Comparative landscape of genetic dependencies in human and chimpanzee stem cells

Richard She; Tyler Fair; Nathan K Schaefer; Reuben A Saunders; Bryan J Pavlovic; Jonathan S Weissman; Alex A Pollen

doi:10.1016/j.cell.2023.05.043

Comparative landscape of genetic dependencies in human and chimpanzee stem cells

Cell. 2023 Jul 6;186(14):2977-2994.e23. doi: 10.1016/j.cell.2023.05.043. Epub 2023 Jun 20.

Authors

Richard She¹, Tyler Fair², Nathan K Schaefer³, Reuben A Saunders⁴, Bryan J Pavlovic³, Jonathan S Weissman⁵, Alex A Pollen⁶

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
² Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
³ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁴ Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA, USA.
⁵ Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute Technology, Cambridge, MA 02142, USA. Electronic address: weissman@wi.mit.edu.
⁶ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: alex.pollen@ucsf.edu.

PMID: 37343560
PMCID: PMC10461406 (available on 2024-07-06)
DOI: 10.1016/j.cell.2023.05.043

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 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.

Keywords: CRISPR screening; G1-phase length hypothesis; cellular anthropology; genetic dependencies; human-specific evolution; neural progenitor cells; pluripotent stem cells.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Hominidae*
Humans
Neural Stem Cells*
Pan troglodytes / genetics
Pluripotent Stem Cells*
Stem Cells*

Abstract

Publication types

MeSH terms

Grants and funding