Mosaicism in Preimplantation Human Embryos: When Chromosomal Abnormalities Are the Norm

Abstract

Along with errors in meiosis, mitotic errors during post-zygotic cell division contribute to pervasive aneuploidy in human embryos. Relatively little is known, however, about the genesis of these errors or their fitness consequences. Rapid technological advances are helping to close this gap, revealing diverse molecular mechanisms contributing to mitotic error. These include altered cell cycle checkpoints, aberrations of the centrosome, and failed chromatid cohesion, mirroring findings from cancer biology. Recent studies are challenging the idea that mitotic error is abnormal, emphasizing that the fitness impacts of mosaicism depend on its scope and severity. In light of these findings, technical and philosophical limitations of various screening approaches are discussed, along with avenues for future research.

Keywords: aneuploidy; fertility; mitosis; preimplantation genetic screening.

Figure 1. Characteristics of day-3 blastomeres with putative meiotic or mitotic errors

Data from [11]. Trisomies including both maternal or paternal homologs are classified as maternal or paternal meiotic errors, respectively, and arise through non-disjunction or PSSC. Mitotic errors, meanwhile, are identified as those non-meiotic errors involving paternal homologs (including those that also involve maternal homologs). Note that some forms of aneuploidy (e.g., maternal monosomy) are ambiguous in origin and thus cannot be classified as meiotic or mitotic based on these data. (a) Incidence of various forms of aneuploidy with respect to maternal age. (b) Per-chromosome incidences of meiotic- and mitotic-origin aneuploidies.

Figure 2. Forms of mosaic aneuploidy affecting preimplantation human embryos

For each example, deviations from diploidy are indicated with the number of extra or missing maternal or paternal homologs.

Figure 3. Centrosomal defects can induce mitotic aneuploidy via multiple routes

Oocytes fertilized by two sperm or cells that experience centriole amplification will possess more than two centrosomes. When cell cycle checkpoints are relaxed, as is the case in cleavage-stage embryos, cells with extra centrosomes may undergo multipolar mitosis, resulting in severe aneuploidy. Alternatively, centrosomes may cluster, allowing for bipolar spindle formation, but predisposing chromosomes to aberrant kinetochore-microtubule attachments. Such attachments may lead to anaphase lag, whereby the chromosome fails to be incorporated into the daughter nucleus. These chromosomes may be sequestered in micronuclei, incur DNA damage, and induce cellular fragmentation.

Figure 4, Key Figure. Models to explain the declining incidence of mosaicism from the cleavage to blastocyst stages of preimplantation development

The embryonic mortality model invokes selection against embryos based on the proportion of aneuploid cells. The clonal depletion model describes apoptosis or reduced propagation of aneuploid cells within mosaic embryos. Monosomic and trisomic rescue are proposed mechanisms by which aneuploid cells can give rise to diploid cells through mitotic chromosome gain or loss, respectively.

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