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Please use this identifier to cite or link to this item: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/48783

Title: B型肝炎病毒在東亞地區之分子演化與親緣動態分析
Molecular Evolution and Phylodynamics of Hepatitis B virus in East Asia
Authors: Lin, Serena Y.C.
林語蓁
Contributors: 國立臺灣海洋大學:生命科學暨生物科技學系
Keywords: B型肝炎病毒;演化動態;共同祖先;SARS;瓶頸效應;外來基因型
HBV;phylodynamics;MRCA;SARS;bottleneck;foreign genotype
Date: 2016
Issue Date: 2018-08-22T06:31:16Z
Abstract: B型肝炎病毒感染為肝硬化與肝癌的重要風險因子,全球目前有兩億四千萬人口為B型肝炎病毒慢性感染的帶原者。B型肝炎病毒分為十種基因型(A到J),基因型B和C尤其高度盛行於東亞地區。臺灣的主要B型肝炎病毒為基因型B,基因型C次之,但基因型C在東亞其他各國皆為主要型別。基因型B和C在東亞地區各國的廣泛分布與臨床重要性,值得對其演化動態與傳播路徑進行研究。本論文分成三個章節: (1) B型肝炎病毒基因型C於東亞地區的演化起源與傳播 (2) B型肝炎病毒在日本的演化動態 (3) B型肝炎病毒基因型B在東亞地區的演化地理分析 本研究以貝氏演化分析法為基礎,搭配分子時鐘方法和地理資訊所發展出的時空模擬分析。以及各式演化軟體來觀察基因序列的選汰壓力、基因流向、親緣演化樹以及病毒的演化動態和演化地理分析。在臺灣與日本的部分病毒序列是由血清檢體所分離得出。而其他東亞國家與部分的臺灣和日本病毒序列則是大量採用公開基因資料庫GenBank上所擷選的病毒序列。 結果中看見東亞地區的基因型C演化起源(共同祖先)為中國,約從1940年起,病毒族群開始成長並傳播至東亞各國,期間至少有三次進入臺灣並造成流行。整個演化樹建構出兩個大的脈絡,一個傳播路線於1956年後由中國傳進日本,再進入韓國。另一個在中國內地傳播開來,並且在1965年後,疑似因1966年文化大革命的難民潮輾轉隨之進入美國。由基因型C的族群動態分析中可以看見1975年後病毒在日、韓地區的指數成長;在日本的演化動態章節中亦看見1960年後整體族群的指數成長。然而兩條傳播路線的病毒族群皆在2003年遇到強烈的瓶頸效應。並與2003年爆發的SARS-CoV大流行所造成的出入境人口暫時性銳減,有統計上的高度相關性。 在日本則觀察到外來基因型A盛行率的增加,主要經由性行為和血液傳染。從族群動態分析之中亦可看見,基因型A自1990~2003年為相對穩定增加。日本自1986年開始實施全國性的B型肝炎疫苗接種計畫,而在此研究中,證實了日本整體B型肝炎病毒有效族群數從1995年後就明顯的衰退。然而不同傳播方式的病毒,可能存在不同的族群動態(例如:垂直傳染與靜脈注射藥癮者)。本論文中取樣於臺灣的檢體,有部分是完成B肝疫苗施打,但卻在血液中發現B型肝炎病毒的突破性感染案例。雖然現行B肝疫苗有良好的保護效力而使病毒族群衰退,但部分個體於青春期後會喪失抗體,以及30歲以上沒有免疫抗體的成年人亦可能是B型肝炎病毒基因型A族群成長的潛在因子。突破性感染病毒株序列上的密碼子共演化位點數,高於慢性感染病毒株,此結果對於實際上胺基酸的改變影響並未可知,但這些共演化位點的存在可能增加了蛋白質改變的風險。 基因型B在東亞地區的最近共同祖先為臺灣,一方面傳播到中國造成流行,另一方面傳播到日本輾轉進入美國。基因型B的演化動態在1980年初期呈現平緩生長,到1989年開始呈現指數成長。臺灣於1989年推動十四項國家建設,引進大量東南亞外籍勞工並逐年增加。以國籍區分人數最多者為印尼,越南次之。這些國家最主要的HBV型別皆為基因型B,每年流動的龐大勞工人口,可能成為增加HBV/B基因多樣性的潛在來源,因此亦是建議相關單位觀察監控的重點。未來若納入東南亞的基因亞型,則有機會推算出基因型B更久遠的共同祖先。 本論文為第一篇以分子演化模型來觀察一個流行病的傳播如何影響人類移動並且影響另一個流行於相同族群的病毒消長。鑑於21世紀全球化的世界中新興與再新興病毒的持續挑戰,我們的結果除了突顯出更貼合實際的,共同傳播之傳染病的空間生態學模型的發展重要性之外,還需要持續監控臺灣與國際間人口流動所形成的潛在風險因子。
Hepatitis B virus (HBV) chronic infection is an important risk factor of liver cirrhosis and hepatocellular carcinoma. In ten genotypes, A to J, genotype B and C are most prevalent in East Asia. The major genotype in Taiwan is genotype B (HBV/B) and the minor is genotype C (HBV/C) while the most prevalent genotype of other East Asia countries is all genotype C. We used Bayesian phylogenetic method combining molecular clock methods with geographic informations to simulate the spatial-temporal dissemination of HBV/C and HBV/B. Other advanced phylogenetic tools are implemented to investigate the selection pressure, gene flow, phylogenetic tree, phylodynamics and phylogeography of HBV sequences. There are three chapters in this dissertation. (1) HBV/C evolutional origin and spread in East Asia. (2) HBV phylodynamics in Japan. (3) HBV/B phylogeography in East Asia. The evolution origin (MRCA) of HBV/C was traced back to the early 1900s in China, where it eventually diverged into