Figure 8.

Model explaining formation of MMB-TIs and their possible genomic MMBIR outcomes. (i) Initation: Stalling of leading, lagging strand, or induction of a double strand break lead to replication problems or induction of BIR. (ii) Process: 3′ single-strand (ss) DNA ends are formed by dissociation of a nascent strand from its template during S-phase replication or by 5′ to 3′ resection of DSB ends. Dissociated or resected 3′-ssDNA anneals at microhomology to nearby exposed ssDNA or invades nearby dsDNA at microhomology to prime DNA synthesis. (iii) Outcomes: Additional rounds of template switching, or invasion mediated by microhomology can lead to either a return to the original template or more complex rearrangements. (iv) Context: MMB-TI events that do not disrupt genes are more likely to accumulate as germline variants over the course of evolution. More complex MMB-TI events, especially those that disrupt genes or lead to gross chromosomal rearrangements, may only appear in pathogenic contexts.