本文選題：Y染色體 + 精子發(fā)生　； 參考：《復(fù)旦大學(xué)》2007年博士論文

【摘要】： 人類Y染色體上的AZFc區(qū)及其中的多拷貝基因在精子發(fā)生過程中有著重要的作用。近年來(lái)的研究發(fā)現(xiàn)，AZFc區(qū)中存在各種染色體結(jié)構(gòu)的變化，包括染色體片斷的缺失、倒位和重復(fù)等。其中，AZFc區(qū)的全缺失是男性不育最常見的致病因素之一，它會(huì)導(dǎo)致精子發(fā)生過程產(chǎn)生障礙。AZFc區(qū)中還發(fā)現(xiàn)有部分缺失(包括gr／gr缺失和b2／b3缺失)存在，，但是學(xué)術(shù)界對(duì)它們?cè)诰影l(fā)生過程中的影響作用存在爭(zhēng)論。研究AZFc區(qū)各種染色體結(jié)構(gòu)的變化及其導(dǎo)致的基因拷貝數(shù)的變化對(duì)精子發(fā)生過程的影響，將幫助我們弄清AZFc區(qū)中不同基因及其不同拷貝在精子發(fā)生過程中的作用。 本研究中，我們對(duì)中國(guó)人群中的7個(gè)AZFc全缺失家系，296例無(wú)精癥或者少精癥病例，以及280例健康對(duì)照進(jìn)行了缺失篩查，DAZ基因的定量分析，和Y染色體單倍群的分型。在我們研究的人群中，gr／gr缺失及b2／b3缺失與精子發(fā)生障礙之間沒有明顯的關(guān)聯(lián)。另外，對(duì)中國(guó)8個(gè)民族15個(gè)不同人群的gr／gr缺失篩查后發(fā)現(xiàn)，該AZFc部分缺失在中國(guó)人群中較為常見。綜合以前的報(bào)道，我們的結(jié)果顯示，AZFc部分缺失對(duì)精子發(fā)生過程的影響存在群體差異性。導(dǎo)致這種差異的原因之一可能是DAZ基因不同拷貝間生精功能的差異，也可能是不同群體間不同的Y染色體遺傳背景的影響。 對(duì)gr／gr缺失中涉及的DAZ基因拷貝進(jìn)行分析后發(fā)現(xiàn)，本研究中的gr／gr缺失主要涉及的是DAZ1和DAZ2基因拷貝的缺失，而在歐洲人群中的研究卻發(fā)現(xiàn)這兩個(gè)基因拷貝對(duì)于精子發(fā)生是重要的。可見，DAZ基因拷貝的功能也存在群體差異性。對(duì)Y染色體的單倍群分型后發(fā)現(xiàn)，AZFc的各類結(jié)構(gòu)變化在各單倍群中的分布差異較大。我們不僅驗(yàn)證了已報(bào)道的b2／b3缺失單倍群N，而且發(fā)現(xiàn)了一個(gè)新的gr／gr缺失單倍群Q1。Y染色體遺傳背景對(duì)缺失分布的巨大影響提示我們，在進(jìn)行與Y染色體相關(guān)的疾病研究時(shí)，對(duì)樣本進(jìn)行Y染色體分型，檢測(cè)病例和對(duì)照的匹配性是很重要的。 另外，我們?cè)?個(gè)AZFc全缺失家系中還發(fā)現(xiàn)有一例特殊的家系，其中的全缺失是由AZFc部分缺失發(fā)生進(jìn)一步的缺失后產(chǎn)生的。這說明，除了常見的一步法缺失方式，AZFc全缺失存在分步缺失的第二種缺失方式。同時(shí)，我們還發(fā)現(xiàn)AZFc全缺失在部分缺失單倍群N和Q1中的頻率顯著高于其他非缺失單倍群。這些結(jié)果表明，AZFc部分缺失會(huì)增加全缺失發(fā)生的風(fēng)險(xiǎn)。 此外，我們還發(fā)現(xiàn)了AZFc中DAZ基因的重復(fù)現(xiàn)象，并且過高的DAZ基因拷貝可能不利于精子的發(fā)生。 AZFc中的基因都是多拷貝的。對(duì)于這些重復(fù)拷貝在精子發(fā)生中的作用形式，有人提出了拷貝劑量模型，認(rèn)為拷貝數(shù)的降低會(huì)導(dǎo)致精子發(fā)生障礙。但是，很多已報(bào)道的實(shí)驗(yàn)結(jié)果與這一模型相左。綜合以前的結(jié)果和本研究的數(shù)據(jù)，我們提出了一個(gè)新的假說——突變積累模型。我們認(rèn)為，突變的積累是導(dǎo)致AZFc結(jié)構(gòu)變化在某些群體中對(duì)精子發(fā)生過程產(chǎn)生不利影響的原因。我們的這一模型和已經(jīng)報(bào)道的結(jié)果基本一致，為我們的后續(xù)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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2007
【分類號(hào)】：R394;R698.2

【參考文獻(xiàn)】

相關(guān)博士學(xué)位論文 前1條

1 文波;Y染色體、mtDNA多態(tài)性與東亞人群的遺傳結(jié)構(gòu)[D];復(fù)旦大學(xué);2004年

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