歐竑宇

微生物比較基因組學

（1）以科學問題為導向的生物信息學應用研究－細菌可移動遺傳元件的比較分析

細菌的染色體骨架通常相對保守，但有些菌株通過擁有某些特殊的可移動遺傳元件，如原噬菌體、整合型接合元件和基因組島等，維持或增強了它們在選擇壓力下的競爭優勢和遺傳穩定性。圍繞可移動元件功能研究中遇到的關鍵科學問題，我們開發了一系列生物信息學工具和數據庫：（i）元件識別：我們在MobilomeFINDER中提出了搜索臨牀和環境菌株特有基因組島的新策略，即“tRNAcc工具識別島插入熱點，tRIP-PCR技術搜索島，酵母捕捉質粒克隆新島”；而我們創建的mGenomeSubtractor則實現了在2～3分鐘內高速識別幾十個細菌染色體序列中的保守骨架或特異片段，利用並行計算解決了在比對數目、大小和運算時間上的難點。（ii）元件轉移：ICEberg數據庫通過生物信息學預測和文獻挖掘，系統地識別了上百個細菌中400多個整合型接合元件，比較分析了島的位點特異整合、切出環化和接合等典型的自行轉移特性，聚焦了它們所編碼的DNA硫修飾限制系統、致病性、抗菌素抗性和重金屬降解等重要生物學性狀。（iii）元件與宿主的互作：宿主菌可能會藉助與程序性死亡相關的毒素-抗毒素系統來調控新獲得可移動元件。TADB數據庫比較分析了1萬多個廣泛存在於細菌可移動元件上的II型毒素-抗毒素操縱子，系統分類為14個家族。

（2）可移動遺傳元件的功能解析－革蘭氏陰性條件致病菌致病和耐藥傳播機制的研究

條件致病菌肺炎克雷伯菌是醫源性感染最主要的革蘭氏陰性菌之一，可引起肺炎、尿路感染、敗血症等多種疾病。在廣譜抗生素濫用造成的強大選擇壓力下，肺炎克雷伯菌通過獲得質粒或基因組島介導的抗菌素抗性基因，成為多重耐藥菌或極度耐藥菌。多年來我們廣泛收集不同來源的肺炎克雷伯菌，包括各種環境株臨牀多重耐藥株和。通過MobilomeFINDER策略考察了這些不同生境肺炎克雷伯菌的基因組多樣性。此外，我們還關注銅綠假單胞菌和鮑曼不動桿菌等重要耐藥條件致病菌致病。

（3）“幹-濕”科學緊密的結合－細菌基因組島編碼的DNA硫修飾及其限制系統

我們與多個研究組展開優勢互補的合作，圍繞微生物代謝過程中關鍵科問題開展開了一系列比較分析研究。合作研究發現了DNA硫修飾系統通過水平轉移以基因組島的形式，廣泛存在於分類地位和生態差異很大的細菌和古細菌中；對預測的天藍色鏈黴菌基因組島深入分析，首次發現了DNA硫修飾依賴的限制系統，其中一個島編碼了能切割磷硫酰化DNA的IV型核酸內切酶。這些合作結晶有助於闡明DNA硫修飾的生物學意義。

2006年6月到上海交通大學分子微生物學實驗室擔任副教授 ^[1]  ，2010年遴選為博士生導師，2012年任教授，致力於比較基因組學領域的開拓。從菌種資源發掘和建立生物信息學平台開始，聚焦在細菌可移動基因組功能解析的若干關鍵科學問題，將研究小組引入到條件致病菌耐藥性傳播和DNA硫修飾系統水平轉移等重要課題的探索。以分子微生物學和生物信息學交叉互動策略來突顯研究特色，業已取得了一些系統性進展，至2012年2月已發表20篇SCI論文；其中，9篇為通訊作者或第一作者，發表在Nucleic Acids Research、Journal of Bacteriology、Journal of Molecular Diagnostics、PLoS ONE等國際生物學雜誌上。多次擔任國內外生物學刊物的審稿人，曾多次在國際國內會議上作學術報告和擔任分會場主持人。承擔多項863計劃課題和國家自然科學基金課題。2007年入選上海市“青年科技啓明星計劃”；2008年獲得了明治乳業生命科學獎；2009年入選上海交通大學晨星青年學者獎勵計劃SMC優秀青年教師 (A類)；2010年入選教育部新世紀優秀人才支持計劃。

(20) D. Bi, Z. Xu, E. Harrison, C. Tai, Y. Wei, X. He, S. Jia, Z. Deng., K. Rajakumar* and H.Y. Ou* (2012) ICEberg: a web-based resource for integrative and conjugative elements found in Bacteria. Nucleic Acids Research, 40, D621-D626.

(19) P. Liu, P. Li, X. Jiang, D. Bi, Y. Xie, C. Tai, Z. Deng, and H.Y. Ou* (2012) Complete genome sequence of Klebsiella pneumonia subsp. pneumoniae hs11286, a multidrug-resistant strain isolated from human sputum. Journal of Bacteriology, in press.

(18) Y. Shao, E.M. Harrison, D. Bi, C. Tai, X. He, H.Y. Ou*, K. Rajakumar and Z. Deng (2011) TADB: a web-based resource for Type 2 toxin-antitoxin loci in bacteria and archaea. Nucleic Acids Research, 39, D606-D611.

