A research lab led by Prof. SU Bing from Kunming Institute of Zoology of the Chinese Academy of Sciences, in collaboration with scientists from Tibetan University and Zhengzhou University, have discovered the key gene explaining the genetic adaptation of skin color of Tibetans.
Due to the long-time settlement at high altitude, Tibetans have been adapted to high altitude extreme environmens. Previous studies on the adaptation of Tibetans have been focusing on hypobaric hypoxia, and many genes have been discovered, such as the EPAS1 gene encoding hypoxia-inducible factor 2a (HIF2a). However, the adaptation to the other key high-altitude stress, i.e. strong UV radiation remains elusive.
It is well known that the adaption of humans to UV radiation is to increase the production of melanin in the skin for protection. Therefore, among the world populations, those living near the equator (such as Africa and Southeast Asia) usually have dark constitutive skin color (the skin areas not exposed to sunlight, such as buttock and underarm). Notably, the intensity of UV radiation at the Qinghai-Tibetan Plateau is much stronger than most of the lowland areas( lowland cities at the same latitude, and even higher than those of Southeast Asian countries). Accordingly, both the constitutive and facultative (the skin area exposed to sunlight, such as forehead) colors of Tibetans are relatively dark, though the underlying genetic regulation conferring the dark skin is yet to be understood.
The identified gene which can explain the genetic adaptation of skin color of Tibetans is GNPAT, a gene involved in the melanin production pathway, and the gene upstream contains an adaptive mutation (rs75356281) that has been enriched in Tibetans (58%) due to natural selection, while it is relatively rare in other world populations (0-18%).
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 indicate 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 suggests 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, researchers propose that Tibetans have darker baseline skin color compared to lowland Han Chinese, 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.
This study, entitled “Genetic adaptation of skin pigmentation in highland Tibetans”, was published in Proceedings of the National Academy of Sciences. Dr. SU Bing, Dr. YANG Zhaohui and Dr. QI Xuebin are the co-corresponding authors. Drs. BAI Caijuan, PU Youwei, KONG Qinghong and GUO Yongbo are the co-first authors. This project was financially supported by grants from Strategic Priority Research Program of the Chinese Academy of Sciences (XDA20040102), and the National Natural Science Foundation of China (32070579 and 31601016), as well as other provincial funding.
