Genome-wide abnormalities in embryos: Origins and clinical consequences

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. Key Points What is already known about this topic? Ploidy aberrations, that is triploidy, mixoploidy, chimerism, and uniparental diploidy lead to embryonic lethality and birth defects. Human embryos are burdened by chromosomal aberrations. What does this review add? Overview of different genome-wide aberrations and their clinical consequences. Overview of historically proposed mechanisms for ploidy aberrations. Overview of the discovery of a noncanonical zygotic cleavage leading to blastomere ploidy variation in embryos. Heterogoneic division as unifying theory on the origin of different forms of genome-wide abnormalities.

Automated summary

This review provides an overview of genome-wide abnormalities and their clinical consequences, historical proposed mechanisms for ploidy aberrations, and the discovery of a noncanonical zygotic cleavage leading to blastomere ploidy variation in embryos, suggesting a unifying theory for different forms of genome-wide abnormalities.