Mosaic loss of chromosome Y

LOY in a small proportion of leukocytes has been associated with a number of diseases such as cancer,^[3] Alzheimer's disease,^[6] and cardiovascular disease.^[7] The exact biological pathways explaining these connections are currently unknown.^[8] LOY can also occur in cells of the buccal mucosa and dorsolateral prefrontal cortex.^[5]

The accurate detection and quantification of mosaic loss of the Y chromosome (mLOY) are crucial for understanding its prevalence, risk factors, and health implications. Over time, methodologies have evolved from basic microscopic observations to highly sensitive molecular techniques.

The initial discovery of age-related Y chromosome loss in the 1960s was made using karyotyping. Karyotyping has limited sensitivity, it can only detect LOY when a substantial proportion of cells are affected, and cannot precisely quantify the percentage of cells with LOY.

Modern Molecular Techniques include Single Nucleotide Polymorphism (SNP) Arrays, where for mLOY detection, researchers look for a significant reduction in the signal intensity of Y-chromosome-specific markers compared to autosomal (non-sex) chromosomes. Since males typically have one X and one Y chromosome, a loss of the Y chromosome results in a measurable decrease in the Y-specific signal.^[9] In Droplet Digital PCR (ddPCR), genes unique to the Y chromosome (e.g., SRY or AMELY) are targeted and their copy number is compared to a reference autosomal gene.^[10] Single-Cell Approaches are more powerful for mLOY research because it can identify which specific cell types (e.g., different types of white blood cells like T cells, B cells, or monocytes) are affected by Y chromosome loss and how the gene expression within those individual cells is altered.

Regardless of the method, the core principle for quantifying mLOY involves comparing the dosage of Y chromosome material to a stable reference (like an autosomal chromosome or the X chromosome in males). A ratio significantly below the expected 1:1 (Y:autosome) or 1:1 (Y:X) indicates the proportion of cells that have lost the Y chromosome.^[8]