博碩士論文 952211001 詳細資訊




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姓名 李懿瑋(Yi-wei Lee)  查詢紙本館藏   畢業系所 系統生物與生物資訊研究所
論文名稱 精神分裂症病患與正常人之DNA甲基化網絡的差異
(The difference of DNA methylation network between schizophrenic and normal individuals)
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摘要(中) 精神分裂症屬於complex disease之一,主要會造成病患無法區分虛實之間的差異,嚴重者將有危及生命的行為發生,但目前針對精神分裂症的相關研究,有許多假說相繼成立,包括:神經傳導素分泌失調、腦部發育不正常等,但仍無法明確地指出何種因素才是引發疾病的主要因子;故目前人類僅可藉由藥物阻斷特定神經傳導物質,以緩和病患發病的症狀。在此研究中我們採用不同於以往僅著重於研究基因序列的方式,反而以表觀基因體學研究方式為主。而分析數據主要來自精神分裂症病患與正常人兩組別,藉由微陣列偵測CpG island的甲基化程度,再將偵測到的數據,首先挑選出不含重複序列共7,843 個spots,接著選擇7,843 spots 當中甲基化程度差異大者前2,005個spots,此2,005 spots可作為分析觀察條件之一;另外,若僅以去除NA值為條件篩選7,843 spots,則可得到7,647 spots。所以在前述兩篩選條件中,分別可得2,005 spots與7,647 spots兩組基因,再利用計算partial correlation coefficient即可推測具甲基化程度相關性的基因對,以此為依據建立CpG island co-methylation network。接著再對各組網絡進行基本特性分析,而由我們分析結果得知,在病患所構成的網絡中不論在top 2,005 variable spots或是7,647 spots,其具關聯性的基因主要功能傾向以神經發育、訊號傳遞、DNA甲基化相關過程為主;但正常人所建立的網絡卻無此特徵。雖然藉由甲基化分析,仍無法確認甲基化程度的失常是否會影響腦中基因表現量,但我們分析結果可確定精神分裂症病患CpG islands甲基化程度的相關性比正常人還要密切,使得基因之間容易互相影響,導致基因在面對環境變化時缺少預防變異的機制,而增加基因失調的機率。
摘要(英) Schizophrenia is a complex disease. It affects the most basic human processes of perception, emotion, and judgment. However, progress in schizophrenia has been slow. Previous researches have shown many contentions about pathogenic factors, including deregulated neurotransmitter, development of the brain, and genetic risk factors. But these studies have not identified a key factor which directly induces people suffering from schizophrenia. Now, people use drugs to treat schizophrenia despite studies can not provide clear understanding of the pathogenesis of the disease. In this research, we investigate the difference of DNA methylation networks between schizophrenia and normal persons. First, we selected 2,005 spots and 7,647 spots from microarray, consisting a total of 13,056 spots. In order to establish the DNA methylation networks, we calculated partial correlation coefficients between methylation patterns of CpG islands. Our results found that major gene functions of the networks, from either 2005 spots or 7647 spots from patients , involved neural development, signal transduction, and the process of DNA methylation. By contrast, no specific functions in the networks of normal persons were observed. These results revealed the stronger correlation of gene methylation patterns in patients than in normal persons. We suggest that genes in patients with schizophrenia, having the above properties, hold defect in handling environmental changes, and might raise the possibility of alterations in gene regulation.
關鍵字(中) ★ 精神分裂症
★ 網絡
★ 甲基化
關鍵字(英) ★ DNA methylation
★ network
★ schizophrenia
論文目次 目錄
中文摘要 ---------------------------------------------i
Abstract ---------------------------------------------ii
誌謝 ---------------------------------------------iii
目錄 ---------------------------------------------iv
圖目錄 ---------------------------------------------vii
表目錄 ---------------------------------------------viii
第一章 緒論 --------------------------------------1
一、Epigenetics -------------------------------------1
二、DNA甲基化 -------------------------------------1
2-1 DNA甲基化機制 ----------------------------------1
2-1-1 甲基化狀態的維持(maintenance methylation)-----3
2-1-2 甲基化重新組合(de novo methylation) ----------3
2-2 DNA甲基化對於基因表現的影響---------------------5
2-2-1 甲基化CpG結合蛋白
(methyl CpG binding protiens, MBP)-----------6
2-3 組蛋白修飾---------------------------------------8
2-3-1 DNA甲基化和組蛋白修飾之關係------------------9
2-3-2 DNA 甲基化、組蛋白去乙醯化、組蛋白甲基化
三者之間的關係-------------------------------10
2-4 DNA甲基化抑制基因表達---------------------------11
三、Imprinting----------------------------------------13
3-1 銘印基因的重要性--------------------------------13
3-2 germ-line銘印基因的建立與維持-----------------14
3-2-1 擦去(Erasure)與建立---------------------------14
3-2-2 銘印基因的維持--------------------------------14
3-3 銘印基因的特性----------------------------------15
