Sarah Tishkoff led a collaborative team of researchers who have discovered key insights into the molecular basis of skin color differences among Africans. Credit: Sarah Tishkoff and Alessia Ranciaro
Key points:
- Researchers found that skin pigmentation, particularly among African populations, is influenced by 165 functional genomic variants – mostly in noncoding regions.
- Key regulatory variants in signaling pathways that regulate melanocyte differentiation may contribute to the distinctive light skin color seen in the San population.
- Conducting future functional studies on the impact of noncoding variants will enhance understanding of genetics underlying complex human traits.
Recent findings have expanded the current understanding of human evolution and the complex genetics underlying human diversity. These findings, published in Nature Genetics, provide new perspective on the molecular basis of skin color variations among African populations.
Skin color is an adaptive trait that evolved based on environmental pressure. For example, darker skin evolved to shield humans from the sun’s intense ultraviolet radiation, while lighter skin tones are an adaptation to maximize vitamin D production.
Researchers used genome-wide association studies of skin color from more than 1,500 eastern and southern African individuals. They scanned the entire genome to locate genetic variants that were highly differentiated between the lightly pigmented San population and other darkly pigmented African populations.
Their analysis revealed that pigmentation is influenced by hundreds of genomic variants – mostly in noncoding regions. The team used parallel reporter assays to determine the variants’ regulatory activity and narrowed down the candidates to 165 functional variants. Next, they identified their target genes with chromatin conformation capture assays in melanocytic cells.
Using CRISPR/Cas-9 genome editing, the team found mutations in an enhancer of OCA2, a gene associated with albinism, could result in a 75% reduction in melanin relative to control cells. Within OCA2, they identified two closely located regulatory variants that they estimated to be 1.2 million and 57 thousand years old, with the latter coinciding with human migration from Africa.
In the next stages of the study, researchers identified key regulatory variants near genes—MITF, LEF1, and TRPS1—involved in signaling pathways regulating melanocyte differentiation and hair development. These variants may contribute to the distinctive light skin color and hair morphology seen in the San population. Researchers also found a new gene—CYB561A3—that impacts both skin pigmentation and melanin levels in melanocytic cells.
“Our findings underscore the complexity of genetic factors influencing skin color and the benefits of including ethnically diverse and underrepresented populations in genetic studies,” explained senior author Sarah Tishkoff. “Conducting functional studies on the impact of noncoding variants will enhance our comprehension of genetics underlying complex human traits and disease risk.”