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系統識別號 U0026-2608201317040500
論文名稱(中文) 解析A群鏈球菌株A20之全基因體
論文名稱(英文) Genomic analysis of group A streptococcus A20
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 鍾昆達
研究生(英文) Kun-Ta Chung
電子信箱 kuntachung@gmail.com
學號 T16991088
學位類別 碩士
語文別 中文
論文頁數 95頁
口試委員 指導教授-吳俊忠
召集委員-何漣漪
口試委員-鄧景浩
口試委員-江倪全
中文關鍵字 A群鏈球菌  A20  全基因體  比對 
英文關鍵字 group A streptococcus  A20  whole genome  comparison 
學科別分類
中文摘要 A群鏈球菌為革蘭氏陽性菌,是一人類致病菌。舉凡咽喉炎、壞死性筋膜炎或是急性腎絲球腎炎都和此菌有關。在分類上,A群鏈球菌依據M蛋白質基因序列分成250多種基因型,但在流行病學上的分析只有數種基因型與重大疾病相關。本實驗室於1990年代獲得一株從壞死性筋膜炎病患的血液中分離之emm1基因型的A群鏈球菌,並命名為A20。該菌株高度表現熱源性外毒素B與Sda1。為了解該菌株與其他相同emm基因型的菌株的差異點,本研究採用全基因體定序並著重在核酸序列比對。此外,也分析A20及SF370基因體上之差異,以期能找出兩者在內皮細胞存活的差異。A20全基因體長1,837,281 bp,在親緣關係樹上極相似MGAS5005,一株被廣泛用於實驗的臨床菌株,其基因型同為emm1。在全基因體序列比對上,兩者並沒有大片段的缺失或插入。細部的比較中有66個單核苷酸多型性、41個插入或刪除與3個跳躍基因區段差異。利用功能性分析驗證這兩株的變異,顯示A20在指數生長期生長較迅速、溶血能力較差,但蛋白質水解能力較高,係源自於熱源性外毒素B的表現。先前我們團隊已經證實了A20較SF370更容易在內皮細胞 (HMEC-1) 存活。比對兩者的全基因體序列,明顯的差異在於原噬菌體、36 –kb重組區域以及4個跳躍基因區段差異。此外,我們發現有兩個雙因子調控系統的感應激酶 (A20_1313c和salK) 有序列變異,會造成基因缺失。然而突變這兩個基因卻不影響A群鏈球菌在內皮細胞的複製能力。本論文發現A20在序列上相似MGAS5005,但細微的變異導致表徵不同,可能是調節因子的差異所致。另外A20較SF370更容易在內皮細胞存活,並不是因為SF370缺乏A20_1313c和salK所致。
英文摘要 Streptococcus pyogenes (group A streptococcus, GAS) is a Gram positive human pathogen, which causes various diseases. There are more than 250 emm types of GAS, but only few types associated with serious diseases. A clinical isolate, A20, was isolated from the blood of necrotizing fasciitis patient. A20 is M1 type and expresses high level of virulence factors such as SpeB and Sda1. To identify the difference in same emm type but different strains, genome or nucleotide comparison was used in this study. In addition, the difference of survival in endothelial cell was observed between A20 and SF370. We also used genomic comparison to search for genes that might be related to this effect. The whole genome sequencing was adopted of Illumina, and results showed the full length of A20 is 1,837,281 bp. By NCBI calculation, A20 genome was aligned with other published M1 reference sequences and it is similar with MGAS5005, which is also a clinical strain. The detail comparison between MGAS5005 and A20 showed that there are 66 single nucleotide polymorphisms (SNPs), 41 insertions and deletions (indels) and 3 transposases variation. The functional assay showed that A20 grew faster than MGAS5005 in the exponential phase and the protease activity was higher in A20 than in MGAS5005. A20 was lower in the hemolysis than MGAS5005 in the stationary phase. Previously, our group found that A20 but not SF370 could survive in the endothelial cells. The bioinformatics search showed the variation of prophage’s number, 36-kbp recombination region, and 4 transposons are different between A20 and SF370. Among these, two sensor kinases, A20_1313c and salK, have lost their functions in SF370 due to the stop codon mutation. However, no significant difference was found in survival ability between wild-type and sensor kinase mutants. In this study we found similar sequences between A20 and MGAS5005, but they present different phenotype. This may be due to the small variations in the regulated system. We also confirmed that A20_1313c and salK are not essential for GAS survival in endothelial cells.
