---
title: Biological Relevance
slug: biological-relevance
createdAt: 2026-01-20T12:26:46.684Z
---

# Gene Networks Reflect Tissue and Condition-Specific Biology

Mavatar Discovery co-expression gene networks successfully capture meaningful biological relationships. By quantifying pairwise correlations between gene expression profiles and integration of vast number of datasets and samples, we obtained networks that represent the coordinated activity of genes within and across tissues. The resulting structures revealed clear biological organization, consistent with expected tissue-specific patterns and functional groupings, supporting the utility of this approach for biological interpretation.

## Methodology

To evaluate biological relevance and uncover characteristic gene interactions within DINA networks, we applied a network comparison framework that identifies both conserved molecular processes and context-specific functional processes across the networks. This approach yields two complementary outcomes: DINA network core genes and Network-specific genes capturing the distinctive functional wiring of each network. The analysis revealed both underlying common core biological functions and distinct, context-specific functionalities reflecting specialized activity in the biological condition of interest.

For each DINA context-specific network, iterative subnetwork comparisons are performed against all the other networks using the DeltaCon method ([1](docId\:m3yWqJ3arjsY4ZAf7WTHc)). Biologically relevant DeltaCon null distributions are used as a background ensuring that the similarities and differences reflect true biological organization rather than structural noise (see [DINA Network Similarity Analysis](docId\:Fx907VIxMfPwg4dpJ8-R5) for more details). This analysis yields two complementary gene lists for each network comparison: similarity genes representing conserved patterns and dissimilarity genes representing network-specific wiring.

These lists are subsequently aggregated and filtered to produce two network-specific outputs: DINA network core genes and DINA network-specific signature genes. For biological validation analysis we grouped these genes into Louvain communities based on the network of interest and performed Over-Representation Analysis (ORA) per network community for Reactome, GO\:BP, GO\:MF and GO\:CC pathway databases through g\:Profiler ([2](docId\:m3yWqJ3arjsY4ZAf7WTHc))

This approach provides a statistically grounded way to pinpoint functional gene modules that are conserved or rewired between biological contexts, enabling interpretation of tissue-specific or disease-specific pathways of the networks. Within the platform, users have access to the global DINA Network Core Gene list and all the DINA Network-Specific Signature Gene lists.

## Results and Conclusions

Analysis of subnetworks allowed us to identify modules (gene groups) that are either conserved across tissues or uniquely present in one tissue or condition (see [Methodology](docId\:m3yWqJ3arjsY4ZAf7WTHc)). Shared subnetworks are likely to correspond to fundamental cellular processes active across multiple biological contexts, whereas tissue- or disease-specific subnetworks represent specialized or perturbed functions.

Here we present the biological validation results from the following networks: [Pancreas– General](docId\:m3yWqJ3arjsY4ZAf7WTHc), [Brain – General](docId\:m3yWqJ3arjsY4ZAf7WTHc), [Skin – General](docId\:m3yWqJ3arjsY4ZAf7WTHc), [Liver – General](docId\:m3yWqJ3arjsY4ZAf7WTHc), [Breast – Breast cancer/tissue](docId\:m3yWqJ3arjsY4ZAf7WTHc) and [PBMC – General](docId\:m3yWqJ3arjsY4ZAf7WTHc).

Across tissues, conditions, and disease states, the modules frequently showed enrichment for broad functional categories such as extracellular matrix organization, mitochondrial and respiratory processes, translation and ribosome biogenesis, immune response, RNA splicing regulation, and cell cycle or DNA replication. In the following sections, we focus specifically on modules exhibiting tissue-specific functional enrichment, which provide insight into biological processes characteristic of each network

### Pancreas – General

Based on the enrichment analysis, the pancreas network-specific signature genes in Module 9 showed strong association with pancreatic physiological functions (Table 1). The top enriched terms within this module include protein digestion and absorption related terms, which represent core functional processes of the pancreas. In contrast, the similarity tail enrichment (Table 2) results highlight subnetworks related to metal ion homeostasis and detoxification, including metallothionein binding metals and response to metal ions, consistent with the pancreas’ function in metal metabolism and stress response regulation.

