造血系统嵌合型Y染色体丢失:从人群队列到致病机制  

Hematopoietic mosaic loss of Y chromosome:from population cohorts to pathogenic mechanisms

作　　者：朱丽娜 汪旭[1,2] 郭锡汉 Lina Zhu;Xu Wang;Xihan Guo(School of Life Sciences,Yunnan Normal University,Kunming 650500,China;Yeda Institute of Gene and Cell Therapy,Taizhou 318000,China)

机构地区：[1]云南师范大学生命科学学院,昆明650500 [2]台州耶大基因与细胞治疗研究院,台州318000

出　　处：《遗传》2025年第4期409-427,共19页Hereditas(Beijing)

基　　金：国家自然科学基金项目(编号:32260148,31900410);云南省兴滇英才-青年人才项目资助。

摘　　要：嵌合型Y染色体丢失(mosaic loss of Y chromosome(LOY),m LOY)是指男性部分体细胞因Y染色体(Y chromosome,Chr Y)丢失而与非LOY细胞形成的遗传嵌合现象。m LOY主要发现于血液中,不仅因为血细胞易取样,更因为发生LOY突变的造血干细胞在获得竞争优势后可驱动克隆性造血,产生大量携带LOY突变的血细胞。由于结构的特殊性,人Chr Y在有丝分裂时易发生异常分离,同时在种系突变、环境暴露、衰老微环境等因素的驱动下,m LOY成为男性体细胞中最常见的获得性突变。早期的人群队列研究显示造血系统m LOY与男性预期寿命缩短以及癌症、阿尔茨海默病和心血管疾病等慢病风险增加显著相关,近期的小鼠模型研究表明m LOY是白血病和心血管疾病的诱发因素。因此,m LOY不仅为众多慢病的发生发展提供了共同的遗传学基础,也为研究人类寿命与疾病风险中的性别差异提供了新的内核。本文首先简述了LOY驱动克隆性造血的人群队列研究进展,随后梳理出m LOY的危险因素、检测方法和小鼠模型的构建策略,并总结了m LOY诱发多种重大慢病的潜在分子机制,最后对m LOY领域的挑战和发展机遇提出了前瞻展望。相关综述成果为深入研究Chr Y的生物学功能和慢病的性别差异提供参考。Mosaic loss of Y Chromosome(mLOY)refers to genetic mosaicism in males where some somatic cells have lost the Y chromosome(ChrY)while other cells remain their ChrY.mLOY is primarily found in the blood,not only because blood cells are easily accessible,but also because hematopoietic stem cells with LOY mutation gain competitive advantages,therefore producing a large number of LOY-positive blood cells via clonal hematopoiesis.Due to the specific structures,human ChrY is prone to be missegregated during mitosis,and driving by the germline variants,environmental insults and aging microenvironments,mLOY becomes the most commonly acquired age-related mutation in male genomes.Population-based cohort studies have shown that men with a certain degree of mLOY is associated with significantly reduced life expectancy and increased risks of cancer,Alzheimer’s disease,cardiovascular diseases and among others.Recent studies using mouse models have further demonstrated that mLOY is a driving factor of leukemia and cardiovascular diseases.These findings suggest that mLOY not only provides a common genetic explanation for the occurrence of many chronic diseases in men,but also provides a new kernel for studying sex differences in human lifespan and disease risk.Here,we briefly summarize the findings from the population-based cohort studies on clonal hematopoiesis driven by LOY.Subsequently we sort out the risk factors of mLOY,methods for detecting mLOY and developing mLOY mouse models,and the potential mechanisms of mLOY in promoting a myriad of chronic diseases.Finally,we provide our own forward-looking perspectives for the future challenges and opportunities in mLOY.The findings from this review provide references for studying the biological role of Y chromosome and sex difference of chronic diseases.

关 键 词：嵌合型Y染色体丢失 克隆性造血 阿尔茨海默病 白血病 心血管疾病 

分 类 号：R394[医药卫生—医学遗传学]