Chromosomal rearrangements and instability caused by the LINE-1 retrotransposon

LINE-1 (L1) retrotransposition is widespread in many cancers, especially those with a high burden of chromosomal rearrangements. However, whether and to what degree L1 activity directly impacts genome integrity is unclear. Here, we apply whole-genome sequencing to experimental models of L1 expression to comprehensively define the spectrum of genomic changes mediated by L1. We provide definitive evidence that L1 retrotransposition frequently and directly causes chromosomal rearrangements including ring chromosomes, large segmental copy-number alterations, and subclonal copy-number heterogeneity due to ongoing chromosomal instability. Mechanistically, these alterations arise from L1-encoded ORF2p-mediated double-strand breaks (DSBs) resulting in reciprocal translocations that generate either stable chromosomes, or unstable dicentric or acentric chromosomes that undergo subsequent evolution through breakage-fusion bridge cycles or DNA fragmentation via chromothripsis. The mutagenic potential of L1-mediated DNA breakage is further supported by diverse genomic alterations of the target sequences inferred to arise from DSB end processing prior to ligation to L1 insertions. Together, these findings suggest L1 is a potent mutagenic force capable of driving genome evolution beyond simple insertions.