Homo sapiens Genome sequencing

Human cleavage stage embryos frequently acquire chromosomal aneuploidies during mitosis. We recently showed that the failure to repair double strand breaks (DSBs) introduced by Cas9 results in both segmental as well as whole chromosome aneuploidies. Here we show that spontaneous DSBs arise de novo during embryonic DNA replication and present as chromosomal breaks that occur primarily in centromeric, pericentromic, and gene-poor areas. While transcription-replication conflicts are not the drivers of chromosome fragility, gene-poor regions show late replication complete replication late in G2 phase, hours after most of the genome has been duplicated. Incomplete replication at these sites in both human and mouse zygotes results in DSBs, whole and segmental chromosome errors, micronucleation, chromosome fragmentation and poor embryo quality. Thus, DNA replication in human preimplantation embryos displays a pattern with late replication completion of gene poor regions, which predisposes them to fragility, and the embryo to the formation of aneuploidies.