Structural variation in genomes and its role in disease

Technological advances in DNA sequencing techniques provide new resources and opportunities to study genetic contributions to disease. Still, it remains a challenge to determine which of the many detected genetic changes have an effect and through which mechanism they contribute to phenotypes and disease. This is especially challenging for structural variants, which are larger genomic changes that can affect both coding and non-coding regions on the genome.
Cancer is a genetic disease with generally unstable genomes thereby continuing to accumulate somatic DNA changes including structural variants. In this thesis, we studied recurrent structural alterations in the aryl hydrocarbon receptor (AHR) gene that we identified in the whole-genome sequencing data of urinary tract cancer tumors. We propose activating alterations in the AHR gene as a driver event in urinary tract cancer. Furthermore, we studied the causative relationship between certain cancer driver genes and the accumulation of patterns of structural variants in various tumor types to gain insights into the molecular mechanisms of the development of SVs and their contribution to tumorigenesis.
Structural variants are also present in the germline and although de novo SVs in the germline are a rare event, such structural variations are causative for congenital disorders such as intellectual disability and autism spectrum disorders. Integration of different layers of genomic and phenotypic information was found to provide additional benefit in determining the molecular consequences and interpreting pathogenicity of structural variations in patients with congenital disorders. Finally, we describe the discovery of inherited splice site mutations in the POLR3GL gene that cause teeth and bone abnormalities that fit in the spectrum of POLR3 pathologies and suggest that POLR3GL mutations should be considered in patients with POLR3 pathology.