Related Experiment Video

Updated: Oct 1, 2025

Combined DNA-RNA Fluorescent In situ Hybridization FISH to Study X Chromosome Inactivation in Differentiated Female Mouse Embryonic Stem Cells
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Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution

Xiansong Wang1,2, Wei Hu3, Xiangchun Li4

  • 1Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.

Cancer Research
|March 5, 2022
PubMed

Insights

Tumor suppressor genes (TSGs) on the X chromosome may be vulnerable to cancer due to single-hit inactivation. Evolution favored relocating these genes to autosomes, potentially enhancing tumor suppression and survival.

Area of Science:

  • Evolutionary biology
  • Genetics
  • Cancer research

Background:

  • Cancer-related genes face evolutionary pressures.
  • X-linked tumor suppressor genes (TSGs) may not be protected by Knudson's two-hit mechanism.
  • This suggests X-linked TSGs are subject to negative selection.

Purpose of the Study:

  • To investigate the evolutionary dynamics of X-linked TSGs.
  • To determine if TSGs have relocated from the X chromosome to autosomes during evolution.
  • To understand the implications for tumor suppression and cancer development.

Main Methods:

  • Comparative genomics and synteny analysis across mammalian and nonmammalian species.
  • Phylogeny-based modeling to assess gene relocation.
  • Ortholog mapping between human/mammalian TSGs and Xenopus tropicalis.
  • Pan-cancer analysis of somatic mutations in X-linked TSGs.

Main Results:

  • Mammalian X chromosomes show lower TSG-to-noncancer gene ratios compared to nonmammals.
  • X-linked TSGs were depleted on the mammalian X chromosome after the emergence of the XY system.
  • Significant X chromosome-to-autosome relocation flux of human TSGs was observed.
  • X-linked TSGs are younger/larger in humans and exhibit more frequent nonsynonymous mutations.

Conclusions:

  • Extensive evolutionary trafficking of TSGs from the X chromosome to autosomes has occurred.
  • X-linked TSGs represent a potential genetic vulnerability in tumor suppression.
  • Relocation of TSGs from the X chromosome may provide a survival advantage by evading single-hit inactivation.

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