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58
Analysis of RNA Sequence Structure Maps by Exhaustive Enumeration
, 1996
"... Global relations between RNA sequences and secondary structues are understood as mappings from sequence space into shape space. These mappings are investigated by exhaustive folding of all GC and AU sequences with chain lengths up to 30. The technique od tries is used for economic data storage and f ..."
Abstract

Cited by 73 (35 self)
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Global relations between RNA sequences and secondary structues are understood as mappings from sequence space into shape space. These mappings are investigated by exhaustive folding of all GC and AU sequences with chain lengths up to 30. The technique od tries is used for economic data storage and fast retrieval of information. The computed structural data are evaluated through exhaustive enumeration and used as an exact reference for testing analytical results derived from mathematical models and sampling based of statistical methods. Several new concepts of RNA sequence to secondary structure mappings are investigated, among them the structure of neutral networks (being sets of sequences folding into the same structure), percolation of sequence space by neutral networks, and the principle of shape space covering . The data of exhaustive enumeration are compared to the analytical results of a random graph model that reveals the generic properties of sequence to structure mappings based on some base pairing logic. The differences between the numerical and the analytical results are interpreted in terms of specific biophysical properties of RNA molecules.
Fitness Landscapes
 Appl. Math. & Comput
, 2002
"... . Fitness landscapes are a valuable concept in evolutionary biology, combinatorial optimization, and the physics of disordered systems. A fitness landscape is a mapping from a configuration space that is equipped with some notion of adjacency, nearness, distance or accessibility, into the real numbe ..."
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Cited by 64 (14 self)
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. Fitness landscapes are a valuable concept in evolutionary biology, combinatorial optimization, and the physics of disordered systems. A fitness landscape is a mapping from a configuration space that is equipped with some notion of adjacency, nearness, distance or accessibility, into the real numbers. Landscape theory has emerged as an attempt to devise suitable mathematical structures for describing the "static" properties of landscapes as well as their influence on the dynamics of adaptation. This chapter gives a brief overview on recent developments in this area, focusing on "geometrical" properties of landscapes. 1 Introduction The concept of a fitness landscape originated in theoretical biology more than seventy years ago [1]. It can be thought of as a kind of "potential function" underlying the dynamics of evolutionary optimization. Implicit in this idea is both a fitness function f that assigns a fitness value to every possible genotype (or organism), and the arrangement of t...
Plasticity, evolvability, and modularity in RNA
 J EXP ZOOL
, 2000
"... RNA folding from sequences into secondary structures is a simple yet powerful, biophysically grounded model of a genotype–phenotype map in which concepts like plasticity, evolvability, epistasis, and modularity can not only be precisely defined and statistically measured but also reveal simultaneou ..."
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Cited by 62 (2 self)
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RNA folding from sequences into secondary structures is a simple yet powerful, biophysically grounded model of a genotype–phenotype map in which concepts like plasticity, evolvability, epistasis, and modularity can not only be precisely defined and statistically measured but also reveal simultaneous and profoundly nonindependent effects of natural selection. Molecular plasticity is viewed here as the capacity of an RNA sequence to assume a variety of energetically favorable shapes by equilibrating among them at constant temperature. Through simulations based on experimental designs, we study the dynamics of a population of RNA molecules that evolve toward a predefined target shape in a constant environment. Each shape in the plastic repertoire of a sequence contributes to the overall fitness of the sequence in proportion to the time the sequence spends in that shape. Plasticity is costly, since the more shapes a sequence can assume, the less time it spends in any one of them. Unsurprisingly, selection leads to a reduction of plasticity (environmental canalization). The most striking observation, however, is the simultaneous slowdown and eventual halting of the evolutionary process. The reduction of plasticity entails genetic canalization, that is, a dramatic loss of variability (and hence a loss of evolvability) to the point of lockin. The causal bridge between environmental canalization and genetic canalization
Shaping Space: The Possible and the Attainable in RNA GenotypePhenotype Mapping
 J. THEOR. BIOL
, 1998
"... Understanding which phenotypes are accessible from which genotypes is fundamental for understanding the evolutionary process. This notion of accessibility can be used to define a relation of nearness among phenotypes, independently of their similarity. Because of neutrality, phenotypes denote equiva ..."
