Evidence map›Paper›PMID 31668799›Full record

ArticleCell systems2020

Highly Combinatorial Genetic Interaction Analysis Reveals a Multi-Drug Transporter Influence Network.

Albi Celaj, Marinella Gebbia, Louai Musa, Atina G Cote, Jamie Snider, Victoria Wong, Minjeong Ko, Tiffany Fong, Paul Bansal, Joseph C Mellor and 9 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell systems, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
1.0field-weighted citation impact, top 24% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

15 citing papers in PubMed, 29 citations in OpenAlex.

  1. Review
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  3. Three's company: Simultaneous trimodal genome engineering using orthologous Cas proteins.Molecular therapy : the journal of the American Society of Gene Therapy · 2025
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors at 6 institutions in 4 countries.

Albi CelajDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada.
Marinella GebbiaDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Louai MusaDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Atina G CoteDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Jamie SniderDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Victoria WongDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Minjeong KoDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada.
Tiffany FongDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Paul BansalDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Joseph C MellorDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Gireesh SeesankarDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Maria NguyenDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Shijie ZhouDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Liangxi WangDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada.
Nishka KishoreDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Igor StagljarDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Mediterranean Institute for Life Sciences, Split 21 000, Croatia.
Yo SuzukiDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Nozomu YachieDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Synthetic Biology Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan; Department of Biological Sciences, School of Science, University of Tokyo, Tokyo 113-0033, Japan; Institute for Advanced Biosciences, Keio University, Yamagata 997-0035, Japan; PRESTO, Japan Science and Technology Agency, Tokyo 153-8904, Japan. Electronic address: yachie@synbiol.rcast.u-tokyo.ac.jp.
Frederick P RothDonnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: fritz.roth@utoronto.ca.
University of Toronto · CAMount Sinai Hospital · CALunenfeld-Tanenbaum Research Institute · CAHarvard University · USMediterranean Institute for Life Sciences · HRThe University of Tokyo · JP

Funding

Genomic Analysis of Network Perturbations in Human DiseaseP50HG004233 · NHGRI · DANA-FARBER CANCER INST · PI VIDAL, MARC · 2007 to 2017
$31.6M
The C. elegans Interactome ProjectR01HG001715 · NHGRI · MASSACHUSETTS GENERAL HOSPITAL · PI HILL, DAVID E., ROTH, FREDERICK P · 1998 to 2010
$16.5M
Mapping the first half of the REFERENCE human binary protein interactomeU01HG001715 · NHGRI · DANA-FARBER CANCER INST · PI HILL, DAVID E., ROTH, FREDERICK P · 2012 to 2014
$5.4M
Resource ProjectU41HG001715 · NHGRI · DANA-FARBER CANCER INST · PI HILL, DAVID E. · 2015 to 2017
$4.7M
Technology for large-scale genetic interaction discovery in S. cerevisiaeR21HG004756 · NHGRI · HARVARD MEDICAL SCHOOL · PI ROTH, FREDERICK P · 2008 to 2009
$466k
Methods for engineering S. cerevisiae strains carrying multiple precise deletionsR21CA130266 · NCI · HARVARD MEDICAL SCHOOL · PI ROTH, FREDERICK P · 2007 to 2008
$372k
CIHRNCI NIH HHS R21 CA130266NHGRI NIH HHS P50 HG004233NHGRI NIH HHS R01 HG001715NHGRI NIH HHS R21 HG004756NHGRI NIH HHS U01 HG001715NHGRI NIH HHS U41 HG001715
6 · The paper itself

Abstract

Many traits are complex, depending non-additively on variant combinations. Even in model systems, such as the yeast S. cerevisiae, carrying out the high-order variant-combination testing needed to dissect complex traits remains a daunting challenge. Here, we describe "X-gene" genetic analysis (XGA), a strategy for engineering and profiling highly combinatorial gene perturbations. We demonstrate XGA on yeast ABC transporters by engineering 5,353 strains, each deleted for a random subset of 16 transporters, and profiling each strain's resistance to 16 compounds. XGA yielded 85,648 genotype-to-resistance observations, revealing high-order genetic interactions for 13 of the 16 transporters studied. Neural networks yielded intuitive functional models and guided exploration of fluconazole resistance, which was influenced non-additively by five genes. Together, our results showed that highly combinatorial genetic perturbation can functionally dissect complex traits, supporting pursuit of analogous strategies in human cells and other model systems.

Indexed as

Biological TransportHumansMembrane Transport ProteinsMembrane Transport ProteinsABC transporterscombinatorial genetic analysisdrug effluxdrug resistanceepistasisgenetic modelinggenotype-to-phenotype modelinghigh-order genetic interactionsinterpretable neural networkvisible neural network

Identifiers

PMID31668799
PMCPMC6989212
OpenAlexW2981570282

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.