人类X染色体遗传变异在精子生成中的作用及其机制

项目名称： 人类X染色体遗传变异在精子生成中的作用及其机制

项目编号： No.81471500

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陆春城

作者单位： 南京医科大学

项目金额： 78万元

中文摘要： 精子发生是生殖健康领域研究的热点。男性携带性染色体X和Y各一条，相关基因的遗传缺陷无法得到同源基因的弥补，更易致病。Y染色体在精子生成障碍的研究中备受关注，但X染色体在生精过程中的作用却一直被忽视。近年研究发现，X染色体基因在维持正常男性生殖功能中具有重要意义。本项目拟以前期工作提出的X连锁变异及母系遗传和剂量敏感等非梗阻性无精子症发病机理模型为理论基础，以大样本人群关联研究为切入点，针对X染色体外显子组点突变及基因拷贝数变异等不同变异形式，应用高通量测序等基因组学手段，鉴定X染色体上与生精障碍相关的遗传变异，并通过体外试验，阐明X染色体基因在精子生成中的重要作用；在此基础上，通过核心家系分析，定位新产生（de novo）的致病性基因突变，发现X染色体上具有生精功能的关键基因。本项目研究可揭示X染色体及其基因在生精障碍中的作用方式与分子机制，为不育症的分子诊断和治疗提供新的途径。

中文关键词： 非梗阻性无精子症；精子生成障碍；X染色体；遗传变异；拷贝数变异

英文摘要： Spermatogenesis is the main research hotspots in the field of reproductive health. As males have only one X chromosome and one Y chromosome, therefore it is impossible to be compensated by a normal allele, and is susceptible to diseases. The role of the Y chromosome in spermatogenesis has been well established, while less attention is paid to X chromosome in the process of spermatogenesis. Recently, several studies have demonstrated that X chromosome was important in maintaining the normal male reproductive function. According to our previous studies, we have proposed the X-linked Maternal Inheritance (XMI) formation model of non-obstructive azoospermia (NOA), and the dosage sensitive pathogenesis model of X-linked multicopy gene in NOA. We will start with large population association studies, combine the information of X chromosome exome mutations and copy number variations (CNVs) of multicopy genes and apply methods in high throughput sequencing to investigate the mechanism of X chromosome genetic variations involved in spermatogenesis. Besides, through analyzing the trios' data, we will locate the de novo pathogenic mutation and identify the crucial spermatogenesis genes in X chromosome. This project will determine the role of X chromosome in spermatogenic failure and open avenues for the diagnosis and treatment of male infertility.

英文关键词： non-obstructive azoospermia (NOA);spermatogenic impairment;X chromosome;genetic variation;copy number variation(CNV)