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PubMed1999

Mathematical models of metabolic pathways.

There have been recent advances in metabolic flux analysis. In particular, the marriage of traditional flux balancing with NMR isotopomer distribution analysis holds great promise for the detailed quantification of physiology. Nevertheless, flux analysis yields only static snap-shots of metabolism. To robustly predict the time evolution of metabolic networks, dynamic mathematical models, especially those that contain a description of both gene expression as well as enzyme activity, must be utilized. When mechanistic control and regulatory information is not available, heuristic-based methods, such as the cybernetic framework, can be employed to describe the action of these control mechanisms. In the 'high-information' future, as more biological information becomes available, such heuristic-based approaches can be replaced by mechanistic mass-action representations of physiology that stem directly from genetic sequence.

Animals↗

PubMed2003

Enigmatic variations: divergent modes of regulating eukaryotic DNA replication.

Proteins involved in DNA replication are conserved from yeast to mammals, suggesting that the mechanism was established at an early stage of eukaryotic evolution. In spite of this common origin, recent findings have revealed surprising variations in how replication initiation is controlled, implying that a conserved mechanism has not necessarily resulted in regulatory conservation.

Animals↗

PubMedDate not supplied

Evidence for the evolution of a single component phenol/cresol hydroxylase from a multicomponent toluene monooxygenase.

We have previously reported on the organization of a unique toluene-3-monooxygenase pathway for the degradation of alkyl-substituted petroleum hydrocarbons including characteristics of the second step in the pathway transforming phenols to catechols. In the present work we have focused on the regulation and unusual genetic organization of this metabolic step. In particular, we have sequenced the 3-kb DNA interval between the region encoding the tbuD gene product (phenol/cresol hydroxylase) and part of the toluene-3-monooxygenase operon of strain PKO1. Then, various regions of this DNA were fused to a LacZ expression system to ascertain the location of the tbuD gene promoter and the binding site for its regulator, TbuT. The 5' end for transcripts for the putative promoter of the tbuD gene was also analyzed using primer extension analysis. Collectively, these results revealed that the promoter was located 2.5-kb upstream of the region encoding the tbuD gene product whose N-terminal region had been previously determined by peptide sequencing. Remarkably, the intervening 2.5-kb region showed sequence identity to results we reported previously for a multi-subunit toluene-2-monooxygenase cloned from a different bacterium, strain JS150, for which phenols are also substrates and effectors. When the DNA sequence for the tbuD gene and its contiguous 2.5-kb upstream region were compared to the entire toluene-2-monooxygenase sequence cloned from strain JS150, a promoter proximal region encoding three reading frames showed 99% identity to subunits for the toluene-2-monooxygenase operon. Within the contiguous tbuD gene region, however, DNA sequence homology was reduced to 64% overall identity and deduced amino acid sequence homology was only 21% similar. Although regions internal to the tbuD gene showed homology to corresponding toluene-2-monooxygenase subunits, domains associated with the putative functions proposed for such subunits were deleted. We believe that these results suggest that through evolution either tbuD was derived from the 2-monooxygenase pathway by deletions and molecular rearrangements, or alternatively the tbuD gene recruited part of the 2-monooxygenase pathway and its regulatory system which is activated by benzene, alkyl-substituted benzenes and phenols.

Amino Acid Sequence↗

PubMed2004

Search for organising principles: understanding in systems biology.

