遗传 ›› 2025, Vol. 47 ›› Issue (4): 409-427.doi: 10.16288/j.yczz.24-211
收稿日期:
2024-07-17
修回日期:
2024-09-24
出版日期:
2025-04-20
发布日期:
2024-09-26
通讯作者:
郭锡汉,博士,副教授,研究方向:Y染色体丢失的病理生理学效应。E-mail: guo_xihan@163.com作者简介:
朱丽娜,硕士研究生,专业方向:Y染色体丢失与阿尔茨海默病。E-mail: 3117698437@qq.com
基金资助:
Lina Zhu1(), Xu Wang1,2, Xihan Guo1(
)
Received:
2024-07-17
Revised:
2024-09-24
Published:
2025-04-20
Online:
2024-09-26
Supported by:
摘要:
嵌合型Y染色体丢失(mosaic loss of Y chromosome (LOY), mLOY)是指男性部分体细胞因Y染色体(Y chromosome, ChrY)丢失而与非LOY细胞形成的遗传嵌合现象。mLOY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ChrY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,mLOY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mLOY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mLOY是白血病和心血管疾病的诱发因素。因此,mLOY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mLOY的危险因素、检测方法和小鼠模型的构建策略,并总结了mLOY诱发多种重大慢病的潜在分子机制,最后对mLOY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ChrY的生物学功能和慢病的性别差异提供参考。
朱丽娜, 汪旭, 郭锡汉. 造血系统嵌合型Y染色体丢失:从人群队列到致病机制[J]. 遗传, 2025, 47(4): 409-427.
Lina Zhu, Xu Wang, Xihan Guo. Hematopoietic mosaic loss of Y chromosome: from population cohorts to pathogenic mechanisms[J]. Hereditas(Beijing), 2025, 47(4): 409-427.
图2
人ChrY的结构特征及LOY的微核模型 A:人ChrY的结构特征。Yq含大量扩增和回文序列,常见的微缺失发生在无精子症因子(azoospermia factor,AZF)区域,包括AZFa、AZFb和AZFc[35]。B:LOY的微核模型。在有丝分裂过程中,ChrY因错误分离,进而直接产生LOY细胞,或者通过微核化产生LOY细胞。包括以下途径:①两条ChrY姐妹染色单体未分离,产生一个含有两条ChrY的子细胞和一个LOY细胞;②其中一个为正常子细胞,另一个子细胞的ChrY发生微核化,当微核被排出或降解后便产生LOY细胞;③其中一个为LOY细胞,另一个子细胞的细胞核和细胞质中各有一条ChrY,细胞质中微核化的ChrY被排出或降解后产生正常细胞;④其中一个为LOY细胞,另一个子细胞的细胞质中含两条ChrY,微核化的ChrY被排出或降解后产生形成LOY细胞;⑤两个子细胞的ChrY均在细胞质中,微核化的ChrY被排出或降解后形成LOY细胞。图绘制网址: https://www.biorender.com。"
表1
环境暴露与大规模人群血液中mLOY研究汇总"
人群 来源 | 队列 人数 | 环境 暴露 | 携带mLOY人数(检出率) | 环境暴露与mLOY相关性 | 检测 方法 | 检测位点 | 主要科学发现 | 参考 文献 |
---|---|---|---|---|---|---|---|---|
