Loss of Y in leukocytes, dysregulation of autosomal immune genes and disease risks

Mosaic loss of chromosome Y (LOY) in blood is linked to increased risk for morbidity and mortality in men. LOY is the most common acquired mutation and is associated with diseases such as cancer and Alzheimers disease. We studied DNA, RNA and proteins in bulk, sorted- and single-cells in vivo and in vitro. We show that Alzheimers disease and prostate cancer patients had more LOY in NK cells and CD4+ T-lymphocytes, respectively. Furthermore, gene expression was profoundly altered in cells with LOY in a pleiotropic fashion and autosomal genes important for normal immune cell functions showed LOY associated transcriptional effect. Proteomic analysis also indicated that LOY leaves a footprint in the plasma proteome. We provide the first mechanistic explanation for the associations between LOY in blood and risk for disease in other organs.