Zhou Weiyin, Huang Wen-Yi, Freedman Neal D, Machiela Mitchell
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
BMC Bioinformatics. 2025 Feb 19;26(1):60. doi: 10.1186/s12859-025-06076-6.
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 R ratio across the male-specific region of Y chromosome (mLRR_Y) are needed for detecting mLOY on these platforms.
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 = 0.98). Additionally, we compared the correlation between phase-based BAF and mLRR_Y methods for CF estimation, achieving a high correlation with R > 0.80.
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.
循环白细胞中的Y染色体嵌合缺失（mLOY）是男性中最常检测到的与年龄相关的染色体嵌合事件。当前的mLOY检测方法使用基因分型阵列，并采用基于相位的方法来识别X和Y染色体之间共享的假常染色体区域（PAR）中的B等位基因频率（BAF）偏差。由于一些广泛使用的基因分型阵列缺乏对PAR的足够探针覆盖，因此需要利用Y染色体男性特异性区域的中位数对数R比率（mLRR_Y）来准确测量mLOY的方法，以在这些平台上检测mLOY。
我们从mLRR_Y推导出一个公式来估计Y缺失细胞的细胞分数（CF），并验证了该方法，发现与来自女性数据和实验室生成的qPCR数据的CF估计高度一致（R = 0.98）。此外，我们比较了基于相位的BAF和mLRR_Y方法在CF估计方面的相关性，相关系数R> 0.80，具有高度相关性。
尽管相对于BAF，mLRR_Y是检测嵌合染色体改变的噪声更大的指标，但我们证明跨非PAR变体的mLRR_Y可以准确估计mLOY CF，特别是对于高CF的mLOY。
