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PubMed2005

Positive autoregulation of cI is a dispensable feature of the phage lambda gene regulatory circuitry.

Complex gene regulatory circuits contain many features that are likely to contribute to their operation. It is unclear, however, whether all these features are necessary for proper circuit behavior or whether certain ones are refinements that make the circuit work better but are dispensable for qualitatively normal behavior. We have addressed this question using the phage lambda regulatory circuit, which can persist in two stable states, the lytic state and the lysogenic state. In the lysogenic state, the CI repressor positively regulates its own expression by stimulating transcription from the P(RM) promoter. We tested whether this feature is an essential part of the regulatory circuitry. Several phages with a cI mutation preventing positive autoregulation and an up mutation in the P(RM) promoter showed near-normal behavior. We conclude that positive autoregulation is not necessary for proper operation of the lambda circuitry and speculate that it serves a partially redundant function of stabilizing a bistable circuit, a form of redundancy we term "circuit-level redundancy." We discuss our findings in the context of a two-stage model for evolution and elaboration of regulatory circuits from simpler to more complex forms.

Bacteriophage lambda↗
PubMed1984

Tissue-specific expression of major urinary protein (MUP) genes in mice: characterization of MUP mRNAs by restriction mapping of cDNA and by in vitro translation.

The major urinary proteins (MUPs) in mice are coded for by a gene family which consists of ca. 30 members. The number of MUP genes that are expressed is not known. Previous studies have shown that MUP mRNAs are present in several secretory tissues in addition to the liver, in which they were originally identified. In this paper we show, through restriction analysis of MUP cDNAs, that distinct sets of MUP mRNAs are synthesized in each of the tissues studied and that these mRNAs are most likely coded for by different genes. As is shown, MUP mRNAs of different tissues are related to an extent that precludes the use of gene-specific probes in differentiating among them. The regions of homology also include the 3' untranslated regions of MUP mRNAs. The question of differential expression was thus investigated by searching for restriction polymorphisms in MUP mRNAs. We demonstrate that subtle differences in the sequences of even scarce mRNAs can be recognized by this particular approach. In addition, it is shown that MUP mRNAs of different tissues code for different, nonoverlapping sets of polypeptides, as determined by gel electrophoresis of in vitro-translated precursors to MUPs. The relevance of these results to models of evolution of tissue-specific regulation in a multigene family is discussed.

Animals↗
PubMed1994

In pursuit of a molecular mechanism for adaptive mutation.

An unexpected way of making mutations in bacteria has challenged concepts of the genetic mechanisms behind evolution for the past 6 years. Work on the molecular mechanism of these so called "adaptive" mutations is rapidly revealing a surprising and novel molecular mechanism, and it is altering our understanding of how mutations form in nondividing cells.

Adaptation, Physiological↗
PubMed2002

Evolution of a student model-building program.

We describe the design and development of a highly interactive model-building program to assist students from a diverse range of academic backgrounds to understand the baroreceptor reflex. Our approach is to have students work in small groups to construct their own simple model of such a control system. This model then provides the basis for a structural framework for students to add further complexity without losing overall perspective and allows exploration of deeper issues. Our program is suitable for many disciplines and student backgrounds and provides a visual representation of a difficult concept, providing a basis to ground further knowledge. Audit trail data have been analyzed to identify and resolve areas of student difficulty, and extensive surveys and observations on students' use of the program over three years in several courses have been used to test and improve its effectiveness.

Baroreflex↗
PubMed2006

The evolutionary continuum from lung development to homeostasis and repair.

