Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development

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.

Mosaicism between trophectoderm and inner cell mass

“…Consistent with aneuploidies affecting preimplantation development, recent studies claimed a higher incidence of chaotic chromosome aneuploidies in biopsies taken from 8-cell embryos (day 3) compared with blastocysts (25) derived from putative mitotic events (7). In particular, results from a survey of 385 cleavage-stage embryos found that survival to blastocyst formation correlates with the number of chromosomal abnormalities detected in blastomeres (25).…”

“…Apart from uniform aneuploidies originating because of meiotic errors in both gametes, postzygotic errors in chromosome segregation can also occur and contribute to human aneuploidies and may be associated with developmental arrest or congenital abnormalities (7). Mitotic errors during the first cleavage divisions result in mosaicism within the preimplantation embryo and potentially in cell lines with different karyotypes.…”

Functional Human Oocytes Generated by Transfer of Polar Body Genomes

“…Aneuploidy rates in human embryos increase with maternal age as a result of meiosis I or II errors (Hassold and Hunt, 2001;Nagaoka et al, 2012;Petronczki et al, 2003). In addition, mitotic errors during-post zygotic cleavage divisions may occur producing mosaic blastomeres containing multiple distinct karyotypes within a preimplantation embryo (McCoy et al, 2015). While PBNT is unlikely to correct meiosis I errors, functional cytoplasm from young donors may reduce incidences of aneuploidy resulting from meiosis II or mitotic errors.…”

Early embryo mortality in natural human reproduction: What the data say

“…Widely held views on early embryo mortality may reflect an entrenched and biased view of the biology. For example, the Macklon “Black Box” review 20 has been cited over 200 times (Web of Knowledge citations on 10 th October 2016) with many articles explicitly referencing its 30% survival/70% failure value 8, 21, 113, 127– 133 . Macklon’s quantitative summary in his “Pregnancy Loss Iceberg” (30% implantation failure; 30% early pregnancy loss; 10% clinical miscarriage; 30% live births) is a direct, unedited reproduction of estimates published over 10 years previously 19 .…”