteines and histidines. The zinc finger domain defines one of the largest protein superfamilies in mammalian genomes;46 different conserved zinc finger domains are listed in InterPro (http://www.ebi.ac.uk/InterPro). Zinc finger proteins can bind to DNA, RNA, other proteins, or lipids as a modular domain in combination with other conserved structures. Owing to this combinatorial diversity, different members of zinc finger superfamilies contribute to many distinct cellular processes, including transcriptional regulation, mRNA stability and processing, and protein turnover. Accordingly, mutations of zinc finger genes lead to aberrations in a broad spectrum of biological processes such as development, differentiation, apoptosis, and immunological responses. This study provides the first comprehensive classification of zinc finger proteins in a mammalian transcriptome. Specific detailed analysis of the SP/Krüppel-like factors and the E3 ubiquitin-ligase RING-H2 families illustrates the importance of such an analysis for a more comprehensive functional classification of large protein families. We describe the characterization of a new family of C2H2 zinc-finger-containing proteins and a new conserved domain characteristic of this family, the identification and characterization of Sp8, a new member of the Sp family of transcriptional regulators, and the identification of five new RING-H2 proteins.

Alternative Splicing↗

Functional anatomy of forebrain vocal control pathways in the budgerigar (Melopsittacus undulatus).

Budgerigars throughout life are capable of learning to produce many different sounds including those of human speech. Like humans, budgerigars use multiple craniomotor systems and coordinate both orosensory and auditory feedback in specialized forebrain nuclei. Although budgerigar auditory-vocal learning has a different evolutionary origin from that of human speech, both the human and budgerigar systems can control F0 and can alter the distribution of energy in spectral bands by adjusting the filter properties of the vocal tract. This allows budgerigars to produce an extremely diverse array of calls including many broadband and highly complex sounds.

Animals↗

Computer assisted promoter analysis of a human sperm specific nucleoprotein gene cluster.

The promoter regions of the clustered human spermatid-specific nucleoprotein PRM1, PRM2 arid TNP2 genes were compared to define regulatory elements that may govern their expression. Sequence alignment revealed two wll conserved motifs, despite a lack of extensive homology. They are located at similar positions within the first 400 nt of their 5' UTRs. Conservation of these motifs may reflect selective evolutionary pressure to maintain their structure. This supports the view that these elements assume a central role in the coordinate regulation of this gene cluster during spermiogenesis. The distribution of binding sites of known transcription factors was also assessed within the regions flanking the 5' ends of these genes. This analysis should prove useful in directing studies that define the signals necessary for the coordinate regulation of this spermatid specific gene cluster.

Base Sequence↗

The role of mitochondrial respiration in physiological and evolutionary adaptation.

Aerobic mitochondria serve as the power sources of eukaryotes by producing ATP through oxidative phosphorylation (OXPHOS). The enzymes involved in OXPHOS are multisubunit complexes encoded by both nuclear and mitochondrial DNA. Thus, regulation of respiration is necessarily a highly coordinated process that must organize production, assembly and function of mitochondria to meet an organism's energetic needs. Here I review the role of OXPHOS in metabolic adaptation and diversification of higher animals. On a physiological timescale, endocrine-initiated signaling pathways allow organisms to modulate respiratory enzyme concentration and function under changing environmental conditions. On an evolutionary timescale, mitochondrial enzymes are targets of natural selection, balancing cytonuclear coevolutionary constraints against physiological innovation. By synthesizing our knowledge of biochemistry, physiology and evolution of respiratory regulation, I propose that we can now explore questions at the interface of these fields, from molecular translation of environmental cues to selection on mitochondrial haplotype variation.

Adaptation, Physiological↗

Cranial integration in Homo: singular warps analysis of the midsagittal plane in ontogeny and evolution.