Co-occurrence of metal ion homeostasis within the same module as the pancreatic secretion and digestion terms may suggests that the pancreas-specific functional programs are built upon a conserved regulatory backbone of metal ion metabolism and detoxification ([3](docId\:m3yWqJ3arjsY4ZAf7WTHc)).

**

*Table 1. Top Enrichment Results for Pancreas – General Module 9 Specific Signature Genes.*

| Source | Term                               | Adjusted P-Value |
| ------ | ---------------------------------- | ---------------- |
| REAC   | Digestion                          | 2.98E-06         |
| REAC   | Digestion and Absorption           | 7.36E-06         |
| GO\:MF | Serine-Type Endopeptidase Activity | 9.81E-06         |

**

*Table 2. Top Enrichment Results for Pancreas – General Module 9 Genes, Co-Expressed Between Multiple Networks.*

| Source  | Term                               | Adjusted P-Value |
| ------- | ---------------------------------- | ---------------- |
| REAC    | Metallothioneins Bind Metals       | 1.93E-06         |
| GO\:BP  | Cellular Response to Zinc Ion      | 2.17E-06         |
| REAC    | Response to Metal Ions             | 5.82E-06         |
| GO\:BP  | Intracellular Zinc Ion Homeostasis | 1.77E-05         |
| GO\:BP  | Detoxification of Copper Ion       | 3.34E-05         |
| GO\:BP  | Stress Response to Copper Ion      | 3.34E-05         |



### Brain – General

Brain network Module 6 exhibited exclusive dissimilarity tail enrichment for neural and glial developmental pathways (Table 3), such as: axon ensheathment, myelination, oligodendrocyte differentiation, and glial cell differentiation. Additional terms such as neurogenesis, gliogenesis, and midbrain/substantia nigra development further support a central nervous system–specific module. The absence of similarity tail enrichment indicates that these processes are strongly tissue-specific and reflect specialized subnetwork organization within the brain network.

Module 12 showed limited similarity tail enrichment (Table 4) but extensive dissimilarity tail enrichment for synaptic structure and function, such as: vesicle-mediated transport in synapse, synaptic/postsynaptic membranes, NMDA receptor–associated pathways, neurexin/neuroligin interactions, and exocytosis (Table 5). This pattern indicates a brain-specific synaptic module whose subnetwork organization is distinct in brain compared with other networks.

**

*Table 3. Top Enrichment Results for Brain – General Module 6 Specific Signature Genes.*

| Source | Term                               | Adjusted P-Value |
| ------ | ---------------------------------- | ---------------- |
| GO\:BP | Axon Ensheathment                  | 1.43E-19         |
| GO\:BP | Ensheathment of Neurons            | 1.43E-19         |
| GO\:BP | Myelination                        | 5.35E-18         |
| GO\:BP | Oligodendrocyte Differentiation    | 1.81E-15         |
| GO\:BP | Glial Cell Differentiation         | 4.05E-14         |
| GO\:BP | Central Nervous System Myelination | 1.28E-13         |
| GO\:BP | Substantia Nigra Development       | 9.41E-04         |

**

*Table 4. Enrichment Results for Brain – General Module 12 Genes, Co-Expressed Between Multiple Networks.*

| Source | Term                     | Adjusted P-Value |
| ------ | ------------------------ | ---------------- |
| GO\:CC | Presynaptic Active Zone  | 1.55E-02         |
| GO\:BP | Developmental Maturation | 2.46E-02         |

