Metascape Gene List Analysis Report

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Heatmap Summary

Figure 1. Heatmap of enriched terms across input gene lists, colored by p-values.
Metascape only visualizes the top 20 clusters. Up to 100 enriched clusters can be viewed here.
The top-level Gene Ontology biological processes can be viewed here.

The heatmap can be interactively viewed using JTreeView2 (.cdt, .gtr and .atr files can be found in the Zip package).

Gene Lists

User-provided gene identifiers are first converted into their corresponding H. sapiens Entrez gene IDs using the latest version of the database (last updated on 2023-01-01). If multiple identifiers correspond to the same Entrez gene ID, they will be considered as a single Entrez gene ID in downstream analyses. Each gene list is assigned a unique color, which is used throughout the analysis. The gene lists are summarized in Table 1.

Table 1. Statistics of input gene lists.
Name Total Unique Color Code
NEGATIVELY 50 48
POSITIVELY 221 221
The overlaps between these lists are shown in a Circos3 plot (Figure 2.a). Another useful representation is to overlap genes based on their functions or shared pathways. The overlaps between gene lists can be significantly improved by considering overlaps between genes sharing the same enriched ontology term(s) (Figure 2.b). Only ontology terms that contain less than 100 genes are used to calculate functional overlaps to avoid linking genes using very general annotation. (We do not want to link all genes, only genes that belong to specific biological processes.)
Figure 2. Overlap between gene lists: (a) only at the gene level, where purple curves link identical genes; (b) including the shared term level, where blue curves link genes that belong to the same enriched ontology term. The inner circle represents gene lists, where hits are arranged along the arc. Genes that hit multiple lists are colored in dark orange, and genes unique to a list are shown in light orange. The publication-quality version of the figures is included in the Zip package as a .svg file under the Overlap_circos folder (readable by popular web browsers and Adobe Illustrator).

Gene Annotation

The following are the list of annotations retrieved from the latest version of the database (last updated on 2023-01-01) (Table 2).

Table 2. Gene annotations extracted
Name Type Description
Gene Symbol Description Primary HUGO gene symbol.
Description Description Short description.
Biological Process (GO) Function/Location Descriptions summarized based on gene ontology database, where up to three most informative GO terms are kept.
Kinase Class (UniProt) Function/Location Detailed kinase classes.
Protein Function (Protein Atlas) Function/Location Protein Function (Protein Atlas)
Subcellular Location (Protein Atlas) Function/Location Subcellular Location (Protein Atlas)
Drug (DrugBank) Genotype/Phenotype/Disease Drug information for the given gene as target.
Canonical Pathways Ontology Canonical Pathways
Hallmark Gene Sets Ontology Hallmark Gene Sets

Pathway and Process Enrichment Analysis

For each given gene list, pathway and process enrichment analysis have been carried out with the following ontology sources: KEGG Pathway, GO Biological Processes, Reactome Gene Sets, Canonical Pathways, CORUM, WikiPathways, and PANTHER Pathway. All genes in the genome have been used as the enrichment background. Terms with a p-value < 0.01, a minimum count of 3, and an enrichment factor > 1.5 (the enrichment factor is the ratio between the observed counts and the counts expected by chance) are collected and grouped into clusters based on their membership similarities. More specifically, p-values are calculated based on the cumulative hypergeometric distribution4, and q-values are calculated using the Benjamini-Hochberg procedure to account for multiple testings5. Kappa scores6 are used as the similarity metric when performing hierarchical clustering on the enriched terms, and sub-trees with a similarity of > 0.3 are considered a cluster. The most statistically significant term within a cluster is chosen to represent the cluster.

When multiple gene lists are provided, all lists are merged into one list called "_FINAL". A term may be found enriched in several individual gene lists and/or in the _FINAL gene list, and the best p-value among them is chosen as the final p-value. The pathway/process clusters that are found to be of interest (either shared or unique based on specific list enrichment) are used to prioritize the genes that fall into those clusters (membership is presented as 1/0 binary columns in the Excel spreadsheet). Note that individual gene lists containing more than 3000 genes are ignored during the enrichment analysis to avoid superficial terms; this is because long gene lists are often not random and generally trigger too many terms that are not of direct relevance to the biology under study.

