Biomedical subjects

Christoph Flamm

Publications and source records attributed to Christoph Flamm.

11 recordsLinked to original sources

PubMed2007

RNAs everywhere: genome-wide annotation of structured RNAs.

Starting with the discovery of microRNAs and the advent of genome-wide transcriptomics, non-protein-coding transcripts have moved from a fringe topic to a central field research in molecular biology. In this contribution we review the state of the art of "computational RNomics", i.e., the bioinformatics approaches to genome-wide RNA annotation. Instead of rehashing results from recently published surveys in detail, we focus here on the open problem in the field, namely (functional) annotation of the plethora of putative RNAs. A series of exploratory studies are used to provide non-trivial examples for the discussion of some of the difficulties.

Biological Evolution↗

PubMed2006

A generalized model of the repressilator.

The repressilator is a regulatory cycle of n genes where each gene represses its successor in the cycle: [see text]. The system is modelled by ODEs for an arbitrary number of identical genes and arbitrarily strong repressor binding. A detailed mathematical analysis of the dynamical behavior is provided for two model systems: (i) a repressilator with leaky transcription and single-step cooperative repressor binding, and (ii) a repressilator with auto-activation and cooperative regulator binding. Genes are assumed to be present in constant amounts, transcription and translation are modelled by single-step kinetics, and mRNAs as well as proteins are assumed to be degraded by first order reactions. Several dynamical patterns are observed: multiple steady states, periodic and aperiodic oscillations corresponding to limit cycles and heteroclinic cycles, respectively. The results of computer simulations are complemented by a detailed and complete stability analysis of all equilibria and of the heteroclinic cycle.

Binding Sites↗

PubMed2006

Partition function and base pairing probabilities of RNA heterodimers.

BACKGROUND: RNA has been recognized as a key player in cellular regulation in recent years. In many cases, non-coding RNAs exert their function by binding to other nucleic acids, as in the case of microRNAs and snoRNAs. The specificity of these interactions derives from the stability of inter-molecular base pairing. The accurate computational treatment of RNA-RNA binding therefore lies at the heart of target prediction algorithms. METHODS: The standard dynamic programming algorithms for computing secondary structures of linear single-stranded RNA molecules are extended to the co-folding of two interacting RNAs. RESULTS: We present a program, RNAcofold, that computes the hybridization energy and base pairing pattern of a pair of interacting RNA molecules. In contrast to earlier approaches, complex internal structures in both RNAs are fully taken into account. RNAcofold supports the calculation of the minimum energy structure and of a complete set of suboptimal structures in an energy band above the ground state. Furthermore, it provides an extension of McCaskill's partition function algorithm to compute base pairing probabilities, realistic interaction energies, and equilibrium concentrations of duplex structures.

Journal Article↗

PubMed2006

The SBML ODE Solver Library: a native API for symbolic and fast numerical analysis of reaction networks.

The SBML ODE Solver Library (SOSlib) is a programming library for symbolic and numerical analysis of chemical reaction network models encoded in the Systems Biology Markup Language (SBML). It is written in ISO C and distributed under the open source LGPL license. The package employs libSBML structures for formula representation and associated functions to construct a system of ordinary differential equations, their Jacobian matrix and other derivatives. SUNDIALS' CVODES is incorporated for numerical integration and sensitivity analysis. Preliminary benchmarking results give a rough overview on the behavior of different tools and are discussed in the Supplementary Material. The native application program interface provides fine-grained interfaces to all internal data structures, symbolic operations and numerical routines, enabling the construction of very efficient analytic applications and hybrid or multi-scale solvers with interfaces to SBML and non SBML data sources. Optional modules based on XMGrace and Graphviz allow quick inspection of structure and dynamics.

Algorithms↗

PubMed2006

The expansion of the metazoan microRNA repertoire.

