Aleksandra Nowicka

High correlation between the turnover of nucleotides under mutational pressure and the DNA composition

BackgroundAny DNA sequence is a result of compromise between the selection and mutation pressures exerted on it during evolution. It is difficult to estimate the relative influence of each of these pressures on the rate of accumulation of substitutions. However, it is important to discriminate between the effect of mutations, and the effect of selection, when studying the phylogenic relations between taxa.ResultsWe have tested in computer simulations, and analytically, the available substitution matrices for many genomes, and we have found that DNA strands in equilibrium under mutational pressure have unique feature: the fraction of each type of nucleotide is linearly dependent on the time needed for substitution of half of nucleotides of a given type, with a correlation coefficient close to 1. Substitution matrices found for sequences under selection pressure do not have this property. A substitution matrix for the leading strand of the Borrelia burgdorferi genome, having reached equilibrium in computer simulation, gives a DNA sequence with nucleotide composition and asymmetry corresponding precisely to the third positions in codons of protein coding genes located on the leading strand.ConclusionsParameters of mutational pressure allow us to count DNA composition in equilibrium with this mutational pressure. Comparing any real DNA sequence with the sequence in equilibrium it is possible to estimate the distance between these sequences, which could be used as a measure of the selection pressure. Furthermore, the parameters of the mutational pressure enable direct estimation of the relative mutation rates in any DNA sequence in the studied genome.

Evolution Rates of Genes on Leading and Lagging DNA Strands

Abstract. One of the main causes of bacterial chromosome asymmetry is replication-associated mutational pressure. Different rates of nucleotide substitution accumulation on leading and lagging strands implicate qualitative and quantitative differences in the accumulation of mutations in protein coding sequences lying on different DNA strands. We show that the divergence rate of orthologs situated on leading strands is lower than the divergence rate of those situated on lagging strands. The ratio of the mutation accumulation rate for sequences lying on lagging strands to that of sequences lying on leading strands is rather stable and time-independent. The divergence rate of sequences which changed their positions, with respect to the direction of replication fork movement, is not stable—sequences which have recently changed their positions are the most prone to mutation accumulation. This effect may influence estimations of evolutionary distances between species and the topology of phylogenetic trees.

How many protein-coding genes are there in the Saccharomyces cerevisiae genome?

We have compared the results of estimations of the total number of protein‐coding genes in the Saccharomyces cerevisiae genome, which have been obtained by many laboratories since the yeast genome sequence was published in 1996. We propose that there are 5300–5400 genes in the genome. This makes the first estimation of the number of intronless ORFs longer than 100 codons, based on the features of the set of genes with phenotypes known in 1997 to be correct. This estimation assumed that the set of the first 2300 genes with known phenotypes was representative for the whole set of protein‐coding genes in the genome. The same method used in this paper for the approximation of the total number of protein‐coding sequences among more than 40 000 ORFs longer than 20 codons gives a result that is only slightly higher. This suggests that there are still some non‐coding ORFs in the databases and a few dozen small ORFs, not yet annotated, which probably code for proteins. Copyright

The Differential Killing of Genes by Inversions in Prokaryotic Genomes

We have elaborated a method which has allowed us to estimate the direction of translocation of orthologs which have changed, during the phylogeny, their positions on chromosome in respect to the leading or lagging role of DNA strands. We have shown that the relative number of translocations which have switched positions of genes from the leading to the lagging DNA strand is lower than the number of translocations which have transferred genes from the lagging strand to the leading strand of prokaryotic genomes. This paradox could be explained by assuming that the stronger mutation pressure and selection after inversion preferentially eliminate genes transferred from the leading to the lagging DNA strand.

Replication associated mutational pressure generating long-range correlation in DNA

There are many biological mechanisms which introduce long-range correlations into the DNA molecule. One of the most important is replication of chromosomes, its mechanisms and topology. Replication associated mutational pressure, defined as specific preferences in nucleotide substitutions during replication, generates asymmetry in the genome. On the other hand, substitution rates, which determine the evolutionary turnover time of a nucleotide, are highly correlated with the fraction of that nucleotide in the genome. Assuming the Azbel hypothesis that the number of mutations per genome per generation is invariant and universal, a general rule for mutational pressure can be formulated: the half-time of a nucleotide turnover in the genome is linearly dependent on the number of this nucleotide in the genome.

