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標題: | 自閉症家庭四位成員之轉錄組與等位基因特異性表現的全基因組分析 Transcriptomic and Allelic-specific Expression Analysis in a Family Quartet with Autism Spectrum Disorder |
作者: | Chun-Yen Lin 林俊言 |
指導教授: | 黃憲松 |
關鍵字: | 等位基因特異性表現,自閉症,神經表觀遺傳學,基因印記,核糖核酸編輯,神經發育,前額葉, Allele-specific expression,autism,neuroepigenetics,genomic imprinting,neurodevelopment,prefrontal cortex,RNA editing, |
出版年 : | 2017 |
學位: | 碩士 |
摘要: | 自閉症(autism spectrum disorder)乃一群異質性極高的神經精神疾患之總稱,其致病原因目前仍陸續被發現,可大致歸納為遺傳因素,環境因素,以及兩者交互作用之因素。根據同卵雙胞胎的研究,同時患有自閉症的比率可高達90%,但表現型(phenotype)卻可能有很大的差異,這代表遺傳因素在自閉症的致病原因中佔有重要角色,但仍有其他調控基因表現的微觀環境因素,造成帶有相同基因的同卵雙胞胎具有不同的表現型,而表觀遺傳學(epigenetics)則提供了能夠連結遺傳與環境因素的可能機制。眾多表觀遺傳機制中,目前已知印記基因(imprinted gene)的表現失調(dysregulation)與自閉症有關,並有其他研究顯示自閉症的患者之等位基因特異性表現(allelic-specific expression)具有不平衡(imbalance)的現象,但該研究因缺乏親代的遺傳資訊,無法確認是否為基因印記作用。為了改進前人研究不足之處以找出基因印記在自閉症致病機轉中扮演之角色,本項研究針對一個核心家庭之四位家庭成員(雙親與兩姊妹,姐姐為自閉症患者)的前額葉組織(prefrontal cortex)進行轉錄組(transcriptome)與等位基因特異性表現(allelic-specific expression)的全基因組分析(包括初級微核糖核酸分析),來尋找等位基因特異性表現與印痕作用在自閉症致病機轉之可能角色。結果我們並無發現自閉症的子代特有之基因印記作用,但於其LRP2BP(與細胞訊息傳遞相關)與ZNF407(與轉錄調控相關)基因發現有單至雙等位基因表現的變化(mono-to-biallelic expression) ,並且實驗證實對於基因表現量有相應的影響,而此現象並沒有出現在無自閉症的子代中。另外,我們還發現了與腦部發育階段相關的母方表現基因DUSP22,父方表現的微核糖核酸miR-335,以及KMT2C基因的核糖核酸編輯位置(RNA editing site),而在過往文獻中顯示核糖核酸編輯機制與神經精神疾病有諸多相關,此機制將是我們實驗室未來可能繼續探索的方向之一。 Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, and the exact causal mechanism is still under extensive investigation. Dysregulated imprinting genes and allele-specific expression (ASE) has been identified in patients with ASD; however, a comprehensive analysis of these epigenetic phenomenon has not been conducted in a family quartet with ASD. To fill this gap, we analyzed ASE and genomic imprinting using genomic DNA from parent and offspring and RNA from offspring’s postmortem prefrontal cortex (PFC); one of the two offspring had been diagnosed with ASD. DNA- and RNA-sequencing(including primary microRNA) revealed distinct ASE patterns from both offspring PFC. As a result, only the PFC of the offspring with ASD exhibited a mono-to-biallelic switch for LRP2BP (related with cell-signaling) and ZNF407 (related with transcriptional regulation) genes. We also identified a novel RNA-editing site of KMT2C gene (related with transcriptional co-activation) in addition to mono-allelically expressed genes and miRNAs, a novel development stage- and brain-specific maternally-expressed gene, DUSP22 (Dual specificity phosphatase 22), and a novel development stage-specific paternally-expressed miRNA, miR-335 in the PFC of both offspring. Our results demonstrate the prevalence of ASE in human PFC and ASE abnormalities in the PFC of a person with ASD. Taken together, these findings may provide mechanistic insights into the pathogenesis of ASD and genome-wide screening of novel RNA editing sites is one of our future directions of research. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69080 |
DOI: | 10.6342/NTU201703454 |
全文授權: | 有償授權 |
顯示於系所單位: | 腦與心智科學研究所 |
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