鸡新城疫、鸡传染性支气管炎基因芯片的构建及其检测技术研究
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摘要
鸡新城疫(Newcasttle Disease，ND)和鸡传染性支气管炎(Infectious Bronchitis，IB)是鸡的主要呼吸道传染病，严重危害养鸡业的发展。基因芯片技术是近年来发展起来的一种生物新技术，该技术可应用于基因表达谱分析、基因位点突变分析和疫病检测等方面。本研究首次构建制备了NDV-IBV基因检测芯片，建立了检测NDV、IBV基因芯片检测新技术，该技术对NDV、IBV的检测具有同步检测和鉴别诊断的功能，是动物疫病病原检测方法新的突破和进步。本研究的主要研究内容包括以下三个方面：
1、NDV-IBV检测基因芯片的靶基因克隆及鉴定研究
对NDV和IBV等病原进行分子生物学特征分析，根据文献和GenBank中报道NDV、IBV、AIV和IBDV的基因序列，用DNA Club2.0或Arraydesigner 2.0软件设计了5对NDV靶基因引物、4对IBV靶基因引物、2对AIV和1对IBDV对照靶引物。试验以NDV Lasota株、NDV F48E9株、IBV M41株、IBV SM株、IBD中等毒力疫苗株和AIV株为材料，用RNA／DNA抽提试剂盒抽提病毒RNA，反转录合成cDNA。以cDNA为模板，PCR扩增获得了5个NDV靶基因、3个IBV靶基因、2个AIV基因和1个IBDV基因，分别命名为ND1、ND2、ND3、ND4、ND5、IB1、IB2、IB3、AI1、AI2、IBD1。其中ND1系NDV HN基因片段，长487bp；ND2系NDV NP基因片段，长135bp；ND3、ND4系NDV L基因片段，分别长334bp和540bp；ND5系NDV F基因片段，长522bp；IB1和IB2系IBV NP基因片段，分别长276bp和1010bp；IB3系IBV M基因片段，长315bp；1个末鉴定基因WZ，长为364bp；AI1系AIV M基因片段，长789bp；AI2系AIV NP基因片段，长522bp；IBD1系IBD VP3基因片段，长428bp。同时用pMD18-T Vector载体成功地克隆筛选出T／ND1(F48E9)，T／ND2(Lasota)，T／ND3(Lasota)，T／ND4(F48E9)，T／ND5(Lasota)，T／ND5(F48E9)，T／IBI(SM)，T／IBI(M4 J)，T／IB2 (SM)，T／IB3 (M41)，T／WZ，T／AI1，T／AI2，T／IBD1等14个重组质粒，经BamH Ⅰ酶切、PCR和核酸序列测定鉴定了克隆重组质粒，为NDV-IBV检测基因芯片的构建和制备提供了确实可靠的靶基因材料，是NDV-IBV基因检测芯片构建的关键技术之一。
2、NDV-IBV检测基因芯片构建研究
本试验对基因芯片的制备、探针制备和基因芯片检测方法进行了研究，构建了NDV-IBV检测基因芯片和初步研究了NDV强弱毒鉴别基因芯片。
(1) 基因芯片的制备 以靶基因重组质粒DNA为模板，经PCR扩增、异丙醇沉淀纯化靶基因，同时以λDNA模板和设计引物经PCR扩增制备了长为500bp的定位基因，
四川农业大学博士学位论文
靶基因和定位基因浓度为161.88一1218.36ng/pl。用基因芯片点样缓冲液将靶基因
和定位基因稀释成一定浓度后，基因芯片点样仪SpotArray24点样制备芯片。芯片
基片为氨基化基片，点样参数为样点中心间距450 pm，样点直径220协m，点样后室
温干燥Zhrs、水合处理105、紫外线交联25mi n.和0.2%SDS洗涤smin.等系列处理，
制备了NDV一IBV检测基因芯片。
(2)基因芯片探针制备
以cDNA为模板，经
PCR扩增标记体系中，CY3一dCTP的使用终浓度为
:PCR扩增标记荧光素CY3
4.0 pM，dCTP的终浓度为
其他dNTP的终浓度为200.0 pM，制备的探针经试剂盒纯化后浓度为39.
