Abstract

Cause and Consequence of Complex Genomic Rearrangements in Human Disease

Wigard Kloosterman, Assistant Professor, University Medical Center Utrecht

Genomic rearrangements are frequently underlying congenital malformations and cancer. One class of complex genomic rearrangements - termed chromothripsis - has received much recent attention. Chromothripsis involves shattering of one or more chromosomes, followed by repair of the DNA damage and formation of new mosaic chromosomes. We have characterized hundreds of breakpoint junctions from chromothripsis rearrangements, revealing that break repair involves non-homologous mechanisms. Furthermore, we identified that chromothripsis occurs most often on paternal chromosomes and can be stably transmitted to subsequent generations. I will highlight our studies aimed at unraveling details of the functional consequences of chromothripsis, including examination of isolated breakpoint junctions leading to fusion genes. These experiments provide insight in the molecular determinants driving congenital disease associated with chromothripsis. Finally, I will discuss development of model systems to characterize the cellular trigger for chromothripsis in somatic cells and germline.