Adli Mazhar, Przybyla Laralynne, Burdett Tony, Burridge Paul W, Cacheiro Pilar, Chang Howard Y, Engreitz Jesse M, Gilbert Luke A, Greenleaf William J, Hsu Li, Huangfu Danwei, Hung Ling-Hong, Kundaje Anshul, Li Sheng, Parkinson Helen, Qiu Xiaojie, Robson Paul, Schürer Stephan C, Shojaie Ali, Skarnes William C, Smedley Damian, Studer Lorenz, Sun Wei, Vidović Dušica, Vierbuchen Thomas, White Brian S, Yeung Ka Yee, Yue Feng, Zhou Ting
Robert H. Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
Nature. 2025 Feb;638(8050):351-359. doi: 10.1038/s41586-024-08243-w. Epub 2025 Feb 12.
Recent advances in functional genomics and human cellular models have substantially enhanced our understanding of the structure and regulation of the human genome. However, our grasp of the molecular functions of human genes remains incomplete and biased towards specific gene classes. The Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Consortium aims to address this gap by creating a comprehensive catalogue of the molecular and cellular phenotypes associated with null alleles of all human genes using in vitro multicellular systems. In this Perspective, we present the strategic vision of the MorPhiC Consortium and discuss various strategies for generating null alleles, as well as the challenges involved. We describe the cellular models and scalable phenotypic readouts that will be used in the consortium's initial phase, focusing on 1,000 protein-coding genes. The resulting molecular and cellular data will be compiled into a catalogue of null-allele phenotypes. The methodologies developed in this phase will establish best practices for extending these approaches to all human protein-coding genes. The resources generated-including engineered cell lines, plasmids, phenotypic data, genomic information and computational tools-will be made available to the broader research community to facilitate deeper insights into human gene functions.
功能基因组学和人类细胞模型的最新进展极大地增进了我们对人类基因组结构和调控的理解。然而，我们对人类基因分子功能的掌握仍然不完整，且偏向于特定的基因类别。细胞中无效等位基因的分子表型（MorPhiC）联盟旨在通过使用体外多细胞系统创建一个与所有人类基因的无效等位基因相关的分子和细胞表型的综合目录来填补这一空白。在这篇观点文章中，我们阐述了MorPhiC联盟的战略愿景，并讨论了产生无效等位基因的各种策略以及其中涉及的挑战。我们描述了将在联盟初始阶段使用的细胞模型和可扩展的表型读数，重点关注1000个蛋白质编码基因。由此产生的分子和细胞数据将被汇编成一个无效等位基因表型目录。这一阶段开发的方法将为将这些方法扩展到所有人类蛋白质编码基因建立最佳实践。所产生的资源——包括工程细胞系、质粒、表型数据、基因组信息和计算工具——将提供给更广泛的研究群体，以促进对人类基因功能的更深入了解。
