Figure 3. Replication-based mechanisms generate structural variants and single-nucleotide variants.

a | Break-induced replication (BIR) can be triggered by a nick on the template strand that may cause stalling or the collapse of the replication fork. Resection of the 5′ end of the broken single-ended, double-stranded DNA (seDNA) molecule exposes a 3′ tail that can invade an allelic (not shown) or a paralogous genomic segment with shared homology (ectopic recombination) to prime replication. Paralogous segments are represented by horizontal orange arrows. The use of ectopic homology to repair broken molecules by BIR can lead to structural variants (for example, duplication (shown here), triplications, deletions and inversions). A conservative mode of repair was recently proposed for BIR that can contribute to perpetuate repair indels or single-nucleotide variant (SNV) (black asterisks) mutations that are acquired during the replicative repair^116,117. b | Microhomology-mediated break-induced replication (MMBIR) can be triggered by a nick on the template strand that may cause stalling or the collapse of the replication fork⁹². Alternatively, MMBIR can also occur by disrupted BIR¹¹¹. Resection of the 5′ end of the broken seDNA molecule exposes a 3′ tail that can anneal to a single-strand DNA sharing microhomology (colour-matched boxes) to prime replication. The initial polymerase extension and replication is carried out by a low processivity polymerase, rendering this repair process prone to undergoing multiple rounds of disengagement and template switches until a fully processive replication fork is established. Short and/or long template switches during repair can generate complexity due to the insertion of templated segments at the rearrangement junction. DUP, duplication; INV, inversion; TS, template switches.