**

*Table 5. Top Enrichment Results for Brain – General Module 12 Specific Signature Genes.*

| Source | Term                                                 | Adjusted P-Value |
| ------ | ---------------------------------------------------- | ---------------- |
| GO\:BP | Vesicle-Mediated Transport in Synapse                | 3.58E-07         |
| GO\:CC | Synaptic Membrane                                    | 5.76E-07         |
| REAC   | Neuronal System                                      | 1.05E-04         |
| GO\:CC | Postsynaptic Specialization                          | 5.02E-04         |
| GO\:CC | Neuron to Neuron Synapse                             | 7.19E-04         |
| REAC   | Activation of NMDA Receptors and Postsynaptic Events | 1.21E-03         |



### Skin – General

Skin network Module 1 showed striking dissimilarity tail enrichment for epidermis and skin development, keratinocyte differentiation, keratinization, and cornified envelope formation, reflecting canonical skin-barrier and keratinocyte functionalities (Table 6). The corresponding similarity tail was enriched for broad vesicle-membrane processes (Table 7), consistent with conserved cellular regulation. Skin cells use endocytosis for basic functions such as taking in nutrients and signaling molecules which are closely connected to epidermis development. These findings indicate that this module captures a skin-specific functional program built on a shared signaling framework.

Module 2 showed exclusive dissimilarity tail enrichment for melanocyte and pigmentation pathways, such as: melanosome, melanosome membrane, melanin biosynthesis/metabolism, and MITF-dependent programs (Table 8), with no significant terms in the similarity tail. We therefore interpret this as a skin-specific pigmentation module.

Skin Module 16 displayed strong dissimilarity tail enrichment for keratin filament organization, and epidermal development, including intermediate filament cytoskeleton organization, Cornified envelope formation, keratinocyte differentiation”, and hair follicle morphogenesis (Table 9). The similarity tail contained no significant terms. This pattern identifies a skin-specific structural module, representing keratinocyte and epidermal differentiation programs characteristic of stratified epithelial tissue.

**

*Table 6. Top Enrichment Results for Skin – General Module 1 Specific Signature Genes.*

| Source  | Term                                                                            | Adjusted P-Value |
| ------- | ------------------------------------------------------------------------------- | ---------------- |
| GO\:BP  | Epidermis Development                                                           | 4.72E-13         |
| GO\:BP  | Skin Development                                                                | 9.07E-10         |
| GO\:BP  | Establishment of Skin Barrier                                                   | 7.00E-08         |
| GO\:BP  | Epidermal Cell Differentiation                                                  | 1.19E-06         |
| REAC    | Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin | 3.60E-06         |
| GO\:BP  | Skin Epidermis Development                                                      | 8.84E-06         |
| GO\:BP  | Keratinocyte Differentiation                                                    | 5.48E-05         |

**

*Table 7. Enrichment Results for Skin – General Module 1 Genes, Co-Expressed Between Multiple Networks.*

| Source | Term                       | Adjusted P-Value |
| ------ | -------------------------- | ---------------- |
| GO\:CC | Endocytic Vesicle Membrane | 2.03E-02         |

**

*Table 8. Top Enrichment Results for Skin – General Module 2 Specific Signature Genes.*

| Source | Term                         | Adjusted P-Value |
| ------ | ---------------------------- | ---------------- |
| GO\:CC | Melanosome Membrane          | 6.05E-08         |
| GO\:CC | Chitosome                    | 6.05E-08         |
| GO\:CC | Pigment Granule Membrane     | 6.05E-08         |
| GO\:BP | Pigment Metabolic Process    | 7.20E-07         |
| GO\:BP | Pigment Biosynthetic Process | 2.74E-05         |
| GO\:CC | Melanosome                   | 4.43E-05         |
| GO\:BP | Melanin Biosynthetic Process | 3.47E-04         |