Due in large measure to the explosive progress in molecular biology, biology has become arguably the most exciting scientific field. The first half of the 21st century is sometimes referred to as the 'era of biology', analogous to the first half of the 20th century, which was considered to be the 'era of physics'. Yet, biology is facing a crisis--or is it an opportunity--reminiscent of the state of biology in pre-double-helix time. The principal challenge facing systems biology is complexity. According to Hood, 'Systems biology defines and analyses the interrelationships of all of the elements in a functioning system in order to understand how the system works.' With 30000+ genes in the human genome the study of all relationships simultaneously becomes a formidably complex problem. Hanahan and Weinberg raised the question as to whether progress will consist of 'adding further layers of complexity to a scientific literature that is already complex almost beyond measure' or whether the progress will lead to a 'science with a conceptual structure and logical coherence that rivals that of chemistry or physics.' At the core of the challenge is the need for a new approach, a shift from reductionism to a holistic perspective. However, more than just a pronouncement of a new approach is needed. We suggest that what is needed is to provide a conceptual framework for systems biology research. We propose that the concept of a complex system, i.e. a system of systems as defined in mathematical general systems theory (MGST), is central to provide such a framework. We further argue that for a deeper understanding in systems biology investigations should go beyond building numerical mathematical or computer models--important as they are. Biological phenomena cannot be predicted with the level of numerical precision as in classical physics. Explanations in terms of how the categories of systems are organised to function in ever changing conditions are more revealing. Non-numerical mathematical tools are appropriate for the task. Such a categorical perspective led us to propose that the core of understanding in systems biology depends on the search for organising principles rather than solely on construction of predictive descriptions (i.e. models) that exactly outline the evolution of systems in space and time. The search for organising principles requires an identification/discovery of new concepts and hypotheses. Some of them, such as coordination motifs for transcriptional regulatory networks and bounded autonomy of levccels in a hierarchy, are outlined in this article. Experimental designs are outlined to help verify the applicability of the interaction balance principle of coordination to transcriptional and posttranscriptional networks.

Cell Physiological Phenomena↗

PubMed2005

Metabolic functions of duplicate genes in Saccharomyces cerevisiae.

The roles of duplicate genes and their contribution to the phenomenon of enzyme dispensability are a central issue in molecular and genome evolution. A comprehensive classification of the mechanisms that may have led to their preservation, however, is currently lacking. In a systems biology approach, we classify here back-up, regulatory, and gene dosage functions for the 105 duplicate gene families of Saccharomyces cerevisiae metabolism. The key tool was the reconciled genome-scale metabolic model iLL672, which was based on the older iFF708. Computational predictions of all metabolic gene knockouts were validated with the experimentally determined phenotypes of the entire singleton yeast library of 4658 mutants under five environmental conditions. iLL672 correctly identified 96%-98% and 73%-80% of the viable and lethal singleton phenotypes, respectively. Functional roles for each duplicate family were identified by integrating the iLL672-predicted in silico duplicate knockout phenotypes, genome-scale carbon-flux distributions, singleton mutant phenotypes, and network topology analysis. The results provide no evidence for a particular dominant function that maintains duplicate genes in the genome. In particular, the back-up function is not favored by evolutionary selection because duplicates do not occur more frequently in essential reactions than singleton genes. Instead of a prevailing role, multigene-encoded enzymes cover different functions. Thus, at least for metabolism, persistence of the paralog fraction in the genome can be better explained with an array of different, often overlapping functional roles.

Gene Duplication↗

PubMed2003

Molecular and phylogenetic analyses of the complete MADS-box transcription factor family in Arabidopsis: new openings to the MADS world.

MADS-box transcription factors are key regulators of several plant development processes. Analysis of the complete Arabidopsis genome sequence revealed 107 genes encoding MADS-box proteins, of which 84% are of unknown function. Here, we provide a complete overview of this family, describing the gene structure, gene expression, genome localization, protein motif organization, and phylogenetic relationship of each member. We have divided this transcription factor family into five groups (named MIKC, Malpha, Mbeta, Mgamma, and Mdelta) based on the phylogenetic relationships of the conserved MADS-box domain. This study provides a solid base for functional genomics studies into this important family of plant regulatory genes, including the poorly characterized group of M-type MADS-box proteins. MADS-box genes also constitute an excellent system with which to study the evolution of complex gene families in higher plants.

Amino Acid Motifs↗

PubMed1998

Regulatory conservation and divergence of sigma32 homologs from gram-negative bacteria: Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Agrobacterium tumefaciens.

