Genome‐wide abnormalities in embryos: Origins and clinical consequences

Abstract

Ploidy or genome‐wide chromosomal anomalies such as triploidy, diploid/triploid mixoploidy, chimerism, and genome‐wide uniparental disomy are the cause of molar pregnancies, embryonic lethality, and developmental disorders. While triploidy and genome‐wide uniparental disomy can be ascribed to fertilization or meiotic errors, the mechanisms causing mixoploidy and chimerism remain shrouded in mystery. Different models have been proposed, but all remain hypothetical and controversial, are deduced from the developmental persistent genomic constitutions present in the sample studied and lack direct evidence. New single‐cell genomic methodologies, such as single‐cell genome‐wide haplotyping, provide an extended view of the constitution of normal and abnormal embryos and have further pinpointed the existence of mixoploidy in cleavage‐stage embryos. Based on those recent findings, we suggest that genome‐wide anomalies, which persist in fetuses and patients, can for a large majority be explained by a noncanonical first zygotic cleavage event, during which maternal and paternal genomes in a single zygote, segregate to different blastomeres. This process, termed heterogoneic division, provides an overarching theoretical basis for the different presentations of mixoploidy and chimerism.

Prenatal diagnosis of syndromic alobar holoprosencephaly associated with digynic triploidy fetus

“…Digynic triploidies origin result from fertilization of a primary oocyte, a diploid oocyte or retention of a polar body [ 22 ]. The substrate of human triploidy is disputed [ 23 , 24 ]. About 75–86% of cases are diandric triploidy, generally resulting from the fecundation of a female haploid reproductive cell by two male haploid gametes (dispermy) [ 21 , 25 ].…”

Parental genomes segregate into different blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts

“…Here, we demonstrate this occurs in human embryos as well. It was hypothesized that GW mosaic embryos are caused by heterogoneic division, during which the parental genomes in the zygote are segregated into distinct cell lineages (27,39). By tracing division kinetics and determining the genomic structure of all single blastomeres, we provide direct evidence that heterogoneic division is common in embryos that undergo multipolar zygotic division.…”

“…Outgrowth or survival of one or more of the blastomeres following heterogoneic division likely contributes to low human fecundity and provides an overarching explanation for the persistence of GW anomalies in fetuses and patients (Fig. 6) (27). Multipolar zygotic divisions have been linked to impaired embryonic development, implantation and pregnancy rates in both human (98,(103)(104)(105)(106)(107) and bovine (58) embryos.…”

“…Hence, the true mechanistic origin of mixoploidy and chimerism remains elusive. Different models invoking (a combination of) zygotic or polar body fusion, parthenogenetic activation and fertilization or meiotic errors have been put forward to explain their origin (27)(28)(29)(30)(31)(32)(33)(34)(35)(36). However, they remain speculative and largely unsupported by molecular or cell biological data.…”

The origins of aneuploidy research consortium

“…Masset et al. propose that abnormal first zygotic cleavage events in which the maternal and paternal genomes segregate into separate blastomeres (‘heterogoneic division’) are the main cause of mixoploidy 21 …”