ng/pl之间。
制备探针。
100.0抖M，
09一145.76
(3)基因芯片的检测方法及分析试验确定了基因芯片检测技术流程和主要参
数。芯片经95一100℃变性1一Zmi n.后用无水乙醇快速冷却，离心干燥，在44℃下预
杂交30min一6Omi n.，探针95℃变性smi n.，冰浴急冷后加杂交缓冲液配成杂交液，
取25一30 pl用于芯片杂交，在一定温度下杂交时间为7一ghrs。然后用洗液1(2.0%SSc
0.1%SDS)、洗液2(0.2%SSC 0.1%SDS)、洗液3(0.16%SSC 0.1%SDS)先后洗涤1次，每
次3一smin.洗涤后离心干燥，芯片用ScanArray400o扫描仪扫读，数据用QuantArra声
Ver.2.1软件和数据分析软件分析处理。
(4) NDV一IBV检测基因芯片的构建试验研究了不同靶基因的最适杂交温度和靶
基因之间的交叉杂交反应以及制备芯片时靶基因的点样浓度，根据不同靶基因的最适
杂交温度和交叉杂交反应情况将靶基因分类，成功构建了NDV一IBV检测基因芯片。结
果为NDZ、ND3、NDS、IBI、IBZ、IB3、All、AIZ和IBDI在44，C下，NDI、NDZ、ND3、
NDS、IBI、IBZ、All、AIZ或NDI、NDZ、 ND3、ND4、NDS、IBI、IB3、All、AIZ、IBDI
在48，C下和NDI、ND3、ND4、NDS、IB3、AllZ、IBDI在52oC下杂交效果好，各靶基
因之间杂交无交叉反应，靶基因的点样浓度确定为IO0ng/pl。
(5) NDV强弱毒株鉴别检测基因芯片的初步研究。cDNAI、cDNA3为强毒株检测靶
基因，cDNAZ为弱毒株检测靶基因，靶基因点样浓度为20Ong/“1，杂交温度为44℃，
杂交时间为2.0 hrs一4.ohrs。研究表明制备的检测芯片可对NDV F48E9和NDV Lasota
株进行鉴别诊断。
3、NDv‘IBy检侧基因芯片的检侧技术研究
试验制备的NDV一IBV检测基因芯片，芯片上有定位基因LG、靶基因NDI、ND3、
NDS、IBI、IB3、All、AIZ和IBDI等9种基因，研究T芯片检测的标准化条件、特
异性、灵敏性、重复性和结果判断标准。
中文摘要
(1)检测探针制备
Newcastle Disease(ND) and chicken Infectious Bronchitis(IB) are both serious infectious diseases. Microarray is a new kind of biotechnology developed recent years which can be used to detect diseases. In this study, NDV-IBV microarray detecting viruses was constructed which can detect NDV and IBV at the same time.
1. The cloning of NDV-IBV microarray's target genes
Analysing the molecular biological characters and gene sequences of NDV and IBV from literatures and GenBank,5 pairs of NDV primers, 4 pairs of IBV primers, 2 pairs of AIV primers and 1 pair of IBDV primers were designed by DNA Club2.0 or Arraydesigner 2.0 softwares. The Ribonucleotide acids(RNAs) of NDV, IBV.AIV and IBDV were extracted with Viral RNA mini Kit and The target genes were amplified by RT-PCR Acquiring 5 NDV target genes, 3 IBV target genes, 2 AIV target genes , 1 IBDV target gene and 1 unknown gene(WZ) which were named as ND1, ND2, ND3, ND4, ND5, IB1, IB2, IB3, AI1, AI2, IBD1 and WZ .respectively.ND1,part of NDV HN gene, is 487bp ,ND2 , part of NDV NP gene, 135 bp, ND3 and ND4 , part of NDV L gene ,334bp and 540bp ,respectively,ND5,part of NDV F gene, 522 bp; IB1 and IB2 , part of IBV NP gene are 276bp and 1010bp ,respectively, IB3, part of IBV M gene, 315 bp; AI1, part of AIV M gene, 789 bp, AI2 , part of AIV NP gene, 522 bp; IBD1, part of IBD VP3 gene, 428 bp; WZ gene, 364 bp. 14 recombinant
plasmids were cloned using pMD18-T Vector and identified by digestion of RE,PCR and sequence analysis, which were named as T/ND1 (F48E9) ,T/ND2 (Lasota), T/ND3 (Lasota), T/ND4 (F48E9), T/ND5 (Lasota), T/ND5 (F48E9) ,T/IB1 (SM) ,T/IB1 (M41) ,T/IB2 (SM) ,T/IB3 (M41) ,T/AI1, T/AI2, T/IBD1 and T/WZ. These recombinant plasmids provided the reliable materials for microarray .The clone of target gene is a key technique for constructing NDV-IBV detection microarray.