BACKGROUND: MicroRNAs have been identified as crucial regulators in both animals and plants. Here we report on a comprehensive comparative study of all known miRNA families in animals. We expand the MicroRNA Registry 6.0 by more than 1000 new homologs of miRNA precursors whose expression has been verified in at least one species. Using this uniform data basis we analyze their evolutionary history in terms of individual gene phylogenies and in terms of preservation of genomic nearness across species. This allows us to reliably identify microRNA clusters that are derived from a common transcript. RESULTS: We identify three episodes of microRNA innovation that correspond to major developmental innovations: A class of about 20 miRNAs is common to protostomes and deuterostomes and might be related to the advent of bilaterians. A second large wave of innovations maps to the branch leading to the vertebrates. The third significant outburst of miRNA innovation coincides with placental (eutherian) mammals. In addition, we observe the expected expansion of the microRNA inventory due to genome duplications in early vertebrates and in an ancestral teleost. The non-local duplications in the vertebrate ancestor are predated by local (tandem) duplications leading to the formation of about a dozen ancient microRNA clusters. CONCLUSION: Our results suggest that microRNA innovation is an ongoing process. Major expansions of the metazoan miRNA repertoire coincide with the advent of bilaterians, vertebrates, and (placental) mammals.

Animals↗

PubMed2006

Algebraic comparison of metabolic networks, phylogenetic inference, and metabolic innovation.

BACKGROUND: Comparison of metabolic networks is typically performed based on the organisms' enzyme contents. This approach disregards functional replacements as well as orthologies that are misannotated. Direct comparison of the structure of metabolic networks can circumvent these problems. RESULTS: Metabolic networks are naturally represented as directed hypergraphs in such a way that metabolites are nodes and enzyme-catalyzed reactions form (hyper)edges. The familiar operations from set algebra (union, intersection, and difference) form a natural basis for both the pairwise comparison of networks and identification of distinct metabolic features of a set of algorithms. We report here on an implementation of this approach and its application to the procaryotes. CONCLUSION: We demonstrate that metabolic networks contain valuable phylogenetic information by comparing phylogenies obtained from network comparisons with 16S RNA phylogenies. The algebraic approach to metabolic networks is suitable to study metabolic innovations in two sets of organisms, free living microbes and Pyrococci, as well as obligate intracellular pathogens.

Algorithms↗

PubMed2004

Determination of thermodynamic parameters for HIV DIS type loop-loop kissing complexes.

The HIV-1 type dimerization initiation signal (DIS) loop was used as a starting point for the analysis of the stability of Watson-Crick (WC) base pairs in a tertiary structure context. We used ultraviolet melting to determine thermodynamic parameters for loop-loop tertiary interactions and compared them with regular secondary structure RNA helices of the same sequences. In 1 M Na+ the loop-loop interaction of a HIV-1 DIS type pairing is 4 kcal/mol more stable than its sequence in an equivalent regular and isolated RNA helix. This difference is constant and sequence independent, suggesting that the rules governing the stability of WC base pairs in the secondary structure context are also valid for WC base pairs in the tertiary structure context. Moreover, the effect of ion concentration on the stability of loop-loop tertiary interactions differs considerably from that of regular RNA helices. The stabilization by Na+ and Mg2+ is significantly greater if the base pairing occurs within the context of a loop-loop interaction. The dependence of the structural stability on salt concentration was defined via the slope of a T(m)/log [ion] plot. The short base-paired helices are stabilized by 8 degrees C/log [Mg2+] or 11 degrees C/log [Na+], whereas base-paired helices forming tertiary loop-loop interactions are stabilized by 16 degrees C/log [Mg2+] and 26 degrees C/log [Na+]. The different dependence on ionic strength that is observed might reflect the contribution of specific divalent ion binding to the preformation of the hairpin loops poised for the tertiary kissing loop-loop contacts.

Base Pairing↗

PubMed2004

Surveying phylogenetic footprints in large gene clusters: applications to Hox cluster duplications.

