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研究生:林怡彣
研究生(外文):Lin, Yi-Wen
論文名稱:無精症缺失基因特性之探討
論文名稱(外文):Characterization of the Human TestisExpressed DAZ (Deleted in Azoospermia) gene
指導教授:蕭百忍
指導教授(外文):Pauline H. Yen
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:英文
論文頁數:95
中文關鍵詞:無精症缺失基因男性不孕症
外文關鍵詞:Deleted in Azoospermiamale infertility
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中文摘要

第一部分: 無精症缺失基因其基因結構之分析
背景介紹—人類Y染色體是非常獨特的,因為在減數分裂的過程中,除了其偽染色體區域(psudo-autosomal region )之外,其他部分並不參與染色體配對(pairing)及交換(crossing over)。位於Y染色體上的AZFc(Azoospermi factor c)區域是由許多的重複序列所組成,因而導致此區域內基因重組(recombination)的情形經常發生。在非阻塞性無精症(non-obstructive azoospermia)或重症型寡精症(severe oligospermia)的不孕症(infertile)病人中經常可見AZFc區域的缺失情形。AZFc區域中含有幾個只在睪丸中表現(testis-specific expression)的基因組(gene families),其中包含無精症缺失基因(Deleted in Azoospermia; DAZ)組。大部分的男性具有四個DAZ基因,這些基因的蛋白質產物為核糖核苷酸結合蛋白(RNA-binding proteins),其可能與訊息核糖核苷酸轉譯(mRNA translation)的調控有關。這四個DAZ基因應該會分別轉譯出含有不同數量之RNA-binding protein(RRM)及DAZ重複序列(DAZ repeat)的蛋白質。至目前為止,這四個DAZ基因只能藉由單一核苷酸多樣性(single nucleotide variants)來做區分。
方法—基因體南方雜合(Genomic Southern hybridization),螢光原位雜合法(Fluorescence in situ hybridization; FISH)及DAZ基因數量聚合酶鏈反應實驗(DAZ dosage PCR assay)。
結果—
1. 在本研究中,我們設計了一項新的Genomic Southern Hybridization方法來探討及區分四個DAZ基因,由雜合片段定量分析結果,我們發現在82個男性個案中有五位(約佔6%)具有六個DAZ基因,而這似乎是姊妹染色體間發生gr/gr區域重組後,除了造成兩個DAZ基因外的另一個重組後相對產物,我們並進一步利用FISH在其中三位中確認了六個DAZ基因的存在情形,這五位具有六個DAZ基因的個案中,有兩位是不孕症患者。
2. 為了能快速分析DAZ的基因數目,我們設計了DAZ dosage PCR assay,此實驗中利用DAZ同源基因(DAZ-Like gene)作為基因數量的對照,我們更進一步利用Southern hybridization來證實此方法所得結果的可靠性。
3. 我們利用DAZ dosage PCR assay篩檢了580位台灣漢族。將此實驗結果與這些個案AZFc區域中序列標誌點(Sequence tagged-sites; STSs)的存在與否情形整合後,我們發現在580位台灣漢族中約有9.5%有AZFc部分缺失(partial deletion)情形,有2.8%有AZFc部分缺失後再發生複製(partial deletion followed by duplication)的情形,有1.7% 則具有AZFc部分複製(partial duplication)的情形。就整體重組情形而言,在不同單倍群(haplogroups ; Yhgs)間則有顯著差異,在Yhg O3e族群中,只有2.9%具有重組情形,但在Yhg N及Q族群中則全部(100%)都有重組情形。
4. 至目前為止,AZFc duplication與男性不孕症(male fertility)的相關性為何仍不清楚,我們因此分別針對具有生育力(fertile)的107位及不孕症(infertile)的142位個案進行分析,探討他們的DAZ基因數目及AZFc區域的重組(rearrangements)情形。我們發現gr/gr區域缺失(gr/gr deletion)及b2/b3區域缺失(b2/b3 deletion)的情形在fertile及infertile間並無明顯差異,但AZFc partial duplication的情形則是在infertile個案中的出現頻率(7.0%)明顯比在fertile個案中(0.9%)及台灣漢族(1.7%)中來的高。
結論—
1. 我們的研究指出DAZ genes具有多樣性(polymorphisms)的特性。
2. 我們認為姊妹染色體間的交換(sister chromatid exchange)情形在造成Y染色體上基因的缺失(deletions),複製(duplications)及多樣化(polymorphisms)上扮演著著重要的角色。
3. 我們設計的DAZ dosage PCR assay是一個可信賴及快速的分析辦法來探討DAZ的基因數目,此方法可便利的應用在大量樣本的篩檢上。
4. 我們的研究結果指出在台灣漢族中,AZFc partial deletion及partial duplication是普遍存在的多樣性(polymorphisms)情形。
5. 就台灣族群而言,並非AZFc partial deletion,而是AZFc partial duplication才是造成男性不孕(male infertility)的危險因子。

