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Genome Biol. 2020 Jan 24;21(1):19. doi: 10.1186/s13059-020-1928-4.

scMAGeCK links genotypes with multiple phenotypes in single-cell CRISPR screens.

Yang L1,2,3, Zhu Y4,5,6, Yu H4,5, Cheng X1,2, Chen S1,2,3, Chu Y4,5, Huang H4,5, Zhang J7,8, Li W9,10.

Author information

1
Center for Genetic Medicine Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA.
2
Department of Genomics and Precision Medicine, George Washington University, 111 Michigan Ave NW, Washington, DC, 20010, USA.
3
Department of Biochemistry & Molecular Medicine, George Washington University, 2300 Eye St., NW, Washington, DC, 20037, USA.
4
Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.
5
Institute of Hematology, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
6
Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, 314400, Zhejiang, China.
7
Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China. zhgene@zju.edu.cn.
8
Institute of Hematology, Zhejiang University, Hangzhou, 310058, Zhejiang, China. zhgene@zju.edu.cn.
9
Center for Genetic Medicine Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA. wli2@childrensnational.org.
10
Department of Genomics and Precision Medicine, George Washington University, 111 Michigan Ave NW, Washington, DC, 20010, USA. wli2@childrensnational.org.

Abstract

We present scMAGeCK, a computational framework to identify genomic elements associated with multiple expression-based phenotypes in CRISPR/Cas9 functional screening that uses single-cell RNA-seq as readout. scMAGeCK outperforms existing methods, identifies genes and enhancers with known and novel functions in cell proliferation, and enables an unbiased construction of genotype-phenotype network. Single-cell CRISPR screening on mouse embryonic stem cells identifies key genes associated with different pluripotency states. Applying scMAGeCK on multiple datasets, we identify key factors that improve the power of single-cell CRISPR screening. Collectively, scMAGeCK is a novel tool to study genotype-phenotype relationships at a single-cell level.

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