The secret of life lay hid in the night, God said “Let Darwin Be” and all was light
— Modified from Alexander Pope
王弘毅 教授
臺灣大學
臨床醫學研究所
生態及演化研究所
Hurng-Yi Wang
Professor
Graduate Institute of Clinical Medicine &
Institute of Ecology and Evolutionary Biology
National Taiwan University
TEL:
+886 2 23123456 ext 66614
Email:
Address:
7 Chung-Shan South Rd
Taipei, Taiwan 100
Projects
Testing speciation with gene flow by comparing the loci responsible for reproductive isolation with the genomic patterning of differentiation
新種形成的遺傳機制一直是演化學研究的主題。異域種化模型認為物種經過隔離而形成，因此基因組內不同區域的分化程度應該是相當均值的。而根據種化基因交流假說，基因組內與物種形成有關的基因會因為天擇的干預不易在兩物種間交換。在其它基因可以交流的情況下，前述區域會在基因組內形成相對歧異度較大的區段或稱為。然而種化過程中，如果基因組內部突變率或是基因互換率有差異，即便沒有基因交流，也會造成不同區域分化程度的差異。因此問題在於如何區別基因組內的分化不均值性是由基因交流所造成。種化基因交流模型具體的指出基因組內與種間差異有關的基因會有較大程度的分化，而異域種化模型則沒有這樣的推測。本研究預計整合族群分化以及與物種性狀有關的遺傳學研究來探討基因交流在物種形成時所扮演的角色。
我們首先會以模式物種黑腹果蠅進行先期研究。黑腹果蠅的兩個品系，Z and M，有不同的交配行為，而影響這些行為的基因主要在體染色體。因此我們預測Z/M兩品系果蠅的體染色體比性染色體要有較大的分化。此外過去研究發現薜荔與愛玉小蜂小蜂因為不同生活環境，而有不同的溫度適應。我們預測兩者之間與能量產生有關的基因比起其他的基因會有較大的分化。
The genetic details of how new species arise have been major topics of evolutionary research. Allopatric mode speciation considers that all genes between two species were diverged at the same time, thus genetic differentiation across the genomes between two species should be homogenous. An alternative model of speciation with gene flow presumes that the loci involved in reproductive isolation or ecological specialization would result in strong selection against their introgression between species, leading to heterogeneous pattern or “genomic islands” of differentiation in the genome. Nevertheless, level of divergence between two species can be heterogeneous in the absence of gene flow, if some biological processes, including variation in local mutation and recombination rates and selection, have been involved. The problem is whether the observed heterogeneous landscape of genomic differentiation can be explained solely by a combination of several biological processes, or gene flow has to be invoked. Speciation with gene flow specifically predicts that genomic regions with elevated divergence will contain genes responsible for species isolation, whereas other models make no such prediction. This proposal aims to test the speciation with gene flow model by integrating studies of population differentiation with genetic studies of phenotypes responsible for species distinction.
We first conduct a pilot study on model organism, Drosophila melanogaster. The genes responsible for behavior differences between two races, Z and M, are majorly mapped on autosomes. Thus, we expect autosomal loci exhibit greater divergence than X-linked loci. We next test this hypothesis on fig wasps. Jelly-fig wasp, Wiebesia pumilae, which is the pollinator of endemic fig tree, Ficus pumilae var. awkeotsang or jelly fig, and creeping-fig wasp, pollinator of F. pumilae var. pumila or creeping fig. From previous studies, two fig wasps are separated by different altitudes of their host figs, > 800 m for jelly fig and < 500 m for creeping fig. While two wasps show different temperature adaptations related to their different living environments, gene flow between them is observed. Therefore, we should expect to see the elevated divergence in the genetic regions responsible for energy production and metabolism. The divergence in the rest of genome would be homogenous because of constant gene flow.
