TY - JOUR T1 - Genotypic Complexity in Initial Cleavage Divisions of Mammalian Embryos is Contributed by Defective BUB1B/BUBR1 Signaling JF - bioRxiv DO - 10.1101/2020.07.24.220475 SP - 2020.07.24.220475 AU - Kelsey E. Brooks AU - Brittany L. Daughtry AU - Brett Davis AU - Melissa Y. Yan AU - Suzanne S. Fei AU - Lucia Carbone AU - Shawn L. Chavez Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/24/2020.07.24.220475.abstract N2 - Embryonic aneuploidy is highly complex, often leading to developmental arrest, implantation failure, and/or spontaneous miscarriage in both natural and assisted reproduction. Despite our knowledge of mitotic missegregation in somatic cells, the molecular pathways regulating chromosome fidelity during the error-prone cleavage-stage of mammalian preimplantation development remain largely undefined. Using bovine embryos and live-cell fluorescent imaging, we observed frequent micro-/multi-nucleation of missegregated chromosomes in initial divisions that persisted, re-fused with the primary nucleus, or formed a chromatin bridge with neighboring cells. A correlation between a lack of syngamy, multipolar cytokinesis, and uniparental genome segregation was also revealed and single-cell DNA-seq showed complex genotypes propagated by subsequent divisions. Depletion of the checkpoint protein, BUB1B/BUBR1, resulted in atypical cytokinesis, micro-/multi-nuclei formation, chaotic aneuploidy, and developmental arrest. This demonstrates that embryonic micronuclei sustain multiple fates, provides an explanation for blastomeres with uniparental origins, and substantiates defective BUB1B/BUBR1 signaling as a major contributor to mitotic aneuploidy.Competing Interest StatementThe authors have declared no competing interest. ER -