MULTIPLE BASE SUBSTITUTION CORRECTIONS IN DNA SEQUENCE EVOLUTION

We discuss the Jukes and Cantors one-parameter model and Kimuras two-parameter model unability to describe evolution of asymmetric DNA molecules. The standard distance measure between two DNA sequences, which is the number of substitutions per site, should include the effect of multiple base substitutions separately for each type of the base. Otherwise, the respective tables of substitutions cannot reconstruct the asymmetric DNA molecule with respect to the composition. Basing on Kimuras neutral theory, we have derived a linear law for the correlation of the mean survival time of nucleotides under constant mutation pressure and their fraction in the genome. According to the law, the corrections to Kimuras theory have been discussed to describe evolution of genomes with asymmetric nucleotide composition.We consider the particular case of the strongly asymmetric Borrelia burgdorferi genome and we discuss in detail the corrections, which should be introduced into the distance measure between two DNA sequences to include multiple base substitutions.

Correlation between mutation pressure, selection pressure, and occurrence of amino acids

With the help of the empirical mutation table for nucleotides in the Borrelia burgdorferi genome we have performed Monte Carlo simulation of the pure mutation pressure experienced by the genes of the genome. We have examined the divergence of the mutated genes from the ancestral ones and we have constructed MPM1 matrix (Mutation Probability Matrix) of the substitution rates between amino acids of the diverging genes. The results have been compared to mutation data matrix PAM1 PET91 representing mutation and selection data of 16130 homologous genes od different organisms. We have found that the effective survival time of amino acids in organisms follows a power law with respect to frequency of their occurrence in genes. This makes possible to find the effect of the pure mutational pressure and the selection on the amino acid composition of genes. The results are universal in the sense that the survival time of amino acids calculated from the higher order PAMk matrices (k > 1) follows the same power law as in the case of PAM1 matrices.

Differential Gene Survival under Asymmetric Directional Mutational Pressure

We have simulated, using Monte Carlo methods, the survival of prokaryotic genes under directional mutational pressure. We have found that the whole pool of genes located on the leading DNA strand differs from that located on the lagging DNA strand and from the subclass of genes coding for ribosomal proteins. The best strategy for most of the non-ribosomal genes is to change the direction of the mutational pressure from time to time or to stay at their recent position. Genes coding for ribosomal proteins do not profit to such an extent from switching the directional pressure which seems to explain their extremely conserved positions on the prokaryotic chromosomes.

How Gene Survival Depends on Their Length

Gene survival depends on the mutational pressure acting on the gene sequences and selection pressure for the function of the gene products. While the probability of the occurrence of mutations inside genes depends roughly linearly on their length, the probability of elimination of their function does not grow linearly with the length because of the intragenic suppression effect. Furthermore, the probability of redefinition of the stop and start codons is independent of the gene length while shortening of gene sequences by generating stop codons inside gene sequences depends on gene length.

Representation of mutation pressure and selection pressure by PAM matrices

This paper analyses the relationship between the mutation data matrix 1PAM/PET91, representing the effect of both mutation and selection pressures exerted on 16 130 homologous proteins of different organisms, and a mutation probability matrix (1PAM/MPM) representing the effect of pure mutation pressure on protein coding sequences of the Borrelia burgdorferi genome. The 1PAM/MPM matrix was derived with the help of computer simulations, which used empirical nucleotide substitution rates found for the B. burgdorferi genome. Here, it is shown that the frequency of amino acid occurrence is strongly related to their effective survival time. We found that the shorter the turnover time of an amino acid under pure mutation pressure, the lower its fraction in the proteins coded by the genome and the more protected by selection pressure is its position in proteins. Results of analyses suggest that during evolution the mutational pressure has been optimised to some extent to the selection requirements.