Characterization of structural chromosomal variants by massively parallel sequencing

Sammanfattning: Chromosomal Structural Variation (SV) such as translocations, inversions, deletions, and duplications are rearrangements of one or several DNA molecules. SVs are widespread across the human genome, and each individual carries thousands of SVs of different types and sizes. SV are known to contribute both to phenotypic diversity and disease traits, and are therefore of interest in multiple fields, including rare diseases research, and clinical diagnostics. Herein, we present five studies, focused on the analysis of SV using whole genome sequencing (WGS). The project has increased our knowledge regarding the frequency, structure and mechanisms of formation of structural variants in the human genome. In Paper I, II, and IV, we develop and evaluate software for detection and analysis of SV using WGS data. In Paper II, III and IV, we utilize WGS data to delineate the structure and determine the mechanism of formation of several complex SVs. In Paper II, we compare multiple sequencing technologies, and apply these technologies to solve the structure of three complex chromosomal rearrangements. Lastly, in Paper V, we validate the use of SV calling from WGS as a routine test in rare disease diagnostics. Through these studies, we developed and tested tools suitable for WGS SV analysis in a clinical setting. These tools are now part of the routine clinical pipeline; and many of the tools are used by researchers and clinics around the world.