第二部分: 無精症缺失基因其基因表現之分析
背景介紹—
DAZ基因家族的蛋白質產物為核糖核苷酸結合蛋白(RNA-binding proteins),其在配子細胞生成(gametogenesis)上扮演重要角色。這個基因家族包含三個成員:在所有單細胞後生動物(metazoans)都具有的BOULE基因;在所有的脊柱動物(vertebrates )都具有的DAZL基因;以及只在舊大陸猴(Old World monkeys)及人類(humans)的Y染色體上特具有DAZ基因。大部分的男性具有四個DAZ基因,這四個DAZ基因應該會分別轉譯出含有不同數量之RNA-binding protein(RRM)及DAZ重複序列(DAZ repeat)的蛋白質。DAZ2 及 DAZ3具有一個RNA-binding protein(RRM),DAZ1具有三個RRMs,DAZ4則具有兩個RRMs。至今,研究結果已清楚的指出DAZL及 BOULE在配子細胞生成上的重要性,但是DAZ在男性精子生成過程(spermatogenesis)所扮演的角色則仍不清楚,而且是否四個DAZ基因都具有功能也仍有待進一步的探討。
方法—反轉錄聚合酶鏈反應(RT-PCR)及西方點墨法(Western blots)。
結果—
1. RT-PCR結果發現,在睪丸中可偵測到四個DAZ基因分別不同長度的核糖核苷酸轉錄片段(RNA transcripts),但其表現量遠比DAZL的RNA transcripts來的低,約只有DAZL transcripts量的1/4,
2. 在Western blots實驗中,我們偵測不到DAZ基因的蛋白質產物。
3. 在轉殖細胞(transfected cell)中,我們發現帶有全長(full length) DAZ cDNA的載體(含有多個DAZ repeats)其在細胞內的蛋白質產量較帶有刪除(truncated) DAZ cDNA載體(只含有兩個DAZ repeats)的來得低,但是其RNA transcripts量並無明顯差異。
結論—
1. 我們的研究指出,在睪丸中,四個DAZ基因都有被轉錄,但其表現量明顯比DAZL的RNA transcripts來的低。
2. 我們發現,在transfected cell中帶有full length DAZ cDNA的載體其蛋白質產量較帶有truncated DAZ cDNA的載體低,但是其RNA transcripts量並無明顯差異,我們推測這可能與全長DAZ cDNA其protein synthesis較低或其蛋白質較不穩定(instability of the proteins)有關,其真正的導因將有賴未來更進一步實驗的探討。
3. 在睪丸中,DAZ基因的表現情形與DAZL相比顯著偏低,我們因此猜測在精子生成過中,DAZ的功能可能相當有限。
Abstract

PART Ⅰ: gene structure analysis of the DAZ genes
Background—The human Y chromosome is unique in that it does not engage in pairing and crossing over during meiosis for most of its length. The azoospermia factor c (AZFc) region of the human Y chromosome consists entirely of very long repeats and is prone to rearrangement. This region is frequently deleted in infertile men with non-obstructive azoospermia or severe oligospermia. Several gene families with testis-specific expression are located within AZFc, including the Deleted in Azoospermia (DAZ) gene family. Most men have 4 DAZ genes that encode RNA-binding proteins implicated in the regulation of mRNA translation. The four DAZ genes encode different copy number of the RNA-recognition motif (RRM) and the DAZ repeat. So far, the four DAZ genes can be distinguished only by the use of single nucleotide variants.
Methods— Genomic Southern hybridization, interphase FISH (Fluorescence in situ hybridization) and DAZ dosage PCR Assay.
Results—
5. We designed a novel Southern hybridization approach to differentiate and characterize the 4 DAZ genes. Based on the quantitative analysis of the southern fragments, we found the likely reciprocal duplication product of gr/gr deletion in 5 (6%) of 82 males. The presence of 6 DAZ genes in three of the 5 cases was also confirmed by interphase FISH analysis. Two of the five individuals with 6 DAZ genes are infertile.
6. In order to quickly determine the copy number of the DAZ gene within AZFc, we also designed a DAZ dosage PCR assay using the autosomal DAZ-Like gene as a dosage control, and verified the results by dosage Southern blot analyses.
7. We studied the DAZ gene copy number in 580 Han Chinese in Taiwan using DAZ dosage PCR assay. Combination the results of the presence or absence of STSs markers within AZFc of these individuals, we found that about 9.5% of our 580 Han Chinese subjects have AZFc partial deletion, 2.8% have partial deletion followed by duplication, and 1.7% have partial duplication. The overall rearrangement frequencies vary significantly between different Y chromosome haplogroups (Yhgs), ranging from 2.9% in O3e to 100% in N and Q.
8. The frequency and the effect of AZFc duplication on male fertility remain unclear. We determined the DAZ gene copy number in 107 fertile men and 142 infertile men, and studied the AZFc rearrangements of these cases. We found no significant difference between the fertile and infertile group in the frequencies of the gr/gr and the b2/b3 deletion. However, the frequency of AZFc partial duplication in the infertile group (7.0%) was significantly higher than that in the fertile control group (0.9%) and the general Taiwanese population (1.7%).
Conclusions—
6. The DAZ genes are highly polymorphic.
7. Sister chromatid exchange plays a significant role in the genesis of deletions, duplications, and polymorphisms of the Y chromosome.
8. Novel DAZ dosage PCR assay we development is a reliable method to quickly determine the copy number of the DAZ gene, and is suitable for large population screening.
9. AZFc partial deletion and partial duplication are common polymorphisms in Han Chinese.
10. We suggested that AZFc partial duplication, but not the AZFc partial deletion, is a risk factor for male infertility in the Taiwanese population.