two major lineages that gave rise to distinct epidemic waves spreading to other East Asian countries as well as the United States. One lineage caused at least three times of introductions into Taiwan and spread to the United States after 1965 which epidemic is likely driven by waves of refugee caused by the ‘’Culture Revolution’’ political persecution since 1966. The other lineage started from China to Japan after 1956 and then spread to Korea. Phylodynamic analysis indicates that HBV/C population encountered strong bottlenecks in 2003. The bottlenecks of two HBV/C lineages are significantly correlated with SARS-CoV outbreak in 2003 which lead to tremendous temporary reduction of departure and arriving numbers at customs check point. The prevalence of foreign genotype A in Japan has increased which transmit maily by horizontal transmission such as sexual contact and blood transfusion. HBV/A phylodynamic showed relatively increasing during 1990~2003 while HBV overall pattern in Japan had significant decrease since 1995. Hepatitis B vaccination has good protection of ‘’mother-to-infant’’vertical transmission. However, the evolution dynamics of viruses may quite vary among different types of transmission (e.g. vertical vs. intravenous injection). Part of Taiwan HBV samples in this dissertation had recorded for complete hepatitis B vaccination and been tested as HBV posititve which so called HBV breakthrough infection. We proposed that endemic Japanese HBV has been controlled by the national wide vaccination as shown by Skyride plot. In contrast, the increasing of phylodynamic pattern of HBV/A might be due to the lost of immunity to HBV in adolescents since HBV/A was introduced to Japan from foreign countries and was transmitted mainly through sexual contact. In antibody-naive adults over 30 years old, those were born before the vaccination program, are also considered as potential factors for HBV/A population growth. Breakthrough infection HBV sequences have more co-evolution codon positions than chronic HBV. The effect of co-evolution sites to amino acid changes remains unknown but these codon positions may increase the risk of protein changes. This is the first documented demonstration of how epidemic spread of one pathogen, impacting human mobility can affect the spread of another pathogen co-circulating among the same host population. Given the continuous challenge of emerging and re-emerging pathogens in the 21st century globalized world, our results not only highlight the need for the development of more realistic spatial ecology models of multiple, co-circulating infectious diseases but also the need for continious monitoring of international human mobility contributing potential risk factor.
URI: http://ethesys.lib.ntou.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=G0029936004.id
http://ntour.ntou.edu.tw:8080/ir/handle/987654321/48783
Appears in Collections:[生命科學暨生物科技學系] 博碩士論文

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