PhD Thesis

Hi! I recently defended my PhD dissertation on bioinformatics and biomedicine. It is written in Spanish, but I thought it would be interesting to share an English abstact as well. If you want to know more about it, don’t hesitate to ask!

P. Garrido-Rodríguez, “Aplicación de la bioinformática en la descripción y resolución de patologías hematológicas y mecanismos biológicos relacionados,” Ph.D dissertation, Universidad de Murcia, Spain, 2025.

The high throughput systems for omics data generation has forced lately the implementation of automated analysis systems allowing the management and interpretability of huge amounts of information.

Hence, the generation of large amounts of data for each patient, the incorporation of different omics and computer modeling in biomedicine lead to the presence of bioinformaticians in the experimental laboratories of this discipline, in order to properly process all this knowledge. The present work is a reflection of these new computational needs in experimental groups. More specifically, in the Hematology and Clinical Experimental Oncology group of the University of Murcia between 2020 and 2024.

This Doctoral Thesis includes results of bioinformatic research in the area of molecular modeling, the calling and study of germline variants, the development of new pipelines to process sequencing data from long reads and their practical application to the study of liver pathophysiology.

Thus, this work shows that, although there have been major advances in recent years in the structural prediction of proteins based on their sequence, progress is still to be dome in order to actually understand the mechanisms that determine the folding of a given sequence, as shown by the results of AlphaFold for different conformations of serpins such as antithrombin, which in this study was unable to show any structure different from the native one, despite the existence, even for the wild-type sequence, of other possible structures not considered by simulation systems to date.

While it has already been described the relationship between vena cava agenesis and higher thrombotic risk, it was confirmed via exome sequencing assays how vena cava agenesis is related to the appearance of thrombophilias in primary hemostasis genes. This would cause an early thrombotic event during the embryo development. This would be the reason behind the malformation, and would also explain the thrombotic events observed during adulthood.

This Thesis also includes the development of two novel analysis protocols for nanopore sequencing data, allowing a standard processing of samples sequenced by this technology, exploiting its capabilities (definition of large haplotypes and repetitive regions, or detection of structural variants), seeking to minimize its limitations, by using tools widely accepted by the scientific community around these technologies, and easing the orchestration of the different steps in workstations with highly variable characteristics, from modest laptops to large computer servers.

This work is also the first, to our knowledge, making a detailed description of the epitranscriptomic profile of the liver in patients with obesity and different degrees of liver disease, which could help to understand new aspects on the evolution of liver conditions and on the metabolic pathways that could be of interest from the diagnostic or therapeutic point of view.

Finally, it was also possible to describe the process of hepatic differentiation from induced pluripotent stem cells (iPSC) differentiated to hepatic organoids. It was observed in the differential expression results the appearance on organoids of annotations related to the formation of anatomical structures associated with internal organs, as well as typical liver functions. At the same time, some light was shed on the epitranscriptomic profile and its changes in both stages, finding that the m6A RNA modifications would be related both to the stability of the transcripts, as well as appear to have a connection with the process of cell specialization itself.