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Deciphering Human Gene Function Through the Comprehensive Characterization of Null Alleles

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Deciphering Human Gene Function Through the Comprehensive Characterization of Null Alleles
BiotechnologyMedicineHUMAN GENOME

The MorPhiC Consortium embarks on a groundbreaking project to map the molecular and cellular phenotypes associated with null alleles of all human genes. This Perspective outlines the consortium's strategic vision, methodologies, and the anticipated impact of its resource for advancing our understanding of human gene functions.

Recent advances in functional genomics and human cellular models have significantly 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.

To address this gap, the Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Consortium aims to create a comprehensive catalogue of the molecular and cellular phenotypes associated with null alleles of all human genes using in vitro multicellular systems. This Perspective presents the strategic vision of the MorPhiC Consortium and discusses various strategies for generating null alleles, along with 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. Large-scale screening efforts have mapped cancer dependencies using genome-scale screens across hundreds of cell lines, enabling the identification of new putative therapeutic targets and genetic similarities across cancer subtypes. The development and demonstration of the CRISPRoff strategy as a programmable epigenetic memory writer that is heritable, reversible, and compatible with genome-wide screening have significantly advanced our understanding of gene function. Furthermore, the creation of human pluripotent stem cell-derived models, such as microglia and cardiomyocytes, has provided powerful tools for studying human development and disease

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Nature /  🏆 64. in US

Biotechnology Medicine HUMAN GENOME NULL ALLELES MORPHIC CONSORTIUM CELLULAR PHENOTYPES CRISPR STEM CELL MODELS

 

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