D998–D1003 Nucleic Acids Research, 2021, Vol.

49, Database issue Published online 21 October 2020

doi: 10.1093/nar/gkaa884

OGEE v3: Online GEne Essentiality database with

increased coverage of organisms and human cell lines
Sanathoi Gurumayum1,† , Puzi Jiang1,† , Xiaowen Hao1 , Tulio L. Campos 2,3 , Neil D. Young2 ,
Pasi K. Korhonen2 , Robin B. Gasser 2 , Peer Bork4,5,6,7 , Xing-Ming Zhao 8,9,* , Li-jie He10,*
and Wei-Hua Chen 1,11,*
1
Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and
Molecular-imaging, Center for Artificial Biology, Department of Bioinformatics and Systems Biology, College of Life
Science and Technology, Huazhong University of Science and Technology (HUST), 430074 Wuhan, Hubei, China,

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2
Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville,
Victoria 3010, Australia, 3 Instituto Aggeu Magalhães, Fundação Oswaldo Cruz (IAM-Fiocruz), Recife, Pernambuco,
Brazil, 4 European molecular biology laboratory (EMBL), Meyerhof Strasse 1, 69117 Heidelberg, Germany,
5
Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120
Heidelberg, Germany, 6 Max-Delbrück-Centre for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin,
Germany, 7 Department of Bioinformatics, Biocenter, University of Würzburg, 97074 Würzburg, Germany, 8 Institute of
Science and Technology for Brain-Inspired Intelligence, Fudan University, 200433 Shanghai, China, 9 Key Laboratory
of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education, China, 10 Department of
Medical Oncology, People’s Hospital of Liaoning Province, 110016 Shenyang, China and 11 College of Life Science,
Henan Normal University, 453007 Xinxiang, Henan, China

Received September 11, 2020; Revised September 24, 2020; Editorial Decision September 25, 2020; Accepted September 28, 2020

ABSTRACT techniques. We also included factors known to con-

tribute to gene essentiality for these cell lines, such
OGEE is an Online GEne Essentiality database. Gene
as genomic mutation, methylation and gene expres-
essentiality is not a static and binary property, rather
sion, along with extensive graphical visualizations
a context-dependent and evolvable property in all
for ease of understanding of these factors. OGEE v3
forms of life. In OGEE we collect not only experimen-
can be accessible freely at https://v3.ogee.info.
tally tested essential and non-essential genes, but
also associated gene properties that contributes to
gene essentiality. We tagged conditionally essential INTRODUCTION
genes that show variable essentiality statuses across
Gene essentiality is a core concept of genetics, and has im-
datasets to highlight complex interplays between
portant relevance in relation to fundamental areas such
gene functions and environmental/experimental per- as evolutionary, and systems and synthetic biology, and
turbations. OGEE v3 contains gene essentiality applicability in drug development. Essential genes (EGs)
datasets for 91 species; almost doubled from 48 are often responsible for important biological processes
species in previous version. To accommodate re- and cellular fitness in an organism, and are critical for its
cent advances on human cancer essential genes (as survival. EGs are of particular importance in mechanis-
known as tumor dependency genes) that could serve tic biological studies and therapeutic applications, such as
as targets for cancer treatment and/or drug devel- studying behavior of a biological system under perturba-
opment, we expanded the collection of human es- tion (1), studying sequential gene deletions to define a min-
sential genes from 16 cell lines in previous to 581. imal genome/organism (2,3) and identifying or prioritiz-
These human cancer cell lines were tested with high- ing of therapeutic targets in pathogens (4–6) and human
cancers (7–11). EGs complements have been identified in
throughput experiments such as CRISPR-Cas9 and
well-characterized small model organisms such as Saccha-
RNAi; in total, 150 of which were tested by both romyces cerevisiae and Caenorhabditis elegans (12,13) and

* To
whom correspondence should be address. Tel: +86 158 2735 4263, Fax: +86 27 8779 2072; Email: [email protected]
Correspondence may also be addressed to Li-Jie He. Email: [email protected]
Correspondence may also be addressed to Xing-Ming Zhao. Email: [email protected]
†
The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors.

