Mixed-up chromosomes: origin and impact of structural variation in human genomes

Abstract

Deoxyribonucleic acid (DNA) is also known as ‘the building block of life’. It unifies us as a species, yet simultaneously identifies us as an individual. The hereditary information in our DNA is passed on from generation to generation and each time the DNA is passed on, new (de novo) changes are introduced. As a consequence we share our looks, character and also disease predisposition with our family members, while individuality is ensured. Pushed by technological advances, the field of genetics has moved at incredible speed in the past decades. This has enabled the detection of genetic variants at ever-increasing resolution, revealing structural variations (SVs) as a major player driving normal variation and disease. These SVs range from single events to highly complex chromothripsis rearrangements that involve tens to hundreds of breaks and can have a detrimental effect on genome architecture. However, unraveling the exact mechanistic origin of these highly complex SVs remains challenging. Also, with the technological advances pushing the resolution and reliability of SV detection, it will become increasingly important to determine the impact of detected SVs. In this thesis, we have set up a method for the recapitulation of chromothripsis and other CCRs (chapter 2). Furthermore, we provided an overview of relevant knowledge, and further evidence for an important role of SVs and CCRs in cancer (chapter 3 and 4). Finally, we demonstrated that the presence of chromothripsis rearrangements in healthy carriers can severely impact reproduction (chapter 5). Taken together, this work has provided important additional insight into the mechanism behind CCRs, like chromothripsis, and the consequences of SVs and specifically CCRs in disease. Our, and other recent findings hold promising opportunities for the future of SV research. However, several questions continue to be unanswered, and important challenges and limitations in SV detection and analysis remain.