Haplotyping-based preimplantation genetic testing reveals parent-of-origin specific mechanisms of aneuploidy formation

• Main Authors: Olga Tšuiko, Michiel Vanneste, Cindy Melotte, Jia Ding, Sophie Debrock, Heleen Masset, Maire Peters, Andres Salumets, Anne De Leener, Céline Pirard, Candice Kluyskens, Katleen Hostens, Arne van de Vijver, Karen Peeraer, Ellen Denayer, Joris Robert Vermeesch, Eftychia Dimitriadou
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-10-01
• Series: npj Genomic Medicine
• Online Access: https://doi.org/10.1038/s41525-021-00246-0

Abstract Chromosome instability is inherent to human IVF embryos, but the full spectrum and developmental fate of chromosome anomalies remain uncharacterized. Using haplotyping-based preimplantation genetic testing for monogenic diseases (PGT-M), we mapped the parental and mechanistic origin of common and rare genomic abnormalities in 2300 cleavage stage and 361 trophectoderm biopsies. We show that while single whole chromosome aneuploidy arises due to chromosome-specific meiotic errors in the oocyte, segmental imbalances predominantly affect paternal chromosomes, implicating sperm DNA damage in segmental aneuploidy formation. We also show that postzygotic aneuploidy affects multiple chromosomes across the genome and does not discriminate between parental homologs. In addition, 6% of cleavage stage embryos demonstrated signatures of tripolar cell division with excessive chromosome loss, however hypodiploid blastomeres can be excluded from further embryo development. This observation supports the selective-pressure hypothesis in embryos. Finally, considering that ploidy violations may constitute a significant proportion of non-viable embryos, using haplotyping-based approach to map these events might further improve IVF success rate.