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Series GSE178179 Query DataSets for GSE178179
Status Public on Aug 31, 2021
Title Discovery of synthetic lethal and tumor suppressive paralog pairs in the human genome
Organisms Homo sapiens; synthetic construct
Experiment type Other
Summary CRISPR knockout screens have accelerated the discovery of important cancer genetic dependencies. However, traditional CRISPR-Cas9 screens are limited in their ability to assay the function of redundant or duplicated genes. Paralogs in multi-gene families constitute two-thirds of the protein-coding genome, so this blind spot is the rule, not the exception. To overcome the limitations of single gene CRISPR knockout screens, we developed paired guide RNAs for Paralog gENetic interaction mapping (pgPEN), a pooled CRISPR/Cas9 approach which targets over a thousand duplicated human paralogs in single knockout and double knockout configurations. We applied pgPEN to two cell lineages and discovered that over 10% of human paralogs exhibit synthetic lethality in at least one cellular context. We recovered known synthetic lethal paralogs such as MAP2K1/MAP2K2, important drug targets such as CDK4/CDK6, and numerous other synthetic lethal pairs such as CCNL1/CCNL2. In addition, we identified ten tumor suppressive paralog pairs whose compound loss promotes cell growth. These findings identify a large number of previously unidentified essential gene families and nominate new druggable targets for oncology drug discovery.
Overall design Paired guide RNA CRISPR screen to identify genetic interactions among human duplicate gene pairs (paralogs)
Contributor(s) Parrish PC, Thomas JD, Gabel AM, Kamlapurkar S, Bradley RK, Berger AH
Citation(s) 34469736
Submission date Jun 14, 2021
Last update date Oct 27, 2021
Contact name Alice Berger
Organization name Fred Hutchinson Cancer Research Center
Street address 1100 Fairview Ave N
City Seattle
State/province WA
ZIP/Postal code 98109
Country USA
Platforms (2)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL19604 Illumina HiSeq 2500 (synthetic construct)
Samples (12)
GSM5381351 PC9_pgPEN_CRISPR_screen_plasmid
GSM5381352 PC9_pgPEN_CRISPR_screen_ETP_RepA
GSM5381353 PC9_pgPEN_CRISPR_screen_ETP_RepB
BioProject PRJNA737515
SRA SRP324035

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE178179_pgPEN_counts.txt.gz 1.3 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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