Estimation of mosaic loss of Y chromosome cell fraction with genotyping arrays lacking coverage in the pseudoautosomal region

Background Mosaic loss of the Y chromosome (mLOY) in circulating leukocytes is the most frequently detected age-related chromosomal mosaic event in men. Current mLOY detection approaches use genotyping arrays and employ a phase-based approach that identifies B allele frequency (BAF) deviations in the pseudo-autosomal region (PAR) shared between the X and Y chromosome. As some widely used genotyping arrays lack sufficient probe coverage of the PAR, methods for accurately measuring mLOY utilizing the median log(2) R ratio across the male-specific region of Y chromosome (mLRR_Y) are needed for detecting mLOY on these platforms. Results We derived a formula from mLRR_Y to estimate the cellular fraction (CF) of cells with Y loss and validated the approach, finding high alignment with the CF estimation from female data and lab-generated qPCR data (R-2 = 0.98). Additionally, we compared the correlation between phase-based BAF and mLRR_Y methods for CF estimation, achieving a high correlation with R-2 > 0.80. Conclusion Although mLRR_Y is a noisier metric for mosaic chromosomal alteration detection relative to BAF, we demonstrate mLRR_Y across non-PAR variants can accurately estimate mLOY CF, especially for high CF mLOY.