Biomedical subjects

Paulien Hogeweg

Publications and source records attributed to Paulien Hogeweg.

9 recordsLinked to original sources

PubMed2006

Feed-forward loop circuits as a side effect of genome evolution.

In this article, we establish a connection between the mechanics of genome evolution and the topology of gene regulation networks, focusing in particular on the evolution of the feed-forward loop (FFL) circuits. For this, we design a model of stochastic duplications, deletions, and mutations of binding sites and genes and compare our results with yeast network data. We show that the mechanics of genome evolution may provide a mechanism of FFL circuit generation. Our simulations result in overrepresentation of FFL circuits as well as in their clustering around few regulator pairs, in concordance with data from transcription networks. The mechanism here proposed and the analysis of the yeast data show that regulator duplication could have played an important role in FFL evolution.

Evolution, Molecular↗

PubMed2006

Moving forward moving backward: directional sorting of chemotactic cells due to size and adhesion differences.

Differential movement of individual cells within tissues is an important yet poorly understood process in biological development. Here we present a computational study of cell sorting caused by a combination of cell adhesion and chemotaxis, where we assume that all cells respond equally to the chemotactic signal. To capture in our model mesoscopic properties of biological cells, such as their size and deformability, we use the Cellular Potts Model, a multiscale, cell-based Monte Carlo model. We demonstrate a rich array of cell-sorting phenomena, which depend on a combination of mescoscopic cell properties and tissue level constraints. Under the conditions studied, cell sorting is a fast process, which scales linearly with tissue size. We demonstrate the occurrence of "absolute negative mobility", which means that cells may move in the direction opposite to the applied force (here chemotaxis). Moreover, during the sorting, cells may even reverse the direction of motion. Another interesting phenomenon is "minority sorting", where the direction of movement does not depend on cell type, but on the frequency of the cell type in the tissue. A special case is the cAMP-wave-driven chemotaxis of Dictyostelium cells, which generates pressure waves that guide the sorting. The mechanisms we describe can easily be overlooked in studies of differential cell movement, hence certain experimental observations may be misinterpreted.

Animals↗

PubMed2005

The RNA silencing pathway: the bits and pieces that matter.

Cellular pathways are generally proposed on the basis of available experimental knowledge. The proposed pathways, however, may be inadequate to describe the phenomena they are supposed to explain. For instance, by means of concise mathematical models we are able to reveal shortcomings in the current description of the pathway of RNA silencing. The silencing pathway operates by cleaving siRNAs from dsRNA. siRNAs can associate with RISC, leading to the degradation of the target mRNA. We propose and analyze a few small extensions to the pathway: a siRNA degrading RNase, primed amplification of aberrant RNA pieces, and cooperation between aberrant RNA to trigger amplification. These extensions allow for a consistent explanation for various types of silencing phenomena, such as virus induced silencing, transgene and transposon induced silencing, and avoidance of self-reactivity, as well as for differences found between species groups.

Journal Article↗

PubMed2005

Phenotypic error threshold; additivity and epistasis in RNA evolution.

BACKGROUND: The error threshold puts a limit on the amount of information maintainable in Darwinian evolution. The error threshold was first formulated in terms of genotypes. However, if a genotype-phenotype map involves redundancy ("mutational neutrality"), the error threshold should be formulated in terms of phenotypes since there is no unique fittest genotype. A previous study formulated the error threshold in terms of phenotypes, and their results showed that a rather low degree of mutational neutrality can increase the error threshold unlimitedly. RESULTS: We obtain an analytical formulation of the phenotypic error threshold by considering the "additive assumption", in which base substitutions do not influence each other (no epistasis). Our formulation shows that an increase of the error threshold due to mutational neutrality is limited. Computer simulations of RNA evolution are conducted to verify our formulation, and the results show a good agreement between the analytical prediction and the simulations. The comparison with the previous formulation illustrates that it is important for the prediction of the error threshold to consider that the number of base substitutions per replication is rather large near the error threshold. To examine the additive assumption, a detailed analysis of additivity and epistasis in RNA folding of a particular sequence is performed. The results show a high degree of epistasis in RNA folding; furthermore, the analysis also elucidates the reason of the success of the additive assumption. CONCLUSIONS: We conclude that an increase of the error threshold by mutational neutrality is limited, and that the additive assumption achieves a good prediction of the error threshold in spite of a high degree of epistasis in RNA folding because the average number of base substitutions of sequences retaining the phenotype per replication is sufficiently small to avoid of the effect of epistasis.

Algorithms↗

PubMed2003

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome.

