Ard Louis

Abstract:

Thymine dimers are a major mutagenic photoproduct induced by UV radiation. While they have been the subject of extensive theoretical and experimental investigations, questions of how DNA supercoiling affects local defect properties, or, conversely, how the presence of such defects changes global supercoiled structure, are largely unexplored. Here, we introduce a model of thymine dimers in the oxDNA forcefield, parametrized by comparison to melting experiments and structural measurements of the thymine dimer induced bend angle. We performed extensive molecular dynamics simulations of double-stranded DNA as a function of external twist and force. Compared to undamaged DNA, the presence of a thymine dimer lowers the supercoiling densities at which plectonemes and bubbles occur. For biologically relevant supercoiling densities and forces, thymine dimers can preferentially segregate to the tips of the plectonemes, where they enhance the probability of a localized tip-bubble. This mechanism increases the probability of highly bent and denatured states at the thymine dimer site, which may facilitate repair enzyme binding. Thymine dimer-induced tip-bubbles also pin plectonemes, which may help repair enzymes to locate damage. We hypothesize that the interplay of supercoiling and local defects plays an important role for a wider set of DNA damage repair systems.

Abstract:

Thymine dimers are a major mutagenic photoproduct induced by UV radiation. While they have been the subject of extensive theoretical and experimental investigations, questions of how DNA supercoiling affects local defect properties, or, conversely, how the presence of such defects changes global supercoiled structure, are largely unexplored. Here, we introduce a model of thymine dimers in the oxDNA forcefield, parametrized by comparison to melting experiments and structural measurements of the thymine dimer induced bend angle. We performed extensive molecular dynamics simulations of double-stranded DNA as a function of external twist and force. Compared to undamaged DNA, the presence of a thymine dimer lowers the supercoiling densities at which plectonemes and bubbles occur. For biologically relevant supercoiling densities and forces, thymine dimers can preferentially segregate to the tips of the plectonemes, where they enhance the probability of a localized tip-bubble. This mechanism increases the probability of highly bent and denatured states at the thymine dimer site, which may facilitate repair enzyme binding. Thymine dimer-induced tip-bubbles also pin plectonemes, which may help repair enzymes to locate damage. We hypothesize that the interplay of supercoiling and local defects plays an important role for a wider set of DNA damage repair systems.

Abstract:

Morphospaces—representations of phenotypic characteristics—are often populated unevenly, leaving large parts unoccupied. Such patterns are typically ascribed to contingency, or else to natural selection disfavoring certain parts of the morphospace. The extent to which developmental bias, the tendency of certain phenotypes to preferentially appear as potential variation, also explains these patterns is hotly debated. Here we demonstrate quantitatively that developmental bias is the primary explanation for the occupation of the morphospace of RNA secondary structure (SS) shapes. Upon random mutations, some RNA SS shapes (the frequent ones) are much more likely to appear than others. By using the RNAshapes method to define coarse-grained SS classes, we can directly compare the frequencies that noncoding RNA SS shapes appear in the RNAcentral database to frequencies obtained upon a random sampling of sequences. We show that: 1) only the most frequent structures appear in nature; the vast majority of possible structures in the morphospace have not yet been explored; 2) remarkably small numbers of random sequences are needed to produce all the RNA SS shapes found in nature so far; and 3) perhaps most surprisingly, the natural frequencies are accurately predicted, over several orders of magnitude in variation, by the likelihood that structures appear upon a uniform random sampling of sequences. The ultimate cause of these patterns is not natural selection, but rather a strong phenotype bias in the RNA genotype–phenotype map, a type of developmental bias or “findability constraint,” which limits evolutionary dynamics to a hugely reduced subset of structures that are easy to “find.”

Abstract:

Understanding how genotypes map onto phenotypes, fitness, and eventually organisms is arguably the next major missing piece in a fully predictive theory of evolution. We refer to this generally as the problem of the genotype-phenotype map. Though we are still far from achieving a complete picture of these relationships, our current understanding of simpler questions, such as the structure induced in the space of genotypes by sequences mapped to molecular structures, has revealed important facts that deeply affect the dynamical description of evolutionary processes. Empirical evidence supporting the fundamental relevance of features such as phenotypic bias is mounting as well, while the synthesis of conceptual and experimental progress leads to questioning current assumptions on the nature of evolutionary dynamics-cancer progression models or synthetic biology approaches being notable examples. This work delves with a critical and constructive attitude into our current knowledge of how genotypes map onto molecular phenotypes and organismal functions, and discusses theoretical and empirical avenues to broaden and improve this comprehension. As a final goal, this community should aim at deriving an updated picture of evolutionary processes soundly relying on the structural properties of genotype spaces, as revealed by modern techniques of molecular and functional analysis.