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// Juan Ji 1, 2, 3, * , Miaofei Xu 1, 2, * , Zhenyao Huang 1, 2, * , Lei Li 4 , Hongxiang Zheng 4 , Shuping Yang 4 , Shilin Li 4 , Li Jin 4 , Xiufeng Ling 1, 3 , Yankai Xia 1, 2 , Chuncheng Lu 1, 2 and Xinru Wang 1, 2 1 State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China 2 Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China 3 Department of Children Health Care, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China 4 State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China * The first three authors have contributed equally to this study and they should be regarded as joint first authors. Correspondence to: Chuncheng Lu, email: chunchenglu@njmu.edu.cn Xinru Wang, email: xrwang@njmu.edu.cn Keywords: oligoasthenospermia, mitochondrial DNA, genetic variant, haplogroup Received: November 09, 2016 Accepted: March 13, 2017 Published: May 08, 2017 ABSTRACT Genetic variants of mitochondrial DNA (mtDNA) were implicated to be associated with male infertility. Our previous whole mitochondrial genome sequencing and association study has identified two susceptibility mtDNA variants for oligoasthenospermia in Han Chinese men. In this study, we tested promising associations in an extended validation using 670 idiopathic oligoasthenospermia cases and 793 healthy controls to identify additional risk variants. We found that the genetic variant of m.11696G>A showed significantly higher frequency in the case group than that in the control group (odds ratio (OR) 2.21, 95% CI 1.21-4.04) ( P =7.90×10 -3 ). To elucidate the exact role of the genetic variants in spermatogenesis, two main sperm parameters (sperm count and motility) were taken into account. We found that m.11696G>A was associated with low sperm motility, with the OR of 2.38 (95 % CI 1.27-4.46) ( P =5.22×10 -3 ). These results advance our understanding of the genetic susceptibility to oligoasthenospermia and more functional studies are needed to provide insights into its pathogenic mechanism.

Human X chromosome has higher densities of microRNAs (miRNAs) compared to the average densities on autosomes. Given that numbers of X-linked miRNAs can escape from meiotic sex chromosome inactivation (MSCI) silencing, it is proposed that X-linked miRNAs may play critical roles in the process of spermatogenesis. To test the hypothesis, we performed DNA capture sequencing of human X-linked miRNAs, which was followed by a two-stage case-control study to identify the non-obstructive azoospermia (NOA) related single nucleotide variants (SNVs) in 1107 NOA cases and 1191 fertile healthy controls. Eventually, we found rs5951785, located near hsa-miRNA-506/507, increased the risk of NOA, while rs1447393, near hsa-miRNA-510, decreased the risk of NOA. Functional analysis revealed that rs5951785 significantly inhibited cell proliferation and induced cell apoptosis. Taken together, our results demonstrated that X-linked miRNAs played important roles in the pathogenesis of NOA.