C The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work
is properly cited. For commercial re-use, please contact [email protected]
 Nucleic Acids Research, 2021, Vol. 49, Database issue D999

some large and complex organisms, such as human (14), us- the same cell line, thus the combined data from two distinct
ing various technologies. methods could offer more robust results and coverage over
The essentiality of a gene is highly dependent on various human essential genes, as a previous study suggested (34).
factors including the genetic context, genetic background In summary, the current version (v3) of OGEE include 16
of the host and environment (15). Hence, gene essential- datasets from 16 non-human eukaryotes and 111 datasets
ity is not a static, but rather a context-dependent property from 75 prokaryotes. Of the 213,608 collected genes, 31,177
of a gene. Since version 1, OGEE has been promoting the were tested in multiple datasets, accounting up to 14.6%
context-dependent concept and its importance for under- of all collected genes. Of the tested genes from multiple
standing on gene essentiality (16). In our last update (17), datasets, 15 440 genes were conditionally essential genes
we focused on the importance of ‘conditionally essential (CEGs) or context-dependent, representing around 49.52%
genes’ (CEGs) or ‘differentially essential genes’ (DEGs) in of genes covered by multiple datasets. In addition, OGEE
cancer cell lines. The current update provides: (a) an in- v3 also includes experimental essentiality results for 581 hu-
creased coverage of essentiality tested genes and species, man cancer cell lines.
(b) up-to-date essentiality status of existing genes, (c) an in-

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creased coverage of human cell lines, (d) an extensive graph-
ical visualization for various factors that influence gene es- Collection of known factors influencing gene essentiality
sentiality and (e) a dedicated domain with secure HTTPS The essentiality of a gene at any given time point depends
protocol, https://v3.ogee.info. on various factors. In OGEE v3, we included several fac-
tors known to influence gene essentiality, including paralogs
DATA GENERATION and orthologs or duplication status (35), functional anno-
Collection and organization of essentiality datasets tation of a gene (36), connectivity of protein-protein inter-
action (PPI) network (37) and early expression during em-
To find large-scale gene essentiality experiments, we exam- bryonic development. OrthoFinder (38) was used to iden-
ined publications from the NCBI PubMed database (18) tify paralogs and orthologs for all species included here. The
identified using the key words ‘essential genes’, ‘gene es- PPI data were downloaded from latest version of STRING
sentiality’, ‘tumor dependency genes’, ‘cancer vulnerable v11.0 database (39); interactions with score ≥900 were used
genes’, and then downloaded all classified essential or non- to compute the connectivity score for all the genes. As de-
essential genes. For model organisms such as Drosophila scribed in previous studies (40,41), the EGs had more in-
melanogaster, Caenorhabditis elegans, Saccharomyces cere- teraction partners at the protein level. Protein sequences
visiae and Arabidopsis thaliana, we also obtained their were obtained from NCBI protein database (18), while their
tested genes from online public databases (19–30). The full functional annotations were obtained from the Gene Ontol-
list of reference databases and publication records are pro- ogy (GO) database (42). For more information, please refer
vided in Supplementary Table S1. The tested results (i.e. the ‘Help’ page of the OGEE database.
essential and non-essential statuses) were organized into For human cell lines, factors known to influence gene es-
datasets, according to their experimental conditions. In to- sentiality included mutation, methylation and gene expres-
tal, we collected 127 datasets for 91 non-human species, sion (43); in fact, factors including these have been used to
containing 213 608 tested genes. This collection represents predict gene essentiality in human (43,44). Thus, for each
a significant increase from our previous version, OGEE cell line, we collected data on gene mutations from cosmic
v2 (17), which contained 99 datasets from 48 non-human (45), on methylation data from NCBI GEO database (18)
species, with in total 167 799 tested genes. and/or on gene expression data from the CCLE database
(46).
Essentiality datasets from human cancer cell lines
Tumor essential genes, also known as tumor dependency Built-in tools for analysis
genes, are potential targets for treatment and/or drug de-
velopment (31,32). During the last decade, cancer cell lines OGEE v3 also has integrated tools to analyze the impact
have been used extensively for tumor essential gene identi- of gene properties on the page ‘Analyze’. The available op-
fication (32,33). We included results for 16 human cell lines tions include developmental vs. non-developmental and du-
in our last version. In OGEE v3, we expanded this collec- plicates vs. singlets, calculated in terms of proportion of es-
tion to include a total of 581 cell lines which were tested by sentiality (PE ). For more detail on built-in tools, please refer
genome-wide CRISPR-Cas9 and RNAi screening. The 581 to our previous publication (17).
cell lines were related to 25 different tissues based on their
histological origins, as shown in Figure 1A.
EXTENSIVE ANNOTATIONS OF HUMAN ESSENTIAL
In total, 150 cell lines were tested by both RNAi- and
GENES
CRISPR-Cas9-based methods (Supplementary Table S2).
As shown in Figure 1B, the CRISPR-Cas9-based method The identification and characterization of human EGs pro-
identified more essential genes than RNAi in most cell lines, vides a better understanding of human diversity, has prac-
likely because of higher efficiency of CRISPR-Cas9 in gene tical medical applications for disease genetics and clinical
knockdown/out. Essential genes identified by RNAi are of- interpretation of disease-associated genetic variants; EGs
ten not a subset of those identified by CRISPR–Cas9 in are associated with the core developmental, metabolic and
D1000 Nucleic Acids Research, 2021, Vol. 49, Database issue