The heat shock response in Escherichia coli is mediated primarily by the rpoH gene, encoding sigma32, which is specifically required for transcription of heat shock genes. A number of sigma32 homologs have recently been cloned from gram-negative bacteria that belong to the gamma or alpha subdivisions of the proteobacteria. We report here some of the regulatory features of several such homologs (RpoH) expressed in E. coli as well as in respective cognate bacteria. When expressed in an E. coli delta rpoH strain lacking its own sigma32, these homologs activated the transcription of heat shock genes (groE and dnaK) from the start sites normally used in E. coli. The level of RpoH in Serratia marcescens and Pseudomonas aeruginosa cells was very low at 30 degrees C but was elevated markedly upon a shift to 42 degrees C, as found previously with E. coli. The increased RpoH levels upon heat shock resulted from both increased synthesis and stabilization of the normally unstable RpoH protein. In contrast, the RpoH level in Proteus mirabilis was relatively high at 30 degrees C and increased less markedly upon heat shock, mostly by increased synthesis; this sigma32 homolog was already stable at 30 degrees C, and little further stabilization occurred upon the shift to 42 degrees C. The increased synthesis of RpoH homologs in all these gamma proteobacteria was observed even in the presence of rifampin, suggesting that the induction occurred at the level of translation. Thus, the basic regulatory strategy of the heat shock response by enhancing the RpoH level is well conserved in the gamma proteobacteria, but some divergence in the actual mechanisms used occurred during evolution.

Agrobacterium tumefaciens↗

PubMed2006

Actin regulation in endocytosis.

Increasing evidence from a variety of cell types has highlighted the importance of the actin cytoskeleton during endocytosis. No longer is actin viewed as a passive barrier that must be removed to allow endocytosis to proceed. Rather, actin structures are dynamically organised to assist the remodelling of the cell surface to allow inward movement of vesicles. The majority of our mechanistic insight into the role of actin in endocytosis has come from studies in budding yeast. Although endocytosis in mammalian cells is clearly more complex and subject to a greater array of regulatory signals, recent advances have revealed actin, and actin-regulatory proteins, to be present at endocytic sites. Furthermore, live cell imaging indicates that spatiotemporal aspects of actin recruitment and vesicle formation are likely to be conserved across eukaryotic evolution.

Actins↗

PubMed2006

Nonadditive regulation of FRI and FLC loci mediates flowering-time variation in Arabidopsis allopolyploids.

Allopolyploidy is formed by combining two or more divergent genomes and occurs throughout the evolutionary history of many plants and some animals. Transcriptome analysis indicates that many genes in various biological pathways, including flowering time, are expressed nonadditively (different from the midparent value). However, the mechanisms for nonadditive gene regulation in a biological pathway are unknown. Natural variation of flowering time is largely controlled by two epistatically acting loci, namely FRIGIDA (FRI) and FLOWERING LOCUS C (FLC). FRI upregulates FLC expression that represses flowering in Arabidopsis. Synthetic Arabidopsis allotetraploids contain two sets of FLC and FRI genes originating from Arabidopsis thaliana and A. arenosa, respectively, and flower late. Inhibition of early flowering is caused by upregulation of A. thaliana FLC (AtFLC) that is trans-activated by A. arenosa FRI (AaFRI). Two duplicate FLCs (AaFLC1 and AaFLC2) originating from A. arenosa are expressed in some allotetraploids but silenced in other lines. The expression variation in the allotetraploids is associated with deletions in the promoter regions and first introns of A. arenosa FLCs. The strong AtFLC and AaFLC loci are maintained in natural Arabidopsis allotetraploids, leading to extremely late flowering. Furthermore, FLC expression correlates positively with histone H3-Lys4 methylation and H3-Lys9 acetylation and negatively with H3-Lys9 methylation, epigenetic marks for gene activation and silencing. We provide evidence for interactive roles of regulatory sequence changes, chromatin modification, and trans-acting effects in natural selection of orthologous FLC loci, which determines the fate of duplicate genes and adaptation of allopolyploids during evolution.

Acetylation↗

PubMed2006

Corynebacterium glutamicum as a model bacterium for the bioremediation of arsenic.

