Bruhn-Olszewska Bozena, Markljung Ellen, Rychlicka-Buniowska Edyta, Sarkisyan Daniil, Filipowicz Natalia, Dumanski Jan P
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
3P-Medicine Laboratory, Medical University of Gdańsk, Gdańsk, Poland.
Nat Rev Genet. 2025 May;26(5):320-335. doi: 10.1038/s41576-024-00805-y. Epub 2025 Jan 2.
Loss of Y chromosome (LOY) is the most commonly occurring post-zygotic (somatic) mutation in male individuals. The past decade of research suggests that LOY has important effects in shaping the activity of the immune system, and multiple studies have shown the effects of LOY on a range of diseases, including cancer, neurodegeneration, cardiovascular disease and acute infection. Epidemiological findings have been corroborated by functional analyses providing insights into the mechanisms by which LOY modulates the immune system; in particular, a causal role for LOY in cardiac fibrosis, bladder cancer and Alzheimer disease has been indicated. These insights show that LOY is a highly dynamic mutation (such that LOY clones expand and contract with time) and has pleiotropic, cell-type-specific effects. Here, we review the status of the field and highlight the potential of LOY as a biomarker and target of new therapeutics that aim to counteract its negative effects on the immune system.
Y染色体丢失（LOY）是男性个体中最常见的合子后（体细胞）突变。过去十年的研究表明，LOY在塑造免疫系统活性方面具有重要作用，多项研究显示了LOY对一系列疾病的影响，包括癌症、神经退行性疾病、心血管疾病和急性感染。功能分析证实了流行病学研究结果，这些分析为LOY调节免疫系统的机制提供了见解；特别是，已表明LOY在心脏纤维化、膀胱癌和阿尔茨海默病中具有因果作用。这些见解表明，LOY是一种高度动态的突变（LOY克隆会随时间扩展和收缩），并具有多效性、细胞类型特异性效应。在此，我们综述该领域的现状，并强调LOY作为生物标志物和旨在抵消其对免疫系统负面影响的新疗法靶点的潜力。
