Chromothripsis: potential origin in gametogenesis and preimplantation cell divisions. A review  Franck Pellestor, Ph.D., Vincent Gatinois, Pharm.D., Jacques Puechberty, M.D., David Geneviève, M.D., Geneviève Lefort, M.D.  Fertility and Sterility  Volume 102, Issue 6, Pages 1785-1796 (December 2014) DOI: 10.1016/j.fertnstert.2014.09.006 Copyright © 2014 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Principle of the chromothripsis process. During a one-step catastrophic event, multiple double-strand breaks occur, restricted to a simple chromosomal segment or to a few closed chromosome domains, leading to the pulverization of chromosomal fragments. Most of them are stitched back together, resulting in chaotic derivative chromosome(s), but some are lost or combined in small circular extra-chromosomes (double-minute chromosomes), usually harboring oncogenes. Fertility and Sterility 2014 102, 1785-1796DOI: (10.1016/j.fertnstert.2014.09.006) Copyright © 2014 American Society for Reproductive Medicine Terms and Conditions

Figure 2 Chromothripsis and micronuclei in gametogenesis. There are several pathways by which a micronucleus can be generated during mitotic division in gametic germ cells, involving abortive apoptosis, mitotic errors, merotelic kinetochore attachment, or telomere erosion and end-to-end fusion. The generated micronucleus can undergo asynchronous DNA replication or chromosome pulverization and chaotic repair, leading to the formation of highly complex derivative chromosome(s). During subsequent cell divisions, the rearranged chromosomes trapped in the micronucleus can be reintegrated into the main nucleus of one of the daughter cells. Fertility and Sterility 2014 102, 1785-1796DOI: (10.1016/j.fertnstert.2014.09.006) Copyright © 2014 American Society for Reproductive Medicine Terms and Conditions

Figure 3 Chromothripsis in preimplantation embryo via micronucleus. Both aneuploidy fertilization and premature chromosome condensation in the male pronucleus can lead to the formation of an embryonic micronucleus sequestrating extra or pulverized chromosome(s) during the first embryonic division. In the micronucleus, the chromosomal materials undergo defective replication and/or chaotic reorganization. The micronucleus can be incorporated into extracellular fragments, often detected in vitro at the two-cell stage in preimplantation embryos, and then be reincorporated later into the blastomere from which it originated or a neighboring blastomere. Thus, the rearranged chromosome(s) can be subsequently reintegrated into the main nucleus of one blastomere and thereafter maintained with chromothripsis-related rearrangements. Fertility and Sterility 2014 102, 1785-1796DOI: (10.1016/j.fertnstert.2014.09.006) Copyright © 2014 American Society for Reproductive Medicine Terms and Conditions