Segmental duplications as a source of innovation in brain development

The human brain is known for its rapid increase in size during recent evolution, which has been associated with the gain of higher cognitive abilities. However, the exact genetic determinants for the size and complexity of the human brain and how evolution has affected its basic developmental program remains elusive. To understand how our brains are built up and how disease can impact its functioning, we first need to know more of how our brain evolved and the genetic changes are underlying this. This work focused on some of the most recently evolved structural variation, which accounts for a major fraction of new DNA sequences in the human genome. Using a variety of experimental techniques, including molecular biology, genomics, and in vitro models such as organoid cultures, we interrogated their role in normal human brain development. As a red line in this work, we repeatedly observed that the beneficial effect of structural genomic adaptations comes at a remarkable price: These beneficial evolutionary adaptations often lead to increased genomic instability, which can result in higher vulnerability to disease caused by genetic defects. From examples described in this thesis, it seems we cannot have one without the other. For human evolution this means that the evolutionary trade-off between beneficial and detrimental effects of the same genetic variations might be central to how we evolved as a species, and how we will keep evolving in the millions of years ahead.