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Cited by 58 (13 self)
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Understanding which phenotypes are accessible from which genotypes is fundamental for understanding the evolutionary process. This notion of accessibility can be used to define a relation of nearness among phenotypes, independently of their similarity. Because of neutrality, phenotypes denote equivalence classes of genotypes. The definition of neighborhood relations among phenotypes relies, therefore, on the statistics of neighborhood relations among equivalence classes of genotypes in genotype space. The folding of RNA sequences (genotypes) into secondary structures (phenotypes) is an ideal case to implement these concepts. We study the extent to which the folding of RNA sequences induces a "statistical topology" on the set of minimum free energy secondary structures. The resulting nearness relation suggests a notion of "continuous" structure transformation. We can, then, rationalize major transitions in evolutionary trajectories at the level of RNA structures by identifying those tra...
The topology of the possible: Formal spaces underlying patterns of evolutionary change
, 2000
"... The current implementation of the NeoDarwinian model of evolution typically assumes that the set of possible phenotypes is organized into a highly symmetric and regular space equipped with a notion of distance, for example, a Euclidean vector space. Recent computational work on a biophysical genoty ..."
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Cited by 48 (20 self)
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The current implementation of the NeoDarwinian model of evolution typically assumes that the set of possible phenotypes is organized into a highly symmetric and regular space equipped with a notion of distance, for example, a Euclidean vector space. Recent computational work on a biophysical genotypephenotype model based on the folding of RNA sequences into secondary structures suggests a rather different picture. If phenotypes are organized according to genetic accessibility, the resulting space lacks a metric and is formalized by an unfamiliar structure, known as a pretopology. Patterns of phenotypic evolution  such as punctuation, irreversibility, modularity  result naturally from the properties of this space. The classical framework, however, addresses these patterns by exclusively invoking natural selection on suitably imposed fitness landscapes. We propose to extend the explanatory level for phenotypic evolution from fitness considerations alone to include the topological st...
Landscapes And Molecular Evolution
, 1996
"... that allows to choose the direction for the next step at random from all directions along which fitness does not decrease. Stationary states of populations correspond to local optima of the fitness landscape. Evolution is seen as a series of transitions between optima with increasing fitness values. ..."
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Cited by 41 (5 self)
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that allows to choose the direction for the next step at random from all directions along which fitness does not decrease. Stationary states of populations correspond to local optima of the fitness landscape. Evolution is seen as a series of transitions between optima with increasing fitness values. Wright's metaphor saw a recent revival when sufficiently simple models of fitness landscapes became available [1, 41]. These models are based on spin glass theory [63, 66] or closely related to it like Kauffman's Nk model [42]. Evolution of RNA molecules has been studied by more realistic models that deal explicitly with molecular structures obtained from folding RNA sequences [23, 24]. Fitness values serving as input parameters for evolutionary dynamics were derived through evaluation of the structures. The complexity of RNA fitness landscapes originates from conflicting consequences of structural changes that are reminiscent of "frustration" in the theory of spin glasses [2]. Fitness in t
Exploring the repertoire of rna secondary motifs using graph theory; implications for rna design
 Nucleic Acids Res
, 2003
"... Understanding the structural repertoire of RNA is crucial for RNA genomics research. Yet current methods for ®nding novel RNAs are limited to small or known RNA families. To expand known RNA structural motifs, we develop a twodimensional graphical representation approach for describing and estimati ..."
