Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publication in refereed journal
香港中文大學研究人員
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替代計量分析
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摘要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.
Significance:
This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression.
Significance:
This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression.
出版社接受日期01.03.2022
著者Wang X, Hu W, Li X, Huang D, Li Q, Chan H, Zeng J, Xie C, Chen H, Liu X, Gin T, Wang MHT, Cheng ASL, Kang W, To KF, Plewczynski D, Zhang Q, Chen X, Chan DCW, Ko H, Wong SH, Yu J, Chan MTV, Zhang L, Wu WKK
期刊名稱Cancer Research
出版年份2022
月份4
卷號82
期次8
頁次1482 - 1491
國際標準期刊號0008-5472
電子國際標準期刊號1538-7445
語言英式英語
