Comparative landscape of genetic dependencies in human and chimpanzee stem cells

• Published in: Cell Vol. 186; no. 14; pp. 2977 - 2994.e23
• Main Authors: She, Richard, Fair, Tyler, Schaefer, Nathan K., Saunders, Reuben A., Pavlovic, Bryan J., Weissman, Jonathan S., Pollen, Alex A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.07.2023
• Subjects: Animals; cellular anthropology; CRISPR screening; G1-phase length hypothesis; genetic dependencies; Hominidae; human-specific evolution; Humans; neural progenitor cells; Neural Stem Cells; Pan troglodytes - genetics; Pluripotent Stem Cells; Stem Cells; human-specific evolution; pluripotent stem cells; G1-phase length hypothesis; CRISPR screening; cellular anthropology; genetic dependencies; neural progenitor cells
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2023.05.043

Comparative studies of great apes provide a window into our evolutionary past, but the extent and identity of cellular differences that emerged during hominin evolution remain largely unexplored. We established a comparative loss-of-function approach to evaluate whether human cells exhibit distinct genetic dependencies. By performing genome-wide CRISPR interference screens in human and chimpanzee pluripotent stem cells, we identified 75 genes with species-specific effects on cellular proliferation. These genes comprised coherent processes, including cell-cycle progression and lysosomal signaling, which we determined to be human-derived by comparison with orangutan cells. Human-specific robustness to CDK2 and CCNE1 depletion persisted in neural progenitor cells and cerebral organoids, supporting the G1-phase length hypothesis as a potential evolutionary mechanism in human brain expansion. Our findings demonstrate that evolutionary changes in human cells reshaped the landscape of essential genes and establish a platform for systematically uncovering latent cellular and molecular differences between species. [Display omitted] •CRISPRi screens reveal distinct genetic dependencies in human and chimpanzee PSCs•Species-specific genetic dependencies converge on conserved biological processes•CDK2/CCNE1 is dispensable for human, but not chimpanzee, PSC and NPC G1/S progression•Cell-cycle alterations are derived in human compared to chimpanzee and orangutan PSCs Latent cellular and molecular differences between humans and non-human primates are uncovered through a genome-scale comparative loss-of-function approach.