PART Ⅱ: Analyses on the expression of DAZ
Background—The DAZ gene family encodes RNA-binding proteins that are essential for gametogenesis. The family includes homologues of BOULE which are found in all metazoans; DAZL, found in all vertebrates; and DAZ, which is present only on the Y chromosome in Old World monkeys, great apes, and humans. Most men have four DAZ genes, and the 4 DAZ genes encode different copy number of the RNA-recognition motif (RRM) and the DAZ repeat. DAZ2 and DAZ3 have one RRM, DAZ1 has 3 RRMs and DAZ4 has two. So far, the requirement of DAZL and BOULE in gamatogenesis is well documented, but the role of DAZ in spermatogenesis remains unclear, and whether all 4 DAZ genes are functional is also unclear.
Methods— RT-PCR, and Western blot.
Results—
4. We carried out RT-PCR on human testis RNA. RNA transcripts of all 4 DAZ genes were found in the testis, but at much lower levels than the DAZL transcripts. The transcription level of DAZ is less than one quarter that of DAZL in human testes.
5. No authentic DAZ protein could be identified in human testes by Western blot.
6. Our results also showed low protein levels of full length DAZ with multiple DAZ repeats in transfected cells when compare with truncated DAZ with only two DAZ repeats, and this difference could not be observed in the RNA transcripts levels.
Conclusions—
4. The four DAZ genes are transcribed in the human testis, but at much lower levels than the DAZL transcripts.
5. We hypothesized that either low protein synthesis or instability of the proteins are associated with the low levels of various full length DAZ proteins with multiple DAZ repeats in transfected cells. The reasons that cause this phenomenon remained to be elucidated by future experiments.
6. DAZ is present at a much lower level than that of DAZL in the human testis, and may have a limited role in spermatogenesis.
Components
Catalog page
Components........................................................................Ⅰ-Ⅲ
Table lists..................................................................…...….....Ⅳ
Figure lists..…………………………………………………...Ⅴ
Appendixes lists……………….………………………….…..Ⅵ
Chinese Abstract……………………………………………...Ⅶ
English Abstract……………………………………………...Ⅹ

Introduction
Infertility, Azoospermia and Azoospermia Factors………………………………..1
Azoospermia Factor C (AZFc) Deletions and Duplications……………………...… 1
The human Y chromosome, the male-specific region of the Y chromosome
(MSY), and recombination………………………………………………………...…3
Gene and protein structures of the 4 DAZ genes……………………………...…….4
The DAZ protein family……………………………………………………………...4
Specific aims of this study………………………………………...…………………. 7

Materials and methods
PART Ⅰ: Structure analysis of the DAZ genes
DNA sample subjects…………………………………………………………………9
Genomic DNA purification………………………………………………..………...10
Southern hybridization……………………………………………………………...10
Interphase Fluorescence in situ hybridization (FISH)……………………….........13
DAZ dosage PCR assay……………………………………………………………...14
DAZ dosage Southern blot……………………………………………………….….14
Multiplex PCR assay for AZF deletions………………….…………………..….…15
U3 homologous sequences assay………………………………………………….…15
PART Ⅱ: Analyses on the expression of DAZ
Human testicular samples……………………………………………………….….16
Reverse Transcription Polymerase Chain Reaction (RT-PCR)………………….16
Production of Anti-DAZ Antibodies…………………………………...……….…..17
Construction of DAZ expression vectors…………………………………………..18
Expression of DAZ and DAZL proteins in cultured cells……………………..…..18
Western blot analysis………………………………………………………….…….18
In Vitro RNA homopolymer Binding Assay…………………………………….…..19

