Melanogenesis Constraints — Project Overview
About this project
This site documents the analysis pipeline for the PEQG 2026 poster: “Testing Network-Based Predictions of Genetic Constraint in Melanogenesis.”
We test whether a gene’s position in the melanogenesis signaling network predicts its evolutionary constraint — combining LoF intolerance (LOEUF), phylogenetic conservation (PhyloP), tissue expression breadth (GTEx), and population genomics (nucleotide diversity π, PBS) across 5 populations.
Gene set: Raghunath et al. 2015 — 129-gene melanocyte signaling network, classified into 6 functional categories.
Analysis phases
| Phase | Analysis | Status |
|---|---|---|
| Initial LOEUF | LOEUF distributions by functional category and disease class (boxplots) | ✓ Complete |
| Phase 0 — KEGG | Network position (betweenness centrality) + KEGG pathway connectivity vs. LOEUF | ✓ Complete |
| Phase 1 — GTEx | PhyloP conservation + GTEx tissue expression breadth vs. LOEUF | ✓ Complete |
| Phase 1.3 — Ancestry LOEUF | gnomAD v4 ancestry-stratified LOEUF (NFE, AFR, EAS, SAS, ASJ) | ✓ Complete |
| Phase 2 — Popgen Selection | Population genomics: π and PBS across African, Melanesian, South Asian, East Asian, European | ✓ Complete |
Key findings
- Pigment-specific genes are significantly more LoF-tolerant than generic signaling genes (Kruskal-Wallis p = 1.70×10⁻⁸), consistent with the recessive biology hypothesis — heterozygous LoF carries no fitness penalty.
- The tolerance ordering is preserved across ancestry groups (NFE/AFR LOEUF concordant), ruling out European ascertainment bias as the sole driver.
- Tissue expression breadth strongly predicts constraint (Spearman ρ > 0, p < 0.001): broadly expressed genes are more LoF-intolerant regardless of pigmentation function.
- MC1R paradox: highest LOEUF (1.967) in the network yet expressed in 53/54 tissues; African PBS elevated (84–87th percentile within network) despite high π — consistent with African purifying selection acting on missense variants, invisible to LoF metrics.