Parental genome unification is highly error-prone in mammalian embryos

Abstract

Summary Most human embryos are aneuploid. Aneuploidy frequently arises during the early mitotic divisions of the embryo, but its origin remains elusive. Human zygotes that cluster their nucleoli at the pronuclear interface are thought to be more likely to develop into healthy euploid embryos. Here, we show that the parental genomes cluster with nucleoli in each pronucleus within human and bovine zygotes, and clustering is required for the reliable unification of the parental genomes after fertilization. During migration of intact pronuclei, the parental genomes polarize toward each other in a process driven by centrosomes, dynein, microtubules, and nuclear pore complexes. The maternal and paternal chromosomes eventually cluster at the pronuclear interface, in direct proximity to each other, yet separated. Parental genome clustering ensures the rapid unification of the parental genomes on nuclear envelope breakdown. However, clustering often fails, leading to chromosome segregation errors and micronuclei, incompatible with healthy embryo development.

Dual spindles assemble in bovine zygotes despite the presence of paternal centrosomes

“…Together, these results demonstrate that dual spindle assembly (i.e., one around each of the two PNi) also occurs in mammalian zygotes that contain two centrosomes and, if the two PNi are distant, remains pronounced until chromosomes segregate. Since neither NE remnants nor the ER physically separate the two genomes and spindles, it is likely that it is the assembly of the dual spindles that keeps the genomes compartmentalized throughout the whole first mitotic division in bovine zygotes ( Cavazza et al, 2021 ), similarly as in the mouse ( Reichmann et al, 2018b ).…”

“…Both the surprising symmetry of acentrosomal and centrosomal spindle halves and strong microtubule nucleation around chromosomes after nocodazole washout suggest that centrosome-independent pathways play a major role for zygotic spindle assembly and maintenance. Nevertheless, centrosomes may have other important functions in the zygote, such as pronuclear migration and the recently reported chromosome clustering at the pronuclear interface ( Cavazza et al, 2021 ).…”

Linker histone H1.8 inhibits chromatin binding of condensins and DNA topoisomerase II to tune chromosome length and individualization

“…Such a mechanism would facilitate effective kinetochore attachment during early embryonic cell divisions when the spindle checkpoint cannot be activated by unattached chromosomes ( Mara et al, 2019 ; Gerhart et al, 1984 ; Hara et al, 1980 ). Indeed, it was recently shown that paternal and maternal chromosomes cluster at the interface of two pronuclei prior to the first zygotic mitosis after fertilization to facilitate rapid and efficient kinetochore microtubule attachment in human and bovine embryos ( Cavazza et al, 2021 ). Another possible reason for the suppressed individualization is related to the fact that oocyte chromosomes completely lose cohesion from arms at the end of meiosis I, while maintaining sister chromatid cohesion only at the centromeres ( Lister et al, 2010 ).…”

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

“…During the fecundation, the parental genomes fuse and cluster to form the embryo. However, clustering often fails, leading to chromosome segregation errors and micronuclei, which are incompatible with healthy embryo development [ 155 ]. Recent advances in sequencing methodology have allowed the detection and the description of complex structural variations inside the genome of patients with developmental disease, as well as in phenotypically normal individuals [ 156 ].…”