A functional, developmental, and comparative biological approach is probably the most effective way for arranging gene regulatory networks (GRNs) in their biological contexts. Evolutionary developmental biology allows comparison of GRNs during development across phyla. For lung evolution, the parathyroid hormone-related protein (PTHrP) GRN exemplifies a continuum from ontogeny to phylogeny, homeostasis, and repair. PTHrP signaling between the lung endoderm and mesoderm stimulates lipofibroblast differentiation by downregulating the myofibroblast Wnt signaling pathway and upregulating the protein kinase A-dependent cAMP signaling pathway, inducing the lipofibroblast phenotype. Leptin secreted by the lipofibroblast, in turn, binds to its receptor on the alveolar type II cell, stimulating surfactant synthesis to ensure alveolar homeostasis. Failure of the PTHrP/PTHrP receptor signaling mechanism causes transdifferentiation of lipofibroblasts to myofibroblasts, which are the hallmark for lung fibrosis. We have shown that by targeting peroxisome proliferator-activated receptor gamma, the downstream target for lipofibroblast PTHrP signaling, we can prevent lung fibrosis. We speculate that the recapitulation of the myofibroblast phenotype during transdifferentiation is consistent with lung injury as lung evolution in reverse. Repair recapitulates ontogeny because it is programmed to express the cross talk between epithelium and mesoderm through evolution. This model demonstrates how epithelial-mesenchymal cross talk, when seen as a recapitulation of ontogeny and phylogeny (in both a forward and reverse direction), predicts novel, effective diagnostic and therapeutic targets.

Animals↗
PubMed1998

A serpin gene cluster on human chromosome 6p25 contains PI6, PI9 and ELANH2 which have a common structure almost identical to the 18q21 ovalbumin serpin genes.

The human genes encoding the "ovalbumin" subgroup of closely related serine proteinase inhibitors (serpins) are located at 18q21.3 and 6p25. Those at 6p25 include proteinase inhibitor 6 (PI-6; gene symbol PI6), proteinase inhibitor 9 (PI-9; gene symbol PI9) and monocyte neutrophil elastase inhibitor (M/NEI; gene symbol ELANH2). Here we describe the fine mapping of these genes to a 200-kb region of chromosome 6 that includes the markers WI-8835 and D6S1338, and the establishment of the gene order: tel-PI6-PI9-ELANH2-cen. PI6 and ELANH2 are transcribed towards the telomere, and structural analysis shows that PI6 and PI9 are organized identically, having seven exons and six introns. PI6 and PI9 are almost identical in structure to the ovalbumin serpin genes at 18q21.3. The 18q21.3 genes have an extra exon and intron, otherwise all the other exon/intron boundaries are conserved between the two groups. These results represent the first detailed map of the chromosome 6 serpin gene cluster, and demonstrate that although they are very closely related, the 6p25 and 18q21-->q23 ovalbumin serpin genes form two structurally distinct groups. These findings do not support a previously proposed model for evolution of the clusters which invoked an inter-chromosomal duplication of the entire 6p25 group to 18q21.3.

Chromosome Mapping↗
PubMed2005

Mental rotation and rotational invariance in the Rhesus monkey (Macaca mulatta).

The mode of visual information processing during visuospatial tasks differs across species and is supposed to depend on evolutionary and ecological factors. Humans show reaction times that increase with angular disparity when tested in mental rotation tasks. Pigeons show a time-independent rotational invariance that possibly evolved in response to the horizontal reference plane birds perceive while flying. As it was suggested that hominids may have secondarily lost the ability of rotational invariance while retreating from arboreal living and evolving upright gait where the vertical reference plane is more important, mental rotation tests with various recent primate species promise to model the evolution of the respective modes of information processing. The results of recent corresponding experiments with a mainly arboreal living primate species could not be explained by either mode, thus supporting the idea of information processing systems having gradually evolved. Here, we conducted mental rotation experiments with three Rhesus monkeys, a more terrestrial living primate species. In a two-alternative matching-to-sample procedure, we measured the monkeys' reaction times for decisions between rotated figures representing image and mirror-image of a previously shown upright sample. The results of our three monkeys were inconsistent. Linear regression analyses showed for one test animal significant correlation coefficients for mean reaction times depending on angular disparity and thus clearly indicated mental rotation. The other two test animals showed reaction times not consistent with mental rotation, whereas rotational invariance might explain the responses to the smaller angles of rotation. Our results suggest that two separately evolved information processing systems may be coexisting to a certain extent in species with correspondingly overlapping ecological demands.

Adaptation, Psychological↗
PubMed2002

Center-crossing recurrent neural networks for the evolution of rhythmic behavior.

A center-crossing recurrent neural network is one in which the null-(hyper)surfaces of each neuron intersect at their exact centers of symmetry, ensuring that each neuron's activation function is centered over the range of net inputs that it receives. We demonstrate that relative to a random initial population, seeding the initial population of an evolutionary search with center-crossing networks significantly improves both the frequency and the speed with which high-fitness oscillatory circuits evolve on a simple walking task. The improvement is especially striking at low mutation variances. Our results suggest that seeding with center-crossing networks may often be beneficial, since a wider range of dynamics is more likely to be easily accessible from a population of center-crossing networks than from a population of random networks.

