期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 78, 期 8, 页码 4019-4033出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-03822-w
关键词
LOY; Mosaic loss of chromosome Y; Differential gene expression; LATE; LOY-associated transcriptional effects
资金
- Uppsala University
- Hjarnfonden
- Swedish Cancer Society
- Swedish Research Council
- Alzheimerfonden
- Konung Gustav V:s och Drottning Viktorias Frimurarestiftelse
- Science for Life Laboratory-Uppsala
- Foundation for Polish Science
- European Research Council ERC [679744]
- Kjell och Marta Beijers Stiftelse
- Swedish Research Council [2017-03762]
- Knut and Alice Wallenberg Foundation
- European Research Council (ERC) [679744] Funding Source: European Research Council (ERC)
- Swedish Research Council [2017-03762] Funding Source: Swedish Research Council
Epidemiological investigations have shown that mosaic loss of chromosome Y (LOY) in leukocytes is associated with increased mortality and morbidity in men. Studies on sorted and single cells revealed significant variations in the presence of LOY across cell types and individuals, suggesting potential pleiotropic effects on gene expression and immune function.
Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer's disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in similar to 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a genetic wasteland, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.
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