Abstract
Whole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring during the initial mitotic cell divisions. The first wave of zygotic genome activation at the 4–8 cell stage results in the arrest of a large proportion of embryos, the vast majority of which contain whole-chromosome abnormalities. Thus, the full spectrum of meiotic and mitotic errors can only be detected by sampling after the initial cell divisions, but prior to this selective filter. Here, we apply 24-chromosome preimplantation genetic screening (PGS) to 28,052 single-cell day-3 blastomere biopsies and 18,387 multi-cell day-5 trophectoderm biopsies from 6,366 in vitro fertilization (IVF) cycles. We precisely characterize the rates and patterns of whole-chromosome abnormalities at each developmental stage and distinguish errors of meiotic and mitotic origin without embryo disaggregation, based on informative chromosomal signatures. We show that mitotic errors frequently involve multiple chromosome losses that are not biased toward maternal or paternal homologs. This outcome is characteristic of spindle abnormalities and chaotic cell division detected in previous studies. In contrast to meiotic errors, our data also show that mitotic errors are not significantly associated with maternal age. PGS patients referred due to previous IVF failure had elevated rates of mitotic error, while patients referred due to recurrent pregnancy loss had elevated rates of meiotic error, controlling for maternal age. These results support the conclusion that mitotic error is the predominant mechanism contributing to pregnancy losses occurring prior to blastocyst formation. This high-resolution view of the full spectrum of whole-chromosome abnormalities affecting early embryos provides insight into the cytogenetic mechanisms underlying their formation and the consequences for human fertility.
Highlights
IntroductionWith pregnancy loss estimated to occur in approximately 70% of all conceptions [1]
Human reproduction is inefficient, with pregnancy loss estimated to occur in approximately 70% of all conceptions [1]
The rate of aneuploidy increases with maternal age, primarily due to chromosome segregation errors arising during egg formation
Summary
With pregnancy loss estimated to occur in approximately 70% of all conceptions [1]. It has long been established that incidence of aneuploidy affecting maternal chromosome copies increases with maternal age [7] This pattern is driven mostly by errors occurring during maternal meiosis, which arrests at the diplotene stage until it resumes at ovulation many years later [3]. Later work demonstrated a greater role of unbalanced predivision—the premature separation and subsequent missegregation of sister chromatids [8]—in contributing to maternal age-related meiotic error and implicated breakdown of cohesin proteins as a possible mechanism [9,10,11] Both non-disjunction and unbalanced chromatid predivision result in a chromosome gain in one daughter cell with a corresponding chromosome loss in the other daughter cell, but can be distinguished when both oocytes or embryos and their corresponding polar bodies are analyzed. A recent study used this approach to confirm the preponderance of unbalanced chromatid predivision and identify a non-canonical segregation pattern whereby sister chromatids separate at the meiosis I (MI), followed by non-random segregation at meiosis II (MII) favoring separation of homologous chromosomes [12]
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