Functional Conservation of Nucleosome Formation Selectively Biases Presumably Neutral Molecular Variation in Yeast Genomes

One prominent pattern of mutational frequency, long appreciated in comparative genomics, is the bias of purine/pyrimidine conserving substitutions (transitions) over purine/pyrimidine altering substitutions (transversions). Traditionally, this transitional bias has been thought to be driven by the underlying rates of DNA mutation and/or repair. However, recent sequencing studies of mutation accumulation lines in model organisms demonstrate that substitutions generally do not accumulate at rates that would indicate a transitional bias. These observations have called into question a very basic assumption of molecular evolution; that naturally occurring patterns of molecular variation in noncoding regions accurately reflect the underlying processes of randomly accumulating neutral mutation in nuclear genomes. Here, in Saccharomyces yeasts, we report a very strong inverse association (r = −0.951, P < 0.004) between the genome-wide frequency of substitutions and their average energetic effect on nucleosome formation, as predicted by a structurally based energy model of DNA deformation around the nucleosome core. We find that transitions occurring at sites positioned nearest the nucleosome surface, which are believed to function most importantly in nucleosome formation, alter the deformation energy of DNA to the nucleosome core by only a fraction of the energy changes typical of most transversions. When we examined the same substitutions set against random background sequences as well as an existing study reporting substitutions arising in mutation accumulation lines of Saccharomyces cerevisiae, we failed to find a similar relationship. These results support the idea that natural selection acting to functionally conserve chromatin organization may contribute significantly to genome-wide transitional bias, even in noncoding regions. Because nucleosome core structure is highly conserved across eukaryotes, our observations may also help to further explain locally elevated transition bias at CpG islands, which are known to destabilize nucleosomes at vertebrate promoters

INDELible: A Flexible Simulator of Biological Sequence Evolution

Many methods exist for reconstructing phylogenies from molecular sequence data, but few phylogenies are known and can be used to check their efficacy. Simulation remains the most important approach to testing the accuracy and robustness of phylogenetic inference methods. However, current simulation programs are limited, especially concerning realistic models for simulating insertions and deletions. We implement a portable and flexible application, named INDELible, for generating nucleotide, amino acid and codon sequence data by simulating insertions and deletions (indels) as well as substitutions. Indels are simulated under several models of indel-length distribution. The program implements a rich repertoire of substitution models, including the general unrestricted model and nonstationary nonhomogeneous models of nucleotide substitution, mixture, and partition models that account for heterogeneity among sites, and codon models that allow the nonsynonymous/synonymous substitution rate ratio to vary among sites and branches. With its many unique features, INDELible should be useful for evaluating the performance of many inference methods, including those for multiple sequence alignment, phylogenetic tree inference, and ancestral sequence, or genome reconstruction

The evolution of transcription-associated biases of mutations across vertebrates

<p>Abstract</p> <p>Background</p> <p>The interplay between transcription and mutational processes can lead to particular mutation patterns in transcribed regions of the genome. Transcription introduces several biases in mutational patterns; in particular it invokes strand specific mutations. In order to understand the forces that have shaped transcripts during evolution, one has to study mutation patterns associated with transcription across animals.</p> <p>Results</p> <p>Using multiple alignments of related species we estimated the regional single-nucleotide substitution patterns along genes in four vertebrate taxa: primates, rodents, laurasiatheria and bony fishes. Our analysis is focused on intronic and intergenic regions and reveals differences in the patterns of substitution asymmetries between mammals and fishes. In mammals, the levels of asymmetries are stronger for genes starting within CpG islands than in genes lacking this property. In contrast to all other species analyzed, we found a mutational pressure in dog and stickleback, promoting an increase of GC-contents in the proximity to transcriptional start sites.</p> <p>Conclusions</p> <p>We propose that the asymmetric patterns in transcribed regions are results of transcription associated mutagenic processes and transcription coupled repair, which both seem to evolve in a taxon related manner. We also discuss alternative mechanisms that can generate strand biases and involves error prone DNA polymerases and reverse transcription. A localized increase of the GC content near the transcription start site is a signature of biased gene conversion (BGC) that occurs during recombination and heteroduplex formation. Since dog and stickleback are known to be subject to rapid adaptations due to population bottlenecks and breeding, we further hypothesize that an increase in recombination rates near gene starts has been part of an adaptive process.</p

Tuning environmental timescales to evolve and maintain generalists

Natural environments can present diverse challenges, but some genotypes remain fit across many environments. Such `generalists' can be hard to evolve, out-competed by specialists fitter in any particular environment. Here, inspired by the search for broadly-neutralising antibodies during B-cell affinity maturation, we demonstrate that environmental changes on an intermediate timescale can reliably evolve generalists, even when faster or slower environmental changes are unable to do so. We find that changing environments on timescales comparable to evolutionary transients in a population enhances the rate of evolving generalists from specialists, without enhancing the reverse process. The yield of generalists is further increased in more complex dynamic environments, such as a `chirp' of increasing frequency. Our work offers design principles for how non-equilibrium fitness `seascapes' can dynamically funnel populations to genotypes unobtainable in static environments

Computational statistics in molecular phylogenetics

Simulation remains a very important approach to testing the robustness and accuracy of phylogenetic inference methods. However, current simulation programs are limited, especially concerning realistic models for simulating insertions and deletions (indels). In this thesis I implement a new, portable and flexible application, named INDELible, which can be used to generate nucleotide, amino acid and codon sequence data by simulating indels (under several models of indel length distribution) as well as substitutions (under a rich repertoire of substitution models). In particular, I introduce a simulation study that makes use of one of INDELible’s many unique features to simulate data with indels under codon models that allow the nonsynonymous/synonymous substitution rate ratio to vary among sites and branches. This data is used to quantify, for the first time, the precise effects of indels and alignment errors on the false-positive rate and power of the widely used branch-site test of positive selection. Several alignment programs are used and assessed in this context. Through the simulation experiment, I show that insertions and deletions do not cause the test to generate excessive false positives if the alignment is correct, but alignment errors can lead to unacceptably high false positives. Previous selection studies that use inferior alignment programs are revisited to demonstrate the applicability of my results in real world situations. Further work uses simulated data from INDELible to examine the effects of tree-shape and branch length on the alignment accuracy of several alignment programs, and the impact of alignment errors on different methods of phylogeny reconstruction. In particular, analysis is performed to explore which programs avoid generating the kind of alignment errors that are most detrimental to the process of phylogeny reconstruction