A B

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Figure 1. Statistics on 581 human cell lines collected in OGEE v3. (A) The 581 cell lines were related to 25 different tissues by their histological origins. (B)
CRISPR-based method often identified more essential genes than RNAi-based method. Each point indicates a cell line, and the x-axis and y-axis mean
the number of identified essential genes of the cell line in CRISPR–Cas9 and RNAi datasets respectively. The colors (blue, green, red, yellow) illustrate the
number of overlapping essential genes between CRISPR–Cas9 and RNAi data. The red line denotes the fitted regression line between numbers of essential
genes in RNAi and CRISPR-Cas9 data. In total 150 cell lines were tested by both techniques.

signaling pathways; and they are less likely to be tolerate To better appraise the pattern of essentiality across hu-
missense variation, and more prone to pathogenicity (41). man cell lines and identify potentially meaningful biological
While effort has been put into identifying targets for can- relationships between genes (47), we selected data of those
cer therapeutics, several research groups (32,33) have iden- tissues with at least ten cell lines from a conditioned ex-
tified cancer dependencies genes and lineage-specific EGs in periment, and assessed gene-gene essentiality relationships
human cell lines using RNAi screening or CRISPR–Cas9 among individual tissues by Spearman and Pearson corre-
technology. Since both RNAi and CRISPR are promising lation. Raw fitness scores instead of binary essentiality as-
complementary methods for identifying EGs, we annotated signments (i.e. essential or non-essential genes) were used
human EGs extensively by considering both of these tech- for such calculations. After filtering the genes with essen-
niques as well as factors influencing gene essentiality. tiality in at least 50% cell lines of a specific tissue, we then
As shown in Figure 1A, the 581 human cell lines collected selected gene pairs with significant correlation results (P-
in OGEE v3 were assigned into 25 groups according to their value < 0.001). The results of this analysis are available via
tissue of origin. The largest number of cell lines were for ‘Correlation co-essentiality’ in OGEE v3 for each human
lung (n = 123), followed by central nervous system (n = 59), gene tested that met the cut-off (see Figure 2B for an exam-
haematopoietic and lymphoid tissue (n = 53), ovary (n = 40) ple).
and breast (n = 38).
We selected the RKO cell line set to exemplify the anno-
Orthology and comparisons with mouse essential genes
tation of essential gene in OGEE v3 (https://v3.ogee.info/
#/cellline/large%20intestine/RKO/summary). The cell line To date, mouse is the only mammalian species for which
RKO is inferred to have 672 essential genes based on RNAi gene essentiality has been tested at organismal level. About
screening, and 1251 essential genes based on CRISPR– 30% of tested mouse genes are essential for survival, which
Cas9 dataset (Figure 2A). To understand more about the is markedly higher than that of human cell lines (21). Thus,
characteristics of essential genes and the relationship with unique essential genes in mouse experiments may be impor-
the influencing factors in human cell lines, we compared tant during growth and development, while those uniquely
tested genes of RKO against the known influencing fac- essential in human cell lines may represent suitable treat-
tors data that we had collected (Figure 2C–E). Mutations, ment and/or drug targets with putatively less side-effects.
methylation and gene expression all contributed signifi- To compare gene essentiality between mouse and human
cantly to gene essentiality in this cell line. For example, cells, we first selected tissues for which at least six cell lines
genes harboring pathogenic mutations are more likely to be were available, and defined 1607 core essential human genes
essential regardless of the experimental methods used (Fig- in >50% of the cell lines (n ≥ 3). We downloaded the mouse
ure 2C); genes with less methylation at their transcription knock-out and associated phenotype data from databases
start site (TSS200) are also more likely to be essential (Fig- IMPC (21) and MGI (22) to deeply understand the func-
ure 2D); in general, lowly-expressed genes are less likely to tions of essential genes in mice; these databases contained
be essential (Figure 2E). information for 5799 and 9693 knockout genes, respectively.
 Nucleic Acids Research, 2021, Vol. 49, Database issue D1001

