Mosaic loss of Chromosome Y in aged human microglia

Area of Science:

• Genetics
• Neuroscience
• Immunology

Background:

• Mosaic loss of chromosome Y (LOY) is a common acquired mutation in aging men's leukocytes.
• LOY is correlated with age-related diseases, including Alzheimer's disease (AD).
• The molecular basis and cell-type specificity of LOY in the brain remain largely uninvestigated.

Purpose of the Study:

• To investigate the cell type-specific burden of mosaic loss of chromosome Y (LOY) in the human brain.
• To determine the association of LOY with Alzheimer's disease (AD) at a single-cell level.
• To identify genes associated with LOY in specific brain cell types.

Main Methods:

• Analysis of a large-scale dataset comprising 851,674 single-cell and single-nuclei RNA sequencing data from human brain samples.
• Comparative analysis of LOY frequencies across different central nervous system (CNS) cell types.
• Differential gene expression (DE) analysis in LOY-enriched cell populations.

Main Results:

• LOY frequencies varied significantly between individuals and CNS cell types.
• LOY was found to be enriched in microglia and rare in neurons, astrocytes, and oligodendrocytes.
• In microglia, LOY was significantly enriched in subjects with Alzheimer's disease (AD), with associated differential expression of autosomal, X-linked, and pseudoautosomal genes.

Conclusions:

• This study provides the first evidence of mosaic loss of chromosome Y (LOY) in human brain microglia.
• The findings highlight the potential role of LOY in microglial function during aging and neurodegeneration, particularly in Alzheimer's disease (AD).
• LOY in microglia may represent a novel molecular mechanism contributing to the pathogenesis of neurodegenerative disorders.