BreakpointJunctions

Breakpoint junctions are the precise DNA sequences formed at the junction where two genomic regions that were previously distant become contiguous as a consequence of a structural variant. They mark the endpoints of rearrangements such as deletions, duplications, inversions, translocations, or more complex rearrangements. The junction sequence itself can provide clues about the mechanism of formation; for example, junctions may display microhomology, small insertions, or blunt joins, patterns associated with repair pathways like non-homologous end joining or microhomology-mediated end joining.

Formation and features: Breakpoint junctions arise when double-strand breaks are repaired or when replication stress creates noncontiguous joining of DNA segments. The sequence at the junction can reflect the repair process, with microhomology indicating microhomology-mediated end joining, or blunt joins suggesting direct ligation. Complex rearrangements can produce multiple adjacent junctions within a single genomic region.

Detection and analysis: Breakpoint junctions are identified through sequencing approaches such as whole-genome sequencing or targeted capture, which enable precise localization of breakpoints. Computational analyses look for discordant read pairs and split reads that span a junction. Validation frequently employs PCR amplification across the junction or fluorescence in situ hybridization in some contexts.

Clinical and research relevance: Breakpoint junctions are central to understanding chromosomal rearrangements in cancer, inherited disorders, and evolutionary genomics. They can activate oncogenic fusion genes, disrupt coding sequences, or alter regulatory landscapes. Well-known examples include translocations that create fusion genes in cancer, such as BCR-ABL, illustrating how breakpoint junctions can drive disease and inform diagnostics and treatment. Breakpoint junctions also contribute to the study of chromothripsis and other complex genome dynamics.