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Figure 2. Extensive annotations on human essential genes provided by OGEE v3. Shown here are graphical visualizations taken from the OGEE v3
(https://v3.ogee.info/#/cellline/large%20intestine/RKO/summary). (A) gene essentiality determined using different experimental methods. (B) Correlational
co-essentiality chart of AAMP gene from central nervous system tissue tested by CRISPR-Cas9 technique. The orange edges denote negative correlation
while the blue edges denote positive correlation among the connected genes. (C) Gene essentiality as function of mutation: mutation outcomes predicted
using FATHMM were used to group all tested genes into three categories, the percentage of essential in each group was then calculated (please consult
‘Help’ page for more details); left panel: gene essentiality tested using RNAi, right panel: gene essentiality tested using CRISPR–Cas9. (D) Gene essentiality
as function of methylation: genes are grouped based on methylation sites and calculate percentage of essential for each sites; red color gradient is used
to denote the methylation score, increasing gradually from 0 to 1; users can select any methylations from the drop down menu. (E) Gene essentiality as
function of gene expression: all 0 rpkm genes are in the first bin and rest of the genes are assigned into equal size nine bins; lastly, percentage of essential
is calculated for each bin.
D1002 Nucleic Acids Research, 2021, Vol. 49, Database issue

ties with the latest experimental records. Specific foci of the

OGEE team will be to include a BLAST function (48) in
the database and to improve the user-interface, visualiza-
tions and crosslinking of resources.

DATA AVAILABILITY
All data are freely accessible to all academic users. This
work is licensed under a Creative Commons Attribution
3.0 Unported License (CC BY 3.0). Users can download
datasets from the ‘Download’ page. Individual datasets or
combined datasets of individual species can be downloaded
via the ‘Browse’ page.

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SUPPLEMENTARY DATA
Supplementary Data are available at NAR Online.
Figure 3. Comparing gene essentiality between human-mouse orthologs.
Here only genes with one-to-one human-mouse orthologous relationships
are included. Mouse essential genes were obtained from IMPC (blue) and FUNDING
MGI (green) databases. The two human essential gene dataset, RNAi and
CRISPR–Cas9 were generated by selecting those that were essential in over National Key Research and Development Program of
50% the cell lines of a tissue; tissues with less than six cell lines were ex- China [2018YFC0910502, 2019YFA0905601 to W.H.C.];
cluded from this analysis. Natural Science Foundation of Shanghai [17ZR1445600];
Shanghai Municipal Science and Technology Major Project
Both MGI and IMPC are generating a knockout mouse line [2018SHZDZX01]; ZJLab; Research at the University of
for each protein-coding gene, collecting the corresponding Melbourne was supported by the Australian Research
phenotypes of mutants and controls, identifying the disease Council (ARC); National Health and Medical Coun-
models, and building a complete functional catalogue for cil (NHMRC) of Australia. Funding for open access
the mouse genome. From the orthogroup data generated charge: National Key Research and Development Program
by OrthoFinder (38) (see ‘Data generation’), we identified of China [2019YFA0905601].
3522 and 6214 knock-out genes for mice in the IMPC (21) Conflict of interest statement. None declared.
and MGI (22) dataset, respectively. We also identified that
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