Table 3. Top 20 clusters with their representative enriched terms (one per cluster). "Count" is the number of genes in the user-provided lists with membership in the given ontology term. "%" is the percentage of all of the user-provided genes that are found in the given ontology term (only input genes with at least one ontology term annotation are included in the calculation). "Log10(P)" is the p-value in log base 10. "Log10(q)" is the multi-test adjusted p-value in log base 10. __PATTERN__ shows the color code used for the gene lists where the term is found statistically significant, i.e., multiple colors indicate a pathway/process that is shared across multiple lists.
_PATTERN_ GO Category Description Count % Log10(P) Log10(q)
R-HSA-6798695 Reactome Gene Sets Neutrophil degranulation 25 11.31 -13.63 -9.28
R-HSA-6809371 Reactome Gene Sets Formation of the cornified envelope 12 5.43 -9.62 -5.66
R-HSA-194315 Reactome Gene Sets Signaling by Rho GTPases 23 10.41 -8.54 -5.01
R-HSA-9711123 Reactome Gene Sets Cellular response to chemical stress 13 5.88 -8.52 -5.01
R-HSA-2262752 Reactome Gene Sets Cellular responses to stress 24 10.86 -8.33 -4.93
R-HSA-199991 Reactome Gene Sets Membrane Trafficking 21 9.50 -7.97 -4.63
R-HSA-3700989 Reactome Gene Sets Transcriptional Regulation by TP53 16 7.24 -7.90 -4.59
R-HSA-9007101 Reactome Gene Sets Rab regulation of trafficking 10 4.52 -7.55 -4.33
WP3888 WikiPathways VEGFA-VEGFR2 signaling pathway 16 7.24 -6.84 -3.72
GO:0010506 GO Biological Processes regulation of autophagy 14 6.33 -6.48 -3.39
CORUM:6182 CORUM PP2A A/C-striatin complex 3 1.36 -6.41 -3.34
GO:0042176 GO Biological Processes regulation of protein catabolic process 14 6.33 -6.29 -3.24
R-HSA-556833 Reactome Gene Sets Metabolism of lipids 22 8.30 -6.09 -3.02
WP4856 WikiPathways Intracellular trafficking proteins involved in CMT neuropathy 5 2.26 -5.85 -2.84
CORUM:938 CORUM FACT complex, UV-activated 3 1.36 -5.42 -2.50
R-HSA-1640170 Reactome Gene Sets Cell Cycle 18 8.14 -5.40 -2.50
GO:0006886 GO Biological Processes intracellular protein transport 18 8.14 -5.37 -2.49
hsa04141 KEGG Pathway Protein processing in endoplasmic reticulum 9 4.07 -5.29 -2.45
M186 Canonical Pathways PID PDGFRB PATHWAY 8 3.62 -5.28 -2.45
CORUM:924 CORUM Toposome 3 1.36 -4.88 -2.13

To further capture the relationships between the terms, a subset of enriched terms has been selected and rendered as a network plot, where terms with a similarity > 0.3 are connected by edges. We select the terms with the best p-values from each of the 20 clusters, with the constraint that there are no more than 15 terms per cluster and no more than 250 terms in total. The network is visualized using Cytoscape7, where each node represents an enriched term and is colored first by its cluster ID (Figure 3.a) and then by its p-value (Figure 3.b). These networks can be interactively viewed in Cytoscape through the .cys files (contained in the Zip package, which also contains a publication-quality version as a PDF) or within a browser by clicking on the web icon. For clarity, term labels are only shown for one term per cluster, so it is recommended to use Cytoscape or a browser to visualize the network in order to inspect all node labels. We can also export the network into a PDF file within Cytoscape, and then edit the labels using Adobe Illustrator for publication purposes. To switch off all labels, delete the "Label" mapping under the "Style" tab within Cytoscape, and then export the network view.

Figure 3. Network of enriched terms: (a) colored by cluster ID, where nodes that share the same cluster ID are typically close to each other; (b) colored by p-value, where terms containing more genes tend to have a more significant p-value.