Results
PART Ⅰ: Structure analysis of the DAZ genes
The 4 DAZ genes can be differentiated by Southern hybridization……………...21
Five individuals with six DAZ genes were identified by Southern hybridization.
……………………………………………………………………………………...…23
Individuals with AZFc partial deletion were also verified by Southern hybridization…………………………………………………………………………25
Quick determination of copy number of the DAZ gene by DAZ dosage PCR
assay………………………………………………………………………...………...26
DAZ dosage Southern blot confirmed the result of DAZ dosage PCR assay….....27
AZFc Rearrangements in Han Taiwanese…………………………………………28
The gr/gr deletion………………………………………………………...…..29
The b2/b3 deletion…………………………………………………….….…..30
Deletion – Duplication………………………………………...……………..30
AZFc partial duplication……………………………………………………..32
AZFc Rearrangements in Infertile Han Taiwanese……………………………….33
PART Ⅱ: Analyses on the expression of DAZ
The four DAZ genes are transcribed at comparable levels in the human testes. 34
The transcription level of DAZ is less than one quarter that of DAZL in
Human testes…………………………………………..……………………………..35
Low level expression of DAZ with multiple DAZ repeats in transfected cells…..36
No authentic DAZ band could be identified in human testes by western blotting
………………………………………………………………………………………...38
All three various DAZ proteins could bind with RNA homopolymers poly G and poly U in vitro………………………………………………………………………...39

Discussions
PART Ⅰ: Structure analysis of the DAZ genes……………..….41
PART Ⅱ: Analyses on the expression of DAZ……………………..…44
Tables…………………………………………………..……...47
Figures……………………………………………….………..50
References…………………………………………………….74
Appendix


























Table lists
Table 1. Partial deletions of the AZFc region of the human Y chromosome…….47
Table 2. AZFc rearrangements in Han Taiwanese……………….………………..47
Table 3. Frequency of AZFc partial deletion/duplication in Han Taiwanese,
and the association of partial deletion/duplication with male infertility..48
Table 4. Characteristics of the infertile patients with AZFc partial Duplication..48
Table 5. Characteristics of the anti-DAZ antibodies…………………………...…49




























Figure lists

Figure 1. Schematic representation of the Y chromosome and of the current
deletion models……………………………………………………………50
Figure 2. Rearrangements at the AZFc region of the human Y chromosome…...51
Figure 3. The structure of the AZFc region. Figure 3. The structure of the
AZFc region……………………………………………………………….52
Figure 4. Genomic structures of the four DAZ genes in the RPCI-11 donor,
and our Southern analyses of the DAZ genes on the Y chromosome….53
Figure 5. Schematic representation of the DAZ repeat region……………………54
Figure 6 . Protein structures of DAZ protein family members…………………..55
Figure 7. Southern analyses of the RRM regions (region A)………………..……56
Figure 8. Southern analyses of the DAZ repeat regions 5’ of the LINE insertion
(region B)…………………………………………………………………57
Figure 9. Southern analyses of the DAZ repeat regions 3’ of the LINE insertion
(region C)………………………………………………………………...58
Figure 10. Interphase FISH analyses of the copy number of the DAZ genes…....59
Figure 11. DAZ dosage PCR assay………………………………………………….60
Figure 12. DAZ Dosage Southern blot analysis……………………………………61
Figure 13. PCR assays for the detection of AZFc deletions and duplications…...62
Figure 14. Southern blot analyses of the DAZ gene structure…………………….63
Figure 15. The presence of sY1191 homologous sequence on the Y
chromosome outside the AZFc region. ………………………..……...65
Figure 16. Expression of the DAZ transcripts in human testes…………………..66
Figure 17. Determination of the relative amounts of the DAZ and the DAZL
transcripts in human testes. …...............................................................68
Figure 18. Expression of DAZ and DAZL in cultured cells……………………….69
Figure 19. Expression of DAZ and DAZL in cell free system.................................70
Figure 20. Expression of DAZL and DAZ in the human testis...............................71
Figure 21. In vitro RNA homopolymers binding assay……………………….…...72
Figure 22. Models of sister chromatid exchanges that generate the DAZ
polymorphisms…………………………………………………………73



Appendix lists

Paper 1. Polymorphisms associated with the DAZ genes on the human Y chromosome
Paper 2. A two-step protocol for the detection of rearrangements at the AZFc
region on the human Y chromosome
Paper 3. Partial Duplication at AZFc on the Y Chromosome Is a Risk Factor for
Impaired Spermatogenesis in Han Chinese in Taiwan
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