The Y chromosome, long regarded as a specialized chromosome dedicated primarily to male sex determination and reproduction, is increasingly recognized as a critical regulator of broader biological processes. Hematopoietic loss of chromosome Y (LOY) represents a striking example of this paradigm shift. As one of the most frequent somatic genomic alterations detected in male blood cells, LOY prevalence rises dramatically with age, affecting a substantial proportion of elderly men. However, recent research has demonstrated that LOY is far more than a passive bystander of the aging process; it is a biologically meaningful event with direct functional consequences for human health.
The mechanistic origins of hematopoietic LOY lie primarily in mitotic chromosome mis-segregation during cell division. During hematopoiesis, hematopoietic stem cells and progenitor cells undergo extensive proliferation, creating ample opportunity for errors in chromosome segregation. The Y chromosome, with its relatively small size and specialized centromeric structure, may be particularly vulnerable to such errors. Additionally, defects in the DNA damage response pathway and centromere dysfunction have been implicated as direct contributors to chromosome Y loss. Beyond these cell-intrinsic mechanisms, the review highlights three categories of indirect factors that modulate LOY risk: genetic factors including variants in TCL1A, TPS3, TSC22D2, and QKI genes; environmental exposures such as smoking and toxin exposure; and the aging process itself, which accumulates somatic mutations and impairs cellular fidelity over time.
Technological advances have been instrumental in advancing LOY research. The review systematically catalogs the approaches available for detecting LOY, ranging from classical cytogenetic techniques such as karyotyping and fluorescence in situ hybridization (FISH), to PCR-based methods, microarray platforms, bulk sequencing, and cutting-edge single-cell sequencing technologies. Each approach offers distinct advantages in terms of resolution, throughput, and cost. Single-cell sequencing, in particular, has revolutionized the field by enabling detection of LOY at the individual cell level, revealing the mosaic nature of hematopoietic cell populations and allowing researchers to trace the clonal dynamics of LOY cells over time.
The clinical implications of hematopoietic LOY are broad and multifaceted. Population-based studies have identified robust associations between LOY and cardiovascular disease, including coronary artery disease and heart failure, suggesting that LOY in immune cells may contribute to inflammatory processes underlying atherosclerosis. In the brain, LOY has been linked to neurodegenerative conditions such as Alzheimer's disease, potentially through altered microglial function and immune surveillance. Immune disorders represent another critical area, as LOY in lymphocytes can disrupt immune regulation and inflammatory responses. Furthermore, LOY has been associated with various cancers, both hematological malignancies and solid tumors, raising the possibility that LOY serves as a biomarker for cancer risk or progression.
Mechanistic studies have begun to unravel how LOY exerts its functional effects. Loss of the Y chromosome alters the expression of genes located on both the Y chromosome itself and autosomal chromosomes, leading to widespread transcriptional changes. Immune dysregulation is a particularly important consequence, as LOY in myeloid and lymphoid cells can skew cytokine production, impair phagocytic function, and alter adaptive immune responses. Clonal expansion of LOY cells represents another key mechanism: cells that have lost the Y chromosome may acquire a competitive fitness advantage, allowing them to outgrow normal cells and dominate the hematopoietic compartment. This clonal expansion can amplify the functional consequences of LOY over time.
Perhaps most compellingly, the review highlights evidence from CRISPR-based LOY mouse models and cellular systems that have successfully recapitulated key disease-related phenotypes. These experimental models have been instrumental in establishing causal relationships between LOY and disease processes, moving beyond correlational observations to mechanistic understanding. By genetically engineering loss of the Y chromosome in specific hematopoietic cell lineages, researchers have demonstrated that LOY directly impairs immune function, promotes inflammatory responses, and accelerates disease progression in mouse models of cardiovascular disease and cancer. Collectively, these findings establish hematopoietic LOY as a biologically meaningful form of somatic mosaicism with important implications for disease susceptibility, male health disparities, and the development of novel therapeutic and preventive strategies.


DOI
10.1007/s11684-026-1246-7