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研究生:徐霈君
研究生(外文):Pei-Chun Hsu
論文名稱:以蛋白質交互作用的觀念解釋精神分裂症NRG1-CACNG2基因交互作用的機制
論文名稱(外文):A protein interaction-based model for NRG1-CACNG2 interaction in schizophrenia
指導教授:楊永正楊永正引用關係
指導教授(外文):Ueng-Cheng Yang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物醫學資訊研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:90
中文關鍵詞:精神分裂症基因交互作用蛋白質網路
外文關鍵詞:schizophreniagene interactionprotein network
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精神分裂症(schizophrenia)是一種複雜性疾病(complex disease),它的患病因子來源十分廣泛,包括環境因素、發育、遺傳等多種因子交錯而成,其中,基因遺傳因子有可能增加這個疾病的罹患率,也就是說精神分裂症屬於高遺傳性疾病,有些致病候選基因是經由已知的功能推論出來的,也有些是經由在染色體上的位置所找到的,具有多重的候選基因可能會增加個體的罹患率,然而目前還是不太清楚哪一種基因的組合會實質的對疾病表現型造成影響,而哪些基因會在一起作用也仍待進一步的研究。
在大部分的反應路徑當中,除了一些代謝相關的反應路徑,都具有一些蛋白質交互作用(protein-protein interactions, PPI)的資訊,而在一些蛋白質網路當中也包含了反應路徑的資訊,雖然這些蛋白質的上下游關係仍須釐清。在本研究中,利用431個從文獻當中擷取的候選基因與其作用蛋白,建構一個精神分裂症的蛋白質網路(schizophrenia interactome),雖然這些候選基因的來源各不相同,但是在蛋白質網路上卻可以形成叢集,根據成對蛋白質在網路上的距離可以鑑定出七個蛋白質交互作用的模組,根據基因語彙的功能性註解,其中幾個比較重要的模組是則是跟突觸訊息傳遞、訊號傳導與免疫反應有關,其中突觸訊息傳遞的蛋白質叢集當中包含了NRG1和CACNG2這兩個重要的候選基因,這兩個基因在連鎖研究和相關性研究當中都有顯著的基因交互作用。
基於蛋白質交互網路的解讀,由NRG1會調控NMDA受器的內化作用,而CACNG2則會調控AMPA受器的再生使用,這兩者可能會在麩胺酸訊號傳導的過程當中產生協同作用,因為NMDA和AMPA受器都屬於離子通道,因此這個協同作用的過程可能會與鈣離子的流量有關,所以我們推測精神分裂症其中一個致病機制可能受到鈣離子流量減少的調控,在本研究最後以基因共表現和mRNA表現量來當作佐證,希望這個蛋白質交互作用網路的分析策略,可以提供生物學家一個研究高遺傳性疾病致病機制的方法。
Schizophrenia is a complex disease with multiple factors contributing to pathogenesis. In addition to the environmental factors, genetic factors may also increase the susceptibility of acquiring this disease. In other words, schizophrenia is a highly heritable disease. Some candidate genes were deduced on the basis of their known function and the others were found on the basis of their chromosomal location. Individuals that have multiple candidate genes may increase the risk further. However, it is not clear what kind of gene combinations may productively lead to the disease phenotype. Furthermore, how these genes may work together to increase the risk is yet to be studied
Most pathways except metabolic pathways are rich in protein-protein interactions (PPI). Thus, the PPI network contains pathway information, even though the upstream-downstream relation of PPI is yet to be explored. Here we have constructed a schizophrenia interactome by extracting the nearest neighbour of the 431 reported candidate genes described in the literature. Although these candidate genes were discovered by different approaches, most of the proteins connected to one another and form a big cluster. Seven major protein interaction modules were identified on the basis of the pair-wise distance among the proteins in this sub-network. The most of the clusters might play roles in the synaptic transmission, signal transduction and immune response, based on gene ontology annotation. The protein interactions in the synaptic transmission cluster were used to explain the interaction between NRG1 and CACNG2 genes, which was found by both linkage and association studies. This working hypothesis is supported by the co-expression analysis based on public microarray gene expression.
