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Integrating population genetics, stem cell biology and cellular genomics to study complex human diseases

Nature Genetics volume 56, pages 758–766 (2024)Cite this article

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Abstract

Human pluripotent stem (hPS) cells can, in theory, be differentiated into any cell type, making them a powerful in vitro model for human biology. Recent technological advances have facilitated large-scale hPS cell studies that allow investigation of the genetic regulation of molecular phenotypes and their contribution to high-order phenotypes such as human disease. Integrating hPS cells with single-cell sequencing makes identifying context-dependent genetic effects during cell development or upon experimental manipulation possible. Here we discuss how the intersection of stem cell biology, population genetics and cellular genomics can help resolve the functional consequences of human genetic variation. We examine the critical challenges of integrating these fields and approaches to scaling them cost-effectively and practically. We highlight two areas of human biology that can particularly benefit from population-scale hPS cell studies, elucidating mechanisms underlying complex disease risk loci and evaluating relationships between common genetic variation and pharmacotherapeutic phenotypes.

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Fig. 1: Schematic overview of population genetics studies of hPS cells to study complex human diseases.
Fig. 2: Experimental design of hPS cell line pools.

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Acknowledgements

Figures were generated with BioRender.com and further developed by A. Garcia, a scientific illustrator from Bio-Graphics. This research was supported by a National Health and Medical Research Council (NHMRC) Investigator grant (J.E.P., 1175781), research grants from the Australian Research Council (ARC) Special Research Initiative in Stem Cell Science, an ARC Discovery Project (190100825), an EMBO Postdoctoral Fellowship (A.S.E.C.) and an Aligning Science Across Parkinson’s Grant (J.E.P., N.F., D.R.N. and L.S.). J.E.P. is supported by a Fok Family Fellowship.

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Author notes

  1. These authors contributed equally: Nona Farbehi, Drew R. Neavin.

Authors and Affiliations

  1. Garvan Weizmann Center for Cellular Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    Nona Farbehi, Drew R. Neavin, Anna S. E. Cuomo & Joseph E. Powell

  2. Graduate School of Biomedical Engineering, University of New South Wales, Sydney, New South Wales, Australia

    Nona Farbehi

  3. Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD, USA

    Nona Farbehi, Lorenz Studer & Joseph E. Powell

  4. Centre for Population Genomics, Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia

    Anna S. E. Cuomo & Daniel G. MacArthur

  5. The Center for Stem Cell Biology and Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA

    Lorenz Studer

  6. Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

    Daniel G. MacArthur

  7. UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, New South Wales, Australia

    Joseph E. Powell

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All authors conceived the topic and wrote and revised the manuscript.

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Correspondence to Joseph E. Powell.

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Competing interests

D.G.M. is a founder with equity in Goldfinch Bio, is a paid advisor to GSK, Insitro, Third Rock Ventures and Foresite Labs, and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Merck, Pfizer and Sanofi-Genzyme; none of these activities is related to the work presented here. J.E.P. is a founder with equity in Celltellus Laboratory and has received research support from Illumina. The other authors declare no conflict of interest.

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Farbehi, N., Neavin, D.R., Cuomo, A.S.E. et al. Integrating population genetics, stem cell biology and cellular genomics to study complex human diseases. Nat Genet 56, 758–766 (2024). https://doi.org/10.1038/s41588-024-01731-9

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