Biomedical subjects

M A Huynen

Publications and source records attributed to M A Huynen.

23 records · Page 2Linked to original sources

PubMed1996

Exploring phenotype space through neutral evolution.

RNA secondary-structure folding algorithms predict the existence of connected networks of RNA sequences with identical secondary structures. Fitness landscapes that are based on the mapping between RNA sequence and RNA secondary structure hence have many neutral paths. A neutral walk on these fitness landscapes gives access to a virtually unlimited number of secondary structures that are a single point mutation from the neutral path. This shows that neutral evolution explores phenotype space and can play a role in adaptation.

Algorithms↗

PubMed1996

Base pairing probabilities in a complete HIV-1 RNA.

We have calculated the base pair probability distribution for the secondary structure of a full length HIV-1 genome using the partition function approach introduced by McCaskill (1990). By analyzing the full distribution of base pair probabilities instead of a restricted number of secondary structures, we gain more complete and reliable information about the secondary structure of HIV-1. We introduce methods that condense the information in the probability distribution to one value per nucleotide in the sequence. Using these methods we represent the secondary structure as a weighted average of the base pair probabilities, and we can identify interesting secondary structures that have relatively well-defined base pairing. The results show high probabilities for the known secondary structures at the 5'-end of the molecule that have been predicted on the basis of biochemical data. The Rev response element (RRE) appears as a distinct element in the secondary structure. It has a meta-stable domain at the high affinity site for the binding of Rev. The overall structure decomposes into fairly small independent structures in the first 4,000 bases of the molecule. The remaining 5,000 bases (excluding the terminal repeat) form a single, large structure, on top of which the RRE is located.

Algorithms↗

PubMed1994

Pattern generation in molecular evolution: exploitation of the variation in RNA landscapes.

Evolution of RNA secondary structure is studied using simulation techniques and statistical analysis of fitness landscapes. The transition from RNA sequence to RNA secondary structure leads to fitness landscapes that have local variations in their "ruggedness." Evolution exploits these variations. In stable environments it moves the quasispecies toward relatively "flat" peaks, where not only the master sequence but also its mutants have a high fitness. In a rapidly changing environment, the situation is reversed; evolution moves the quasispecies to a region where the correlation between secondary structures of "neighboring" RNA sequences is relatively low. In selection for simple secondary structures the movement toward flat peaks leads to pattern generation in the RNA sequences. Patterns are generated at the level of polynucleotide frequencies and the distribution of purines and pyrimidines. The patterns increase the modularity of the sequence. They thereby prevent the formation of alternative secondary structures after mutations. The movement of the quasispecies toward relatively rugged parts of the landscape results in pattern generation at the level of the RNA secondary structure. The base-pairing frequency of the sequences increases. The patterns that are generated in the RNA sequences and the RNA secondary structures are not directly selected for and can be regarded as a side effect of the evolutionary dynamics of the system.

Animals↗

PubMed1993

Multiple coding and the evolutionary properties of RNA secondary structure.

This article evaluates evolutionary properties of the transition from RNA primary sequence to RNA secondary structure. It focuses on the restrictions that the conservation of a protein code in an RNA sequence puts on its potential to evolve towards a specific secondary structure. Restricting the mutations to those that do not affect the coding for a protein restricts both the accessibility and the connectivity of the sequence space. The accessibility is restricted because only certain point mutations are allowed. The connectivity is restricted because no insertions and deletions are allowed. Simulating an evolutionary search process for a specific secondary structure shows that (i) the reduction of allowable point mutations allows for adaptation to some large-scale topology, but strongly reduces the possibility of small-scale adaptations, (ii) the abolition of insertions and deletions has very little effect on the results of the search process. During the evolutionary search process for a secondary structure with a specific topology and a high frequency of base-pairing the quasispecies moves into a subspace in which the similarity between secondary structures of neighboring sequences is relatively high. Increased similarity between second structures of neighboring sequences is also found in the Rev responsive element (RRE) in the lentiviruses Caprine arthritis-encephalitis virus and Visna virus. In these viruses a biased nucleotide frequency in the RRE region suggests that selection for the RRE RNA secondary structure affects the amino acid sequence of the env gene. Our results show a variation in the ruggedness of fitness landscapes which are based on a high degree of epistatic interactions. Fitness landscapes play an essential role, not only in biotic evolution, but also in all kinds of optimization processes (Hill Climbing, Simulated Annealing, Genetic Algorithms, etc). Variation in their ruggedness should therefore be taken into account in the analysis of these processes.

Amino Acid Sequence↗

PubMed1992

Equal G and C contents in histone genes indicate selection pressures on mRNA secondary structure.

Protein-specific versus taxon-specific patterns of nucleotide frequencies were studied in histone genes. The third positions of codons have a (well-known) taxon-specific G+C level and a histone type-specific G/C ratio. This ratio counterbalances the G/C ratio in the first and second positions so that the overall G and C levels in the coding region become approximately equal. The compensation of the G/C ratio indicates a selection pressure at the mRNA level rather than a selection pressure or mutation bias at the DNA level or a selection pressure on codon usage. The structure of histone mRNAs is compatible with the hypothesis that the G/C compensation is due to selection pressures on mRNA secondary structure. Nevertheless, no specific motifs seem to have been selected, and the free energy of the secondary structures is only slightly lower than that expected on the basis of nucleotide frequencies.

Animals↗