A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles

Aravind Subramanian; Rajiv Narayan; Steven M Corsello; David D Peck; Ted E Natoli; Xiaodong Lu; Joshua Gould; John F Davis; Andrew A Tubelli; Jacob K Asiedu; David L Lahr; Jodi E Hirschman; Zihan Liu; Melanie Donahue; Bina Julian; Mariya Khan; David Wadden; Ian C Smith; Daniel Lam; Arthur Liberzon; Courtney Toder; Mukta Bagul; Marek Orzechowski; Oana M Enache; Federica Piccioni; Sarah A Johnson; Nicholas J Lyons; Alice H Berger; Alykhan F Shamji; Angela N Brooks; Anita Vrcic; Corey Flynn; Jacqueline Rosains; David Y Takeda; Roger Hu; Desiree Davison; Justin Lamb; Kristin Ardlie; Larson Hogstrom; Peyton Greenside; Nathanael S Gray; Paul A Clemons; Serena Silver; Xiaoyun Wu; Wen-Ning Zhao; Willis Read-Button; Xiaohua Wu; Stephen J Haggarty; Lucienne V Ronco; Jesse S Boehm; Stuart L Schreiber; John G Doench; Joshua A Bittker; David E Root; Bang Wong; Todd R Golub

doi:10.1016/j.cell.2017.10.049

A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles

Cell. 2017 Nov 30;171(6):1437-1452.e17. doi: 10.1016/j.cell.2017.10.049.

Authors

Aravind Subramanian¹, Rajiv Narayan¹, Steven M Corsello², David D Peck¹, Ted E Natoli¹, Xiaodong Lu¹, Joshua Gould¹, John F Davis¹, Andrew A Tubelli¹, Jacob K Asiedu¹, David L Lahr¹, Jodi E Hirschman¹, Zihan Liu¹, Melanie Donahue¹, Bina Julian¹, Mariya Khan¹, David Wadden¹, Ian C Smith¹, Daniel Lam¹, Arthur Liberzon¹, Courtney Toder¹, Mukta Bagul¹, Marek Orzechowski¹, Oana M Enache¹, Federica Piccioni¹, Sarah A Johnson¹, Nicholas J Lyons¹, Alice H Berger², Alykhan F Shamji¹, Angela N Brooks², Anita Vrcic¹, Corey Flynn¹, Jacqueline Rosains¹, David Y Takeda², Roger Hu¹, Desiree Davison¹, Justin Lamb¹, Kristin Ardlie¹, Larson Hogstrom¹, Peyton Greenside¹, Nathanael S Gray³, Paul A Clemons¹, Serena Silver¹, Xiaoyun Wu¹, Wen-Ning Zhao⁴, Willis Read-Button¹, Xiaohua Wu¹, Stephen J Haggarty⁴, Lucienne V Ronco¹, Jesse S Boehm¹, Stuart L Schreiber⁵, John G Doench¹, Joshua A Bittker¹, David E Root¹, Bang Wong¹, Todd R Golub⁶

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: golub@broadinstitute.org.

Abstract

We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.

Keywords: Functional genomics; chemical biology; gene expression profiling.

MeSH terms

Cell Line, Tumor
Drug Resistance, Neoplasm
Gene Expression Profiling / economics
Gene Expression Profiling / methods*
Humans
Neoplasms / drug therapy
Organ Specificity
Pharmaceutical Preparations / metabolism
Sequence Analysis, RNA / economics
Sequence Analysis, RNA / methods
Small Molecule Libraries

Substances

Pharmaceutical Preparations
Small Molecule Libraries

Abstract

MeSH terms

Substances

Grants and funding