On the basis of the protein interaction network, the NRG1-triggered NMDAR protein internalization and the CACNG2 mediated AMPA receptor recruiting may act together in glutamatergic signalling process. Since both the NMDA and AMPA receptors are calcium channels, this process may regulate the influx of Ca2+. Reducing the cation influx might be one of the disease mechanisms for schizophrenia. This PPI network analysis approach combined with the support from co-expression analysis may provide an efficient way to propose disease mechanisms for various highly heritable diseases.
誌謝 I
中文摘要 II
ABSTRACT III
目錄 IV
表目錄 VII
圖目錄 VIII
緒論 1
I. 複雜性疾病(COMPLEX DISEASE) 1
複雜性人類疾病(complex human disease)牽涉到多重基因遺傳以及環境決定因子 1
II. 精神分裂症(SCHIZOPHRENIA) 2
精神分裂症是一種複雜性疾病 2
精神分裂症的臨床表現 2
麩胺酸假說(Glutamate hypothesis) 4
NRG1-ERBB4訊號對麩胺酸受器(glutamate receptor)的影響 6
III. 精神分裂症候選基因之分子遺傳學研究 8
Neuregulin-1(NRG1)候選基因 8
CACNG2候選基因 10
IV. 蛋白質交互作用網路 11
由蛋白質層次來解釋在基因層次所觀察到的交互作用 11
研究蛋白質交互作用的方法學 11
V. 本論文研究方向 13
基本原理 14
材料與方法 16
I. 基因變異篩選程序(CANDIDATE GENE SCREENING PROCEDURE) 16
步驟一:蒐集候選基因相關資訊(Collect information) 16
異構物的鑑定(Isoform identification) 16
利用比較性基因體分析(Comparative genomics analysis)來找出物種間的高度保留區域 17
定義高度保守區域叢集(highly conserved cluster) 21
步驟二:引子設計(Primer design) 22
設計專一性引子 22
步驟三:設定優先順序(Priority setting) 25
步驟四:定序(Sequencing) 26
定序樣本的選用 26
定序結果的判讀 26
步驟五:尋找基因變異(Look for gene variation) 28
利用PolyPhred尋找基因變異 28
步驟六:基因變異資料整合(integrate information)與品質管制(perform quality control) 31
序列的品質管制與分類 31
基因變異的品質管制與分類 33
基因型頻率的計算與分類 35
II. 蛋白質網路的建構 36
文獻搜尋(Literature searches) 36
建構精神分裂症蛋白質網路(schizophrenia interactome) 39
利用最短路徑來評估網路中所有蛋白質的關係 41
蛋白質叢集的功能性註解(functional annotation) 42
計算基因之間的相關係數(correlation coefficient) 44
結果 47
I. 尋找致病因子中的基因變異 47
流程及策略建立 47
基因剪接的變異造成基因產生不同的異構物 50
基因變異的鑑定 52
II. 建構蛋白質網路 56
由蛋白質層次來解釋在基因層次所觀察到的交互作用 56
在與精神分裂症相關的蛋白質網路中,候選基因的產物會形成特定的功能性叢集(functional cluster) 58
III. 致病機制的探討 63
根據生物意義來解讀NRG1和CACNG2致病因子之間的關係 63
解讀NRG1和CACNG2基因之間交互作用的工作假說(working hypothesis) 64
IV. 假說驗證 68
某些分子在基因表現的層次上會有共同表現的特性 68
位於NRG1 和CACNG2基因上的變異會影響GRIN和GRIA複合物的表現量 錯誤! 尚未定義書籤。
討論 70
基因間交互作用與蛋白質交互作用的關係 70
透過DLG4來調控的麩胺酸訊號傳遞(glutamate signaling transduction) 71
精神分裂症表現型(endophenotype)與基因型之探討 73
蛋白質叢集的交互作用 74
蛋白質交互作用的錯誤資訊 75
參考文獻 78
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