臺灣博碩士論文加值系統

MHC class I polypeptide-related sequence A (MICA) 基因位於染色體6的人類主要組織相容性複合體 (Major Histocompatibility Complex, MHC) 區域。在免疫相關疾病、腫瘤研究與器官移植研究中，MICA都扮演重要角色。MICA基因有著高度多態性 (polymorphism)，在IMGT/HLA資料庫中記載多達105種不同的單套體 (Haplotype)。本研究建立一套利用PCR的定序資料分析MICA基因單套體分型系統，第一部分建立MICA基因資料庫，是依據IMGT/HLA的105種已知分類的MICA基因單套體為資料庫，篩選出EXON 2,3與4中最有分辨力的22個tag SNP (可分辨不同單套體的SNP定義為tag SNP)。利用此22個tag SNP與PHASE程式將長庚醫院所提供2335個檢體資料 (MICA基因EXON 2,3與4之PCR序列)進行鑑定，可重建出4670個單套體。在4670個單套體中有4210個單套體 (90.15%)，可比對到的已知分類的MICA基因單套體中。可是部分單套體會比對到多條已知分類的MICA單套體，因此再利用85個tag SNP，由於進行二次PHASE重建，在4210個單套體中，有750 (17.81%) 個單套體，比對到一個已知分類的MICA單套體。如果要增加比對到一個已知分類的MICA單套體的比例，則需要增加其他序列的資料 (EXON 1, 5 與6)，但是目前的分型結果已經足夠進行單套體的疾病間的病例對照關連性研究。第二部分針對未知樣本的單套體分析，首先讀取待測檢體PCR序列的基因分型，利用第一部分選出的tag SNP，與MICA基因資料庫中樣本比對基因型，找尋相同序列的檢體，即可對應到已知的MICA樣本，來完成待測檢體的單套體分型。

MHC class I polypeptide-related sequence A (MICA) gene locate at chromosome 6, Human Major Histocompatibility Complex (MHC) region. MICA plays critical roles in immune-related diseases, tumor disease, and organ transplant. MICA is highly polymorphism and there are 105 haplotypes reported in IMGT/HLA database. In this study, we develop a pipeline to analyze the haplotype of MICA with polymerase chain reaction base Sanger sequences data of MICA exon 2-4. PART I: There are 85 tag SNPs, which can discriminate the 105 MICA haplotype, in exon 2-4. Among the 85 tag SNPs, we choose the most distinguishing 22 tag SNPs to construct haplotype. From the 2335 normal sample, base one the 22 tag SNPs, we used phase program to construct 4670 haplotypes. Among the 4670 haplotypes, 4210 (90.15%) were map to reported MICA haplotype. However, some of the haplotypes were map to two or more reported MICA haplotype, we using 85 tag SNPs to re-construct the haplotypes and 750 (17.81%) re-construction haplotype can map to unique MICA haplotype. To increase re-construction unique haplotyp mapping rate, we need more exon sequences data (such as exon 1, 5-6). However, current result can be used for the case-control association study between MICA and disease. PART II: Based on construct MICA haplotype database, we can analyze unknown Sanger sequences sample by using the selected tag SNPs from PART I.