**

*Table 9. Top Enrichment Results for Skin – General Module 16 Specific Signature Genes.*

| Source | Term                                            | Adjusted P-Value |
| ------ | ----------------------------------------------- | ---------------- |
| GO\:CC | Intermediate Filament                           | 1.28E-45         |
| GO\:CC | Keratin Filament                                | 2.30E-45         |
| GO\:CC | Intermediate Filament Cytoskeleton              | 7.36E-44         |
| REAC   | Keratinization                                  | 4.28E-42         |
| GO\:BP | Intermediate Filament Organization              | 8.80E-12         |
| GO\:BP | Intermediate Filament Cytoskeleton Organization | 7.19E-11         |
| GO\:BP | Hair Cycle                                      | 6.97E-10         |

### Liver – General

Liver network Module 2 showed dissimilarity tail enrichment for a combination characteristic of hepatic biology, such as: complement and coagulation cascades, acute-phase response, γ-carboxylation of protein precursors, and peroxisomal/fatty-acid and amino-acid metabolism (Table 10). The corresponding similarity tail enrichment (Table 11) highlighted general metabolic processes, such as: small-molecule and amino-acid catabolism, nicotinamide/nucleotide metabolism, and metal-ion response, consistent with conserved cellular functions. Together, these results support this module as liver-specific on the dissimilarity side, built on a conserved metabolic backbone.



*Table 10. Top Enrichment Results for Liver – General Module 2 Specific Signature Genes.*

| Source | Term                                        | Adjusted P-Value |
| ------ | ------------------------------------------- | ---------------- |
| GO\:CC | Blood Microparticle                         | 1.15E-11         |
| GO\:MF | Serine-Type Endopeptidase Activity          | 3.72E-08         |
| REAC   | Intrinsic Pathway of Fibrin Clot Formation  | 1.01E-04         |
| REAC   | Complement Cascade                          | 1.11E-04         |
| REAC   | Formation of Fibrin Clot (Clotting Cascade) | 9.14E-04         |



*Table 11. Top Enrichment Results for Liver – General Module 2 Genes, Co-Expressed Between Multiple Networks.*

| Source | Term                                      | Adjusted P-Value |
| ------ | ----------------------------------------- | ---------------- |
| GO\:BP | Carboxylic Acid Catabolic Process         | 1.12E-03         |
| GO\:BP | Organic Acid Catabolic Process            | 1.12E-03         |
| REAC   | Metabolism of Amino Acids and Derivatives | 1.52E-03         |
| GO\:BP | Pyridine Nucleotide Metabolic Process     | 7.78E-03         |
| GO\:BP | Nicotinamide Nucleotide Metabolic Process | 7.78E-03         |
| REAC   | Metallothioneins Bind Metals              | 7.87E-03         |

### Breast – Breast cancer/tissue

The breast cancer network exhibited several coherent and biologically interpretable modules. The similarity tail of Module 4 could be linked to endoplasmic-reticulum protein folding, unfolded-protein response, rRNA processing, and ribosome biogenesis (Table 12), marking a shared secretory, biosynthetic core typical of highly secretory epithelial tumors. Its dissimilarity tail emphasized transcriptional and RNA-processing regulation, such as major mRNA splicing, RNA polymerase II elongation/pause-release, and WDR5/NSL histone-acetyltransferase complexes (Table 13), reflecting cohort-specific tuning of epigenetic and transcriptional output. Together these patterns indicate that breast cancer networks capture conserved cell cycle, biosynthetic, and stress-response machinery, while the observed dissimilarity enrichments point to meaningful variation in DNA repair, telomere biology, and transcriptional control.

Breast cancer Module 26 similarity tail was characterized by metal-ion homeostasis functions, such as: metallothionein and zinc/copper detoxification processes, a common oxidative-stress signature (Table 14). Its dissimilarity tail highlighted telomere maintenance and telomerase-associated repair, indicating heterogeneity in replicative lifespan control (Table 15).

The similarity tail of a dominant cell cycle/replication module (Module 27) captured chromosome segregation, mitotic checkpoints, and DNA replication, reflecting a conserved proliferative program across tumors (Table 16). The associated dissimilarity signal was enriched for TP53 regulation, checkpoint control, and DNA-damage repair pathways, such as: homologous recombination, BRCA/RAD51, and base-excision repair (Table 17). This was consistent with variation in replicative stress and DNA-repair proficiency among cohorts.



