Abstract
Human-specific insertions play important roles in human phenotypes and diseases. Here we reported a 446-bp insertion (Insert-446) in intron 11 of the TBC1D8B gene, located on chromosome X, and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5. Interestingly, Insert-446 was present in the human Neanderthal and Denisovans genomes, and was fixed in humans after human-chimpanzee divergence. We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques. In addition, over-expression TBC1D8B promoted cell proliferation and migration through “a dual finger” catalytic mechanism (Arg538 and Gln573) in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo. Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells. Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene. These findings provide a significant insight into the effects of human-specific insertions on evolution.
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The relevant data are included in the paper and accompanying Supporting Information, or are available from the corresponding author upon reasonable request.
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Acknowledgement
This work was supported by Key Research and Development Program of Yunnan (202203AC100010), the National Natural Science Foundation of China (31760311, 32160236, 81830087, U2102203), the National Key Research and Development Program of China (2022YFC2601604, 2018YFC2000400, 2020YFA0112300), Spring City Plan: the High-level Talent Promotion and Training Project of Kunming (2022SCP001), the Yunnan Fundamental Research Projects (CY22624104, 202101AS070050), the open project of State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences (GREKF17-01), and Yunnan University’s new round of “Double First-Class” Construction Project—For People’s Life and Health (CY22624104). We thank Q. Sun (Chinese Academy of Medical Sciences) and Z. Yang (Guangzhou Medical University) for technical support.
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Zhao, H., Liu, LL., Sun, J. et al. A human-specific insertion promotes cell proliferation and migration by enhancing TBC1D8B expression. Sci. China Life Sci. 67, 765–777 (2024). https://doi.org/10.1007/s11427-023-2442-3
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DOI: https://doi.org/10.1007/s11427-023-2442-3