In a study published in PNAS, a research team led by Prof. SU Bing from Kunming Institute of Zoology of the Chinese Academy of Sciences, in collaboration with researchers from Tibetan University and Zhengzhou University, discovered the key gene explaining the genetic adaptation of skin color of Tibetans. 

Due to the long-time high altitude settlement, Tibetans have been adapted to extreme environments there. Previous studies on the adaptation of Tibetans have been focusing on hypobaric hypoxia, and many related genes have been discovered, such as the EPAS1 gene encoding hypoxia-inducible factor 2a (HIF2a). For the adaptation to strong UV radiation, the underlying genetic regulation conferring the dark skin of Tibetans needs further exploration. 

The gene identified in this study which can explain the genetic adaptation of the skin color of Tibetans is GNPAT, a gene involved in the melanin production pathway. The gene upstream contains an adaptive mutation (rs75356281) that has been enriched in Tibetans (58%) due to natural selection.  

The genetic association analyses confirmed that the GNPAT mutation is closely related with both the constitutive and the facultative skin colors in Tibetans. 

Furthermore, the functional experiment using cell lines proved that the mutation affects the binding affinity of transcription factor and eventually leads to the change of enhancer activity of GNPAT. Under the lab-controlled UV radiation, the cell line carrying the adaptive allele of rs75356281 is more responsive to UV radiation compared to the ancestral allele. 

Finally, the gene-editing experiment indicated a dramatic change of gene expression profile of the cell line carrying the adaptive allele, resulting in differential expression of 1399 genes, much larger than the number of differentially expressed gene in the control cell line (74 genes). 

The molecular pathway analysis suggested that the adaptive allele of GNPAT promotes melanin synthesis, likely through the interactions of CAT and ACAA1 in peroxisome with other pigmentation genes, and they act synergistically, leading to an improved tanning ability in Tibetans for UV protection. 

In summary, the researchers proposed that Tibetans have darker baseline skin color as well as an improved tanning ability, suggesting a two-level adaptation to boost their melanin production in the strong UV-radiation environment at high altitude. 

The portrait of a Tibetan woman. (Image by YANG Zhaohui)