Alternative splicing: Regulation, function and evolution.
- Autores: Carlos Martí Gómez-Aldaraví
- Directores de la Tesis: Enrique Lara Pezzi (dir. tes.), Fátima Sánchez Cabo (dir. tes.), Luis del Peso Ovalle (tut. tes.)
- Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
- Idioma: inglés
- Número de páginas: 148
- Tribunal Calificador de la Tesis: Josefa González Pérez (presid.), Michael Tress (secret.), Eduardo Eyras Jimenez (voc.), Manuel Irimia (voc.), Miguel Manzanares Fourcade (voc.)
- Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
- Materias:
- Enlaces
- Tesis en acceso abierto en: Biblos-e Archivo
- Resumen
Introns populate eukaryotic genes to a variable extent across species, being widespread in vertebrates and mammals. While the evolutionary advantages, if any, of introns, remain unclear, their expansion has provided the opportunity to splice genes in more than a single way, allowing the production of diferent mRNAs from a single gene through Alternative splicing (AS). AS patterns change during the development of complex organisms and diverge across diferent tissues and experimental conditions. These highly reproducible changes evidences the existence of a regulatory network that ensures repeatable responses to certain stimuli and suggest that, at least some of them, play a role in the overall physiological response or adaptation. Not surprisingly, perturbation of some elements of this network is often associated with pathological conditions. However, not only we are far from a complete characterization of the molecular mechanisms that drive AS changes in most pathologies like those afecting the heart, but the computational tools that are currently used to study these regulatory networks are limiting our ability to extract all the information that is hidden in the data.
It has been long hypothesized that AS contributes to a great expansion of the proteome and facilitates the evolution of new functions from pre-existing ones without gene duplication. While there are very well known examples of how AS enables the production of diferent functional proteins or mRNAs, the proportion of AS isoforms that are actually functional remains large unknown. Indeed, recent studies from diferent perspectives, including both transcriptomic, proteomics and sequence evolutionary analysis suggest that this percentage may be rather small and that much of the observed transcriptomic diversity is driven by non-functional noise in the splicing process.
In this thesis, we have studied global AS patterns through computational analysis of large RNA-seq datasets to characterize the causes and consequences of AS changes from diferent perspectives. First, we have analyzed how AS global patterns change during heart development and disease using data from a variety of mouse models. We found that AS changes modulate diferent biological processes than gene expression ones and are associated to isoform speci c protein-protein interactions. Disease patterns partially recapitulate developmental patterns probably through the upregulation of PTBP1, which is suficient to induce pathological changes in the heart. Second, in an attempt to improve computational tools for identi cation of regulatory elements, we have developed dSreg. This tool leverages the power of bayesian inference and hierarchical models to pool information across the whole transcriptome to infer, not only the changes in the activities of the underlying regulatory elements, but also the changes in inclusion rates, outperforming competing methods and tools made for both purposes separately. Finally, we have studied the evolutionary process driving AS divergence during mammalian evolution using models of phenotypic evolution in a phylogenetic framework. We found that AS patterns have evolved under weak stabilizing selection that allows widespread variability in AS patterns across species, with only about 5% of the genes probably encoding AS isoforms with dif erent functions. Rates of neutral evolution are high, preventing the identi cation of adaptive changes at this long evolutionary scale. In summary, this thesis provides new computational tools and knowledge about the evolution and regulation of AS in diferent biological conditions and helps to better understand its relevance from diferent persepectives.
