Biology subjects

Debrock, S.

Publications and source records attributed to Debrock, S..

3 recordsLinked to original sources

bioRxiv2024

Long-read whole-genome sequencing-based concurrent haplotyping and aneuploidy profiling of single cells

Long-read whole-genome sequencing (lrWGS) enhances haplotyping by providing more phasing information per read compared to short-read sequencing. However, its use for single-cell haplotype phasing remains underexplored. This proof-of-concept study examines lrWGS data from single cells for small variant (SNV and indel) calling and haplotyping using the Genome in a Bottle (GIAB) Ashkenazi trio. lrWGS was performed on single-cell (1 cell) and multi-cell (10 cells) samples from the offspring. Chromosome-length haplotypes were obtained by leveraging both long reads and pedigree information. These haplotypes were further refined by replacing them with matched parental haplotypes. In single-cell and multi-cell samples, 92% and 98% of heterozygous SNVs, and 74% and 78% of heterozygous indels were accurately haplotyped. Applied to human embryos for preimplantation genetic testing (PGT), lrWGS demonstrated 100% consistency with array-based methods for detecting monogenic disorders, without requiring phasing references. Aneuploidies were accurately detected, with insights into the mechanistic origins of chromosomal abnormalities inferred from the parental unique allele fractions. We show that lrWGS-based concurrent haplotyping and aneuploidy profiling of single cells provides an alternative to current PGT methods, with applications potential in areas such as cell-based prenatal diagnosis and animal and plant breeding.

genomics↗

bioRxiv2023

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

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.

developmental biology↗

bioRxiv2021

Parental genomes segregate into different blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts

The zygotic division enables two haploid genomes to segregate into two biparental diploid blastomeres. This fundamental tenet was challenged by the observation that blastomeres with different genome ploidy or parental genotypes can coexist within individual embryos. We hypothesized that whole parental genomes can segregate into distinct blastomere lineages during the first division through "heterogoneic division". Here, we map the genomic landscape of 82 blastomeres from 25 embryos that underwent multipolar zygotic division. The coexistence of androgenetic and diploid or polyploid blastomeres with or without anuclear blastomeres, and androgenetic and gynogenetic blastomeres within the same embryo proofs the existence of heterogoneic division. We deduced distinct segregation mechanisms and demonstrate these genome-wide segregation errors to persist to the blastocyst stage in both human and cattle. Genome-wide zygotic segregation errors contribute to the high incidence of embryonic arrest and provide an overarching paradigm for the development of mixoploid and chimeric individuals and moles.

developmental biology↗