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Loss of chromosome Y shapes the immune cell fate with aging in men

Dawoud, A. A. Z.; Green, L.; Rackham, O.

2025-06-02 genetic and genomic medicine
10.1101/2025.06.01.25328624 medRxiv
Show abstract

The loss of chromosome Y (LOY) in leukocytes is the most prevalent form of clonal mosaicism observed in older men. It is associated with all major causes of mortality, including cardiovascular diseases and cancer. However, LOY effect on individual immune-cell lineages remains unclear. Here, we used single-cell RNA sequencing data from Onek1K cohort and showed that LOY has a wide effect on cell fate across immune cell populations with the largest representation of LOY in classical monocytes. These monocytes exhibit a profibrotic signature marked by downregulation of IL1B and MYC-regulated genes, consistent with previous observations of LOY-associated macrophages in cardiac and pulmonary injury. Additionally, we detected an aberrant expression of XIST, the essential X-chromosome inactivation (XCI) lncRNA expressed in females, and not normally expressed in males. Notably, we observed upregulation of genes known to escape X-inactivation, including male-biased cancer-related genes KDM6A, DDX3X, KDM5C, and ZRSR2. Our results demonstrate the effect of LOY on the fate of immune cells, mediated by cell-type specific transcriptional changes and aberrant XCI characteristics.

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