Mosaic loss of Chromosome Y in aged human microglia

Abstract

Mosaic loss of Chromosome Y (LOY) is a common acquired structural mutation in the leukocytes of aging men that is correlated with several age-related diseases including Alzheimer's disease (AD). The molecular basis of LOY in brain cells has not been systematically investigated. Here, we present a large-scale analysis of single-cell and single-nuclei RNA brain datasets, yielding 851,674 cells, to investigate the cell type–specific burden of LOY. LOY frequencies differed widely between donors and CNS cell types. Among five well-represented neural cell types, LOY was enriched in microglia and rare in neurons, astrocytes, and oligodendrocytes. In microglia, LOY was significantly enriched in AD subjects. Differential gene expression (DE) analysis in microglia found 172 autosomal genes, 3 X-linked genes, and 10 pseudoautosomal genes associated with LOY. To our knowledge, we provide the first evidence of LOY in the microglia, and highlight its potential roles in aging and the pathogenesis of neurodegenerative disorders such as AD.

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood

“…Higher clonal fraction leading to shorter telomere length may promote genomic instability and acquisition of additional CHIP driver mutations 36,38 . Intriguingly, mLOY and CHIP have opposite associations with Alzheimer’s disease (AD) with mLOY being associated with an ∼2.5 fold increased risk and CHIP having a protective effect 4,40,41 . Additional studies of the clonal dynamics of clones harboring mLOY and CHIP mutations may help further elucidate their association with AD.…”

Mosaic Loss of Chromosome Y Is Associated With Functional Outcome After Ischemic Stroke

“…3,4 There is an increased proportion of cells with LOY in postmortem brain tissue from patients with neurodegenerative disorders compared with controls. 1,2 We found that a polygenic risk score for LOY 5 is associated with poor poststroke outcome. 6 Based on this background, we hypothesized that LOY itself is associated to poor ischemic stroke outcome.…”

Why loss of Y? A pan-cancer genome analysis of tumors with loss of Y chromosome

“…LoY might be seen as a quantitative trait starting at the level of an individual cell in a man, spanning over just detectable levels in bulk tissue analyses up to a level where the majority of cells within a tissue is affected. LoY has been detected in microglia on a single cell level with associated expression alterations of autosomal genes suggesting the possibility as a contributing factor in the pathogenesis of neurodegenerative disorders [48] . Multiple epidemiological studies identified LoY in blood cells as a significant risk factor for shortened lifespan and various diseases in males [22] , including increased heart failure mortality and a mouse model for hematopoietic LoY showed macrophage and TGFβ1 mediated cardiac fibrosis [43] .…”