title: Gene copy number alterations in the azoospermia-associated AZFc region and their effect on spermatogenic impairment.
abstract: The azoospermia factor c (AZFc) region in the long arm of human Y chromosome is characterized by massive palindromes. It harbors eight multi-copy gene families that are expressed exclusively or predominantly in testis. To assess systematically the role of the AZFc region and these eight gene families in spermatogenesis, we conducted a comprehensive molecular analysis (including Y chromosome haplogrouping, AZFc deletion typing and gene copy quantification) in 654 idiopathic infertile men and 781 healthy controls in a Han Chinese population. The b2/b3 partial deletion (including both deletion-only and deletion-duplication) was consistently associated with spermatogenic impairment. In the subjects without partial AZFc deletions, a notable finding was that the frequency of DAZ and/or BPY2 copy number alterations in the infertile group was significantly higher than in the controls. Combined patterns of DAZ and/or BPY2 copy number abnormality were associated with spermatogenic impairment when compared with the pattern of all AZFc genes with common level copies. In addition, in Y chromosome haplogroup O1 (Y-hg O1), the frequency of copy number alterations of all eight gene families was significantly higher in the case group than that in the control group. Our findings indicate that the DAZ, BPY2 genes may be prominent players in spermatogenesis, and genomic rearrangements may be enriched in individuals belonging to Y-hg O1. Our findings emphasize the necessity of routine molecular analysis of AZFc structural variation during the workup of azoospermia and/or oligozoospermia, which may diminish the genetic risk of assisted reproduction.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Chuncheng
authors.initials: C
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Ruyang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Miaofei
authors.initials: M
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xuejiang
authors.initials: X
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Bixian
authors.initials: B
authors.lastname: Ni
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Harvard University, Boston, MA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Diao
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jiahao
authors.initials: J
authors.lastname: Sha
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China yankaixia@njmu.edu.cn.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
mesh_terms: D000328:Adult; D044466:Asian People; D053713:Azoospermia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D002681:China; D041322:Chromosomes, Human, Y; D015331:Cohort Studies; D000075364:Deleted in Azoospermia 1 Protein; D017353:Gene Deletion; D018628:Gene Dosage; D020440:Gene Duplication; D056726:Genetic Association Studies; D056426:Genetic Loci; D006801:Humans; D007248:Infertility, Male / Q000209:etiology; D008297:Male; D005810:Multigene Family; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D013091:Spermatogenesis
chemical_list: C466623:BPY2 protein, human; C095668:DAZ1 protein, human; D000075364:Deleted in Azoospermia 1 Protein; D011506:Proteins; D016601:RNA-Binding Proteins
keywords: AZFc; Y chromosome haplogroup; copy number alteration; spermatogenic impairment