*Table 12. Top Enrichment Results for Breast – Breast Cancer/Tissue Module 4 Genes, Co-Expressed Between Multiple Networks.*

| Source | Term                                             | Adjusted P-Value |
| ------ | ------------------------------------------------ | ---------------- |
| GO\:CC | Endoplasmic Reticulum Protein-Containing Complex | 1.06E-15         |
| GO\:BP | Ribosome Biogenesis                              | 3.60E-14         |
| GO\:BP | rRNA Processing                                  | 6.64E-11         |
| GO\:BP | Protein Folding                                  | 6.02E-08         |



*Table 13. Top Enrichment Results for Breast – Breast Cancer/Tissue Module 4 Specific Signature Genes.*

| Source | Term                                               | Adjusted P-Value |
| ------ | -------------------------------------------------- | ---------------- |
| REAC   | mRNA Splicing – Major Pathway                      | 4.24E-07         |
| REAC   | Processing of Capped Intron-Containing Pre-mRNA    | 9.30E-07         |
| REAC   | Epigenetic Regulation of Gene Expression           | 2.70E-06         |
| GO\:BP | Positive Regulation of Gene Expression, Epigenetic | 8.70E-06         |
| GO\:CC | Spliceosomal Complex                               | 8.11E-04         |



*Table 14. Top Enrichment Results for Breast – Breast Cancer/Tissue Module 26 Genes, Co-Expressed Between Multiple Networks.*

| Source | Term                               | Adjusted P-Value |
| ------ | ---------------------------------- | ---------------- |
| REAC   | Metallothioneins Bind Metals       | 2.96E-12         |
| REAC   | Response to Metal Ions             | 1.28E-11         |
| GO\:BP | Detoxification of Copper Ion       | 6.79E-11         |
| GO\:BP | Intracellular Zinc Ion Homeostasis | 9.37E-09         |
| GO\:BP | Response to Toxic Substance        | 2.55E-04         |



*Table 15. Top Enrichment Results for Breast – Breast Cancer/Tissue Module 26 Specific Signature Genes.*

| Source | Term                                                 | Adjusted P-Value |
| ------ | ---------------------------------------------------- | ---------------- |
| REAC   | Polymerase Switching on the C-Strand of the Telomere | 3.45E-05         |
| REAC   | Telomere C-Strand (Lagging Strand) Synthesis         | 1.06E-04         |
| GO\:CC | Telomere Cap Complex                                 | 2.98E-04         |
| REAC   | Chromosome Maintenance                               | 1.21E-03         |
| GO\:MF | Telomeric DNA Binding                                | 1.47E-02         |



*Table 16. Top Enrichment Results for Breast – Breast Cancer/Tissue Module 8 Genes, Co-Expressed Between Multiple Networks.*

| Source | Term                           | Adjusted P-Value |
| ------ | ------------------------------ | ---------------- |
| GO\:BP | Chromosome Segregation         | 7.42E-94         |
| GO\:BP | Nuclear Division               | 5.43E-88         |
| GO\:BP | Organelle Fission              | 2.89E-84         |
| GO\:BP | Nuclear Chromosome Segregation | 1.34E-79         |
| GO\:BP | DNA Replication                | 2.30E-58         |



*Table 17. Top Enrichment Results for Breast – Breast Cancer/Tissue Module 8 Specific Signature Genes.*

| Source | Term                            | Adjusted P-Value |
| ------ | ------------------------------- | ---------------- |
| REAC   | Cell Cycle Checkpoints          | 3.32E-11         |
| REAC   | G2/M Checkpoints                | 3.22E-10         |
| REAC   | DNA Repair                      | 1.38E-07         |
| REAC   | Regulation of TP53 Activity     | 5.64E-07         |
| REAC   | Impaired BRCA2 Binding to RAD51 | 4.42E-05         |

### PBMC – General

Immune-related modules appeared across multiple networks, reflecting conserved co-expression structures underlying innate and adaptive immunity. In PBMCs, this took the form of a stable antigen presentation/MHC-II Module 1, which similarity tail showed baseline immune composition of blood mononuclear cells (Table 18). While similar immune wiring may appear in other contexts, the PBMC module was distinguished by minimal activation signatures in its dissimilarity tail (Table 19), suggesting maintenance of immune identity rather than context-specific inflammatory activation.

