X-linked competition — implications for human development and disease

• Published in: Nature reviews. Genetics Vol. 26; no. 8; pp. 571 - 580
• Main Authors: Boone, Philip M., Buenaventura, Teresa, King, James W. D., Merkenschlager, Matthias
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2025; Nature Publishing Group
• Subjects: 631/208/135; 631/208/176; 692/420/2489/144; Agriculture; Animal Genetics and Genomics; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cells; Chromosomes, Human, X - genetics; Cloning; Competition; Embryos; Epigenetics; Female; Females; Gene Function; Gene silencing; Genes, X-Linked; Genetic Diseases, X-Linked - genetics; Human Development; Human Genetics; Humans; Lymphocytes; Male; Perspective; Propagation; Transgenic animals; X Chromosome Inactivation - genetics; X chromosomes; X-chromosome inactivation
• ISSN: 1471-0056; 1471-0064; 1471-0064
• DOI: 10.1038/s41576-025-00840-3

During early mammalian female development, X chromosome inactivation leads to random transcriptional silencing of one of the two X chromosomes. This inactivation is maintained through subsequent cell divisions, leading to intra-individual diversity, whereby cells express either the maternal or paternal X chromosome. Differences in X chromosome sequence content can trigger competitive interactions between clones that may alter organismal development and skew the representation of X-linked sequence variants in a cell-type-specific manner — a recently described phenomenon termed X-linked competition in analogy to existing cell competition paradigms. Skewed representation can define the phenotypic impact of X-linked variants, for example, the manifestation of disease in female carriers of X-linked disease alleles. Here, we review what is currently known about X-linked competition, reflect on what remains to be learnt and map out the implications for X-linked human disease. Differences in X chromosome sequence content can trigger competitive interactions between clones that may alter organismal development and skew the representation of X-linked sequence variants in a cell-type-specific manner. The authors review this recently described phenomenon of X-linked competition and map out the implications for X-linked human diseases.