A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

Abstract

The frequent acquisition of genomic abnormalities in human preimplantation embryos is a leading cause of pregnancy loss, but does not necessarily prohibit healthy offspring. However, the impact of genomic abnormalities on cellular states and development of the early human embryo remains largely unclear. Here, we characterise aneuploidy and reconstruct gene regulatory networks in human preimplantation embryos, and investigate gene expression and developmental perturbations instigated by aneuploidy using single-cell genome-and-transcriptome sequencing (G&T-seq). At the genomic level, we show that acquired numerical and structural chromosomal aberrations are frequent across all stages of early embryogenesis and in all cell lineages. At the transcriptome level, we identify regulators of cell identity and uncover a network of 248 transcription factors from 10 major gene regulatory modules that characterise the distinct lineages of human preimplantation embryos. By integrating single-cell DNA- with RNA-information, we unveil how expression levels are affected by losses or gains of the corresponding genes in embryonic cells across human preimplantation development, as well as how copy-number aberrant transcription factor genes perturb the expression of their cognate target genes in euploid regions. Furthermore, we reveal a majority of aneuploid cells show a developmental delay and reduced fitness, indicating cell competition within the mosaic diploid-aneuploid embryo, which may contribute to selection against aneuploid cells and the birth of healthy offspring from mosaic diploid-aneuploid embryos. In summary, our multi-modal analyses provide unprecedented insights into early human embryo development.

Mechanistic origin and preimplantation development of uniparental and polyploid blastomeres

“…4D). These results indicate that transcriptomic changes are mainly driven by the natural developmental program rather than variations in genome constitution, aligning with previous single-cell transcriptome analyses of uniparental (Leng et al 2019) and aneuploid (Fernandez Gallardo et al 2023) cells from human preimplantation embryos. We then explored whether the impaired development of blastomeres exhibiting WG abnormalities was reflected in single-cell transcriptome profiles.…”

“…For instance, GATA6 has demonstrated significance in the ICM of mouse, bovine, and human embryos (Niakan and Eggan 2013;Marsico et al 2023). Similarly, CDX2, GATA2 and GATA3 have been implicated in the TE of mouse, bovine and human embryos (Home et al 2017;Fernandez Gallardo et al 2023;Gerri et al 2020;Nagatomo et al 2013;Niakan and Eggan 2013;Negrón-Pérez et al 2017).…”

“…Heterogoneic division, as the natural origin of blastomeres with WG abnormalities, represents a fundamental yet underexplored aspect of embryo development. While research on preimplantation embryo development often focuses on aneuploidies and their implications (Fragouli et al 2013;Fernandez Gallardo et al 2023;Tšuiko et al 2021), there has been a lack of investigation into the developmental trajectory of spontaneously arising blastomeres carrying WG abnormalities. Examining the subsequent development of blastomeres following both heterogoneic and normal first zygotic divisions will provide valuable insights into the developmental disparities between blastomeres with WG abnormalities and normal blastomeres.…”

Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts

“…From these events, 23% (n = 19 of 82) probably occurred before lineage specification, whereas 77% (n = 63 of chromosomes and subchromosomal regions can be examined (27). Two such approaches have been described but are limited by error-prone methods based on single-cell RNA-Seq or by using only a limited number of cells per embryo (27)(28)(29). Comprehensive single-cell chromosome analysis could also reveal important information regarding underlying mechanisms.…”