Journal Article

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

Feng, Yuanqing, Marks, Michael S., Ahituv, Nadav, Nyambo, Thomas, Xie, Ning, Saskin, Joshua, Mpoloka, Sununguko Wata, Njamnshi, Alfred K., Belay, Gurja, Fan, Shaohua, Hansen, Matthew E. B., Fokunang, Charles, Oancea, Elena, Inoue, Fumitaka, Zhang, Fang, Zhang, Chao, Mokone, Gaonyadiwe George, Tishkoff, Sarah A.

2024

Overview

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. Massively parallel reporter assays identify 165 functional variants associated with skin pigmentation in ethnically diverse Africans. Functional characterization of eight variants demonstrates their impact in regulating melanin levels and validates CYB561A3 as a novel gene involved in melanogenesis and pigmentation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/43 / 45/47 / 631/208/191 / 631/208/200 / 631/208/457 / Adaptation / Agriculture / Albinism, Oculocutaneous / Alleles / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Color / CRISPR / Enhancers / Evolution / Evolution & development / Gene Function / Genetic analysis / Genetic diversity / Genetic variance / Genome editing / Genomes / Genomic analysis / Genomics / Haplotypes / Human Genetics / Humans / Melanin / Melanins - genetics / Molecular modelling / Nucleotides / Oxidative phosphorylation / Phosphorylation / Pigmentation / Pigmentation - genetics / Polymorphism, Single Nucleotide - genetics / Regulatory sequences / Repressor Proteins - genetics / Single-nucleotide polymorphism / Skin / Skin pigmentation / Skin Pigmentation - genetics