2. Constructing NDV-IBV microarray
The construction and detection method of microarray were developed in this study.
(1) Preparation of microarray An aminated glass slide was used to make a microarray .The
target genes were amplified by PCR with templates extracted from 14 recombinant
plasmids and purified by isopropanol. The located gene, length of 500bp was amplified with template of XDNA by PCR. The concentrations of products were from 161.88 to 1218.36ng/ul. Target genes were diluted with spotted buffers(baiao ) at certain concentrations,then spotted on aminated glass slides with Microarray Printing System(SpotArray ?4), the space of spots was 450um, the diameter of spot 220um, 19 spots of every gene in a row. The spotted slide was dryed at room temperature for 2hrs, hydrated for 10 Seconds, lighted with UV for 25 mins. and washed with 0.2%SDS soulution for 5 mins., A microarray was successfully made.
(2) Preparation of probe Probes were labeled by PCR with fluorescence CY3.The concentrations of CY3-dCTP and dCTP were 4.0uM or 8.0uM and 100.0uM or 200.0 uM in PCR in a 50ul reaction system, respectively, and the other dNTPs concentrations were 200.0uM.The concentrations of the probes purified with DNA and RNA Purified Kit were from 39.09 to 145.76 ng/ul,
(3) The test method and analysis of microarray The experiment developed the detect program of microarray and its main parameters. After denatured for l-2min. at 95-100C,a microarray was quenched in anhydrous alcohol , centrifugated and dried,then pre-hybridizated for 30-60min. at 44C.The probes was denatured at 95C for 5min. putting in ice-bath immediately.then diluted with cooled hybridization buffer.Adding 25-30ul hybridiziton solution to the microarray,hybridizated for 7-9h at certain temperature. Washed accordingly with washing solution l(2.0%SSC 0.1%SDS), 2(0.2%SSC 0.1%SDS)and 3(0.16%SSC 0.1%SDS) each for 3-5min., then centrifugated and dried.The microarray was scanned with Microarray Analysis System(ScanArray 4000), data were analysed and disposed with QuantArray?Ver.3.0 software and data-analysing software.
(4) The construction of NDV-IBV
1、NDV-IBV检测基因芯片的靶基因克隆及鉴定研究
