Santinha Antonio J, Strano Alessio, Platt Randall J
Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
Department of Chemistry, University of Basel, Basel, Switzerland.
Nat Rev Genet. 2025 Jul 29. doi: 10.1038/s41576-025-00873-8.
A fundamental goal in genetics is to understand the connection between genotype and phenotype in health and disease. Genetic screens in which dozens to thousands of genetic elements are perturbed in a pooled fashion offer the opportunity to generate large-scale, information-rich and unbiased genotype-phenotype maps. Although typically applied in reductionist in vitro settings, methods enabling pooled CRISPR-Cas perturbation screening in vivo are gaining attention as they have the potential to accelerate the discovery and annotation of gene function across cells, tissues, developmental stages, disease states and species. In this Review, we discuss essential criteria for understanding, designing and implementing in vivo screening experiments, with a focus on pooled CRISPR-based screens in mice. We also highlight how the resulting datasets, combined with advances in multi-omics and artificial intelligence, will accelerate progress and enable fundamental discoveries across basic and translational sciences.
遗传学的一个基本目标是了解健康和疾病状态下基因型与表型之间的联系。通过集中方式对数十至数千个遗传元件进行扰动的遗传筛选，为生成大规模、信息丰富且无偏差的基因型-表型图谱提供了机会。尽管这些方法通常应用于简化的体外实验环境，但能够在体内进行集中式CRISPR-Cas扰动筛选的方法正受到关注，因为它们有潜力加速跨细胞、组织、发育阶段、疾病状态和物种的基因功能发现与注释。在本综述中，我们讨论了理解、设计和实施体内筛选实验的基本标准，重点是基于CRISPR的小鼠集中式筛选。我们还强调了由此产生的数据集，结合多组学和人工智能的进展，将如何加速基础科学和转化科学的进步并实现重大发现。
