Integrative functional genomic analyses identify genetic variants influencing skin pigmentation in Africans.

Abstract

Skin color is highly variable in Africans, yet little is known about the underlying molecular mechanism. Here we applied massively parallel reporter assays to screen 1,157 candidate variants influencing skin pigmentation in Africans and identified 165 single-nucleotide polymorphisms showing differential regulatory activities between alleles. We combine Hi-C, genome editing and melanin assays to identify regulatory elements for MFSD12, HMG20B, OCA2, MITF, LEF1, TRPS1, BLOC1S6 and CYB561A3 that impact melanin levels in vitro and modulate human skin color. We found that independent mutations in an OCA2 enhancer contribute to the evolution of human skin color diversity and detect signals of local adaptation at enhancers of MITF, LEF1 and TRPS1, which may contribute to the light skin color of Khoesan-speaking populations from Southern Africa. Additionally, we identified CYB561A3 as a novel pigmentation regulator that impacts genes involved in oxidative phosphorylation and melanogenesis. These results provide insights into the mechanisms underlying human skin color diversity and adaptive evolution.

• Authors: Yuanqing Feng, Ning Xie, Fumitaka Inoue, Shaohua Fan, Joshua Saskin, Chao Zhang, Fang Zhang, Matthew E B Hansen, Thomas Nyambo, Sununguko Wata Mpoloka, Gaonyadiwe George Mokone, Charles Fokunang, Gurja Belay, Alfred K Njamnshi, Michael S Marks, Elena Oancea, Nadav Ahituv, Sarah A Tishkoff
• Journal: Nature genetics (Nat Genet) Vol. 56 Issue 2 Pg. 258-272 (Feb 2024) ISSN: 1546-1718 [Electronic] United States
• PMID: 38200130 (Publication Type: Journal Article)
• Copyright: © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Melanins
• TRPS1 protein, human
• Repressor Proteins

Topics

• Humans
• Skin Pigmentation (genetics)
• Melanins (genetics)
• Alleles
• Genomics
• Pigmentation (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Repressor Proteins (genetics)
• Albinism, Oculocutaneous