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Cited by 39 (9 self)
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Understanding the structural repertoire of RNA is crucial for RNA genomics research. Yet current methods for ®nding novel RNAs are limited to small or known RNA families. To expand known RNA structural motifs, we develop a twodimensional graphical representation approach for describing and estimating the size of RNA's secondary structural repertoire, including naturally occurring and other possible RNA motifs. We employ tree graphs to describe RNA tree motifs and more general (dual) graphs to describe both RNA tree and pseudoknot motifs. Our estimates of RNA's structural space are vastly smaller than the nucleotide sequence space, suggesting a new avenue for ®nding novel RNAs. Speci®cally our survey shows that known RNA trees and pseudoknots represent only a small subset of all possible motifs, implying that some of the `missing ' motifs may represent novel RNAs. To help pinpoint RNAlike motifs, we show that the motifs of existing functional RNAs are clustered in a narrow range of topological characteristics. We also illustrate the applications of our approach to the design of novel RNAs and automated comparison of RNA structures; we report several occurrences of RNA motifs within larger RNAs. Thus, our graph theory approach to RNA structures has implications for RNA genomics, structure analysis and design.
Combinatorial Landscapes
 SIAM REVIEW
, 2002
"... Fitness landscapes have proven to be a valuable concept in evolutionary biology, combinatorial optimization, and the physics of disordered systems. A fitness landscape is a mapping from a configuration space into the real numbers. The configuration space is equipped with some notion of adjacency, ne ..."
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Cited by 33 (2 self)
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Fitness landscapes have proven to be a valuable concept in evolutionary biology, combinatorial optimization, and the physics of disordered systems. A fitness landscape is a mapping from a configuration space into the real numbers. The configuration space is equipped with some notion of adjacency, nearness, distance or accessibility. Landscape theory has emerged as an attempt to devise suitable mathematical structures for describing the "static" properties of landscapes as well as their influence on the dynamics of adaptation. In this review we focus on the connections of landscape theory with algebraic combinatorics and random graph theory, where exact results are available.
Evolutionary Dynamics and Optimization  Neutral Networks as ModelLandscapes for RNA SecondaryStructure FoldingLandscapes
, 1995
"... We view the folding of RNAsequences as a map that assigns a pattern of base pairings to each sequence, known as secondary structure. These preimages can be constructed as random graphs (i.e. the neutral networks associated to the structure s). By interpreting the secondary structure as biological i ..."
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Cited by 26 (6 self)
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We view the folding of RNAsequences as a map that assigns a pattern of base pairings to each sequence, known as secondary structure. These preimages can be constructed as random graphs (i.e. the neutral networks associated to the structure s). By interpreting the secondary structure as biological information we can formulate the so called Error Threshold of Shapes as an extension of Eigen's et al. concept of an error threshold in the single peak landscape [5]. Analogue to the approach of Derrida & Peliti [3] for a flat landscape we investigate the spatial distribution of the population on the neutral network. On the one hand this model of a single shape landscape allows the derivation of analytical results, on the other hand the concept gives rise to study various scenarios by means of simulations, e.g. the interaction of two different networks [29]. It turns out that the intersection of two sets of compatible sequences (with respect to the pair of secondary structures) plays a key role in the search for "fitter" secondary structures.
Replication and Mutation on Neutral Networks
, 2000
"... Folding of RNA sequences into secondary structures is viewed as a map that assigns a uniquely de ned base pairing pattern to every sequence. The mapping is noninvertible since many sequences fold into the same minimum free energy (secondary) structure or shape. The preimages of this map, called ne ..."
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Cited by 26 (8 self)
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Folding of RNA sequences into secondary structures is viewed as a map that assigns a uniquely de ned base pairing pattern to every sequence. The mapping is noninvertible since many sequences fold into the same minimum free energy (secondary) structure or shape. The preimages 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 singlepeak tness landscapes. This concept is extended by considering evolution on degenerate multipeak landscapes which originate from neutral networks by assuming that one particular shape is tter than all others. On such a singleshape landscape the superior tness value is assigned to all sequences belonging