In the case of when multiple gene lists are provided, the nodes are represented as pie charts, where the size of a pie is proportional to the total number of hits that fall into that specific term. The pie charts are color-coded based on the gene list identities, where the size of a slice represents the percentage of genes under the term that originated from the corresponding gene list. This plot is particularly useful for visualizing whether the terms are shared by multiple lists or unique to a specific list, as well as for understanding how these terms associate with each other within the biological context of the meta study (Figure 4).

Figure 4. Network of enriched terms represented as pie charts, where pies are color-coded based on the identities of the gene lists.

Protein-protein Interaction Enrichment Analysis

For each given gene list, protein-protein interaction enrichment analysis has been carried out with the following databases: STRING8, BioGrid9, OmniPath10, InWeb_IM11.Only physical interactions in STRING (physical score > 0.132) and BioGrid are used (details). The resultant network contains the subset of proteins that form physical interactions with at least one other member in the list. If the network contains between 3 and 500 proteins, the Molecular Complex Detection (MCODE) algorithm12 has been applied to identify densely connected network components. The MCODE networks identified for individual gene lists have been gathered and are shown in Figure 5.

Pathway and process enrichment analysis has been applied to each MCODE component independently, and the three best-scoring terms by p-value have been retained as the functional description of the corresponding components, shown in the tables underneath corresponding network plots within Figure 5.

Figure 5. Protein-protein interaction network and MCODE components identified in the gene lists.

NEGATIVELY (Full Connection)

GO Description Log10(P)
GO:0048469 cell maturation -5.5
GO:0007276 gamete generation -5.2
GO:0071695 anatomical structure maturation -5.2

POSITIVELY (Full Connection)

GO Description Log10(P)
R-HSA-6798695 Neutrophil degranulation -15.4
R-HSA-194315 Signaling by Rho GTPases -10.0
R-HSA-2262752 Cellular responses to stress -9.9

POSITIVELY (Keep MCODE Nodes Only)

Color MCODE GO Description Log10(P)
MCODE_1 R-HSA-6809371 Formation of the cornified envelope -11.8
MCODE_1 GO:0030216 keratinocyte differentiation -11.5
MCODE_1 GO:0009913 epidermal cell differentiation -10.5
MCODE_2 R-HSA-9637690 Response of Mtb to phagocytosis -6.6
MCODE_2 R-HSA-9635486 Infection with Mycobacterium tuberculosis -6.4
MCODE_2 M210 PID IL8 CXCR2 PATHWAY -6.1
MCODE_3 R-HSA-450531 Regulation of mRNA stability by proteins that bind AU-rich elements -5.4
MCODE_3 R-HSA-4086400 PCP/CE pathway -5.4
MCODE_3 GO:0042176 regulation of protein catabolic process -5.2
MCODE_4 GO:0072659 protein localization to plasma membrane -4.8
MCODE_4 GO:1990778 protein localization to cell periphery -4.6
MCODE_4 R-HSA-9012999 RHO GTPase cycle -3.8

All lists merged Colored by Counts(Full Connection)

GO Description Log10(P)
R-HSA-6798695 Neutrophil degranulation -15.4
R-HSA-194315 Signaling by Rho GTPases -10.0
R-HSA-9716542 Signaling by Rho GTPases, Miro GTPases and RHOBTB3 -9.8

All lists merged Colored by Counts(Keep MCODE Nodes Only)

Color MCODE GO Description Log10(P)
MCODE_1 R-HSA-6809371 Formation of the cornified envelope -11.8
MCODE_1 GO:0030216 keratinocyte differentiation -11.5
MCODE_1 GO:0009913 epidermal cell differentiation -10.5
MCODE_2 R-HSA-9637690 Response of Mtb to phagocytosis -6.6
MCODE_2 R-HSA-9635486 Infection with Mycobacterium tuberculosis -6.4
MCODE_2 M210 PID IL8 CXCR2 PATHWAY -6.1
MCODE_3 R-HSA-5617472 Activation of anterior HOX genes in hindbrain development during early embryogenesis -4.7
MCODE_3 R-HSA-5619507 Activation of HOX genes during differentiation -4.7
MCODE_3 GO:0009267 cellular response to starvation -4.2
MCODE_4 R-HSA-450531 Regulation of mRNA stability by proteins that bind AU-rich elements -5.4
MCODE_4 R-HSA-4086400 PCP/CE pathway -5.4
MCODE_4 GO:0042176 regulation of protein catabolic process -5.2
MCODE_5 hsa04727 GABAergic synapse -11.4
MCODE_5 hsa04914 Progesterone-mediated oocyte maturation -8.4
MCODE_5 hsa04915 Estrogen signaling pathway -7.8

