Garvan Weizmann Center for Cellular Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Graduate School of Biomedical Engineering, University of New South Wales, Sydney, New South Wales, Australia.
Nat Genet. 2024 May;56(5):758-766. doi: 10.1038/s41588-024-01731-9. Epub 2024 May 13.
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.
人多能干细胞（hPS）理论上可以分化为任何细胞类型，使其成为人类生物学的强大体外模型。最近的技术进步促进了大规模的 hPS 细胞研究，允许研究分子表型的遗传调控及其对高级表型（如人类疾病）的贡献。将 hPS 细胞与单细胞测序相结合，可以识别细胞发育过程中或实验操作时的上下文相关遗传效应。在这里，我们讨论了干细胞生物学、群体遗传学和细胞基因组学的交叉如何有助于解决人类遗传变异的功能后果。我们研究了整合这些领域和方法的关键挑战，以使其具有成本效益和实际可行性。我们强调了两个特别受益于人群规模 hPS 细胞研究的人类生物学领域，阐明了复杂疾病风险位点背后的机制，并评估了常见遗传变异与药物治疗表型之间的关系。