对NDV和IBV等病原进行分子生物学特征分析，根据文献和GenBank中报道NDV、IBV、AIV和IBDV的基因序列，用DNA Club2.0或Arraydesigner 2.0软件设计了5对NDV靶基因引物、4对IBV靶基因引物、2对AIV和1对IBDV对照靶引物。试验以NDV Lasota株、NDV F48E9株、IBV M41株、IBV SM株、IBD中等毒力疫苗株和AIV株为材料，用RNA／DNA抽提试剂盒抽提病毒RNA，反转录合成cDNA。以cDNA为模板，PCR扩增获得了5个NDV靶基因、3个IBV靶基因、2个AIV基因和1个IBDV基因，分别命名为ND1、ND2、ND3、ND4、ND5、IB1、IB2、IB3、AI1、AI2、IBD1。其中ND1系NDV HN基因片段，长487bp；ND2系NDV NP基因片段，长135bp；ND3、ND4系NDV L基因片段，分别长334bp和540bp；ND5系NDV F基因片段，长522bp；IB1和IB2系IBV NP基因片段，分别长276bp和1010bp；IB3系IBV M基因片段，长315bp；1个末鉴定基因WZ，长为364bp；AI1系AIV M基因片段，长789bp；AI2系AIV NP基因片段，长522bp；IBD1系IBD VP3基因片段，长428bp。同时用pMD18-T Vector载体成功地克隆筛选出T／ND1(F48E9)，T／ND2(Lasota)，T／ND3(Lasota)，T／ND4(F48E9)，T／ND5(Lasota)，T／ND5(F48E9)，T／IBI(SM)，T／IBI(M4 J)，T／IB2 (SM)，T／IB3 (M41)，T／WZ，T／AI1，T／AI2，T／IBD1等14个重组质粒，经BamH Ⅰ酶切、PCR和核酸序列测定鉴定了克隆重组质粒，为NDV-IBV检测基因芯片的构建和制备提供了确实可靠的靶基因材料，是NDV-IBV基因检测芯片构建的关键技术之一。
2、NDV-IBV检测基因芯片构建研究
本试验对基因芯片的制备、探针制备和基因芯片检测方法进行了研究，构建了NDV-IBV检测基因芯片和初步研究了NDV强弱毒鉴别基因芯片。
(1) 基因芯片的制备 以靶基因重组质粒DNA为模板，经PCR扩增、异丙醇沉淀纯化靶基因，同时以λDNA模板和设计引物经PCR扩增制备了长为500bp的定位基因，
四川农业大学博士学位论文
靶基因和定位基因浓度为161.88一1218.36ng/pl。用基因芯片点样缓冲液将靶基因
和定位基因稀释成一定浓度后，基因芯片点样仪SpotArray24点样制备芯片。芯片
基片为氨基化基片，点样参数为样点中心间距450 pm，样点直径220协m，点样后室
温干燥Zhrs、水合处理105、紫外线交联25mi n.和0.2%SDS洗涤smin.等系列处理，
制备了NDV一IBV检测基因芯片。
(2)基因芯片探针制备
以cDNA为模板，经
PCR扩增标记体系中，CY3一dCTP的使用终浓度为
:PCR扩增标记荧光素CY3
4.0 pM，dCTP的终浓度为
其他dNTP的终浓度为200.0 pM，制备的探针经试剂盒纯化后浓度为39.
ng/pl之间。
制备探针。
100.0抖M，
09一145.76
(3)基因芯片的检测方法及分析试验确定了基因芯片检测技术流程和主要参
数。芯片经95一100℃变性1一Zmi n.后用无水乙醇快速冷却，离心干燥，在44℃下预
杂交30min一6Omi n.，探针95℃变性smi n.，冰浴急冷后加杂交缓冲液配成杂交液，
取25一30 pl用于芯片杂交，在一定温度下杂交时间为7一ghrs。然后用洗液1(2.0%SSc
0.1%SDS)、洗液2(0.2%SSC 0.1%SDS)、洗液3(0.16%SSC 0.1%SDS)先后洗涤1次，每
次3一smin.洗涤后离心干燥，芯片用ScanArray400o扫描仪扫读，数据用QuantArra声
Ver.2.1软件和数据分析软件分析处理。
(4) NDV一IBV检测基因芯片的构建试验研究了不同靶基因的最适杂交温度和靶
基因之间的交叉杂交反应以及制备芯片时靶基因的点样浓度，根据不同靶基因的最适
杂交温度和交叉杂交反应情况将靶基因分类，成功构建了NDV一IBV检测基因芯片。结
果为NDZ、ND3、NDS、IBI、IBZ、IB3、All、AIZ和IBDI在44，C下，NDI、NDZ、ND3、
NDS、IBI、IBZ、All、AIZ或NDI、NDZ、 ND3、ND4、NDS、IBI、IB3、All、AIZ、IBDI
在48，C下和NDI、ND3、ND4、NDS、IB3、AllZ、IBDI在52oC下杂交效果好，各靶基
因之间杂交无交叉反应，靶基因的点样浓度确定为IO0ng/pl。
(5) NDV强弱毒株鉴别检测基因芯片的初步研究。cDNAI、cDNA3为强毒株检测靶
基因，cDNAZ为弱毒株检测靶基因，靶基因点样浓度为20Ong/“1，杂交温度为44℃，
杂交时间为2.0 hrs一4.ohrs。研究表明制备的检测芯片可对NDV F48E9和NDV Lasota
株进行鉴别诊断。
3、NDv‘IBy检侧基因芯片的检侧技术研究
试验制备的NDV一IBV检测基因芯片，芯片上有定位基因LG、靶基因NDI、ND3、
NDS、IBI、IB3、All、AIZ和IBDI等9种基因，研究T芯片检测的标准化条件、特
异性、灵敏性、重复性和结果判断标准。
中文摘要
(1)检测探针制备
Newcastle Disease(ND) and chicken Infectious Bronchitis(IB) are both serious infectious diseases. Microarray is a new kind of biotechnology developed recent years which can be used to detect diseases. In this study, NDV-IBV microarray detecting viruses was constructed which can detect NDV and IBV at the same time.
