Models of amplification of higher-order repeats (HORs). (Left) In the unequal exchange model, reciprocal recombination between out-of-register tandem repeats can either duplicate or delete individual monomers. As variations accumulate in particular monomers, unequal exchange can generate higher-order repeats (HORs). (Right) In the break-induced replication (BIR) model, replication fork stalling can lead to one-ended double-strand breaks (DSBs). Resection yields a free single-strand 3′ end that can invade a homologous sequence and reinitiate replication. Reinitiating at an out-of-register repeated sequence ahead of the fork will lead to deletion, whereas reinitiating at one behind the fork will lead to duplication (insets with blue outlines). Duplication appears to be favored, perhaps because the chromatin behind the fork is more accessible to strand invasion owing to the new acetylated histones and/or the relaxed torsional state in contrast to the overtwisted DNA ahead of the fork (inset with red outline).
