Biomedical subjects

W Fontana

Publications and source records attributed to W Fontana.

5 recordsLinked to original sources

PubMed1994

From sequences to shapes and back: a case study in RNA secondary structures.

RNA folding is viewed here as a map assigning secondary structures to sequences. At fixed chain length the number of sequences far exceeds the number of structures. Frequencies of structures are highly non-uniform and follow a generalized form of Zipf's law: we find relatively few common and many rare ones. By using an algorithm for inverse folding, we show that sequences sharing the same structure are distributed randomly over sequence space. All common structures can be accessed from an arbitrary sequence by a number of mutations much smaller than the chain length. The sequence space is percolated by extensive neutral networks connecting nearest neighbours folding into identical structures. Implications for evolutionary adaptation and for applied molecular evolution are evident: finding a particular structure by mutation and selection is much simpler than expected and, even if catalytic activity should turn out to be sparse of RNA structures, it can hardly be missed by evolutionary processes.

Base Composition↗

PubMed1994

What would be conserved if "the tape were played twice"?

We develop an abstract chemistry, implemented in a lambda-calculus-based modeling platform, and argue that the following features are generic to this particular abstraction of chemistry; hence, they would be expected to reappear if "the tape were run twice": (i) hypercycles of self-reproducing objects arise; (ii) if self-replication is inhibited, self-maintaining organizations arise; and (iii) self-maintaining organizations, once established, can combine into higher-order self-maintaining organizations.

Biological Evolution↗

PubMed1994

Statistics of RNA melting kinetics.

We present and study the behavior of a simple kinetic model for the melting of RNA secondary structures, given that those structures are known. The model is then used as a map that assigns structure dependent overall rate constants of melting (or refolding) to a sequence. This induces a "landscape" of reaction rates, or activation energies, over the space of sequences with fixed length. We study the distribution and the correlation structure of these activation energies.

Base Sequence↗

PubMed1993

Statistics of RNA secondary structures.

A statistical reference for RNA secondary structures with minimum free energies is computed by folding large ensembles of random RNA sequences. Four nucleotide alphabets are used: two binary alphabets, AU and GC, the biophysical AUGC and the synthetic GCXK alphabet. RNA secondary structures are made of structural elements, such as stacks, loops, joints, and free ends. Statistical properties of these elements are computed for small RNA molecules of chain lengths up to 100. The results of RNA structure statistics depend strongly on the particular alphabet chosen. The statistical reference is compared with the data derived from natural RNA molecules with similar base frequencies. Secondary structures are represented as trees. Tree editing provides a quantitative measure for the distance dt, between two structures. We compute a structure density surface as the conditional probability of two structures having distance t given that their sequences have distance h. This surface indicates that the vast majority of possible minimum free energy secondary structures occur within a fairly small neighborhood of any typical (random) sequence. Correlation lengths for secondary structures in their tree representations are computed from probability densities. They are appropriate measures for the complexity of the sequence-structure relation. The correlation length also provides a quantitative estimate for the mean sensitivity of structures to point mutations.

Base Sequence↗

PubMed1987

A computer model of evolutionary optimization.

Molecular evolution is viewed as a typical combinatorial optimization problem. We analyse a chemical reaction model which considers RNA replication including correct copying and point mutations together with hydrolytic degradation and the dilution flux of a flow reactor. The corresponding stochastic reaction network is implemented on a computer in order to investigate some basic features of evolutionary optimization dynamics. Characteristic features of real molecular systems are mimicked by folding binary sequences into unknotted two-dimensional structures. Selective values are derived from these molecular 'phenotypes' by an evaluation procedure which assigns numerical values to different elements of the secondary structure. The fitness function obtained thereby contains nontrivial long-range interactions which are typical for real systems. The fitness landscape also reveals quite involved and bizarre local topologies which we consider also representative of polynucleotide replication in actually occurring systems. Optimization operates on an ensemble of sequences via mutation and natural selection. The strategy observed in the simulation experiments is fairly general and resembles closely a heuristic widely applied in operations research areas. Despite the relative smallness of the system--we study 2000 molecules of chain length v = 70 in a typical simulation experiment--features typical for the evolution of real populations are observed as there are error thresholds for replication, evolutionary steps and quasistationary sequence distributions. The relative importance of selectively neutral or almost neutral variants is discussed quantitatively. Four characteristic ensemble properties, entropy of the distribution, ensemble correlation, mean Hamming distance and diversity of the population, are computed and checked for their sensitivity in recording major optimization events during the simulation.

Base Sequence↗