Single-cell X-chromosome inactivation analysis links biased chimerism to differential gene expression and epigenetic erosion

Female cells randomly inactivate one X-chromosome, resulting in cellular mosaicism. Determining the bias in X-chromosomal inactivation (XCI) at single cell level may be relevant for understanding diseases prevalent in females. Here, we introduce a computational method that determines XCI profiles at single-cell level using solely sc/snRNA-Seq data. XCI analysis of skin cells from hybrid mice validates our approach and reveals biased inactivation of X-chromosomes among cell types. In human lung and brain cells, XCI status can be determined in 33.8% and 23.6% of cells. Among the patients, cells with opposite inactivation patterns differently express members of specific gene families and pathways. Alzheimer’s disease patients show reversal of XCI in cortical microglia and regional increase in biallelic expression denoting epigenetic erosion. We provide a robust utility to explore the degree and impact of XCI in single cell expression data.