Innate myeloid cells (especially Kupffer cells) and their PRRs in establishing tolerance to hepatitis B virus
B型肝炎病毒是世界上最常見的感染疾病之一。據世界衛生組織，超過三分之一的世界人口（二十億人）已感染B型肝炎病毒。其中，有2.5億人在全球是慢性帶原者。慢性B型肝炎病毒感染很少有肝外表現。他們往往不知道疾病已經法展到肝硬化相關的併發症的存在下，以及肝細胞癌（通常在40歲後），或肝硬化及肝細胞癌兩者存在。雖然，有效的疫苗是目前可行的方法，但它無法幫助慢性感染者已經發展為肝硬化和肝癌的風險。因此，開發有效治療慢性B型肝炎病毒感染, 仍然被認為是必要的。
其中一個B型肝炎病毒感染最顯著特點是在感染時的年齡差別。對於在一歲以下感染成為慢性帶原者的風險為90％。一至五歲之間的兒童風險降至30％。對於5歲以上和成人，從匯集的數據顯示風險降低到2％左右。推測“肝臟耐受性”和“免疫不成熟”對B型肝炎病毒的結果, 在嬰幼童時期具有高病毒的持續性，但在晚期年齡肝臟免疫環境成熟時具有病毒清除能力, 然而，這種成熟的過程尚未闡明。
為了方便我們瞭解B型肝炎病毒感染時年齡相關的免疫活化，我們研究團隊已經建立了一個年齡和腸道菌相關的B型肝炎病毒持續性小鼠模式。在成年（12週齡）的C3H /HeN小鼠約在注射B肝病毒後6週內快速清除B型肝炎病毒，而年輕（6週齡）的C3H /HeN小鼠在注射B型肝炎病毒後26週仍保持B肝病毒呈現陽性。使用抗生素5至12週齡的小鼠, 清除腸道菌群可以防止成年小鼠快速清除B型肝炎病毒。我們還證明肝臟的巨噬細胞在年輕小鼠表現出耐受性的表現型以及在成年小鼠打破耐受性的表現型。
利用這小鼠模式，我們的目標是進一步瞭解年齡和腸道菌在調節肝臟的免疫反應，尤其是肝臟的巨噬細胞，對抗B型肝炎病毒和人類慢性B型肝炎病毒感染的影響。為此目的，我們的目標是（1）在不同年齡組的小鼠中表現型和不同的肝臟巨噬細胞群的功能，（2）識別肝臟的巨噬細胞群的病原體相關分子模式（PAMP），和模式識別接受器（PRRs），（3）檢查的年齡和腸道菌群的作用在調節Kupffer細胞及循環血液外來巨噬細胞的功能來對抗B型肝炎病毒，（4）研究肝臟的巨噬細胞和其他免疫細胞之間的相互作用，和（5）探討在慢性帶原者和其他動物中的肝臟巨噬細胞的表現型和功能。
Hepatitis B virus (HBV) is one of the most common infectious agents in the world. According to world health organization (WHO), more than a third of the world’s population (2 billion people) has been infected with HBV. Of these, 250 million people worldwide are chronic carriers. Patients with chronic HBV infection seldom have extrahepatic manifestations. They are often unaware of the disease until the presence of cirrhosis-related complications, hepatocellular carcinoma (HCC)(usually after the age of 40), or both. Although, the highly effective vaccine is currently available, it does not help those who have already been chronically infected and are at risk of developing cirrhosis and HCC. Thus, efforts of developing the effective treatment of chronic HBV infection are still considered a necessity.
One of the distinctive features of HBV infection is that the risk of chronicity varies greatly with the age at which the infection is acquired. For those who acquire the infection under the age of one the risk of becoming chronic carrier is 90%. The risk drops to 30% for children between one to five years old. For children older than 5 years and for adults, the risk from pooled data decreases to around 2%. It is postulated that “liver tolerance” and “immune immaturity” to HBV result in the high viral persistence in early stage of life, but that the maturation of liver immune environment in late age empowers HBV clearance. However, this maturation process has not been clarified.
In order to facilitate our understanding of age-dependent immune activation during HBV infection, our group has established an age and gut-bacteria related HBV persistent mouse model. While adult (12-week-old) C3H/HeN cleared HBV within 6 week postinjection (wpi), their young (6-week-old) counterparts remained HBV-positive at 26 wpi. Sterilization of gut microbiota from 5 to 12 weeks of age using antibiotics prevented adult mice from rapidly clearing HBV. We also demonstrated liver macrophages showed tolerant phenotypes in young mice, and the tolerant phenotypes were dismissed in adult mice.
