ROMA, GUGLIELMO (2018) IDENTIFICATION AND EXPLORATION OF NOVEL MOLECULAR SIGNATURES IN BIOLOGICAL SYSTEMS THROUGH GENOMICS AND BIOINFORMATICS. [Tesi di dottorato]

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The last two decades have witnessed rapid developments in –omics technologies which enable the study of biological and disease processes in a high throughput manner. Among the -omics approaches, genomics and the related bioinformatic methods have emerged as most popular applications able to accelerate science discoveries in basic research and drug discovery and therapeutics. Genomics is an interdisciplinary field of science focusing on the structure, function, evolution, mapping, and editing of genomes (Wikipedia, url: https://en.wikipedia.org/wiki/Genomics). Over the years, the field of genomics has undergone several revolutions. Prior to the advent of Next Generation Sequencing (NGS), genomics was limited to the characterization of single disease-associated genes (e.g. Huntington disease, cystic fibrosis, cancer) or to the study of small genomes (e.g. bacteria, viruses). As physical mapping with large-insert clones became possible, the subcloned fragments of large genomes could be sequenced as individual projects, and their finished sequences combined together to reconstruct the sequence of entire chromosomes. Using this approach and beginning from 1985, in 2003 the Human Genome Project was able to complete the sequence of the DNA in the human genome (I. H. G. S. Consortium et al., 2001; Venter et al., 2001), thus providing a basic platform for the development of new technologies. In the same period, other large genomes, including those of model organisms, were also decoded (M. G. S. Consortium et al., 2002; R. G. S. P. Consortium et al., 2004; Myers et al., 2000). Hybridization-based methods such as microarrays exploited the information gained from genome projects to develop rapid, high throughput assays to allow the measurement of genetic variation, gene expression and chromatin binding, which spread rapidly in all fields of research. Most recently, these methods were quickly replaced by NGS, which allows similar studies to be conducted with much higher sensitivity and in an unbiased whole-genome and –transcriptome fashion. As a result, sequencing has become an essential and obligatory tool and not only for biologists. In the early days of NGS, the initial focus of every genomic scientist was on the de-novo assembly of novel genomes for species that were never sequenced before. These efforts led to the completion of many novel genomic sequences which include even large genomes of mammals and plants. In the case of de-novo assembly, the genomic sequence is built from scratch without the use of an existing scaffold. Advances in sequencing technology have recently led to a dramatic increase in speed and throughput capacity, and a sharp reduction in costs. These improvements enabled the shift from de-novo to re-sequencing of entire genomes from additional individuals of species already sequenced. In the case of re-sequencing, short reads can be aligned to reference genomes as a substrate for variation discovery or gene expression analysis. Re-sequencing applications provide the scientific community with an unprecedented opportunity to address fundamental evolutionary questions, as well as to extend the use of sequencing to population genetic studies to infer ancient population history. The availability of new data types given by an always increasing number of NGS applications continues to engage and excite the computational biology community working on software development and on the analysis of new data types generated to solve complex biomedical problems. In this context, the main objective of my research was to explore different biological systems to identify new molecular signals through the development and implementation of genomic and bioinformatic methods. This objective was accomplished by participating to three different research projects where I applied genomic and bioinformatic solutions to different areas of biology: genome composition, organization and regulation, malaria biology, and cancer. The first chapter provides an introduction to the main technology and biology concepts explored in my research, while the following three chapters describe in details the research work conducted during my studies.

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