Algorithms↗
PubMed2000

Cooperative coevolution: an architecture for evolving coadapted subcomponents.

To successfully apply evolutionary algorithms to the solution of increasingly complex problems, we must develop effective techniques for evolving solutions in the form of interacting coadapted subcomponents. One of the major difficulties is finding computational extensions to our current evolutionary paradigms that will enable such subcomponents to "emerge" rather than being hand designed. In this paper, we describe an architecture for evolving such subcomponents as a collection of cooperating species. Given a simple string-matching task, we show that evolutionary pressure to increase the overall fitness of the ecosystem can provide the needed stimulus for the emergence of an appropriate number of interdependent subcomponents that cover multiple niches, evolve to an appropriate level of generality, and adapt as the number and roles of their fellow subcomponents change over time. We then explore these issues within the context of a more complicated domain through a case study involving the evolution of artificial neural networks.

Adaptation, Physiological↗
PubMed2000

Embodiment of evolutionary computation in general agents.

Holland's Adaptation in Natural and Artificial Systems largely dealt with how systems, comprised of many self-interested entities, can and should adapt as a whole. This seminal book led to the last 25 years of work in genetic algorithms (GAs) and related forms of evolutionary computation (EC). In recent years, the expansion of the Internet, other telecommunications technologies, and other large scale networks have led to a world where large numbers of semi-autonomous software entities (i.e., agents) will be interacting in an open, universal system. This development cast the importance of Holland's legacy in a new light. This paper argues that Holland's fundamental arguments, and the years of developments that have followed, have a direct impact on systems of general network agents, regardless of whether they explicitly exploit EC. However, it also argues that the techniques and theories of EC cannot be directly transferred to the world of general agents (rather than EC-specific) without examination of effects that are embodied in general software agents. This paper introduces a framework for EC interchanges between general-purpose software agents. Preliminary results are shown that illustrate the EC effects of asynchronous actions of agents within this framework. Building on this framework, coevolutionary agents that interact in a simulated producer/consumer economy are introduced. Using these preliminary results as illustrations, areas for future investigation of embodied EC software agents are discussed.

Algorithms↗
PubMed2001

A convergence analysis of unconstrained and bound constrained evolutionary pattern search.

We present and analyze a class of evolutionary algorithms for unconstrained and bound constrained optimization on R(n): evolutionary pattern search algorithms (EPSAs). EPSAs adaptively modify the step size of the mutation operator in response to the success of previous optimization steps. The design of EPSAs is inspired by recent analyses of pattern search methods. We show that EPSAs can be cast as stochastic pattern search methods, and we use this observation to prove that EPSAs have a probabilistic, weak stationary point convergence theory. This convergence theory is distinguished by the fact that the analysis does not approximate the stochastic process of EPSAs, and hence it exactly characterizes their convergence properties.

Algorithms↗
PubMed2001

Looking beyond selection probabilities: adaptation of the chi(2) measure for the performance analysis of selection methods in GAs.

Viewing the selection process in a genetic algorithm as a two-step procedure consisting of the assignment of selection probabilities and the sampling according to this distribution, we employ the chi(2) measure as a tool for the analysis of the stochastic properties of the sampling. We are thereby able to compare different selection schemes even in the case that their probability distributions coincide. Introducing a new sampling algorithm with adjustable accuracy and employing two-level test designs enables us to further reveal the intrinsic correlation structures of well-known sampling algorithms. Our methods apply well to integral methods like tournament selection and can be automated.

Algorithms↗
PubMed2002

Evolutionary algorithms for the satisfiability problem.

Several evolutionary algorithms have been proposed for the satisfiability problem. We review the solution representations suggested in literature and choose the most promising one - the bit string representation - for further evaluation. An empirical comparison on commonly used benchmarks is presented for the most successful evolutionary algorithms and for WSAT, a prominent local search algorithm for the satisfiability problem. The key features of successful evolutionary algorithms are identified, thereby providing useful methodological guidelines for designing new heuristics. Our results indicate that evolutionary algorithms are competitive to WSAT.

Algorithms↗