人类Y染色体AZFc区结构变化对精子发生的影响

发布时间：2018-06-25 17:47

本文选题：Y染色体 + 精子发生　；参考：《复旦大学》2007年博士论文

【摘要】： 人类Y染色体上的AZFc区及其中的多拷贝基因在精子发生过程中有着重要的作用。近年来的研究发现，AZFc区中存在各种染色体结构的变化，包括染色体片断的缺失、倒位和重复等。其中，AZFc区的全缺失是男性不育最常见的致病因素之一，它会导致精子发生过程产生障碍。AZFc区中还发现有部分缺失(包括gr／gr缺失和b2／b3缺失)存在，，但是学术界对它们在精子发生过程中的影响作用存在争论。研究AZFc区各种染色体结构的变化及其导致的基因拷贝数的变化对精子发生过程的影响，将帮助我们弄清AZFc区中不同基因及其不同拷贝在精子发生过程中的作用。本研究中，我们对中国人群中的7个AZFc全缺失家系，296例无精症或者少精症病例，以及280例健康对照进行了缺失筛查，DAZ基因的定量分析，和Y染色体单倍群的分型。在我们研究的人群中，gr／gr缺失及b2／b3缺失与精子发生障碍之间没有明显的关联。另外，对中国8个民族15个不同人群的gr／gr缺失筛查后发现，该AZFc部分缺失在中国人群中较为常见。综合以前的报道，我们的结果显示，AZFc部分缺失对精子发生过程的影响存在群体差异性。导致这种差异的原因之一可能是DAZ基因不同拷贝间生精功能的差异，也可能是不同群体间不同的Y染色体遗传背景的影响。对gr／gr缺失中涉及的DAZ基因拷贝进行分析后发现，本研究中的gr／gr缺失主要涉及的是DAZ1和DAZ2基因拷贝的缺失，而在欧洲人群中的研究却发现这两个基因拷贝对于精子发生是重要的。可见，DAZ基因拷贝的功能也存在群体差异性。对Y染色体的单倍群分型后发现，AZFc的各类结构变化在各单倍群中的分布差异较大。我们不仅验证了已报道的b2／b3缺失单倍群N，而且发现了一个新的gr／gr缺失单倍群Q1。Y染色体遗传背景对缺失分布的巨大影响提示我们，在进行与Y染色体相关的疾病研究时，对样本进行Y染色体分型，检测病例和对照的匹配性是很重要的。另外，我们在7个AZFc全缺失家系中还发现有一例特殊的家系，其中的全缺失是由AZFc部分缺失发生进一步的缺失后产生的。这说明，除了常见的一步法缺失方式，AZFc全缺失存在分步缺失的第二种缺失方式。同时，我们还发现AZFc全缺失在部分缺失单倍群N和Q1中的频率显著高于其他非缺失单倍群。这些结果表明，AZFc部分缺失会增加全缺失发生的风险。此外，我们还发现了AZFc中DAZ基因的重复现象，并且过高的DAZ基因拷贝可能不利于精子的发生。 AZFc中的基因都是多拷贝的。对于这些重复拷贝在精子发生中的作用形式，有人提出了拷贝剂量模型，认为拷贝数的降低会导致精子发生障碍。但是，很多已报道的实验结果与这一模型相左。综合以前的结果和本研究的数据，我们提出了一个新的假说——突变积累模型。我们认为，突变的积累是导致AZFc结构变化在某些群体中对精子发生过程产生不利影响的原因。我们的这一模型和已经报道的结果基本一致，为我们的后续深入研究指明了方向。
[Abstract]:The AZFc region on the human Y chromosome and its multiple copy genes play an important role in the process of spermatogenesis. In recent years, a variety of chromosomal structures in the AZFc region have been found, including the deletion, inversion and repetition of chromosomal fragments, among which the total loss of AZFc is one of the most common pathogenic factors for male infertility. Partial deletion (including Gr / GR deletion and B2 / B3 deletion) exists in the.AZFc region that causes the disturbance of spermatogenesis, but there is an argument about their influence on the process of spermatogenesis. The changes in the various chromosomal structures in the AZFc region and the changes in the number of copies of the genes in the AZFc region have been studied in the process of spermatogenesis. The effect will help us understand the roles of different genes and their different copies in spermatogenesis in AZFc region.
In this study, we examined 7 AZFc total missing families in the Chinese population, 296 cases of azoospermia or oligospermia, and 280 healthy controls for deletion screening, quantitative analysis of the DAZ gene, and the typing of the Y chromosome unfold group. In our study, there is no clear difference between Gr / GR loss and B2 / B3 deletion and spermatogenesis disorder. In addition, the Gr / GR deletion screening of 15 different people in 8 ethnic groups in China found that the partial deletion of the AZFc was more common in the Chinese population. Our results showed that there was a group difference in the effect of partial AZFc deletion on the process of spermatogenesis. One of the reasons for this difference may be the DAZ base. The difference in spermatogenesis among different copies may also be the effect of different Y chromosome genetic backgrounds among different populations.
The analysis of DAZ gene copies involved in Gr / GR deletion found that GR / GR deletion in this study was mainly involved in the deletion of DAZ1 and DAZ2 copies, while in the European population, the two copies of these genes were found to be important for spermatogenesis. It is found that the distribution of various structural changes in AZFc is larger than that in the haploid group. We not only verified the reported B2 / B3 deletion haploid group N, but also found that a new Gr / GR deletion single fold group of Q1.Y chromosome genetic background has a great effect on the deletion distribution of the Q1.Y chromosome, suggesting that we are on the Y chromosome phase. It is very important to detect the Y chromosome typing of samples and detect the matching of case and control.
In addition, we found a special family in 7 AZFc missing families. The total deletion was caused by further deletion of the partial deletion of AZFc. This indicates that there are second ways of missing AZFc total deletion in addition to the common one-step deletion method. At the same time, we also found that the total deletion of AZFc is in the Department. The frequencies of N and Q1 in the haploid group were significantly higher than those in other non deletion haplogroups. These results indicate that partial deletion of AZFc increases the risk of total deletion.
In addition, we also discovered the duplication of DAZ gene in AZFc, and the high copy of DAZ gene may not be beneficial to spermatogenesis.
All the genes in AZFc are multiple copies. For these duplicates in the form of spermatogenesis, a copy dose model has been proposed, which suggests that the decrease in copy numbers will lead to spermatogenesis. However, many reported experimental results are left to this model. We put forward a combination of previous results and data from this study. A new hypothesis, catastrophe accumulation model. We believe that the accumulation of mutations is the cause of the adverse effects of AZFc structural changes on the process of spermatogenesis in some populations. Our model is basically consistent with the reported results, pointing out the direction for our further in-depth study.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R394;R698.2

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