This study addresses some enduring issues of ontogenetic and evolutionary integration in the form of the hominid cranium. Our sample consists of 38 crania: 20 modern adult Homo sapiens, 14 sub-adult H. sapiens, and four archaic Homo. All specimens were CT-scanned except for two infant H. sapiens, who were imaged by MR instead. For each specimen 84 landmarks and semi-landmarks were located on the midsagittal plane and converted to Procrustes shape coordinates. Integration was quantified by the method of singular warps, a new geometric-statistical approach to visualizing correlations among regions. The two classic patterns of integration, evolutionary and ontogenetic, were jointly explored by comparing analyses of overlapping subsamples that span ranges of different hypothetical factors. Evolutionary integration is expressed in the subsample of 24 adult Homo, and ontogenetic integration in the subsample of 34 H. sapiens. In this data set, vault, cranial base, and face show striking and localized patterns of covariation over ontogeny, similar but not identical to the patterns seen over evolution. The principal differences between ontogeny and phylogeny pertain to the cranial base. There is also a component of cranial length to height ratio not reducible to either process. Our methodology allows a separation of these independent processes (and their impact on cranial shape) that conventional methods have not found.

Adult↗

Extensive gene duplication in the early evolution of animals before the parazoan-eumetazoan split demonstrated by G proteins and protein tyrosine kinases from sponge and hydra.

To know whether genes involved in cell-cell communication typical of multicellular animals dramatically increased in concert with the Cambrian explosion, the rapid evolutionary burst in the major groups of animals, and whether these genes exist in the sponge lacking cell cohesiveness and coordination typical of eumetazoans, we have carried out cloning of the G-protein alpha subunit (Galpha) and the protein tyrosine kinase (PTK) cDNAs from Ephydatia fluviatilis (freshwater sponge) and Hydra magnipapillata strain 105 (hydra). We obtained 13 Galpha and 20 PTK cDNAs. Generally animal gene families diverged first by gene duplication (subtype duplication) that gave rise to diverse subtypes with different primary functions, followed by further gene duplication in the same subtype (isoform duplication) that gave rise to isoform genes with virtually identical function. Phylogenetic trees of Galpha and PTK families including cDNAs from sponge and hydra revealed that most of the present-day subtypes had been established in the very early evolution of animals before the parazoan-eumetazoan split, the earliest branching among the extant animal phyla, by extensive subtype duplication: for PTK and Galpha families, 23 and 9 subtype duplications were observed in the early stage before the parazoan-eumetazoan split, respectively, and after that split, only 2 and 1 subtype duplications were found, respectively. After the separation from arthropods, vertebrates underwent frequent isoform duplications before the fish-tetrapod split. Furthermore, rapid amino acid changes appear to have occurred in concert with the extensive subtype duplication and isoform duplication. Thus the pattern of gene diversification during animal evolution might be characterized by bursts of gene duplication interrupted by considerably long periods of silence, instead of proceeding gradually, and there might be no direct link between the Cambrian explosion and the extensive gene duplication that generated diverse functions (subtypes) of these families.

Amino Acid Substitution↗

Developmental dynamics: toward a biologically plausible evolutionary psychology.

There has been a conceptual revolution in the biological sciences over the past several decades. Evidence from genetics, embryology, and developmental biology has converged to offer a more epigenetic, contingent, and dynamic view of how organisms develop. Despite these advances, arguments for the heuristic value of a gene-centered, predeterministic approach to the study of human behavior and development have become increasingly evident in the psychological sciences during this time. In this article, the authors review recent advances in genetics, embryology, and developmental biology that have transformed contemporary developmental and evolutionary theory and explore how these advances challenge gene-centered explanations of human behavior that ignore the complex, highly coordinated system of regulatory dynamics involved in development and evolution.

Biological Evolution↗

An evolutionary perspective on signaling in behavior and immunology.

