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bioRxiv · 10.1101/2023.03.19.533346

Comparative landscape of genetic dependencies in human and chimpanzee stem cells

She, R.·Fair, T.·Schaefer, N. K.·Saunders, R. A.·Pavlovic, B. J.·Weissman, J. S.·Pollen, A. A.
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Abstract

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 changes in human cells alter requirements for essential genes. 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, providing support for the G1-phase length hypothesis as a potential evolutionary mechanism in human brain expansion. Our findings demonstrate that evolutionary changes in human cells can reshape the landscape of essential genes and establish a platform for systematically uncovering latent cellular and molecular differences between species.

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She, R., Fair, T., Schaefer, N. K., Saunders, R. A., Pavlovic, B. J., Weissman, J. S., Pollen, A. A.. 2023-03-20. Comparative landscape of genetic dependencies in human and chimpanzee stem cells. https://doi.org/10.1101/2023.03.19.533346

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