Arsenic is an extremely toxic metalloid that, when present in high concentrations, severely threatens the biota and human health. Arsenic contamination of soil, water, and air is a global growing environmental problem due to leaching from geological formations, the burning of fossil fuels, wastes generated by the gold mining industry present in uncontrolled landfills, and improper agriculture or medical uses. Unlike organic contaminants, which are degraded into harmless chemical species, metals and metalloids cannot be destroyed, but they can be immobilized or transformed into less toxic forms. The ubiquity of arsenic in the environment has led to the evolution in microbes of arsenic defense mechanisms. The most common of these mechanisms is based on the presence of the arsenic resistance operon (ars), which codes for: (i) a regulatory protein, ArsR; (ii) an arsenite permease, ArsB; and (iii) an enzyme involved in arsenate reduction, ArsC. Corynebacterium glutamicum, which is used for the industrial production of amino acids and nucleotides, is one of the most arsenic-resistant microorganisms described to date (up to 12 mM arsenite and >400 mM arseniate). Analysis of the C. glutamicum genome revealed the presence of two complete ars operons (ars1 and ars2) comprising the typical three-gene structure arsRBC, with an extra arsC1 located downstream from arsC1 (ars1 operon), and two orphan genes (arsB3 and arsC4). The involvement of both ars operons in arsenic resistance in C. glutamicum was confirmed by disruption and amplification of those genes. The strains obtained were resistant to up to 60 mM arsenite, one of the highest levels of bacterial resistance to arsenite so far described. Using tools for the genetic manipulation of C. glutamicum that were developed in our laboratory, we are attempting to obtain C. glutamicum mutant strains able to remove arsenic from contaminated water.

Arsenates↗

PubMed1995

The cold-shock response in bacteria.

The 'cold shock' response that occurs when exponentially growing Escherichia coli at 37 degrees C are transferred to 10 degrees C leads to the cesation of most protein synthesis, however, about 14 'cold shock' proteins continue to be made. These 'cold shock' proteins facilitate growth at low temperatures. Central to the regulation of this switch in gene expression is the 200 fold induction in the relative rate of synthesis of a small cold-shock protein only 70 amino acids in length, known as CS7.4. There is a remarkable conservation through evolution of the primary sequence found in this small cold shock protein and that of a nucleic acid binding domain within the Y-box family of eukaryotic gene regulatory proteins. Parallel studies on CS7.4 and the Y-box proteins have elucidated both molecular mechanisms regulating the cold shock response and a novel site for the regulation of eukaryotic gene expression.

Amino Acid Sequence↗

PubMed2005

Evolution and developmental patterning of the vertebrate skeletal muscles: perspectives from the lamprey.

The myotome in gnathostome vertebrates, which gives rise to the trunk skeletal muscles, consists of epaxial (dorsal) and hypaxial (ventral) portions, separated by the horizontal myoseptum. The hypaxial portion contains some highly derived musculature that is functionally as well as morphologically well differentiated in all the gnathostome species. In contrast, the trunk muscles of agnathan lampreys lack these distinctions and any semblance of limb muscles. Therefore, the lamprey myotomes probably represent a primitive condition compared with gnathostomes. In this review, we compare the patterns of expression of some muscle-specific genes between the lamprey and gnathostomes. Although the cellular and tissue morphology of lamprey myotomes seems uniform and undifferentiated, some of the muscle-specific genes are expressed in a spatially restricted manner. The lamprey Pax3/7 gene, a cognate of gnathostome Pax3, is expressed only at the lateral edge of the myotomes and in the hypobranchial muscle, which we presume is homologous to the gnathostome hypobranchial muscle. Thus, the emergence of some part of a hypaxial-specific gene regulatory cascade might have evolved before the agnathan/gnathostome divergence, or before the evolutionary separation of epaxial and hypaxial muscles.

Animals↗

PubMed1997

Neutral and nonneutral mutations: the creative mix--evolution of complexity in gene interaction systems.