目錄
誌謝 i
中文摘要 ii
English abstract iii
目錄 iv
圖目錄 (LIST OF FIGURES) vii
表目錄 (LIST OF TABLES) viii
第一章 簡介 (INTRODUCTION) 1
第一節 背景 (BACKGROUND) 1
第一項 MHC class I polypeptide-related sequence A (MICA) gene 1
第二項 MICA基因功能 4
第三項人類基因體多樣性 6
第四項 單核苷酸多態性 (SNP)與單套體 (haplotype) 6
第五項 哈溫平衡 7
第六項 MICA 基因單套體分型 (MICA haplotype typing) 8
第七項 基因體測序 8
第八項 IMGT/HLA資料庫 9
第二節 動機 (MOTIVATION) 10
第二章 材料與方法 (MATERIALS AND METHODS) 11
第一節 建立MICA 基因資料庫 12
第一項 樣本資訊 12
第二項 讀取DNA測序資料 12
第三項 樣本篩選 14
第四項 標籤單核苷酸多態性篩選 15
第五項 MICA單套體分型分析 18
第六項 個別樣本單套體對應到已知MICA單套體 20
第二節 輸入未知樣本進行單套體分型分析 24
第一項 輸入DNA測序資料 24
第二項 依據本研究所篩選出的tag SNPs進行基因型分析並與本實驗所建立MICA 基因資料庫進行比對 25
第三章 結果 (RESULTS) 26
第一節MICA 基因資料庫 26
第一項 DNA測序資料 26
第二項 樣本篩選結果 28
第三項 標籤單核苷酸多態性 (tag SNP)篩選結果 29
第四項 MICA單套體分型分析結果 34
第五項 樣本單套體對應到已知MICA單套體結果 36
第二節 輸入未知樣本進行單套體分型分析 38
第一項 DNA測序資料 38
第二項 依據本實驗所篩選出的tag SNPs進行分析並與本實驗所建立MICA 基因資料庫進行比對 39
第四章 討論 (DISCUSSIONS) 41
第一節 分析程式應用與可加強之處 41
第一項 分析程式可加強之處 41
第二項 MICA基因之外顯子5之Trinucleotide repeat polymorphism 42
第三項 增加NGS為資料來源 42
第四項 運用於其它基因分析 43
第二節 MICA基因資料庫 43
第一項 未知樣本的MICA基因單套體分型 43
第二項 與長庚醫院合作開發應用在病例對照研究 (case-control study)的統計軟體及使用者介面 43
第三項 不同族群的MICA基因分布 46
第四項 1000 genome project 51
第五章 結論 (CONCLUSIONS) 52
參考文獻 (REFERENCE) 53

圖目錄 (LIST OF FIGURES)
圖 1 MICA基因組成 3
圖 2 MICA與NKG2D結合，參與免疫反應 5
圖 3 資料庫建立及分析流程 11
圖 4 讀取序列程式 13
圖 5 multiple sequence alignment 13
圖 6 IUPAC code 14
圖 7 篩選樣本邏輯圖 14
圖 8 Multiple Sequence Alignment比對圖 15
圖 9 候選標籤單核苷酸多態性篩選邏輯圖 16
圖 10 候選tag SNP二次篩選 16
圖 11 tag SNP轉換 17
圖 12 tag SNP無法分辨已知MICA基因單套體 21
圖 13 樣本進行二次比較 22
圖 14 未知樣本進行單套體分型分析程式 24
圖 15 未知樣本進行單套體分型分析並比對MICA基因資料庫 25
圖 16 DNA測序程式結果 27
圖 17 tag SNP 二次篩選過程 30
圖 18 使用haploview檢定tag SNP連鎖性 32
圖 19 未知樣本分析程式 38
圖 20 SNP分析統計界面 45
圖 21 單套體分析界面 45
圖 22 43個族群之MICA單套體分布進行階層式分群法分析 50

表目錄 (LIST OF TABLES)
表 1 單套體重新建構結果，可能的單套體集與單套體數量及頻率 19
表 2 單套體重新建構結果，樣本的單套體組合及機率 19
表 3 無法準確重新建構的檢體樣本 23
表 4 樣本數量 28
表 5 22個tag SNP分布 31
表 6 tag SNP部分基本資訊 31
表 7 22個tag SNP對應到已知MICA單套體 33
表 8 PHASE以及R-haplo.stats分析結果 34
表 9 PHASE單套體重新建構結果 35
表 10 R-haplo.stats單套體重新建構結果 35
表 11 重新建構單套體對應已知MICA單套體表 37
表 12 樣本二次比較結果 37
表 13 未知樣本單套體分型分析結果 40
表 14 15個亞洲不同族群之MICA單套體分布 48
表15 27個族群 (歐洲、非洲、北美洲、南美洲、南島語系)之MICA單套體分布 49

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