Human Pigmentation: A Review of Molecular Mechanisms, Genetic Architecture, Evolution, Forensic DNA Phenotyping and Health Implications

Human pigmentation is a quantitative, tissue-specific, and temporally variable phenotype shaped by melanocyte biology, melanosome physiology, regulatory variation, environmental exposure, and population history. This narrative review examines how functional and population-based evidence supports—or limits—the translation of pigmentation genetics into forensic DNA phenotyping (FDP) and health-related applications. A structured search of MEDLINE/PubMed and Google Scholar was conducted through July 2026, prioritizing primary functional studies, independent validations, meta-analyses, and consensus documents. Current evidence supports polygenic and regulatory control of skin, hair, and iris pigmentation, but heterogeneous phenotype definitions, population composition, age, and environmental modulation constrain direct genotype-to-appearance inference. IrisPlex, HIrisPlex, and HIrisPlex-S provide validated probabilistic predictions for selected pigmentation categories; performance is less consistent for intermediate phenotypes, admixed populations, partial profiles, and settings lacking appropriate calibration. Associations with ultraviolet damage and cutaneous cancer are substantial but differ by cancer type, whereas evidence concerning vitamin D, melanin–drug interactions, and broader precision-medicine applications remains context-dependent or preliminary. Progress will require standardized phenotyping, globally representative datasets, transparent uncertainty reporting, and independent forensic and clinical validation.