All lists merged Colored by Cluster(Full Connection)

GO Description Log10(P)
R-HSA-6798695 Neutrophil degranulation -15.4
R-HSA-194315 Signaling by Rho GTPases -10.0
R-HSA-9716542 Signaling by Rho GTPases, Miro GTPases and RHOBTB3 -9.8

All lists merged Colored by Cluster(Keep MCODE Nodes Only)

Color MCODE GO Description Log10(P)
MCODE_1 R-HSA-6809371 Formation of the cornified envelope -11.8
MCODE_1 GO:0030216 keratinocyte differentiation -11.5
MCODE_1 GO:0009913 epidermal cell differentiation -10.5
MCODE_2 R-HSA-9637690 Response of Mtb to phagocytosis -6.6
MCODE_2 R-HSA-9635486 Infection with Mycobacterium tuberculosis -6.4
MCODE_2 M210 PID IL8 CXCR2 PATHWAY -6.1
MCODE_3 R-HSA-5617472 Activation of anterior HOX genes in hindbrain development during early embryogenesis -4.7
MCODE_3 R-HSA-5619507 Activation of HOX genes during differentiation -4.7
MCODE_3 GO:0009267 cellular response to starvation -4.2
MCODE_4 R-HSA-450531 Regulation of mRNA stability by proteins that bind AU-rich elements -5.4
MCODE_4 R-HSA-4086400 PCP/CE pathway -5.4
MCODE_4 GO:0042176 regulation of protein catabolic process -5.2
MCODE_5 hsa04727 GABAergic synapse -11.4
MCODE_5 hsa04914 Progesterone-mediated oocyte maturation -8.4
MCODE_5 hsa04915 Estrogen signaling pathway -7.8

Quality Control and Association Analysis

Gene list enrichments are identified in the following ontology categories: COVID, TRRUST, Transcription_Factor_Targets, Cell_Type_Signatures, DisGeNET, PaGenBase. All genes in the genome have been used as the enrichment background. Terms with a p-value < 0.01, a minimum count of 3, and an enrichment factor > 1.5 (the enrichment factor is the ratio between the observed counts and the counts expected by chance) are collected and grouped into clusters based on their membership similarities. The top few enriched clusters (one term per cluster) are shown in the Figure 6-11. The algorithm used here is the same as that is used for pathway and process enrichment analysis.

Figure 6. Summary of enrichment analysis in COVID13.


_PATTERN_ GO Description Count % Log10(P) Log10(q)
COVID037 RNA_Sun_Calu-3_12h_Down 16 7.20 -9.10 -5.40
COVID039 RNA_Sun_Calu-3_24h_Down 14 6.30 -7.30 -3.90
COVID389 Interactome_Laurent_HEK293_24h_ORF9C 13 5.90 -6.40 -3.30
COVID198 Ubiquitinome_Stukalov_A549-ACE2_24h_Down 10 4.50 -5.70 -2.70
COVID131 Phosphoproteome_Stukalov_A549-ACE2_24h_Up 12 5.40 -5.60 -2.70
COVID172 Proteome_Stukalov_A549_72h_ORF3_Down 12 5.40 -5.60 -2.70
COVID236 Proteome_Klann_Caco-2_24h_Down 12 5.40 -5.60 -2.70
COVID375 Interactome_Laurent_HEK293_24h_NSP4 12 5.40 -5.60 -2.70
COVID385 Interactome_Laurent_HEK293_24h_ORF7A 12 5.40 -5.60 -2.70
COVID124 Interactome_Stukalov_A549_72h_ORF3 11 5.00 -4.80 -2.10
COVID199 Ubiquitinome_Stukalov_A549-ACE2_24h_Up 11 5.00 -4.80 -2.10
COVID363 Interactome_Laurent_HEK293_24h_E 11 5.00 -4.80 -2.10
COVID377 Interactome_Laurent_HEK293_24h_NSP6 11 5.00 -4.80 -2.10
COVID386 Interactome_Laurent_HEK293_24h_ORF7B 11 5.00 -4.80 -2.10
COVID387 Interactome_Laurent_HEK293_24h_ORF8 11 5.00 -4.80 -2.10
COVID390 Interactome_Laurent_HEK293_24h_S 11 5.00 -4.80 -2.10
COVID027 RNA_Lamers_intestinal-organoid_expansion_Down 10 4.50 -4.60 -1.90
COVID235 Phosphoproteome_Klann_Caco-2_24h_Up 10 4.50 -4.10 -1.50
COVID382 Interactome_Laurent_HEK293_24h_ORF3A 10 4.50 -4.10 -1.50
COVID384 Interactome_Laurent_HEK293_24h_ORF6 10 4.50 -4.10 -1.50
Figure 7. Summary of enrichment analysis in TRRUST.