瑞典 | 6,014 | 香烟 | 900(14.96%) | P=0.00094 | SNP 微阵列 | ChrY: 2694521-59034049 | 吸烟与血液中的mLOY有关,且吸烟对mLOY有短暂和剂量依赖的诱变效应。 | [ |
美国 | 933 | PM10 | 66(7.1%) | P=0.03 | SNP 微阵列 | ChrY: 7502455-21979204 | 室外空气污染物如PM10可能会增加白细胞中mLOY。 | [ |
1,606 | 草甘膦 | 342(21.3%) | P=0.07 | SNP 微阵列 | PAR | 老年男性农民长期大量使用草甘膦可能与mLOY呈正相关。 | [ | |
中国 | 954 | 多环芳烃 | 23(2.4%) | P<0.05 | SNP 微阵列 | ChrY: 2655180-59034049 | 多环芳烃暴露与mLOY之间存在线性剂量效应关系。 | [ |
888 | 重金属 (1-OHNa, Sb, Mo) | - | P<0.01 | SNP 微阵列 | ChrY: 2655180-59034049 | 1-OHNa、Sb和Mo是与mLOY相关的重要的化学物质,其增加DNA损伤可能对血液mLOY增加有联合作用。 | [ | |
10,158 | PM2.5 | - | P<0.05 | SNP 微阵列 | ChrY: 2655180-59034049 | PM2.5暴露对mLOY有加速效应,并验证了PM10对mLOY的有害影响。 | [ | |
孟加 拉国 | 1,364 | 砷 | 178(13.05%) | P=0.065 | SNP 微阵列 | ChrY: 2 694521-59034049; 2781480-56887902 | 砷暴露与mLOY的增加有关;mLOY还与砷引起的皮肤损伤的风险增加有关。 | [ |
图3
mLOY的检测技术 A:利用光学显微镜和荧光显微镜可以直观地检测整条ChrY是否存在。B:利用SNP微阵列和二代测序检测LOY。利用Illumina SNP 微阵列芯片获得的归一化强度数据(Log R Ratio,LRR)可反映基因组不同区域的DNA拷贝数。因此,LOY的量化可以由位于MSY区域内的探针的LRR值的中位数(mLRRY)计算得出。若其中没有LOY的个体mLRRY值显示在零附近,若mLRRY值降低,表明mLOY水平增加。利用二代测序也可检测基因组拷贝数变异。C:利用PCR技术检测LOY。多重定量荧光PCR(QF-PCR)和微滴式数字PCR(ddPCR)通常以AMELY和AMELX 的比值评估LOY,二者的平均比值近似反映了LOY率。实时荧光定量PCR(RT-qPCR):在PCR扩增的指数时期,DNA模板的Ct值和该模板的起始拷贝数存在线性关系,可作为LOY定量的依据。图绘制网址: https://www.biorender.com。"
图4
mLOY小鼠模型的构建及其促进急性髓系白血病和心血管疾病研究 A:mLOY诱发小鼠急性髓系白血病。Zhang等[11]将sgSsty1-sgCas9、sgSsty2-sgCas9或sgScr-sgCas9和AML1-ETO共转染到HSPCs (Trp53-/-;Cas9)中,并将其通过尾静脉注射移植到亚致死辐照的野生型雌鼠中,发现mLOY协同AML1-ETO能诱发AML;B:mLOY促进小鼠克隆性造血。Zhang等[11]将sgSsty1-sgCas9、sgSsty2-sgCas9或sgScr-sgCas9转导至HSPCs (mCD45.1;Cas9)中,并将其移植到亚致死辐照的野生型雌鼠中,发现mLOY促进小鼠的克隆性造血。C:mLOY促进小鼠心脏功能下降。Sano等[12]把编码ChrY着丝粒的向导RNA(gRNA)和荧光标记物转导至ROSA26-Cas9小鼠HSCs中,通过眶后注射移植到亚致死辐射C57BL/6雄鼠中,发现mLOY能加速组织和心脏纤维化。此外,将mLOY雄鼠进行横向主动脉收缩手术后,发现小鼠心脏功能下降[12]。图绘制网址:https://www.biorender.com。"
表2
大规模人群队列血液中mLOY与各类慢病研究汇总"
人群 来源 | 研究疾病 | 与疾病的 相关性 | 检测方法 | 检测位点 | 主要科学发现 | 参考 文献 |
---|---|---|---|---|---|---|