Using this model, we aim to understand the influence of age and gut bacteria in regulating liver immune response, especially liver macrophages, against HBV and the possible connection with human chronic HBV infection. To that end, we aim to (1) characterize the phenotypes and functions of different liver macrophage subsets in different age groups of mice, (2) identify pathogen associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) within a subset of liver macrophages, (3) examine the role of age and gut bacteria in regulating the function of KC and MoMs against HBV, (4) study the interaction between liver macrophages and other immune cells, and (5) investigate phenotypes and function of liver macrophages in chronic carriers and other animals.
Selected publications (2013- )
Zhang Y, Li Y, Shen X, Zhu T, Tao Y, Li T, Li X, Wang D, Ma Q, Hu Z, Liu J, Zheng C, Ruan J, Cai J, Wu C-I, Wang H-Y*, Lu X*. 2018. Genetic load and potential mutational meltdown in cancer cell populations. Molecular Biology and Evolution, 2018. in press. (IF: 10.217; Genetics and heredity 6/167=3%)
Wu L-L, Peng W-H, Wu H-L, Miaw S-C, Yeh S-H, Yang H-C, Liao P-H, Lin J-S, Chen Y-R, Hong Y-T, Wang H-Y*, Chen P-J and Chen D-S*. 2018. Ly6C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice. Hepatology, in press (IF: 14.079; Gastroenterology and hepatology 4/79=5%)
Wen H, Wang H-Y, He H, and Wu C-I. 2018. On the low reproducibility of cancer studies. National Science Review, in press (IF: 9.408; Multidisciplinary Sciences 5/64=8%)
Wang H-Y, Chen Y, Tong D, Ling S, Hu Z, Tao Y, Lu X, Wu C-I. 2018. Is the evolution in tumors Darwinian or non-Darwinian? National Science Review, 5: 15-17 (IF: 9.408; Multidisciplinary Sciences 5/64=8%)
Lin Y-Y, Hsieh C-H, Chen J-H, Lu X, Kao J-H, Chen P-J, Chen D-S, and Wang H-Y*. 2017. De novo assembly of highly polymorphic metagenomic data using in situ generated reference sequences and a novel BLAST-based assembly pipeline. BMC Bioinformatics, 18:223 (IF: 2.448; Mathematical and computational biology 10/57=18%)
Wu C-I, Wang H-Y, Ling S. Lu X. 2016. The Ecology and Evolution of Cancer: The Ultra-Microevolutionary Process. Annu Rev Genet, 50: 347-369. (IF: 9.589; Genetics and heredity 9/167=5%)
Chou H.-H., Chien W.-H., Wu L.-L., Cheng C.-H., Chung C.-H., Horng J.-H., Ni Y.-H., Tseng H.-T., Wu D., Lu X, Wang H.-Y*, Chen P.-J., and Chen D.-S* 2015. Age-Related Immune Clearance of Hepatitis B Virus Infection Requires the Establishment of Gut Microbiota. PNAS, 112: 2175-2180. (IF: 9.661; Multidisciplinary Sciences 4/64=6%)
Lin Y.-Y, Liu C, Chien W.-H, Wu L-L, Tao Y, Wu D, Lu X, Hsieh C-H, Chen P-J, Wang H-Y*, Kao J-H*, and Chen D-S. 2015. New insights into the evolutionary rate of hepatitis B virus at different biological scales. Journal of Virology. doi:10.1128/JVI.03131-14 (IF: 4.663; Virology 6/64=18%)