3-4 調控銘印基因表現的方法--------------------------16
3-5 X-inactivation----------------------------------19
四、精神分裂症(Schizophrenia)-------------------------20
4-1 基因表觀因子與人類疾病之關係---------------------20
4-2 表觀基因體和精神疾病-----------------------------21
4-3 精神分裂症---------------------------------------22
4-3-1 精神分裂症在神經病理上的發現------------------24
4-3-2 精神分裂症在基因體上的發現--------------------25
4-3-3 精神分裂症與表觀基因體的關係------------------28
五、研究動機------------------------------------------32
第二章 研究方法---------------------------------------33
一、實驗樣品------------------------------------------33
二、歸一化(normalization)-----------------------------33
三、扣除M值為NA的基因---------------------------------34
四、計算M值標準差 -------------------------------------34
五、Rest數值的計算------------------------------------34
六、Partial Correlation Coefficients的計算------------34
七、網路特性分析--------------------------------------35
八、GO term檢定---------------------------------------37
第三章 結果-------------------------------------------38
一、基因的篩選結果------------------------------------38
二、網絡的建立----------------------------------------39
三、網絡的結果與特性分析------------------------------40
3-1 網絡的組成--------------------------------------40
3-2 網絡degree的分布--------------------------------46
3-3 Clustering coefficient--------------------------48
3-4 Assortativity (同類性)--------------------------50
3-5 Module sizes的分布------------------------------52
四、篩選的spots在人類染色體位置的分布-----------------54
4-1 2,005 spots在人類染色體中的分布-----------------54
4-2 7,647 spots在人類染色體中的分布-----------------54
五、網絡modules 經GO term統計計算後結果----------------58
5-1 modules 的生物意義( 2,005spots組成的網絡)-------58
5-2 modules 的生物意義( 7,647spots組成的網絡)-------59
六、hubs的生物意義-------------------------------------59
6-1 網絡中前十名hubs的生物功能(2,005spots組成的網絡)-59
6-2 網絡中前十名hubs的生物功能(7,647spots組成的網絡)-60
七、7,674網絡各link的基因功能--------------------------60
7-1 正常人網絡中links的基因功能---------------------60
7-2 病患網絡中links的基因功能-----------------------61
第四章 討論-------------------------------------------63
第五章 結論-------------------------------------------65
第六章 參考文獻---------------------------------------87
圖目錄
Fig. 1、基因甲基化修飾過程-----------------------------2
Fig. 2、Germ cell與受精後胚胎中,基因甲基化程度的變化關係
-----------------------------------------------4
Fig. 3、在cell cycle中MBD1利用組蛋白甲基化進行DNA甲基化修
飾過程-----------------------------------------7
Fig. 4、Igf2-H19基因ICR區域的甲基化修飾的建立與維持----18
Fig. 5、晶片spots篩選步驟------------------------------38
Fig. 6、non-overlapping spots--------------------------39
Fig. 7、2,005 spots甲基化程度相關性網絡----------------43
Fig. 8、7,647 spots甲基化程度相關性網絡----------------44
Fig. 9、random組別在2,005 spots與7,647 spots條件下的網絡
-----------------------------------------------45
Fig.10、degree distribution ---------------------------47
Fig.11、各degrees值所對應平均clustering coefficient值的分
布圖-------------------------------------------49
Fig.12、各degrees值所對應平均assortativity值的分布圖---51
Fig.13、Module sizes的分布-----------------------------53
Fig.14、篩選spots在人類染色體的分布--------------------55
Fig.15、2,005 spots網絡中帶有degrees的nodes在染色體中的位
置---------------------------------------------56
Fig.16、7,647 spots網絡中帶有degrees的nodes在染色體中的位
置---------------------------------------------57
表目錄
Table 1、各MBP酵素的組成與功能整理---------------------6
Table 2、各組partial correlation經檢定後符合限定門檻的
edges數---------------------------------------39
Table 3、網絡基本特性----------------------------------42
Table 4、正常人網絡modules在2,005個基因中有統計意義的GO
terms-----------------------------------------67
Table 5、病患網絡modules在2,005個基因中有統計意義的GO
terms-----------------------------------------70
Table 6、病患或正常人網絡modules在7,647個基因中有統計意義
的GO terms------------------------------------72
Table 7、2,005 spots網絡hubs的基因ID與基因名稱---------73
Table 8、7,647 spots網絡hubs的基因ID與基因名稱---------74
Table 9、正常人組別中7,647 spots組成網絡,其參與link的兩基
因對應基因功能--------------------------------77
Table 10、病人組別中7,647 spots組成網絡,其參與link的兩基
因對應生物功能--------------------------------86
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指導教授 王孫崇(Sun-chong Wang) 審核日期 2008-7-14
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