TY - JOUR
T1 - Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
AU - Wang, Xiansong
AU - Hu, Wei
AU - Li, Xiangchun
AU - Huang, Dan
AU - Li, Qing
AU - Chan, Hung
AU - Zeng, Judeng
AU - Xie, Chuan
AU - Chen, Huarong
AU - Liu, Xiaodong
AU - Gin, Tony
AU - Wang, Maggie Haitian
AU - Cheng, Alfred Sze Lok
AU - Kang, Wei
AU - To, Ka-Fai
AU - Plewczynski, Dariusz
AU - Zhang, Qingpeng
AU - Chen, Xiaoting
AU - Chan, Danny Cheuk Wing
AU - Ko, Ho
AU - Wong, Sunny Hei
AU - Yu, Jun
AU - Chan, Matthew Tak Vai
AU - Zhang, Lin
AU - Wu, William Ka Kei
PY - 2022/4/15
Y1 - 2022/4/15
N2 - 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.Aphylogeny-basedmodel unveiled a higher Xchromosometo- 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.
AB - 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.Aphylogeny-basedmodel unveiled a higher Xchromosometo- 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.
UR - http://www.scopus.com/inward/record.url?scp=85128469757&partnerID=8YFLogxK
UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85128469757&origin=recordpage
U2 - 10.1158/0008-5472.CAN-21-3458
DO - 10.1158/0008-5472.CAN-21-3458
M3 - RGC 21 - Publication in refereed journal
C2 - 35247889
SN - 0008-5472
VL - 82
SP - 1482
EP - 1491
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -
