Abstract
Mosaic loss of chromosome Y (LOY) is the acquired absence of the Y chromosome in a fraction of cells, is most readily observed in the haematopoietic compartment, and represents the most common form of clonal mosaicism in older men. Once dismissed as a benign correlate of aging, LOY is now recognized as a clinically meaningful biomarker associated with reduced survival and an expanding range of age-related disorders, including multiple solid and haematological cancers, cardiovascular disease, Alzheimer's disease, and type 2 diabetes mellitus. Large-scale genome-wide analyses have shown that susceptibility to LOY is highly heritable and associated with genes involved in cell cycle regulation, the DNA damage response, and apoptosis, supporting a model in which detectable LOY in blood reflects broader genomic instability across tissues. In parallel, functional studies in genetically engineered mice have demonstrated that haematopoietic LOY can contribute causally to pathologic processes such as cardiac fibrosis, indicating that loss of dosage-sensitive Y-linked genes in immune cells may exert direct effects rather than merely serving as a passive marker. Progress in this field has been constrained by detection methods that are laborious, costly, or insufficiently sensitive at low mutant cell fractions. This constraint is now easing on two fronts. Haplotype- and coverage-based callers can detect LOY from whole-genome and exome sequencing data generated for other purposes, extending measurement to ancestrally diverse cohorts and tumour genomes, while newer single-cell droplet-based approaches permit accurate quantification of LOY and its female counterpart, mosaic loss of chromosome X (LOX), at single-cell resolution. Here, we summarize the biology, genetic architecture, disease associations, and proposed mechanisms of LOY and discuss how improved detection may help clarify its causal contribution to human aging and disease.