造血系统嵌合型Y染色体丢失：从人群队列到致病机制

doi:10.16288/j.yczz.24-211

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Hereditas(Beijing) ›› 2025, Vol. 47 ›› Issue (4): 409-427.doi: 10.16288/j.yczz.24-211

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

Lina Zhu¹(), Xu Wang¹^,², Xihan Guo¹()

1. School of Life Sciences, Yunnan Normal University, Kunming 650500, China
2. Yeda Institute of Gene and Cell Therapy, Taizhou 318000, China

Received:2024-07-17 Revised:2024-09-24 Online:2025-04-20 Published:2024-09-26
Contact: Xihan Guo E-mail:3117698437@qq.com;guo_xihan@163.com
Supported by:
National Natural Science Foundation of China(32260148);National Natural Science Foundation of China(31900410);Xing Dian Plan “Youth Talent Program” of Yunnan Province

Abstract

Abstract:

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.

Key words: mosaic loss of Y chromosome, clonal hematopoiesis, Alzheimer’s disease, leukemia, cardiovascular diseases

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.

Figures/Tables 7

Fig. 1

Fig. 2

Table 1

Fig. 3

Fig. 4

Table 2

Summary of studies on the mLOY in blood from large populations and its association with various chronic diseases"

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。	[55]
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。	[62]
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。	[63]
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。	[13]
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。	[57]
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。	[44]
瑞典	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。	[21]
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。	[64]
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%。	[65]
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。	[53]
意大利	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。	[54]
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。	[10]
	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。	[66]
	糖尿病、高血压和血胆固醇过多症	P=6.71×10^-7P<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。	[9]
	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。	[12]
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。	[67]
	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。	[68]
	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。	[69]
	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。	[16]

Table 2

Fig. 5

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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。	[44]
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。	[45]
美国	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。	[46]
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。	[47]
	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。	[48]
	10,158	PM_2.5	-	P<0.05	SNP 微阵列	ChrY: 2655180-59034049	PM_2.5暴露对mLOY有加速效应，并验证了PM₁₀对mLOY的有害影响。	[49]
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。	[50]

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

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