_PATTERN_ GO Description Count % Log10(P) Log10(q)
TRR01256 Regulated by: SP1 13 5.90 -3.80 -1.40
TRR00280 Regulated by: ETS1 5 2.30 -3.40 -1.00
TRR00011 Regulated by: AR 5 2.30 -3.00 -0.69
TRR00781 Regulated by: MYCN 3 1.40 -2.30 -0.33
TRR00484 Regulated by: HIF1A 4 1.80 -2.20 -0.24
TRR00125 Regulated by: CREB1 4 1.80 -2.10 -0.21
TRR00780 Regulated by: MYC 4 1.80 -2.00 -0.15
Figure 8. Summary of enrichment analysis in Transcription Factor Targets14.


_PATTERN_ GO Description Count % Log10(P) Log10(q)
M14948 NRF2 01 11 5.00 -5.20 -2.40
M30060 MCRS1 TARGET GENES 5 2.30 -5.00 -2.20
M29976 FOXR2 TARGET GENES 10 4.50 -5.00 -2.20
M40729 CUX1 TARGET GENES 16 7.20 -4.60 -2.00
M11821 CEBPB 01 10 4.50 -4.50 -1.90
M30100 NR1I2 TARGET GENES 11 5.00 -4.30 -1.70
M171 GCCATNTTG YY1 Q6 12 5.40 -4.00 -1.50
M30333 ZNF507 TARGET GENES 15 6.80 -4.00 -1.50
M8812 SF1 Q6 9 4.10 -3.90 -1.40
M3403 GTGACGY E4F1 Q6 15 6.80 -3.90 -1.40
M40757 MXD1 TARGET GENES 7 3.20 -3.70 -1.30
M10498 TGCGCANK UNKNOWN 13 5.90 -3.60 -1.20
M29941 DLX2 TARGET GENES 9 4.10 -3.50 -1.10
M30170 SNIP1 TARGET GENES 15 6.80 -3.20 -0.88
M8004 TGASTMAGC NFE2 01 7 3.20 -3.20 -0.88
M30018 HOXD11 TARGET GENES 6 2.70 -3.10 -0.79
M30011 HOXB6 TARGET GENES 13 5.90 -3.00 -0.75
M40826 CIC TARGET GENES 10 4.50 -3.00 -0.73
M7937 AP1 C 8 3.60 -3.00 -0.71
M11820 TTGCWCAAY CEBPB 02 4 1.80 -2.90 -0.67
Figure 9. Summary of enrichment analysis in Cell Type Signatures.


