Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution

• Main Authors: Wang, Xiansong, Hu, Wei, Li, Xiangchun, Huang, Dan, Li, Qing, Chan, Hung, Zeng, Judeng, Xie, Chuan, Chen, Huarong, Liu, Xiaodong, Gin, Tony, Wang, Maggie Haitian, Cheng, Alfred Sze Lok, Kang, Wei, To, Ka-Fai, Plewczynski, Dariusz, Zhang, Qingpeng, Chen, Xiaoting, Chan, Danny Cheuk Wing, Ko, Ho, Wong, Sunny Hei, Yu, Jun, Chan, Matthew Tak Vai, Zhang, Lin, Wu, William Ka Kei
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Medicine; Cancer; Expression
• Online Access: https://hdl.handle.net/10356/163562
• Institution: Nanyang Technological University

Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in Xenopus tropicalis. In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation.