Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.
We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies.
Department of Medicine, Division of Genetics, University of California, San Diego, La Jolla, California, USA.|Moores UCSD Cancer Center, La Jolla, California, USA.|The Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California, USA.
John Paul
http://orcid.org/0000-0003-4588-2775
JP
Shen
The Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California, USA.|Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.
Dongxin
D
Zhao
Center for Computational Biology &Bioinformatics, University of California, San Diego, La Jolla, California, USA.
Roman
R
Sasik
Bioinformatics &Systems Biology Program, University of California, San Diego, La Jolla, California, USA.
Jens
J
Luebeck
Center for Computational Biology &Bioinformatics, University of California, San Diego, La Jolla, California, USA.
Amanda
A
Birmingham
Department of Medicine, Division of Genetics, University of California, San Diego, La Jolla, California, USA.
Ana
A
Bojorquez-Gomez
Department of Medicine, Division of Genetics, University of California, San Diego, La Jolla, California, USA.
Katherine
K
Licon
Department of Medicine, Division of Genetics, University of California, San Diego, La Jolla, California, USA.
Kristin
K
Klepper
Department of Medicine, Division of Genetics, University of California, San Diego, La Jolla, California, USA.
Daniel
D
Pekin
Department of Medicine, Division of Genetics, University of California, San Diego, La Jolla, California, USA.
Alex N
AN
Beckett
Department of Medicine, Division of Genetics, University of California, San Diego, La Jolla, California, USA.
Kyle Salinas
KS
Sanchez
Bioinformatics &Systems Biology Program, University of California, San Diego, La Jolla, California, USA.|Novo Nordisk Center for Biosustainability at the University of California, San Diego, La Jolla, California, USA.
Alex
A
Thomas
Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.|Novo Nordisk Center for Biosustainability at the University of California, San Diego, La Jolla, California, USA.
Chih-Chung
CC
Kuo
The Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California, USA.|Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA.
Dan
http://orcid.org/0000-0002-3470-2890
D
Du
The Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California, USA.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
Assen
A
Roguev
Novo Nordisk Center for Biosustainability at the University of California, San Diego, La Jolla, California, USA.|Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
Nathan E
NE
Lewis
Center for Computational Biology &Bioinformatics, University of California, San Diego, La Jolla, California, USA.
Aaron N
AN
Chang
Department of Medicine, Division of Genetics, University of California, San Diego, La Jolla, California, USA.|The Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California, USA.
Jason F
JF
Kreisberg
The Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California, USA.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
Nevan
N
Krogan
The Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California, USA.|Department of Bioengineering, Stanford University, Stanford, California, USA.
Lei
http://orcid.org/0000-0002-3965-3223
L
Qi
Department of Medicine, Division of Genetics, University of California, San Diego, La Jolla, California, USA.|Moores UCSD Cancer Center, La Jolla, California, USA.|The Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California, USA.|Center for Computational Biology &Bioinformatics, University of California, San Diego, La Jolla, California, USA.
Trey
T
Ideker
Moores UCSD Cancer Center, La Jolla, California, USA.|The Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California, USA.|Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.
Prashant
P
Mali
D000072283:A549 Cells; D045744:Cell Line, Tumor; D002874:Chromosome Mapping / Q000379:methods*; D064112:Clustered Regularly Interspaced Short Palindromic Repeats / Q000235:genetics*; D020650:Combinatorial Chemistry Techniques; D004843:Epistasis, Genetic / Q000235:genetics*; D006367:HeLa Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*
D009363:Neoplasm Proteins