Mapping the Genetic Landscape of Human Cells.

TitleMapping the Genetic Landscape of Human Cells.
Publication TypeJournal Article
Year of Publication2018
AuthorsHorlbeck, MA, Xu, A, Wang, M, Bennett, NK, Park, CY, Bogdanoff, D, Adamson, B, Chow, ED, Kampmann, M, Peterson, TR, Nakamura, K, Fischbach, MA, Weissman, JS, Gilbert, LA
JournalCell
Volume174
Issue4
Pagination953-967.e22
Date Published2018 08 09
ISSN1097-4172
KeywordsBiomarkers, Cholesterol, Clustered Regularly Interspaced Short Palindromic Repeats, Epistasis, Genetic, Gene Regulatory Networks, High-Throughput Nucleotide Sequencing, Humans, Jurkat Cells, K562 Cells, Protein Interaction Mapping
Abstract

<p>Seminal yeast studies have established the value of comprehensively mapping genetic interactions (GIs) for inferring gene function. Efforts in human cells using focused gene sets underscore the utility of this approach, but the feasibility of generating large-scale, diverse human GI maps remains unresolved. We developed a CRISPR interference platform for large-scale quantitative mapping of human GIs. We systematically perturbed 222,784 gene pairs in two cancer cell lines. The resultant maps cluster functionally related genes, assigning function to poorly characterized genes, including TMEM261, a new electron transport chain component. Individual GIs pinpoint unexpected relationships between pathways, exemplified by a specific cholesterol biosynthesis intermediate whose accumulation induces deoxynucleotide depletion, causing replicative DNA damage and a synthetic-lethal interaction with the ATR/9-1-1 DNA repair pathway. Our map provides a broad resource, establishes GI maps as a high-resolution tool for dissecting gene function, and serves as a blueprint for mapping the genetic landscape of human cells.</p>

DOI10.1016/j.cell.2018.06.010
Alternate JournalCell
PubMed ID30033366
PubMed Central IDPMC6426455
Grant ListU01 CA217882 / CA / NCI NIH HHS / United States
R00 CA204602 / CA / NCI NIH HHS / United States
T32 GM007618 / GM / NIGMS NIH HHS / United States
DP1 DK113598 / DK / NIDDK NIH HHS / United States
R01 AR073017 / AR / NIAMS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
DP2 GM119139 / GM / NIGMS NIH HHS / United States
P30 AR057235 / AR / NIAMS NIH HHS / United States
R00 AG047255 / AG / NIA NIH HHS / United States
K99 AG047255 / AG / NIA NIH HHS / United States
U01 CA168370 / CA / NCI NIH HHS / United States
K99 CA181494 / CA / NCI NIH HHS / United States
R00 CA181494 / CA / NCI NIH HHS / United States
R01 AG062359 / AG / NIA NIH HHS / United States
K99 CA204602 / CA / NCI NIH HHS / United States
R01 NS091902 / NS / NINDS NIH HHS / United States
P50 GM102706 / GM / NIGMS NIH HHS / United States
R01 DA036858 / DA / NIDA NIH HHS / United States