Signaling and communication are important at different levels of biological organization. Signals exchanged between cells of the immune system initiate and coordinate the immune response; signals exchanged between individuals often coordinate social behavior. Behavioral ecologists interested in the evolution and functional design of signals exchanged between individuals have produced a theory of signaling and communication that stresses the importance of cooperation and conflict; if a conflict of interest between signaler and receiver is great enough, signals evolve towards greater reliability. We suggest that the application of signaling system theory to signals exchanged between cells within an individual will allow for a better understanding of immunity and intra-individual communication in general, with potential for novel approaches to the treatment of disease.

Allergy and Immunology↗

How many processes are responsible for phenotypic evolution?

In addressing phenotypic evolution, this article reconsiders natural selection, random drift, developmental constraints, and internal selection in the new extended context of evolutionary developmental biology. The change of perspective from the "evolution of phenotypes" toward an "evolution of ontogenies" (evo-devo perspective) affects the reciprocal relationships among these different processes. Random drift and natural selection are sibling processes: two forms of post-productional sorting among alternative developmental trajectories, the former random, the latter nonrandom. Developmental constraint is a compound concept; it contains even some forms of natural ("external" and "internal") selection. A narrower definition ("reproductive constraints") is proposed. Internal selection is not a selection caused by an internal agent. It is a form of environment-independent selection depending on the level of the organism's internal developmental or functional coordination. Selection and constraints are the main deterministic processes in phenotypic evolution but they are not opposing forces. Indeed, they are continuously interacting processes of evolutionary change, but with different roles that should not be confused.

Alleles↗

Phenotypic plasticity of adult myocardium: molecular mechanisms.

Cardiac phenotypic plasticity (so-called cardiac remodelling, CR) is characterized by changes in myocardial structure that happen in response to either mechanical overload or a loss of substance such as that occurring after myocardial infarction. Mechanosensation is a widespread biological process and is inextricably mixed with other transduction systems from hormones and vasopeptides, which ultimately produce post-translational modifications of transcription factors. The expression of the four main transcription factors during cardiogenesis is also enhanced as a link to foetal reprogramming. CR results from re-expression of the foetal programme, which is mostly adaptive, but also from several other phenotypic modifications that are not usually adaptive, such as fibrosis. (i) The initial determinant is mechanical, and re-expression of the foetal programme includes a global increase in genetic expression with cardiac hypertrophy, re-expression of genes that are normally not expressed in the adult ventricles, repression of genes not expressed during the foetal life, and activation of pre-exisiting stem cells. Microarray technology has revealed a coordinated change in expression of genes pertaining to signal transduction, metabolic function, structure and motility, and cell organism defence. The physiological consequence is a better adapted muscle. (ii) During clinical conditions, the effects of mechanics are modified by several interfering determinants that modify CR, including senescence, obesity, diabetes, ischemia and the neurohormonal reaction. Each of these factors can alter myocardial gene expression and modify molecular remodelling of mechanical origin. Finally, as compared to evolutionary phenotypic plasticity described in plants and insects in response to variations in environmental conditions, in CR, the environmental factor is internal, plasticity is primarily adaptive, and it involves coordinated changes in over 1400 genes. Study of reaction norms showed that the genotypes from different animal species are similarly plastic, but there are transgenic models in which adaptation to mechanics is not caused by hypertrophy but by qualitative changes in gene expression.

Adaptation, Physiological↗

Comparison of conformational characteristics in structurally similar protein pairs.

Although it is known that three-dimensional structure is well conserved during the evolutionary development of proteins, there have been few studies that consider other parameters apart from divergence of the main-chain coordinates. In this study, we align the structures of 90 pairs of homologous proteins having sequence identities ranging from 5 to 100%. Their structures are compared as a function of sequence identity, including not only consideration of C alpha coordinates but also accessibility, Ooi numbers, secondary structure, and side-chain angles. We discuss how these properties change as the sequences become less similar. This will be of practical use in homology modeling, especially for modeling very distantly related or analogous proteins. We also consider how the average size and number of insertions and deletions vary as sequences diverge. This study presents further quantitative evidence that structure is remarkably well conserved in detail, as well as at the topological level, even when the sequences do not show similarity that is significant statistically.

