Biomedical subjects

C V Forst

Publications and source records attributed to C V Forst.

4 recordsLinked to original sources

PubMed2001

Replication and mutation on neutral networks.

Folding of RNA sequences into secondary structures is viewed as a map that assigns a uniquely defined base pairing pattern to every sequence. The mapping is non-invertible since many sequences fold into the same minimum free energy (secondary) structure or shape. The pre-images of this map, called neutral networks, are uniquely associated with the shapes and vice versa. Random graph theory is used to construct networks in sequence space which are suitable models for neutral networks. The theory of molecular quasispecies has been applied to replication and mutation on single-peak fitness landscapes. This concept is extended by considering evolution on degenerate multi-peak landscapes which originate from neutral networks by assuming that one particular shape is fitter than all the others. On such a single-shape landscape the superior fitness value is assigned to all sequences belonging to the master shape. All other shapes are lumped together and their fitness values are averaged in a way that is reminiscent of mean field theory. Replication and mutation on neutral networks are modeled by phenomenological rate equations as well as by a stochastic birth-and-death model. In analogy to the error threshold in sequence space the phenotypic error threshold separates two scenarios: (i) a stationary (fittest) master shape surrounded by closely related shapes and (ii) populations drifting through shape space by a diffusion-like process. The error classes of the quasispecies model are replaced by distance classes between the master shape and the other structures. Analytical results are derived for single-shape landscapes, in particular, simple expressions are obtained for the mean fraction of master shapes in a population and for phenotypic error thresholds. The analytical results are complemented by data obtained from computer simulation of the underlying stochastic processes. The predictions of the phenomenological approach on the single-shape landscape are very well reproduced by replication and mutation kinetics of tRNA(phe). Simulation of the stochastic process at a resolution of individual distance classes yields data which are in excellent agreement with the results derived from the birth-and-death model.

Base Pairing↗

PubMed2001

Phylogenetic analysis of metabolic pathways.

The information provided by completely sequenced genomes can yield insights into the multi-level organization of organisms and their evolution. At the lowest level of molecular organization individual enzymes are formed, often through assembly of multiple polypeptides. At a higher level, sets of enzymes group into metabolic networks. Much has been learned about the relationship of species from phylogenetic trees comparing individual enzymes. In this article we extend conventional phylogenetic analysis of individual enzymes in different organisms to the organisms' metabolic networks. For this purpose we suggest a method that combines sequence information with information about the underlying reaction networks. A distance between pathways is defined as incorporating distances between substrates and distances between corresponding enzymes. The new analysis is applied to electron-transfer and amino acid biosynthesis networks yielding a more comprehensive understanding of similarities and differences between organisms.

Animals↗

PubMed2000

Molecular evolution of catalysis.

In this paper, we consider the evolutionary dynamics of catalytically active species with a distinct genotype-phenotype relationship. Folding landscapes of RNA molecules serve as a paradigm for this relationship with essential neutral properties. The landscape itself is partitioned by phenotypes (realized as RNA secondary structures). To each genotype (represented as a sequence) a structure is assigned in a unique way. The set of all sequences which map into a particular structure is modeled as a random graph in sequence space (the so-called neutral network). A catalytic network is realized as a random digraph with maximal out-degree two and secondary structures as vertex sets. A population of catalytic RNA molecules shows significantly different behavior compared to a deterministic description: hypercycles are able to co-exist and out-compete a parasite with superior catalytic support. A "switching" between different dynamic organizations of the network can be observed, dynamical stability of hypercyclic organizations against errors and the existence of an error-threshold of catalysis can be reported.

Animals↗

PubMedDate not supplied

Evolution of metabolisms: a new method for the comparison of metabolic pathways using genomics information.

The abundance of information provided by completely sequenced genomes defines a starting point for new insights in the multilevel organization of organisms and their evolution. At the lowest level enzymes and other protein complexes are formed by aggregating multiple polypeptides. At a higher level enzymes group conceptually into metabolic pathways as part of a dynamic information-processing system, and substrates are processed by enzymes yielding other substrates. A method based on a combination of sequence information with graph topology of the underlying pathway is presented. With this approach pathways of different organisms are related to each other by phylogenetic analysis, extending conventional phylogenetic analysis of individual enzymes. The new method is applied to pathways related to electron transfer and to the Krebs citric acid cycle. In addition to providing a more comprehensive understanding of similarities and differences between organisms, this method indicates different evolutionary rates between substrates and enzymes.

Animals↗