Evolutionarily conserved non-coding genomic sequences represent a potentially rich source for the discovery of gene regulatory regions. Since these elements are subject to stabilizing selection they evolve much more slowly than adjacent non-functional DNA. These so-called phylogenetic footprints can be detected by comparison of the sequences surrounding orthologous genes in different species. Therefore the loss of phylogenetic footprints as well as the acquisition of conserved non-coding sequences in some lineages, but not in others, can provide evidence for the evolutionary modification of cis-regulatory elements. We introduce here a statistical model of footprint evolution that allows us to estimate the loss of sequence conservation that can be attributed to gene loss and other structural reasons. This approach to studying the pattern of cis-regulatory element evolution, however, requires the comparison of relatively long sequences from many species. We have therefore developed an efficient software tool for the identification of corresponding footprints in long sequences from multiple species. We apply this novel method to the published sequences of HoxA clusters of shark, human, and the duplicated zebrafish and Takifugu clusters as well as the published HoxB cluster sequences. We find that there is a massive loss of sequence conservation in the intergenic region of the HoxA clusters, consistent with the finding in [Chiu et al., PNAS 99 (2002) 5492]. The loss of conservation after cluster duplication is more extensive than expected from structural reasons. This suggests that binding site turnover and/or adaptive modification may also contribute to the loss of sequence conservation.

Animals↗

PubMedDate not supplied

A graph-based toy model of chemistry.

Large scale chemical reaction networks are a ubiquitous phenomenon, from the metabolism of living cells to processes in planetary atmospheres and chemical technology. At least some of these networks exhibit distinctive global features such as the "small world" behavior. The systematic study of such properties, however, suffers from substantial sampling biases in the few networks that are known in detail. A computational model for generating them is therefore required. Here we present a Toy Model that provides a consistent framework in which generic properties of extensive chemical reaction networks can be explored in detail and that at the same time preserves the "look-and-feel" of chemistry: Molecules are represented as labeled graphs, i.e., by their structural formulas; their basic properties are derived by a caricature version of the Extended Hückel MO theory that operates directly on the graphs; chemical reaction mechanisms are implemented as graph rewriting rules acting on the structural formulas; reactivities and selectivities are modeled by a variant of the Frontier Molecular Orbital Theory based on the Extended Hückel scheme. The approach is illustrated for two types of reaction networks: Diels-Alder reactions and the formose reaction implicated in prebiotic sugar synthesis.

Journal Article↗

PubMedDate not supplied

Counterexamples in chemical ring perception.

Ring information is a large part of the structural topology used to identify and characterize molecular structures. It is hence of crucial importance to obtain this information for a variety of tasks in computational chemistry. Many different approaches for "ring perception", i.e., the extraction of cycles from a molecular graph, have been described. The chemistry literature on this topic, however, reports a surprisingly large number of incorrect statements about the properties of chemically relevant ring sets and, in particular, about the mutual relationships of different sets of cycles in a graph. In part these problems seem to have arisen from a sometimes rather idiosyncratic terminology for notions that are fairly standard in graph theory. In this contribution we translate the definitions of concepts such as the Smallest Set of Smallest Rings, Essential Set of Essential Rings, Extended Set of Smallest Rings, Set of Smallest Cycles at Edges, Set of Elementary Rings, K-rings, and beta-rings into a more widely used mathematical language. We then outline the basic properties of different cycle sets and provide numerous counterexamples to incorrect claims in the published literature. These counterexamples may have a serious practical impact because at least some of them are molecular graphs of well-known molecules. As a consequence, we propose a catalog of desirable properties for chemically useful sets of rings.

Journal Article↗

PubMedDate not supplied

Visualization of barrier tree sequences.

Dynamical models that explain the formation of spatial structures of RNA molecules have reached a complexity that requires novel visualization methods that help to analyze the validity of these models. Here, we focus on the visualization of so-called folding landscapes of a growing RNA molecule. Folding landscapes describe the energy of a molecule as a function of its spatial configuration; thus they are huge and high dimensional. Their most salient features, however, are encapsulated by their so-called barrier tree that reflects the local minima and their connecting saddle points. For each length of the growing RNA chain there exists a folding landscape. We visualize the sequence of folding landscapes by an animation of the corresponding barrier trees. To generate the animation, we adapt the foresight layout with tolerance algorithm for general dynamic graph layout problems. Since it is very general, we give a detailed description of each phase: constructing a supergraph for the trees, layout of that supergraph using a modified DoT algorithm, and presentation techniques for the final animation.

Base Sequence↗