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Studying human development by single-cell profiling of primary human tissues and genetic perturbations of novel developmental models


Understanding human development is critical to understanding human evolution, treating developmental disorders, and creating regenerative therapeutics. Single-cell methods have enabled the high-resolution profiling of developmental trajectories and novel organoid models have facilitated a greater understanding of difficult to access developmental periods, especially through the use of perturbation experiments. Here, we used a novel multi-lineage developmental model along with profiling of the developing human prefrontal cortex to better understand human development and evolution. First, we developed a novel visualization method, Similarity Weighted Nonnegative Embedding (SWNE), which both preserves the structure of single-cell datasets and enables key marker genes and relevant genesets to be embedded alongside the cells. We then leveraged a novel multi-lineage developmental model, the teratoma, to study the role of key developmental genes. We conducted a pooled CRISPR knockout screen of those regulators in the teratoma with a single cell RNA-seq readout, enabling us to better understand the function of these genes across all major human lineages. Finally, we used both single-cell RNA-seq and single-cell chromatin accessibility profiling to study the role of human accelerated regions (HARs), genomic regions thought to influence human-specific evolution, in human corticogenesis. The chromatin accessibility enabled us to assess the activity of HARs in specific developmental cell types and link those HARs to genes using co-accessibility of the HARs and gene promoters, while the RNA-seq enabled us to validate the expression of those HAR-linked genes.

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