論文目次 摘要 I
ABSTRACT II
致謝 IV
目錄 V
表目錄 IX
圖目錄 X
符號與縮寫 XI
緒論 1
材料與方法 12
I. 本研究之實驗藥品、溶液配方分述於附錄III、IV 12
II. 菌種、質體來源 12
III. 實驗菌種培養及其保存 12
IV. DNA 之操作 12
A. 大腸桿菌 E. coli 12
B. A群鏈球菌 14
C. 聚合酶連鎖反應 (PCR) 16
V. RNA 之操作 16
A. A群鏈球菌 RNA 之萃取 16
B. 反轉錄聚合酶連鎖反應 (RT-PCR) 分析 17
VI. 蛋白質操作 17
A. A群鏈球菌培養液中總蛋白質 17
B. 蛋白質濃度之測定- Bradfoed assay 18
C. 蛋白質膠體電泳 18
D. 西方墨點法 18
VII. A群鏈球菌表現型之分析 19
A. 生長曲線 19
B. 蛋白質水解酶活性測試 19
C. A群鏈球菌於內皮細胞內複製能力測試 19
D. 紅血球溶血測試 20
VIII. 細胞培養 20
IX. 次世代定序 20
X. 生物資訊分析工具 21
A. 全基因體註解工具-Integrative Services for Genomic Analysis, ISGS 21
B. 全基因體瀏覽與註解工具-Artemis 21
C. 全基因體比較工具- the SEED 21
D. 全基因體比較工具-Microbial Genome Database for Comparative Analysis, MGDB 21
E. 胺基酸序列的domain尋找工具 -InterPro 22
F. 脈衝式電泳結果模擬工具 -PFGE Predictor 22
G. 穿膜結構模擬工具 - TMHMM 22
H. 胺基酸3級結構模擬工具 - Phyre 2 22
XI. 分析方法 22
A. BLOck SUbstitution Matrix (BLOSUM) 80 22
B. 序列變異在基因體上發生率計算 23
C. Dot plot 23
D. 統計方法 23
結果 24
I. A20全基因體分析 24
A. 利用次世代定序分析A20序列 24
B. 註解A20基因體 24
C. A20的親緣關係 24
II. 比較A20與MGAS5005 24
A. 比較A20與MGAS5005在序列上之基本差異性 25
B. 比較A20與MGAS5005之跳躍基因區段 25
C. 比較A20與MGAS5005間的SNPs 25
D. 比較A20與MGAS5005間之indels 25
E. 比較A20與MGAS5005間的差異所影響的基因族群 26
F. 比較A20與MGAS5005間的差異產生的可能性 26
G. 比較A20與MGAS5005在調控系統差異 26
H. 比較A20與MGAS5005外觀表現 (phenotype) 之差異 27
III. A20與其他已知A群鏈球菌基因體不同之處 27
A. A20獨有的跳躍基因區段 27
B. A20獨有的SNPs 28
C. A20獨有的indel 28
IV. 比較A20與SF370 28
A. 利用MBGD比較A20與SF370 28
B. 利用the SEED與RAST比較A20與SF370 28
C. 比較A20與SF370在跳躍基因區段的差異 29
D. 比較A20與SF370在SLO與SLS的序列差異 29
E. 比較A20與SF370在調控系統差異 30
V. 構築A20_1313c與salK突變株 30
A. 利用雙置換同源性重組法來構築A20_1313c突變株 30
B. 利用雙置換同源性重組法構築salK突變株 31
C. 突變株不影響細菌生長 31
VI. SW952和SW953在內皮細胞的複製能力與野生株相同 32
討論 33
參考文獻 40
圖表 50
附錄 87
I. 附錄圖 87
II. 附錄表 90
III. 藥品與廠商 92
IV. 溶液配方 93
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