Algorithms↗

A Calpha model for the transmembrane alpha helices of gap junction intercellular channels.

Gap junction channels connect the cytoplasms of apposed cells via an intercellular conduit formed by the end-to-end docking of two hexameric hemichannels called connexons. We used electron cryomicroscopy to derive a three-dimensional density map at 5.7 angstroms in-plane and 19.8 angstroms vertical resolution, allowing us to identify the positions and tilt angles for the 24 alpha helices within each hemichannel. The four hydrophobic segments in connexin sequences were assigned to the alpha helices in the map based on biochemical and phylogenetic data. Analyses of evolutionary conservation and compensatory mutations in connexin evolution identified the packing interfaces between the helices. The final model, which specifies the coordinates of Calpha atoms in the transmembrane domain, provides a structural basis for understanding the different physiological effects of almost 30 mutations and polymorphisms in terms of structural deformations at the interfaces between helices, revealing an intimate connection between molecular structure and disease.

Amino Acid Sequence↗

Evolutionary conservation of the 14-3-3 protein.

The novel family of 14-3-3 proteins may be involved in the regulation of neuronal activity. During our search for proteins coordinately expressed with the prohormone proopiomelanocortin in the melanotrope cells of the Xenopus intermediate pituitary gland, we cloned and sequenced a pituitary cDNA encoding a Xenopus 14-3-3 protein. Alignment of the Xenopus protein with known mammalian, Drosophila and plant 14-3-3 polypeptide and with a mammalian protein kinase C inhibitor protein revealed that the neuron-specific 14-3-3-related proteins are highly conserved (60-88%) throughout eukaryotic evolution.

14-3-3 Proteins↗

Investigating hypoxic tumor physiology through gene expression patterns.

Clinical evidence shows that tumor hypoxia is an independent prognostic indicator of poor patient outcome. Hypoxic tumors have altered physiologic processes, including increased regions of angiogenesis, increased local invasion, increased distant metastasis and altered apoptotic programs. Since hypoxia is a potent controller of gene expression, identifying hypoxia-regulated genes is a means to investigate the molecular response to hypoxic stress. Traditional experimental approaches have identified physiologic changes in hypoxic cells. Recent studies have identified hypoxia-responsive genes that may define the mechanism(s) underlying these physiologic changes. For example, the regulation of glycolytic genes by hypoxia can explain some characteristics of the Warburg effect. The converse of this logic is also true. By identifying new classes of hypoxia-regulated gene(s), we can infer the physiologic pressures that require the induction of these genes and their protein products. Furthermore, these physiologically driven hypoxic gene expression changes give us insight as to the poor outcome of patients with hypoxic tumors. Approximately 1-1.5% of the genome is transcriptionally responsive to hypoxia. However, there is significant heterogeneity in the transcriptional response to hypoxia between different cell types. Moreover, the coordinated change in the expression of families of genes supports the model of physiologic pressure leading to expression changes. Understanding the evolutionary pressure to develop a 'hypoxic response' provides a framework to investigate the biology of the hypoxic tumor microenvironment.

Animals↗

Computational neurogenetic modelling: a pathway to new discoveries in genetic neuroscience.

The paper presents a methodology for using computational neurogenetic modelling (CNGM) to bring new original insights into how genes influence the dynamics of brain neural networks. CNGM is a novel computational approach to brain neural network modelling that integrates dynamic gene networks with artificial neural network model (ANN). Interaction of genes in neurons affects the dynamics of the whole ANN model through neuronal parameters, which are no longer constant but change as a function of gene expression. Through optimization of interactions within the internal gene regulatory network (GRN), initial gene/protein expression values and ANN parameters, particular target states of the neural network behaviour can be achieved, and statistics about gene interactions can be extracted. In such a way, we have obtained an abstract GRN that contains predictions about particular gene interactions in neurons for subunit genes of AMPA, GABAA and NMDA neuro-receptors. The extent of sequence conservation for 20 subunit proteins of all these receptors was analysed using standard bioinformatics multiple alignment procedures. We have observed abundance of conserved residues but the most interesting observation has been the consistent conservation of phenylalanine (F at position 269) and leucine (L at position 353) in all 20 proteins with no mutations. We hypothesise that these regions can be the basis for mutual interactions. Existing knowledge on evolutionary linkage of their protein families and analysis at molecular level indicate that the expression of these individual subunits should be coordinated, which provides the biological justification for our optimized GRN.

