Breaking the paradigm: early insights from mammalian DNA breakomes

DNA double‐strand breaks (DSBs) can result from both exogenous and endogenous sources and are potentially toxic lesions to the human genome. If improperly repaired, DSBs can threaten genome integrity and contribute to premature ageing, neurodegenerative disorders and carcinogenesis. Through decades of work on genome stability, it has become evident that certain regions of the genome are inherently more prone to breakage than others, known as genome instability hotspots. Recent advancements in sequencing‐based technologies now enable the profiling of genome‐wide distributions of DSBs, also known as breakomes, to systematically map these instability hotspots. Here, we review the application of these technologies and their implications for our current understanding of the genomic regions most likely to drive genome instability. These breakomes ultimately highlight both new and established breakage hotspots including actively transcribed regions, loop boundaries and early‐replicating regions of the genome. Further, these breakomes challenge the paradigm that DNA breakage primarily occurs in hard‐to‐replicate regions. With these advancements, we begin to gain insights into the biological mechanisms both invoking and protecting against genome instability.