_PATTERN_ GO Description Count % Log10(P) Log10(q)
M40004 BUSSLINGER ESOPHAGEAL LATE SUPRABASAL CELLS 17 7.70 -15.00 -11.00
M41679 TRAVAGLINI LUNG MESOTHELIAL CELL 26 12.00 -12.00 -7.50
M41652 TRAVAGLINI LUNG PROXIMAL BASAL CELL 25 11.00 -11.00 -7.30
M40010 BUSSLINGER GASTRIC ISTHMUS CELLS 20 9.00 -9.70 -5.90
M40122 DESCARTES MAIN FETAL SQUAMOUS EPITHELIAL CELLS 11 5.00 -8.50 -4.90
M40237 DESCARTES FETAL LUNG SQUAMOUS EPITHELIAL CELLS 13 5.90 -8.30 -4.90
M41717 FAN OVARY CL15 SMALL ANTRAL FOLLICLE GRANULOSA CELL 21 9.50 -7.80 -4.40
M41700 TRAVAGLINI LUNG OLR1 CLASSICAL MONOCYTE CELL 22 10.00 -7.60 -4.20
M41703 FAN OVARY CL1 GPRC5A TNFRS12A HIGH SELECTABLE FOLLICLE STROMAL CELL 15 6.80 -6.80 -3.50
M41715 FAN OVARY CL13 MONOCYTE MACROPHAGE 16 7.20 -6.50 -3.30
M41697 TRAVAGLINI LUNG EREG DENDRITIC CELL 18 8.10 -6.50 -3.30
M41751 RUBENSTEIN SKELETAL MUSCLE MYELOID CELLS 14 6.30 -6.50 -3.30
M39174 MURARO PANCREAS ACINAR CELL 20 9.00 -6.30 -3.20
M41748 RUBENSTEIN SKELETAL MUSCLE SATELLITE CELLS 13 5.90 -6.30 -3.20
M40024 BUSSLINGER DUODENAL STEM CELLS 13 5.90 -6.20 -3.20
M40299 DESCARTES FETAL STOMACH SQUAMOUS EPITHELIAL CELLS 7 3.20 -6.20 -3.20
M39238 LAKE ADULT KIDNEY C19 COLLECTING DUCT INTERCALATED CELLS TYPE A MEDULLA 13 5.90 -6.00 -3.00
M39269 HU FETAL RETINA RGC 15 6.80 -6.00 -3.00
M41710 FAN OVARY CL8 MATURE CUMULUS GRANULOSA CELL 2 18 8.10 -5.80 -2.80
M39229 LAKE ADULT KIDNEY C10 THIN ASCENDING LIMB 13 5.90 -5.60 -2.70
Figure 10. Summary of enrichment analysis in DisGeNET15.


_PATTERN_ GO Description Count % Log10(P) Log10(q)
C0022596 Palmoplantar Keratosis 8 3.60 -9.40 -5.80
C4551675 Keratoderma, Palmoplantar 12 5.40 -8.40 -4.90
C0853087 Nail abnormality 8 3.60 -7.50 -4.10
C0870082 Hyperkeratosis 11 5.00 -7.10 -3.80
C0041834 Erythema 12 5.40 -6.90 -3.60
C0037277 Skin Diseases, Genetic 7 3.20 -6.70 -3.50
C0221270 Acanthosis 6 2.70 -6.60 -3.30
C1847514 Postnatal microcephaly 7 3.20 -6.40 -3.30
C0153381 Malignant neoplasm of mouth 20 9.00 -6.10 -3.00
C0020758 Congenital ichthyosis 7 3.20 -5.70 -2.70
C0221260 Dystrophia unguium 7 3.20 -5.60 -2.70
C0220641 Lip and Oral Cavity Carcinoma 19 8.60 -5.60 -2.70
C4551630 Ichthyosis Congenita I 3 1.40 -5.40 -2.60
C1838625 Warburg Sjo Fledelius syndrome 4 1.80 -5.30 -2.50
C0265962 Ichthyosis linearis circumflexa 6 2.70 -5.10 -2.30
C1334015 High Grade Intraepithelial Neoplasia 5 2.30 -5.10 -2.30
C0020678 Hypotrichosis 6 2.70 -4.90 -2.20
C0011615 Dermatitis, Atopic 18 8.10 -4.90 -2.20
C0079153 Hyperkeratosis, Epidermolytic 4 1.80 -4.90 -2.20
C0020757 Ichthyoses 9 4.10 -4.80 -2.10
Figure 11. Summary of enrichment analysis in PaGenBase16.


_PATTERN_ GO Description Count % Log10(P) Log10(q)
PGB:00156 Tissue-specific: Tongue 9 4.10 -12.00 -7.50
PGB:00017 Tissue-specific: skin 16 7.20 -11.00 -7.50
PGB:00081 Cell-specific: Bronchial Epithelial Cells 9 4.10 -6.10 -3.00
PGB:00005 Tissue-specific: tonsil 3 1.40 -2.00 -0.13

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