Guo Xihan, Dai Xueqin
School of Life Sciences, Yunnan Normal University, Kunming, 650500, Yunnan, China.
Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
Geroscience. 2025 Feb;47(1):631-651. doi: 10.1007/s11357-024-01468-7. Epub 2024 Dec 16.
Mosaic loss of Y chromosome (mLOY) is an acquired condition wherein a sizeable proportion of an organ's cells have lost their Y. Large-scale cohort studies have shown that mLOY is age-dependent and a strong risk factor for all-cause mortality and adverse outcomes of age-related diseases. Emerging multi-omics approaches that combine gene expression, epigenetic and mutational profiling of human LOY cell populations at single-cell levels, and contemporary work in in vitro cell and preclinical mouse models have provided important clues into how mLOY mechanistically contributes to disease onset and progression. Despite these advances, what has been missing is a system-level insight into mLOY. By integrating the most recent advances in wide-ranging aspects of mLOY research, we summarize a unified model to understanding the cause and consequence of mLOY at the molecular, cellular, and organismal levels. This model, referred to as the "Unstable Y Cascade model," states that (i) the rise and expansion of LOY result from interaction by the inherently unstable Y, germline genetic and epigenetic variants, and numerous cell-intrinsic and external factors; (ii) LOY initiates genomic, epigenomic, and transcriptomic alterations in X and autosomes, thereafter induces a cascade of tissue-specific cellular alterations that contribute locally to the onset and progression of diseases; and (iii) LOY cells exert paracrine effects to non-LOY cells, thereby amplifying LOY-associated pathological signaling cascades to remote non-LOY cells. This new model has implications in the development of therapeutic interventions that could prevent or delay age-related diseases via mitigating mLOY burden.
Y染色体镶嵌性缺失（mLOY）是一种后天获得的状况，即器官中相当一部分细胞失去了Y染色体。大规模队列研究表明，mLOY与年龄相关，是全因死亡率和年龄相关疾病不良结局的强风险因素。新兴的多组学方法结合了单细胞水平上人类LOY细胞群体的基因表达、表观遗传和突变谱分析，以及体外细胞和临床前小鼠模型的当代研究工作，为mLOY在发病机制上如何促进疾病发生和发展提供了重要线索。尽管取得了这些进展，但仍缺乏对mLOY的系统层面的认识。通过整合mLOY研究广泛领域的最新进展，我们总结了一个统一模型，以在分子、细胞和机体水平上理解mLOY的原因和后果。这个模型被称为“不稳定Y级联模型”，它指出：（i）LOY的出现和扩增是由内在不稳定的Y染色体、生殖系遗传和表观遗传变异以及众多细胞内在和外部因素相互作用导致的；（ii）LOY引发X染色体和常染色体的基因组、表观基因组和转录组改变，进而诱导一系列组织特异性细胞改变，局部促进疾病的发生和发展；（iii）LOY细胞对非LOY细胞发挥旁分泌作用，从而将与LOY相关的病理信号级联放大到远处的非LOY细胞。这个新模型对开发治疗干预措施具有启示意义，这些干预措施可以通过减轻mLOY负担来预防或延缓年龄相关疾病。