Random drift, while indifferent to the functionality of the molecular features on which it acts, may nevertheless affect evolving molecular mechanisms. It can lead to functional novelty in either gene structure or regulation. In particular, a nearly neutral (in the sense of Ohta), somewhat deleterious mutation can result in a loss of efficiency in gene regulation, and this loss is expected at times to be compensated by a selected event of a particular type: the use of an additional regulatory factor. An accumulation of additional regulatory factors, implying a combination of events of drift and selection, can permit regulatory systems to achieve an increase in both specificity and complexity as mere byproducts of a particular repair process. Nearly neutral mutations thus may, at times, constitute a required pathway for increases in gene interaction complexity. The process seems to point to an inbuilt drive-built into the gene interaction system itself-toward the evolution of higher organisms. This is a matter worthy of experimental exploration, since the general foundations for the evolution of "higher" from "lower" organisms seems so far to have largely eluded analysis.

Animals↗

PubMed2005

Neural connectivity and cortical substrates of cognition in hominoids.

Cognitive functions and information processing recruit discrete neural systems in the cortex and white matter. We tested the idea that specific regions in the cerebrum are differentially enlarged in humans and that some of the neural reorganizational events that took place during hominoid evolution were species-specific and independent of changes in absolute brain size. We used magnetic resonance images of the living brains of 10 human and 17 ape subjects to obtain volumetric estimates of regions of interest. We parcellated the white matter in the frontal and temporal lobes into two sectors, including the white matter immediately underlying the cortex (gyral white matter) and the rest of white matter (core). We outlined the dorsal, mesial, and orbital subdivisions of the frontal lobe and analyzed the relationship between cortex and gyral white matter within each subdivision. For all regions analyzed, the observed human values are as large as expected, with the exception of the gyral white matter, which is larger than expected in humans. We found that orangutans had a relatively smaller orbital sector than any other great ape species, with no overlap in individual values. We found that the relative size of the dorsal subdivision is larger in chimpanzees than in bonobos, and that the ratio of gyral white matter to cortex stands out in Pan in comparison to Gorilla and Pongo. Individual variability, possible sex differences, and hemispheric asymmetries were present not only in humans, but in apes as well. Differences in the distribution of neural connectivity and cortical sectors were identified among great ape species that share similar absolute brain sizes. Given that these regions are part of neural systems with distinct functional attributes, we suggest that the observed differences may reflect different evolutionary pressures on regulatory mechanisms of complex cognitive functions, including social cognition.

Anatomy, Comparative↗

PubMed2003

The diversity and evolution of the T4-type bacteriophages.

Recent studies suggest that viruses are the most numerous entities in the biosphere; bacteriophages, the viruses that infect Eubacteria and Archaea, constitute a substantial fraction of this population. In spite of their ubiquity, the vast majority of phages in the environment have never been studied and nothing is known about them. For the last 10 years our research has focused on an extremely widespread group of phages, the T4-type. It has now become evident that phage T4 has a myriad of relatives in nature that differ significantly in their host range. The genomes of all these phages have homology to the T4 genes that determine virion morphology. Although phylogenetically related, these T4-type phages can be subdivided into four groups that are increasingly distant from T4: the T-evens, the pseudo T-evens, the schizo T-evens and the exo T-evens. Genomic comparisons between the various T4-type phages and T4 indicate that these genomes share homology not only for virion structural components but also for most of the essential genes involved in the T4 life cycle. This suggests that horizontal transmission of the genetic information may have played a less general role in the evolution of these phages than has been supposed. Nevertheless, we have identified several regions of the T4-type genome, such as the segment containing the tail fiber genes that exhibit evidence of extensive modular shuffling during evolution. The T4-type genomes appear to be a mosaic containing a large and fixed group of essential genes as well as highly variable set of non-essential genes. These non-essential genes are probably important for the adaptation of these phages to their particular life-style. Furthermore, swapping autonomous domains within the essential proteins may slightly modify their function(s) and contribute to the adaptive ability of the T4-type phage family. Regulatory sequences also display considerable evolutionary plasticity and this too may facilitate the adaptation of phage gene expression to new environments and stresses.

