New research may have discovered the molecular mechanism influencing skin pigmentation variation and local adaptations in African populations, according to a novel study published by Feng et al in Nature Genetics. Researchers involved over 1,500 individuals residing in eastern and southern Africa in the study. They performed massively parallel reporter assays to analyze the regulatory functions of 1,157 candidate variants potentially affecting skin pigmentation. The researchers narrowed down their search to 165 single-nucleotide polymorphisms demonstrating differential regulatory activities between alleles. Using Hi-C genome editing and melanin assays, they then identified the regulatory elements affecting melanin levels in vitro in the MFSD12, HMG20B, OCA2, MITF, LEF1, TRPS1, BLOC1S6, and CYB561A3 genes. The researchers revealed that enhancers of OCA2 may reduce melanin levels by 75% compared with control cells. Two closely related regulatory variants that are approximately 1.2 million and 57,000 years old, respectively, may coincide with landmark events in human evolution and the continued adaptations of human skin pigmentation diversity. They indicated that enhancers of MITF, LEF1, and TRPS1 may modulate lighter skin pigmentation, melanocyte differentiation, and hair development, as well as signal local adaptations in the Khoesan-speaking San population of southern Africa. Additionally, CYB561A3 was found to influence genes taking part in oxidative phosphorylation, iron homeostasis, and melanogenesis. Prior studies have shown that the administration of intravenous iron infusions may lead to skin hyperpigmentation, signifying a correlation between the gene and skin pigmentation. The researchers hope their new findings may illuminate the evolutionary history that gave rise to contemporary skin pigmentation diversity across human populations. In a companion press release on the findings from the University of Pennsylvania, the study authors concluded: “Our [research] underscores the complexity of genetic factors influencing skin color and the benefits of including ethnically diverse and underrepresented populations in genetic studies. Conducting functional studies on … noncoding variants will enhance our comprehension of the genetics underlying complex human traits and disease risk.”