1. The cloning of NDV-IBV microarray's target genes
Analysing the molecular biological characters and gene sequences of NDV and IBV from literatures and GenBank,5 pairs of NDV primers, 4 pairs of IBV primers, 2 pairs of AIV primers and 1 pair of IBDV primers were designed by DNA Club2.0 or Arraydesigner 2.0 softwares. The Ribonucleotide acids(RNAs) of NDV, IBV.AIV and IBDV were extracted with Viral RNA mini Kit and The target genes were amplified by RT-PCR Acquiring 5 NDV target genes, 3 IBV target genes, 2 AIV target genes , 1 IBDV target gene and 1 unknown gene(WZ) which were named as ND1, ND2, ND3, ND4, ND5, IB1, IB2, IB3, AI1, AI2, IBD1 and WZ .respectively.ND1,part of NDV HN gene, is 487bp ,ND2 , part of NDV NP gene, 135 bp, ND3 and ND4 , part of NDV L gene ,334bp and 540bp ,respectively,ND5,part of NDV F gene, 522 bp; IB1 and IB2 , part of IBV NP gene are 276bp and 1010bp ,respectively, IB3, part of IBV M gene, 315 bp; AI1, part of AIV M gene, 789 bp, AI2 , part of AIV NP gene, 522 bp; IBD1, part of IBD VP3 gene, 428 bp; WZ gene, 364 bp. 14 recombinant
plasmids were cloned using pMD18-T Vector and identified by digestion of RE,PCR and sequence analysis, which were named as T/ND1 (F48E9) ,T/ND2 (Lasota), T/ND3 (Lasota), T/ND4 (F48E9), T/ND5 (Lasota), T/ND5 (F48E9) ,T/IB1 (SM) ,T/IB1 (M41) ,T/IB2 (SM) ,T/IB3 (M41) ,T/AI1, T/AI2, T/IBD1 and T/WZ. These recombinant plasmids provided the reliable materials for microarray .The clone of target gene is a key technique for constructing NDV-IBV detection microarray.
2. Constructing NDV-IBV microarray
The construction and detection method of microarray were developed in this study.
(1) Preparation of microarray An aminated glass slide was used to make a microarray .The
target genes were amplified by PCR with templates extracted from 14 recombinant
plasmids and purified by isopropanol. The located gene, length of 500bp was amplified with template of XDNA by PCR. The concentrations of products were from 161.88 to 1218.36ng/ul. Target genes were diluted with spotted buffers(baiao ) at certain concentrations,then spotted on aminated glass slides with Microarray Printing System(SpotArray ?4), the space of spots was 450um, the diameter of spot 220um, 19 spots of every gene in a row. The spotted slide was dryed at room temperature for 2hrs, hydrated for 10 Seconds, lighted with UV for 25 mins. and washed with 0.2%SDS soulution for 5 mins., A microarray was successfully made.
(2) Preparation of probe Probes were labeled by PCR with fluorescence CY3.The concentrations of CY3-dCTP and dCTP were 4.0uM or 8.0uM and 100.0uM or 200.0 uM in PCR in a 50ul reaction system, respectively, and the other dNTPs concentrations were 200.0uM.The concentrations of the probes purified with DNA and RNA Purified Kit were from 39.09 to 145.76 ng/ul,
(3) The test method and analysis of microarray The experiment developed the detect program of microarray and its main parameters. After denatured for l-2min. at 95-100C,a microarray was quenched in anhydrous alcohol , centrifugated and dried,then pre-hybridizated for 30-60min. at 44C.The probes was denatured at 95C for 5min. putting in ice-bath immediately.then diluted with cooled hybridization buffer.Adding 25-30ul hybridiziton solution to the microarray,hybridizated for 7-9h at certain temperature. Washed accordingly with washing solution l(2.0%SSC 0.1%SDS), 2(0.2%SSC 0.1%SDS)and 3(0.16%SSC 0.1%SDS) each for 3-5min., then centrifugated and dried.The microarray was scanned with Microarray Analysis System(ScanArray 4000), data were analysed and disposed with QuantArray?Ver.3.0 software and data-analysing software.
(4) The construction of NDV-IBV
引文
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