Impact of Y-Chromosome Loss on Age-Related Gene Expression

Background: Loss of Y chromosome (LOY) is associated with compromised DNA repair, increased inflammation, and diminished immune surveillance. Single-cell RNA sequencing (scRNA-seq) elucidates the impact of LOY in the kidney, which may provide insight into how LOY heightens susceptibility to chronic kidney disease (CKD), acute kidney injury (AKI) and renal cancer. This study analyzes a large scRNA-seq dataset from the Kidney Precision Medicine Project (KPMP) to examine the effects of aging and LOY in different kidney cell types. Methods: The KPMP dataset comprised 174 participants: 87 males, 85 females, and 2 individuals with an unspecified sex, aged 20 to 89. These data include samples from healthy individuals (n=55) and patients with CKD (n=82), AKI (n=33), and diabetes mellitus without CKD (n=3). scRNA-seq raw data was realigned, preprocessed to remove doublets, and integrated using scvi-tools. LOY cells were genotyped based on the lack of Y chromosome transcripts in cells meeting prespecified filters. Differential expression was compared between groups using scanpy. Results: We observed significant age-related changes in gene expression among multiple kidney cell types. In aged men, TTTY14 and USP9Y (Y chromosome transcripts) were significantly decreased in healthy proximal tubule (PT) and injured PT subsets, parietal epithelial cells, and distal nephron cell types. Cell types with the highest proportion of LOY were injured subsets of proximal tubule: PT_MT (22%), PT_PROM1 (17%), and PT_VCAM1 (13%). LOY in PT was associated with enrichment of multiple pathways, including calcium reabsorption, immune response, and metabolic pathways. Conclusion: LOY significantly impacts gene expression in PT of aging males. Elevated LOY in PT cell types correlates with enrichment of pathways linked to calcium reabsorption, immune response and metabolic pathways. These data suggest LOY contributes to cellular dysfunction and may predispose men to kidney disease. Funding: Other NIH Support - DK126847