Models for the evolution of the iAMP21 chromosome. (A) The rob(15;21)c is a constitutional dicentric chromosome fusing the short arms of 1 copy each of chromosomes 15 and 21. Usually, 1 centromere is inactive to allow ordered separation of chromatids in mitosis. The model depicts the hypothesis that the 2 centromeres become active and confound attachment of mitotic spindles to the sister kinetochores, such that each chromatid connects to spindles emanating from opposite poles (step 1). During anaphase, this merotelic attachment would lead to lagging of both sister chromatids, rendering them jointly prone to chromothripsis (shattering and then repair) (step 2), leading to a grossly rearranged rob(15;21)c-associated iAMP21 (step 3). (B) Sporadic-iAMP21 formation is initiated by telomere attrition or double-strand breakage (step 1). Following replication, the unprotected chromosome ends fuse (step 2), leading to the formation of anaphase bridges and mitotic chromosome double-strand breakage typical of BFB cycles (step 3). This process is often repeated (step 4). Chromothripsis of the resultant dicentric chromosome is initiated (step 5) in the same manner as described for the rob(15;21)c-associated iAMP21 (step 2 in Figure 1A). The final step (step 6) is repair of the shattered chromosome leading to generation of a stable abnormal chromosome 21.