Join us at Universidad Carlos III (Adoración de Miguel room, Betancourt building, Leganés campus), on Thursday 20th June, at 11 am
This thesis deals with the mathematical modeling of evolutionary processes that take place in heterogeneous populations. Its leitmotif is the response of complex ensembles of replicating entities to multiple -and often opposite- selection pressures. Even though the speci fic problems here addressed belong to di fferent organizational levels (genome, population and community) all of them can be conceptualized as the evolution of a heterogeneous population (let it be a population of genomic elements, viruses or prokaryotic hosts and phages) facing a complex environment. As a result, the mathematical tools required for their study are quite similar. In contrast, the strategies that each population has discovered to perpetuate vary according to the diff erent evolutionary challenges and environmental constraints that the population experiences.
Along this thesis, there has been a special interest on connecting theoretical models with experimental results. To that end, most of the work presented here has been motivated either by laboratory findings or by the bioinformatic analysis of sequenced genomes. We strongly believe that such a multidisciplinary approach is necessary in order to improve our knowledge on how evolution works. Moreover, experiments are a must when it comes to propose antiviral strategies based on theoretical predictions.
This thesis is structured in two main blocks. The first one focuses on studying instances of viral evolution under the action of mutagenic drugs, paying particular attention to their possible application to the development of novel antiviral therapies. Within this block, we fi rst discuss the phenomenon of lethal defection, by which defective individuals that appear in a viral population after treatment with small doses of a mutagenic drug can lead to the stochastic extinction of the virus. We analyze the factors required for this phenomenon to occur, and fi nd two key conditions: fi rst, the size of the intracellular viral population must be relatively small; second, the viral infection must be persistent. If both conditions are ful filled, lethal defection becomes possible. Next, we study the optimal way of combining mutagens and inhibitors in multidrug antiviral treatments. According to our model, that has later been experimentally tested, the optimal protocol for drug administration depends in a predictable way on the action mechanism of the drugs and the drug doses. When a mutagen and an inhibitor are selected, the best choice for most drug doses is a sequential inhibitor-mutagen therapy. The convenience of a sequential protocol has strong implications for clinical practice, as it allows to reduce the risk of side-eff ects and undesired interactions among drugs. The second block of the thesis is devoted to the study of the evolutionary forces that shape genome structure. Based on experimental observations, we propose a mechanism through which multipartite viruses could have originated. Interestingly, the pathway leading to genome segmentation shares some steps with lethal defection, but each outcome is reached at speci c environmental conditions. Going deeper at the genomic scale, we dedicate a chapter to analyse the abundance distribution of transposable elements in prokaryotic genomes, with the aim of determining the key processes involved in their spreading. We explicitly explore the hypothesis that transposable elements follow a neutral dynamics, so that they entail a negligible fitness cost for their host genomes. We also propose a mechanism for explaining transient episodes of transposon proliferation (punctuations), that according to some authors would be of great relevance for understanding evolution at greater scales. In the fi nal part of this block, a higher level of organization is studied. There, an agent based coevolutionary model based on Lotka-Volterra interactions is used to investigate the evolutionary dynamics of the prokaryotic antiviral immunity system CRISPR-Cas. We examine the environmental factors that are responsible of its maintenance of loss, concluding that there exists a critical value of viral diversity that makes CRISPR-Cas useless. According to that, CRISPR-Cas is preferentially found in prokaryotes that live in extreme environments, where phage populations are small and not very diverse.
In sum, this thesis shows how biological populations at a variety of scales share some properties that derive from their fast evolution and high adaptability, that giving rise to a series of (sometimes counterintuitive) characteristic evolutionary phenomena where opposite selection pressures come into play. A common set of mathematical and computational tools can be employed to study such populations and build models that, once experimentally validated, provide useful knowledge with applications that range from understanding genome evolution to developing novel antiviral therapies.