Intracellular proteins are degraded largely by proteasomes. In cells stimulated with gamma interferon, the active proteasome subunits are replaced by "immuno" subunits that form immunoproteasomes. Phylogenetic analysis of the immunosubunits has revealed that they evolve faster than their constitutive counterparts. This suggests that the immunoproteasome has evolved a function that differs from that of the constitutive proteasome. Accumulating experimental degradation data demonstrate, indeed, that the specificity of the immunoproteasome and the constitutive proteasome differs. However, it has not yet been quantified how different the specificity of two forms of the proteasome are. The main question, which still lacks direct evidence, is whether the immunoproteasome generates more MHC ligands. Here we use bioinformatics tools to quantify these differences and show that the immunoproteasome is a more specific enzyme than the constitutive proteasome. Additionally, we predict the degradation of pathogen proteomes and find that the immunoproteasome generates peptides that are better ligands for MHC binding than peptides generated by the constitutive proteasome. Thus, our analysis provides evidence that the immunoproteasome has co-evolved with the major histocompatibility complex to optimize antigen presentation in vertebrate cells.

Animals↗

PubMed2003

Multilevel selection in models of prebiotic evolution: compartments and spatial self-organization.

In this paper we explore the impact of new levels of selection in models of early evolution. We contrast two types of higher levels of selection. On the one hand we look at spatially explicit models of replicators in which, by a process of self-organization, new levels of selection arise as large scale spatial patterns with a dynamics of their own. Alternatively externally imposed levels of selection above the basic replicators are created by enclosing the replicators in vesicles. In this paper we first review some results on the impact of emerging higher levels of selection on the evolutionary persistence of interacting co-evolving replicator systems. Moreover, we present a vesicle model, which can potentially integrate emerging and imposed levels of selection. We use the models to examine the classical problem information integration in early evolution.

Biological Evolution↗

PubMed2002

Space and the persistence of male-killing endosymbionts in insect populations.

Male-killing bacteria are bacteria that are transmitted vertically through the females of their insect hosts. They can distort the sex ratio of their hosts by killing infected male offspring. In nature, male-killing endosymbionts (male killers) often have a 100% efficient vertical transmission, and multiple male-killing bacteria infecting a single population are observed. We use different model formalisms to study these observations. In mean-field models a male killer with perfect transmission drives the host population to extinction, and coexistence between multiple male killers within one population is impossible; however, in spatially explicit models, both phenomena are readily observed. We show how the spatial pattern formation underlies these results. In the case of high transmission efficiencies, waves with a high density of male killers alternate with waves of mainly wild-type hosts. The male killers cause local extinction, but this creates an opportunity for uninfected hosts to re-invade these areas. Spatial pattern formation also creates an opportunity for two male killers to coexist within one population: different strains create spatial regions that are qualitatively different; these areas then serve as different niches, making coexistence possible.

Animals↗

PubMed2002

Modelling Dictyostelium discoideum morphogenesis: the culmination.

The culmination of the morphogenesis of the cellular slime mould Dictyostelium discoideum involves complex cell movements which transform a mound of cells into a globule of spores on a slender stalk. We show that cyclic AMP signalling and differential adhesion, combined with cell differentiation and slime production, are sufficient to produce the morphogenetic cell movements which lead to culmination. We have simulated the process of culmination using a hybrid cellular automata/partial differential equation model. With our model we have been able to reproduce the main features that occur during culmination, namely the straight downward elongation of the stalk, its anchoring to the substratum and the formation of the long thin stalk topped by the spore head. We conclude that the cyclic AMP signalling system is responsible for the elongation and anchoring of the stalk, but in a roundabout way: pressure waves that are induced by the chemotaxis towards cyclic AMP squeeze the stalk through the cell mass. This mechanism forces the stalk to elongate precisely in the direction opposite to that of the chemotactically moving cells. The process turns out to be 'guided' by inactive 'pathfinder' cells, which form the tip of the stalk. We show that the entire development is enacted by means of the aforementioned building blocks. This means that no global gradients or different modes of chemotaxis are needed to complete the culmination.

Animals↗

PubMed2002

Computing an organism: on the interface between informatic and dynamic processes.

The importance of interactions between processes at diverse space and time scales in biological information processing is a recurrent theme in the work of Michael Conrad (BioSystems, 1995: 35, 157-160; BioSystems, 1999: 52, 99-100). In this paper I present some results of explicit computational models that aim to capture and exploit some of the essential features of such multi-level processes. In the model formulation, I try to minimize the explicit definition of inter-level interactions, while providing the possibility of such interactions to develop. As often argued by Conrad inter-level interactions limit programmability. Indeed, we use an evolutionary process to derive the specific models. We study morphogenesis. We show that the interplay between cell adhesion and cell differentiation provides interesting mechanisms for morphogenesis. We also show that the interplay can both reduce and enhance small random fluctuations. We show that unequal cell cleavage in the early embryo-genesis reduces inter-individual variation of the morphemes developed from the same 'genome'. Our results suggest that, during evolution, the interplay between levels is exploited while it is at the same time reduced so as to give a certain primacy to inherited information.

Animals↗