Identification and characterization of essential genes in the human genome.

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Abstract

Large-scale genetic analysis of lethal phenotypes has elucidated the molecular underpinnings of many biological processes. Using the bacterial clustered regularly interspaced short palindromic repeats (CRISPR) system, we constructed a genome-wide single-guide RNA library to screen for genes required for proliferation and survival in a human cancer cell line. Our screen revealed the set of cell-essential genes, which was validated with an orthogonal gene-trap-based screen and comparison with yeast gene knockouts. This set is enriched for genes that encode components of fundamental pathways, are expressed at high levels, and contain few inactivating polymorphisms in the human population. We also uncovered a large group of uncharacterized genes involved in RNA processing, a number of whose products localize to the nucleolus. Last, screens in additional cell lines showed a high degree of overlap in gene essentiality but also revealed differences specific to each cell line and cancer type that reflect the developmental origin, oncogenic drivers, paralogous gene expression pattern, and chromosomal structure of each line. These results demonstrate the power of CRISPR-based screens and suggest a general strategy for identifying liabilities in cancer cells.

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Journal

Journal ID (iso-abbrev): Science

Title: Science (New York, N.Y.)

ISSN (Electronic): 1095-9203

ISSN (Print): 0036-8075

Publication date (Electronic): Nov 27 2015

Volume: 350

Issue: 6264

Affiliations

[1 ] Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.

[2 ] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.

[3 ] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.

[4 ] Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.

[5 ] Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139, USA. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. lander@broadinstitute.org sabatini@wi.mit.edu.

[6 ] Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. lander@broadinstitute.org sabatini@wi.mit.edu.

Article

Publisher Item ID: science.aac7041 Mid ID: NIHMS732683

DOI: 10.1126/science.aac7041

PubMed ID: 26472758

SO-VID: acac1004-649e-4d27-b2fd-f19dd2ed4cb6

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