德国 | 骨髓增生异常综合征 | P=0.005 | FISH | Yq12 | mLOY外周血细胞在年龄相关易感性骨髓增生异常综合征中是克隆性的。 | [ |
德国 | 年龄相关黄斑变性 | P=1.60e-08 | SNP微阵列 | ChrY: 2694521-59034049 | mLOY与年龄相关黄斑变性风险存在相关性。 | [ |
荷兰 | 心血管疾病 | P=0.02 | SNP微阵列、RT-PCR | TSPY1 | 在严重动脉粥样硬化人群中,血液中的mLOY与继发性心血管疾病独立相关。 | [ |
美国 | 膀胱癌、肺癌和前列腺癌 | P=0.12 | SNP微阵列、 WGS | ChrY: 6671498-22919969 | mLOY作为男性3种常见癌症的强危险因素的证据有限,并且没有观察到其与癌症诊断后生存率的关联。 | [ |
马其顿 | 前列腺癌、结直肠癌 | P=1.17×10-9 | QF-PCR | AMELY、AMELX | 外周血白细胞中mLOY与前列腺癌、结直肠癌发生风险显著相关。 | [ |
瑞典 | 非血液癌 | P=0.003 | SNP微阵列 | ChrY: 2694521-59034049 | mLOY与全因死亡率和非血液学癌症死亡率的风险相关。 | [ |
阿尔茨海默病 | P=0.0184 | SNP微阵列 | ChrY: 2694521-59034049 | 阿尔茨海默病患者mLOY流行率是非阿尔茨海默病群体的2.8倍。 | [ | |
瑞典、 波兰 | 阿尔茨海默病、前列腺癌 | P=0.0026 | SNP微阵列、ddPCR、WGS | ChrY: 2694521-59034049; AMELY、AMELX | 阿尔茨海默病患者和前列腺癌患者的自然杀伤细胞和CD4+T淋巴细胞中有更多的mLOY。 | [ |
西班牙 | 由冠状病毒2引起的严重急性呼吸系统综合征 | P=0.004 | SNP微阵列 | PAR1、PAR2 | 具有克隆嵌合事件(嵌合染色体改变和/或mLOY)的个体显示新冠肺炎致死风险增加了54%。 | [ |
意大利 | 自身免疫甲状腺炎 | P=0.037 | FISH | DYZ3、DYZ1 | 患自身免疫甲状腺炎男性血液中mLOY更高且这种现象随着年龄的增长而增加。 | [ |
原发性胆汁肝硬化 | P=0.0038 | FISH | DYZ3、DYZ1 | 患原发性胆汁肝硬化男性血液中mLOY更高且这种现象随着年龄的增长而增加。 | [ | |
英国 | 糖尿病、心血管疾病或中风 | P=0.0065 | SNP微阵列 | ChrY: 2658271-28767492 | mLOY与一些健康相关因素(即酒精、体重指数、吸烟、糖尿病和中风)以及种族有关。 | [ |
肺癌 | P=0.002 | SNP微阵列 | ChrY: 2658271-28767492 | 外周血白细胞中mLOY与肺癌发生风险增加相关。 | [ | |
糖尿病、高血压和血胆固醇过多症 | P=6.71×10-7 P<5×10-324 | SNP微阵列 | - | mLOY与循环血细胞总数之间存在显著的人群关联。 | [ | |
心血管疾病 | P=0.001 | SNP微阵列 | ChrY: 2649520-59034050 | mLOY白细胞中与男性由心血管疾病引起的死亡相关。 | [ | |
中国 | 急性髓系白血病 | P=0.048 | 核型分析 | - | 在接受高剂量阿糖胞苷治疗的男性患者中,mLOY与急性髓系白血病高复发风险相关。 | [ |
肺癌 | P=2.03×10-2 | SNP微阵列 | ChrY: 2694521-59034049 | 非吸烟男性血液中自发性LOY与健康个体肺癌风险降低以及肺癌患者更好的预后密切相关,而在吸烟群体中并未发现相关性。 | [ | |
精神分裂症 | - | ddPCR | AMELY、AMELX | 在中国汉族人群中,精神分裂症组与对照组之间的外周血mLOY无显著性差异。 | [ | |
肺癌 | P=0.046 | SNP微阵列 | - | 携带mLOY尤其是克隆性mLOY会显著增加肺癌的发病风险。 | [ |
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