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Aneuploidy Common in Early-Stage Human Embryos, Single-Cell RNA-Seq Study Reveals

NEW YORK – Aneuploidy appears to be common among early-stage human embryos, according to a new single-cell study, a finding that may have implications for in vitro fertilization approaches.

Aneuploidy is the leading cause of pregnancy loss and birth defects among humans, and in vitro fertilization clinics often pass over embryos with aneuploidy or that are mosaic for aneuploidy for implantation. But it has been unclear how common chromosomal mosaicism is among human embryos, as previous studies indicated that anywhere between 4 percent and 90 percent of human embryos are mosaic.

Using existing single-cell genomic data from human embryos, researchers from Johns Hopkins University have now conducted a new examination of aneuploidy and mosaicism. As they reported in Genome Research on Wednesday, they found mitotic and meiotic aneuploidies to be widespread and to affect some 80 percent of embryos.

"Clinicians have wrestled with the decision to transfer embryos featuring mosaic aneuploidy when no other embryos are available," senior author Rajiv McCoy, a biology professor at Johns Hopkins, said in a statement. "In recent years, some have implanted such embryos and reported healthy births, indicating embryos may have resilience or self-correction of mosaicism."

Many previous analyses of mosaicism in embryos have relied on bulk DNA assays, which yields an average picture across cells, or on multiple biopsies of a few embryonic cells, which may not represent the full embryo. McCoy and his colleagues instead sifted through previously published single-cell RNA sequencing data generated for more than 1,000 cells from 74 human embryos, obtained between the morula and blastocyst stages. To detect aneuploidies, they looked for chromosome dosage-associated changes in gene expression and for signatures of allelic imbalance.

Eighty percent of the embryos they examined contained at least one cell that was aneuploid. In particular, 5 percent of embryos harbored only meiotic aneuploidies, which affect all embryonic cells; 49 percent had only mitotic aneuploidies, which lead to mosaicism; and 26 percent had both aneuploidy types.

For instance, one blastocyst dubbed E7.17 exhibited evidence of meiotic monosomy affecting chromosomes 4 and 13, while chromosome 8 appeared to have mosaic monosomy in about half the cells.

Rates of aneuploidy did not appear to differ across cell type or by day of differentiation. The researchers likewise did not note an enrichment of aneuploidy in the outer layer of trophectoderm cells versus the inner cell mass. However, they noted a wide confidence interval in their analysis, suggesting they could not rule out modest differences.

Meanwhile, the researchers reported that nearly 3,000 genes were differentially expressed between euploid and aneuploid cells. The most significant association involved the upregulation of GDF15 in aneuploid cells as compared to euploid cells. GDF15, which had previously been linked to aneuploidy in a cell line study, is a cytokine whose expression goes up in response to stress. At the same time, the most significantly downregulated gene was ZFP42, which encodes a zinc-finger protein that is a marker of pluripotency.

The researchers further noted a broader pattern of the upregulation of immune response genes and downregulation of proliferation, metabolism, and protein-response genes, which they said was consistent with stress response.

With these findings, McCoy said he hoped "we can move on from the debate about whether mosaicism is common or not to understanding what the features of mosaicism are that are associated with good or bad outcomes in pregnancy."