Tseng SP, Li SH, Hsieh CH, Wang HY*, Lin SM*. 2014. Influence of gene flow on divergence dating – implications for the speciation history of Takydromus grass lizards. Molecular Ecology, 23: 4770-4784 (IF:6.086; Biochemistry and Molecular Biology 39/290=13%)
Hsieh, C.-H., Ko, C.-C., Chung, C.-H, Wang, H.-Y.* 2014. Multilocus approach to clarify species status and the divergence history of the Bemisia tabaci (Hemiptera: Aleyrodidae) species complex. Molecular Phylogenetics and Evolution, 76: 172-180. (IF: 4.419; Genetics and heredity 32/167=19%)
Chiou HY, Hsieh CH, Jeng CR, Chan FT, Wang HY*, Pang VF*. 2014. Molecular characterization of cryptically circulating rabies virus from ferret badgers, Taiwan. Emerging Infectious Disease, 20: 790-798 (IF: 8.222; Infectious disease 3/84=4%)
Wang, H.-Y., Chieh, C.-H., Huang, C.-G., Kong, S.-W., Chang, H.-C, Lee, H.-H., Wang, W.-K., Chen, S.-L., Tzeng, H.-Y., and Wu, W.-J. 2013. Genetic and physiological data suggest demographic and adaptive responses in complex interactions between populations of figs (Ficus pumila) and their pollinating wasps (Wiebesia pumilae). Molecular Ecology, 22: 3814-3832. (IF:6.086; Biochemistry and Molecular Biology 39/290=13%)
Full publication list
http://ah.ntu.edu.tw/web/Teacher!one.action?tid=651#researcher-tab-3
Teachings
Fall Semester
Population Genetics
Evolution
Spring semester
Evolution Medicine
Molecular Evolution
Research Interests
The researches in my lab are concentrated on molecular evolution and population genetics. To our knowledge, we are the ONLY group working mainly on evolutionary related topics in medical campus, National Taiwan University. Currently, there are two major domains in our lab. The first one is virus related research. We focus on patterns of viral diversity change within host, rate of viral evolution, and interaction between pathogen and host. The second domain is to understand the mechanisms that drive population divergence. If you are interested in our lab, contact us or stop by for more details.
（1）B型肝炎病毒的演化與宿主的交互作用
B型肝炎病毒（HBV）造成全世界兩億四千萬人慢性感染。然而對於其起源，散布以及演化速率等知識仍然付之闕如，此外HBV如何造成慢性感染的機制仍然不清楚。本實驗室自2010年起即積極研究這兩項議題。
若以親緣地理的方式分析HBV的演化速率約為10-6 substitution/site/year，但追蹤同一宿主感染HBV數十年所得的演化速率則為10-5 ～ 10-4 substitution/site/year。我們推測這樣的差異是因為HBV為了適應宿主間與宿主內不同環境所造成的。分析HBV在家庭內不同個體間與個體內的演化發現，HBV在宿主體內大部份的變異無法傳遞給下一個宿主，因此個體內所累積的變異會高估演化速率。我們據此建立了一個HBV長期的演化模型，此模型可以解釋為何兒童感染HBV有很長的免疫耐授期，以及不同HBV基因型是如何達到目前的分布狀況。部分研究成果已經被Journal of Virology以及BMC Bioinformatics發表。
關於造成HBV慢性感染的機制方面，我們首先建立C3H/HeN小鼠的HBV感染模式，此一小鼠品系在6周齡transfect HBV會造成慢性感染。但若在12周齡才transfect HBV，則會將HBV清除。但若在小鼠6至12周時以廣效型抗生素清除其腸道的共生菌，則會造成12周齡的小鼠 HBV慢性感染，顯示腸道的共生菌與造成HBV的慢性感染有關，此一研究成果已被PNAS接受。進一步的研究發現腸道菌可能經由toll-like 4 receptor 影響肝臟巨噬細胞的功能，並干擾肝臟對於HBV免疫反應。
（2）基因交流在物種分化所扮演的角色
物種形成（speciation）一直是生物學重要的課題，但其機制仍然非常隱晦。本實驗室自2008年起即研究基因交流在種形成過程中所扮演的角色，及其對於分化時間估計所造成的影響。我們分析了不同尺度的物種，包含廣泛分佈的Bemesia屬昆蟲，侷限於東亞分布的榕果小蜂，以及台灣特有種草蜥。我們的結果與過去的認知相反，顯示不論在何種情況下，基因交流在物種分化的過程中扮演非常重要的角色。若忽略此一因素，會錯估物種形成的時間，以及建立錯誤的物種形成機制。相關研究已發表在Molecular Ecology （2013, 2014）與Molecular Phylogenetics and Evolution （2014）。