Algorithms↗

Chloroplast division site placement requires dimerization of the ARC11/AtMinD1 protein in Arabidopsis.

Chloroplast division is mediated by the coordinated action of a prokaryote-derived division system(s) and a host eukaryote-derived membrane fission system(s). The evolutionary conserved prokaryote-derived system comprises several nucleus-encoded proteins, two of which are thought to control division site placement at the midpoint of the organelle: a stromal ATPase MinD and a topological specificity factor MinE. Here, we show that arc11, one of 12 recessive accumulation and replication of chloroplasts (arc) mutants in Arabidopsis, contains highly elongated and multiple-arrayed chloroplasts in developing green tissues. Genomic sequence analysis revealed that arc11 contains a missense mutation in alpha-helix 11 of the chloroplast-targeted AtMinD1 changing an Ala at position 296 to Gly (A296G). Introduction of wild-type AtMinD1 restores the chloroplast division defects of arc11 and quantitative RT-PCR analysis showed that the degree of complementation was highly dependent on transgene expression levels. Overexpression of the mutant ARC11/AtMinD1 in transgenic plants results in the inhibition of chloroplast division, showing that the mutant protein has retained its division inhibition activity. However, in contrast to the defined and punctate intraplastidic localization patterns of an AtMinD1-YFP fusion protein, the single A296G point mutation in ARC11/AtMinD1 results in aberrant localization patterns inside chloroplasts. We further show that AtMinD1 is capable of forming homodimers and that this dimerization capacity is abolished by the A296G mutation in ARC11/AtMinD1. Our data show that arc11 is a loss-of-function mutant of AtMinD1 and suggest that the formation of functional AtMinD1 homodimers is paramount for appropriate AtMinD1 localization, ultimately ensuring correct division machinery placement and chloroplast division in plants.

Amino Acid Sequence↗

Regulation of muscle mitochondrial design.

Mitochondria are responsible for the generation of ATP to fuel muscle contraction. Hypermetabolic stresses imposed upon muscles can lead to mitochondrial proliferation, but the resulting mitochondria greatly resemble their progenitors. During the mitochondrial biogenesis that accompanies phenotypic adaptation, the stoichiometric relationships between functional elements are preserved through shared sensitivities of respiratory genes to specific transcription factors. Although the properties of muscle mitochondria are generally thought to be highly conserved across species, there are many examples of mitochondrial differences between muscle types, species and developmental states and even within single cells. In this review, we discuss (1) the nature and regulation of gene families that allow coordinated expression of genes for mitochondrial products and (2) the regulatory mechanisms by which mitochondrial differences can arise over physiological and evolutionary time.

Journal Article↗

Regulation of muscle mitochondrial design.

Mitochondria are responsible for the generation of ATP to fuel muscle contraction. Hypermetabolic stresses imposed upon muscles can lead to mitochondrial proliferation, but the resulting mitochondria greatly resemble their progenitors. During the mitochondrial biogenesis that accompanies phenotypic adaptation, the stoichiometric relationships between functional elements are preserved through shared sensitivities of respiratory genes to specific transcription factors. Although the properties of muscle mitochondria are generally thought to be highly conserved across species, there are many examples of mitochondrial differences between muscle types, species and developmental states and even within single cells. In this review, we discuss (1) the nature and regulation of gene families that allow coordinated expression of genes for mitochondrial products and (2) the regulatory mechanisms by which mitochondrial differences can arise over physiological and evolutionary time.

Animals↗