New research provides molecular insight into mechanisms behind pigmentation variation

Researchers at the University of Pennsylvania have discovered key insights into the molecular basis of skin color variations among African populations. Their findings, published in Natural geneticsexpand the understanding of human evolution and the genetics that underlie the contemporary diversity of human skin colors.

“Despite the abundant genetic diversity within African populations, they have been historically underrepresented in genetic studies,” says lead author Sarah Tishkoff, a Penn Integrates Knowledge professor and appointee in the School of Medicine. Perelman and the School of Arts and Sciences.

“Our results offer new insights into the genetic basis and evolutionary history of skin color diversity, contributing to a clearer depiction of human evolution.”

The history of human evolution is as rich and diverse as the adaptations seen in populations around the world, Tishkoff says. She notes that, among many adaptive traits, skin color stands out as one of the best known. Darker skin tones, prevalent in equatorial regions, provide a natural sunscreen, evolving over millennia to protect these populations from the sun’s intense ultraviolet radiation.

Conversely, lighter pigmentation, as observed in populations closer to the poles, is an adaptation to mitigate the risks of insufficient sun exposure by maximizing vitamin D production, triggered by exposure to UV.

“Our approach involved genome-wide association studies of skin color in more than 1,500 individuals from eastern and southern Africa, as well as genome analysis to identify highly differentiated between the lightly pigmented Khoesan-speaking San population and other darkly pigmented Africans. may play a role in the local adaptation of this population,” says Yuanqing Feng, first author of the paper and a postdoctoral researcher in the Tishkoff lab.

The researchers note that pigmentation is a complex trait influenced by hundreds of variants scattered throughout the genome, with the majority located in non-coding regions. These non-coding variants can affect the expression of genes up to a million bases away.

The large number of mutations associated with skin color and the uncertainty surrounding the target genes regulated by these mutations make it particularly difficult for researchers to find the precise genetic mechanisms governing this trait.

Feng and colleagues used massively parallel reporter analyzes to discern the regulatory activities of thousands of variants. This high-throughput technique reduced thousands of candidates to 165 functional variants. To identify the target genes of these functional variants, Feng further constructed high-resolution chromatin interaction maps in melanocytic cells using chromatin conformation capture assays.

“This is a high-resolution 3D genomic map of melanoma cells that will be valuable for gene regulation studies in pigmentation and melanoma biology,” says Feng.

Using CRISPR/Cas9-based genome editing, researchers found that mutations in an enhancer of OCA2, a gene associated with albinism, could lead to a 75% reduction in melanin levels compared to cells witnesses. Within the same OCA2 enhancer, the researchers identified two closely localized regulatory variants, estimated to be 1.2 million years old and 57,000 years old, the latter coinciding with the period of human migration from Africa.

“This case illustrates the continuous evolution of human skin color, and it is remarkable to observe the significant effects on skin pigmentation attributed to a single activator,” says Feng.

The San have relatively lighter pigmentation than other African populations and have the oldest genetic lineages in humans. Although it is hypothesized that the light skin color of the San may result from adaptation to a southern African environment, the genetic basis of this adaptation remains elusive. Researchers identified several crucial regulatory variants near MITF, LEF1, and TRPS1 that contribute to the skin color adaptation observed in the San.

“MITF, LEF1, and TRPS1 are involved in signaling pathways regulating both melanocyte differentiation and hair development,” says Tishkoff. “This suggests that variants influencing the lighter skin pigmentation seen in the San people may also contribute to their distinctive hair morphology.”

Notably, the variant close to TRPS1 associated with lighter skin color is at a frequency close to 100% among the San and most non-Africans, whereas the variant associated with darker skin color is common in most other African populations and in the darkly pigmented Melanesian population. a striking example of global adaptations to UV exposure.

Additionally, researchers discovered a new gene impacting human skin pigmentation, CYB561A3, which regulates iron homeostasis and influences melanin levels in melanocyte cells.

“To our knowledge, the role of CYB561A3 in skin pigmentation has not been previously reported. Intriguingly, reports have linked intravenous iron infusion to skin hyperpigmentation. Since CYB561A3 encodes an iron reductase, I’m curious about the role of this protein in this process,” says Tishkoff.

“Our findings highlight the complexity of genetic factors influencing skin color and the benefits of including ethnically diverse and underrepresented populations in genetic studies,” she says. “Performing functional studies on the impact of non-coding variants will improve our understanding of the genetics underlying complex human traits and disease risk.”

“The populations included in this study come from remote areas of Africa and required the use of a mobile laboratory set up in the field,” says Tishkoff. “Collaboration with our partners in Africa was key to the success of this research project.”

In future research, the Tishkoff lab would like to use its innovative functional genomics approach to identify more genetic variants contributing to human pigmentation and other adaptive traits in a larger sample of ethnically diverse Africans.