In addition to PBMC Module 1, two related immune modules were identified. The first module captured innate effector and antigen-processing functions, including neutrophil degranulation, phagocytosis, vesicle lumen, and lysosomal organization, while the corresponding dissimilarity enrichments highlighted Toll-like receptor and MyD88-dependent signaling. The second module represented broad cytokine signaling processes, encompassing TNF, IL-17, IL-10, and NF-κB pathways, together with downstream transcriptional regulators. These patterns reflect the mixed cellular composition and variable activation states characteristic of peripheral blood, indicating that the framework recovers coherent immune modules spanning both basal myeloid functions and cytokine-mediated responses.



*Table 18. Top Enrichment Results for PBMC – General Module 1 Genes, Co-Expressed Between Multiple Networks.*

| Source | Term                                                                                      | Adjusted P-Value |
| ------ | ----------------------------------------------------------------------------------------- | ---------------- |
| GO\:CC | MHC Class II Protein Complex                                                              | 4.01E-23         |
| GO\:CC | MHC Protein Complex                                                                       | 2.04E-20         |
| GO\:BP | Antigen Processing and Presentation of Peptide or Polysaccharide Antigen via MHC Class II | 4.19E-19         |
| GO\:CC | Lysosomal Membrane                                                                        | 9.76E-16         |



*Table 19. Enrichment Results for PBMC – General Module 1 Specific Signature Genes.*

| Source | Term                               | Adjusted P-Value |
| ------ | ---------------------------------- | ---------------- |
| GO\:CC | Cell Cortex                        | 6.82E-04         |
| REAC   | Maturation of Spike Protein        | 3.50E-03         |
| REAC   | Translation of Structural Proteins | 1.98E-02         |
| REAC   | Calnexin/Calreticulin Cycle        | 4.15E-02         |
| REAC   | Late SARS-CoV-2 Infection Events   | 4.44E-02         |

### Summary

Our investigations confirm that Mavatar Discovery networks represent biologically coherent structures. Across all comparisons, the modules identified in both similarity and dissimilarity tails align with well-established tissue and disease biology. Shared subnetworks capture conserved cellular and metabolic functions, while unique modules reflect context-specific biology, such as immune regulation, tissue specialization, or microenvironmental interactions. The consistency of these findings across multiple tissues and orientations demonstrates that the networks faithfully represent the underlying biological systems and capture both common and specialized processes relevant to each context.

In Mavatar Discovery, these results have been made accessible for graph construction. The “Network-specific gene lists” represent genes with local connectivity patterns that differ from other networks, defining the functional rewiring unique to each context. In contrast, the “DINA network core genes” comprise one list of genes with connectivity profiles closely matching those in other networks, representing the shared cellular scaffold common to many systems.

# References

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2. L. Kolberg, U. Raudvere, I. Kuzmin, P. Adler, J. Vilo, H. Peterson, g\:Profiler-interoperable web service for functional enrichment analysis and gene identifier mapping (2023 update). Nucleic Acids Res 51, W207–W212 (2023). [https://pubmed.ncbi.nlm.nih.gov/37144459](https://pubmed.ncbi.nlm.nih.gov/37144459)
3. E. Y. Chen, C. M. Tan, Y. Kou, Q. Duan, Z. Wang, G. V. Meirelles, N. R. Clark, A. Ma’ayan, Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128 (2013).