Excess of Rare Variants in Genes that are Key Epigenetic Regulators of Spermatogenesis in the Patients with Non-Obstructive Azoospermia

被引：39

作者：

Li, Zesong ^{[1
,2
,3
]}

Huang, Yi ^{[2
,3
]}

Li, Honggang ^{[4
]}

Hu, Jingchu ^{[5
]}

Liu, Xiao ^{[5
]}

Jiang, Tao ^{[5
]}

Sun, Guangqing ^{[5
]}

Tang, Aifa ^{[2
,3
]}

Sun, Xiaojuan ^{[2
,3
]}

Qian, Weiping ^{[6
]}

Zeng, Yong ^{[7
]}

Xie, Jun ^{[1
]}

Zhao, Wei ^{[5
]}

Xu, Yu ^{[5
]}

He, Tingting ^{[5
]}

Dong, Chengliang ^{[5
]}

Liu, Qunlong ^{[6
]}

Mou, Lisha ^{[1
,2
,3
]}

Lu, Jingxiao ^{[2
]}

Lin, Zheguang ^{[1
]}

Wu, Song ^{[2
,3
]}

Gao, Shengjie ^{[5
]}

Guo, Guangwu ^{[5
]}

Feng, Qiang ^{[5
]}

Li, Yingrui ^{[5
]}

Zhang, Xiuqing ^{[5
]}

Wang, Jun ^{[5
]}

Yang, Huanming ^{[5
]}

Wang, Jian ^{[5
]}

Xiong, Chengliang ^{[4
]}

Cai, Zhiming ^{[2
,3
]}

Gui, Yaoting ^{[1
]}

机构：

[1] Peking Univ, Shenzhen Hosp, Shenzhen PKU HKUST Med Ctr, Inst Urol,Guangdong & Shenzhen Key Lab Male Repro, Shenzhen 518036, Peoples R China

[2] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Shenzhen Key Lab ofGenitourinary Canc, Shenzhen 518035, Peoples R China

[3] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Natl Reg Engn Lab Clin Applicat Canc Genom, Shenzhen 518035, Peoples R China

[4] Huazhong Univ Sci & Technol, Tongji Med Coll, Ctr Reprod Med, Family Planning Res Inst, Wuhan 430030, Peoples R China

[5] BGI Shenzhen, Shenzhen 518083, Peoples R China

[6] Peking Univ, Shenzhen Hosp, Ctr Reprod Med, Shenzhen 518036, Peoples R China

[7] Shenzhen Zhongshan Urol Hosp, Shenzhen Key Lab Reprod Immunol Periimplantat, Shenzhen 518045, Peoples R China

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

关键词：

GENOME-WIDE; MICE DEFICIENT; MICRODELETIONS; ASSOCIATION; METHYLATION; INFERTILITY; BROMODOMAIN; MUTATIONS; CHROMATIN; BIOLOGY;

D O I：

10.1038/srep08785

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Non-obstructive azoospermia (NOA), a severe form of male infertility, is often suspected to be linked to currently undefined genetic abnormalities. To explore the genetic basis of this condition, we successfully sequenced similar to 650 infertility-related genes in 757 NOA patients and 709 fertile males. We evaluated the contributions of rare variants to the etiology of NOA by identifying individual genes showing nominal associations and testing the genetic burden of a given biological process as a whole. We found a significant excess of rare, non-silent variants in genes that are key epigenetic regulators of spermatogenesis, such as BRWD1, DNMT1, DNMT3B, RNF17, UBR2, USP1 and USP26, in NOA patients (P = 5.5 x 10(-7)), corresponding to a carrier frequency of 22.5% of patients and 13.7% of controls (P = 1.4 x 10(-5)). An accumulation of low-frequency variants was also identified in additional epigenetic genes (BRDT and MTHFR). Our study suggested the potential associations of genetic defects in genes that are epigenetic regulators with spermatogenic failure in human.

引用

页数：7

共 30 条

[1] Genome-Wide Study of Single-Nucleotide Polymorphisms Associated With Azoospermia and Severe Oligozoospermia
Aston, Kenneth I.
Carrell, Douglas T.
[J]. JOURNAL OF ANDROLOGY, 2009, 30 (06): : 711 - 725
[2] Statistical analysis strategies for association studies involving rare variants
Bansal, Vikas
Libiger, Ondrej
Torkamani, Ali
Schork, Nicholas J.
[J]. NATURE REVIEWS GENETICS, 2010, 11 (11) : 773 - 785
[3] Simultaneous Genotype Calling and Haplotype Phasing Improves Genotype Accuracy and Reduces False-Positive Associations for Genome-wide Association Studies
Browning, Brian L.
Yu, Zhaoxia
[J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2009, 85 (06) : 847 - 861
[4] Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition
Chen, ZT
Karaplis, AC
Ackerman, SL
Pogribny, IP
Melnyk, S
Lussier-Cacan, S
Chen, MF
Pai, A
John, SWM
Smith, RS
Bottiglieri, T
Bagley, P
Selhub, J
Rudnicki, MA
James, SJ
Rozen, R
[J]. HUMAN MOLECULAR GENETICS, 2001, 10 (05) : 433 - 443
[5] Uncovering the roles of rare variants in common disease through whole-genome sequencing
Cirulli, Elizabeth T.
Goldstein, David B.
[J]. NATURE REVIEWS GENETICS, 2010, 11 (06) : 415 - 425
[6] Male infertility: role of genetic background
Ferlin, Alberto
Raicu, Florina
Gatta, Valentina
Zuccarello, Daniela
Palka, Giandomenico
Foresta, Carlo
[J]. REPRODUCTIVE BIOMEDICINE ONLINE, 2007, 14 (06) : 734 - 745
[7] The Sperm Epigenome: Implications for the Embryo
Gannon, John R.
Emery, Benjamin R.
Jenkins, Timothy G.
Carrell, Douglas T.
[J]. GENETIC DAMAGE IN HUMAN SPERMATOZOA, 2014, 791 : 53 - 66
[8] Chromatin and Transcription Transitions of Mammalian Adult Germline Stem Cells and Spermatogenesis
Hammoud, Saher Sue
Low, Diana H. P.
Yi, Chongil
Carrell, Douglas T.
Guccione, Ernesto
Cairns, Bradley R.
[J]. CELL STEM CELL, 2014, 15 (02) : 239 - 253
[9] Biochemistry and biology of mammalian DNA methyltransferases
Hermann, A
Gowher, H
Jeltsch, A
[J]. CELLULAR AND MOLECULAR LIFE SCIENCES, 2004, 61 (19-20) : 2571 - 2587
[10] A genome-wide association study in Chinese men identifies three risk loci for non-obstructive azoospermia
Hu, Zhibin
Xia, Yankai
Guo, Xuejiang
Dai, Juncheng
Li, HongGang
Hu, Hongliang
Jiang, Yue
Lu, Feng
Wu, Yibo
Yang, Xiaoyu
Li, Huizhang
Yao, Bing
Lu, Chuncheng
Xiong, Chenliang
Li, Zheng
Gui, Yaoting
Liu, Jiayin
Zhou, Zuomin
Shen, Hongbing
Wang, Xinru
Sha, Jiahao
[J]. NATURE GENETICS, 2012, 44 (02) : 183 - 186

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