Bacteriophage T4↗

PubMed2005

Topology, tinkering and evolution of the human transcription factor network.

Patterns of protein interactions are organized around complex heterogeneous networks. Their architecture has been suggested to be of relevance in understanding the interactome and its functional organization, which pervades cellular robustness. Transcription factors are particularly relevant in this context, given their central role in gene regulation. Here we present the first topological study of the human protein-protein interacting transcription factor network built using the TRANSFAC database. We show that the network exhibits scale-free and small-world properties with a hierarchical and modular structure, which is built around a small number of key proteins. Most of these proteins are associated with proliferative diseases and are typically not linked to each other, thus reducing the propagation of failures through compartmentalization. Network modularity is consistent with common structural and functional features and the features are generated by two distinct evolutionary strategies: amplification and shuffling of interacting domains through tinkering and acquisition of specific interacting regions. The function of the regulatory complexes may have played an active role in choosing one of them.

Algorithms↗

PubMed2004

Positive autoregulation of the Myocyte enhancer factor-2 myogenic control gene during somatic muscle development in Drosophila.

The myocyte enhancer factor-2 (MEF2) transcription factor plays a central role in the activation and maintenance of muscle gene expression in fruit flies and vertebrates. The mechanism of action and downstream target genes of MEF2 have been defined in considerable detail, but relatively little is known about the mechanisms that regulate MEF2 expression during muscle development. Here we demonstrate that MEF2 maintains its own expression in all differentiated muscle cell types during late embryonic and larval development in Drosophila by binding a conserved MEF2 site in a muscle-specific regulatory enhancer. Ectopic expression of Mef2 is sufficient to directly activate this enhancer in some, but not all, non-muscle cells. Furthermore, activation of the Mef2 enhancer normally in muscle cells and ectopically in non-muscle cells is dependent upon the integrity of the MEF2 binding site. These findings suggest an evolutionarily conserved mechanism whereby MEF2 can stabilize the muscle phenotype by sustaining its own expression through a myogenic autoregulatory loop.

Animals↗

PubMed1997

Evolution of male tail development in rhabditid nematodes related to Caenorhabditis elegans.

The evolutionary pathway that has led to male tails of diverse morphology among species of the nematode family Rhabditidae was reconstructed. This family includes the well-studied model species Caenorhabditis elegans. By relating the steps of male tail morphological evolution to the phenotypic changes brought about by developmental mutations induced experimentally in C. elegans, the goal is to identify genes responsible for morphological evolution. The varying morphological characters of the male tails of several rhabiditid species have been described previously (Fitch and Emmons, 1995, Dev. Biol. 170:564-582). The developmental events preceding differentiation of the adult structures have also been analyzed; in many cases the origins of varying adult morphological characters were traced to differences during ontogeny. In the present work, the evolutionary changes producing these differences were reconstructed in the context of the four possible phylogenies supported independently by sequences of 18S ribosomal RNA genes (rDNA). Two or more alternative states were defined for 36 developmental and adult morphological characters. These characters alone do not provide sufficient data to resolve most species relationships; however, when combined with the rDNA characters, they provide stronger support for one of the four rDNA phylogenies. Assuming a model of ordered transformations for multistate developmental characters generally results in greater resolution. Transformations between character states can be assigned unequivocally by parsimony to unambiguous branches for most of the characters. Correlations are thereby revealed for some of the developmental characters, indicating a probability of a shared developmental or genetic regulatory pathway. Four of the unequivocal character state changes on unambiguously supported branches closely resemble the phenotypic changes brought about by known mutations in C. elegans. These mutations define genes that are known to act in genetic regulatory hierarchies controlling pattern formation, differentiation, and morphogenesis. Although these studies are still at an early stage, these results strongly suggest that parallel studies of developmental mutants in C. elegans and of morphological and developmental evolution among related nematodes will help define genetic changes underlying the evolution of form.

Animals↗