Chromothripsis and human disease: piecing together the shattering process

Abstract

The unprecedented resolution of high-throughput genomics has enabled the recent discovery of a phenomenon by which specific regions of the genome are shattered and then stitched together via a single devastating event, referred to as chromothripsis. Potential mechanisms governing this process are now emerging, with implications for our understanding of the role of genomic rearrangements in development and disease.

Figure 1. Chromothripsis reshapes the genomic landscape in a single devastating event

Overview of chromothripsis. Stress stimulus may help trigger the shattering process in localized regions that are subsequently stitched back together. Left, stress simultaneously generates double strand breaks (triangle) that are joined together to generate a derivative chromosome and potentially resulting in regions being deleted. The breakpoint junction reveals microhomology, without insertions, thereby supporting NHEJ. Right, a replicative stress generates a nick in the chromosome causing a replication fork to collapse. Microhomology-mediated break-induced replication (MMBIR) results in the duplication and triplication represented by two or three rectangles above the altered chromosome, respectively. An example breakpoint junction reveals microhomology as well as a short insert.