(17) J. Zhang, J. Jurriaan van Aartsen, X. Jiang, Y. Shao, C. Tai, X. He, Z. Tan, Z. Deng, S. Jia*, K. Rajakumar and H.Y. Ou* (2011) Expansion of the known Klebsiella pneumoniae species gene pool by characterization of novel alien DNA islands integrated into tmRNA gene sites. Journal of Microbiological Methods, 84, 283-289.

(16) H.Y. Ou* and K. Rajakumar* (2011) Book chapter: “ArrayOme- & tRNAcc-facilitated mobilome discovery: comparative genomics approaches for identifying rich veins of bacterial novel DNA sequences”, Handbook of Molecular Microbial Ecology I: Metagenomics and Complementary Approaches, Editor F. J. de Bruijn, John Wiley & Sons, Inc.

(15) G. Liu, H.Y. Ou, T. Wang, L. Li, H. Tan, X. Zhou, K. Rajakumar, Z. Deng* and X. He* (2010) Cleavage of Phosphothioated DNA and Methylated DNA by the Type IV Restriction Endonuclease ScoMcrA. PLoS Genetics, 6, e1001253.

(14) Y. Shao, X. He, C. Tai, H.Y. Ou*, K. Rajakumar and Z. Deng (2010) mGenomeSubtractor: a web-based tool for parallel in silico subtractive hybridization analysis of multiple bacterial genomes. Nucleic Acids Research, 38, W194-W200.

(13) N. Chen¶, H.Y. Ou¶, J.J. van Aartsen, X. Jiang, M. Li, Z. Yang, Q.Wei, X. Chen, X. He, Z.Deng, K. Rajakumar,Y. Lu* (2010) The pheV phenylalanine tRNA gene in Klebsiella pneumoniae clinical isolates is an integration hotspot for possible niche-adaptation genomic islands. Current Microbiology, 60, 210-6.( ¶ These authors contributed equally to this work.)

(12) H.Y. Ou, X. He, Y. Shao, C. Tai, K. Rajakumar and Z. Deng* (2009) dndDB: a database focused on phosphorothioation of the DNA backbone. PLoS ONE, 4, e5132.

(11) H.Y. Ou ¶, C.T.S. Ju ¶, K.L. Thong, N. Ahmad, Z. Deng, M.R. Barer and K. Rajakumar* (2007). Translational Genomics to Develop a Salmonella enterica Serovar Paratyphi A Multiplex PCR Assay. Journal of Molecular Diagnostics, 2007, 9, 624-630. (¶ These authors contributed equally to this work.) (Cover Figure and Comment in: J Mol Diagn. 2007, 9, 572-573.)

(10) H.Y. Ou, X. He, E.M. Harrison, B.R. Kulasekara, A.B. Thani, A. Kadioglu, S. Lory, J.C. Hinton, M.R. Barer, Z. Deng* and K. Rajakumar* (2007). MobilomeFINDER: web-based tools for in silico and experimental discovery of bacterial genomic islands. Nucleic Acids Research, 35, W97-W104.

(9) X. He, H.Y. Ou, Q. Yu, X. Zhou, J. Wu, J. Liang, W. Zhang, K. Rajakumar and Z. Deng* (2007). Analysis of a genomic island housing genes for DNA S-modification system in Streptomyces lividans 66 and its counterparts in other distantly related bacteria. Molecular Microbiology, 65, 1034-48.

(8) H.Y. Ou, L.L. Chen, J. Lonnen, R.R. Chaudhuri, A.B. Thani, R. Smith, N.J. Garton, J.C. Hinton, M. Pallen, M. Barer and K. Rajakumar* (2006). A novel strategy for identification of genomic islands by comparative analysis of the contents and contexts of tRNA sites in closely related bacteria. Nucleic Acids Research, 34, e3.

(7) H.Y. Ou , R. Smith, S. Lucchini, J.C. Hinton, R.R. Chaudhuri, M. Pallen, M. Barer and K. Rajakumar* (2005). ArrayOme: a program for estimating the sizes of the microarray-visualised genomes. Nucleic Acids Research , 33, e3.

(6) H.Y. Ou, F.B. Guo and C.T. Zhang* (2004). GS-Finder: a program to find bacterial gene start sites with a self-training method. Int. J. Biochem. Cell Biol. 36, 535-544.

(5) R. Zhang, H.Y. Ou and C.T. Zhang* (2004). DEG, a Database of Essential Genes. Nucleic Acids Research, 32, D271-D272.

(4) H.Y. Ou, F.B. Guo and C.T. Zhang* (2003). Analysis of nucleotide distribution in the genome of Streptomyces coelicolor A3(2) using the Z curve method. FEBS Letters, 540, 188-194.

(3) F.B. Guo, H.Y. Ou and C.T. Zhang* (2003). ZCURVE: a new system for recognizing protein-coding genes in bacterial and archaeal genomes. Nucleic Acids Research, 31, 1780-1789.

(2) L.L. Chen¶, H.Y. Ou¶, R. Zhang and C.T. Zhang* (2003). ZCURVE_CoV: a new system to recognize protein coding genes in coronavirus genomes, and its applications in analyzing SARS-CoV genomes. Biochem. Biophys. Res. Commun., 307, 382-388. (¶ These authors contributed equally to this work.)

(1) F. Gao, H.Y. Ou, L.L. Chen, W.X. Zheng and C.T. Zhang* (2003). Prediction of proteinase cleavage sites in polyproteins of coronaviruses and its applications in analyzing SARS-CoV genomes. FEBS Letters, 553, 451-456。