MBL2基因与奶牛乳腺炎抗性研究
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摘要
本研究以中国荷斯坦奶牛为研究素材，运用real time-RT-PCR、基因定点突变、缺失启动子活性分析、基因克隆表达、PCR-SSCP等技术，测定MBL2mRNA在奶牛不同组织、不同基因型个体中的表达；对牛MBL25′调控区分析，对启动子功能鉴定和核心启动子进行研究；体外表达牛MBL-C蛋白，研究其野生型与突变型的抗菌机制及抗菌能力差异；MBL遗传多态性，确定其基因型、单倍型；在此基础上，统计分析MBL突变与高产奶牛生产性能测定数据，血清补体溶血活性的相关性，结果如下:
中国荷斯坦牛MBL2基因外显子上存在单核苷酸多态性（g.1164G>A，g.1197C>A，g.1198G>A，1207T>C）与奶牛生产性状、奶牛血清补体活性和血清MBL-C蛋白含量相关分析表明，g.1164G>A，g.1197C>A位点的突变与体细胞评分有显著相关（P<0.01），与血清补体活性没有明显相关，g.1164G>A位点与血清MBL-C蛋白含量显著相关。实验成功突变了MBL2g.1164G>A位点，并体外表达了牛MBL-C野生型和突变型重组蛋白，证明重组蛋白对金黄色葡萄球菌有抑菌效果；扫描电镜观察发现野生型的抗菌能力要强于突变型。
克隆了牛MBL25’调控区2285bp的DNA序列，用EGFP报告基因瞬时转染技术鉴定了该区域具有启动子功能。通过双荧光素酶报告基因检测系统筛选到牛MBL2基础启动子和调控组件，发现牛MBL2基因5′调控区的-85～+52bp区域具有基本的启动子功能，结合序列分析发现牛MBL2基因上存在多个正调控和负调控组件。通过对牛MBL2基因5’调控区的SNPs分析，首次发现了3个SNPs位点：g.905C>G，g.956C>T，g.895A>T，分析发现这三个位点位于HNF-1、C-Myb、TATA box转录组件，可能具有重要的功能。通过荧光定量RT-PCR方法表明牛MBL2mRNA在肝脏、甲状腺、心脏、脾脏、乳腺、肺脏、肾脏组织均有表达，在肝脏组织中表达量最高；对应g.905C>G和g.956C>T位点不同基因型间乳腺组织mRNA表达没有明显差异。可以初步推断MBL2基因可能是影响奶牛乳腺炎抗性的主效基因或是与乳腺炎抗性相关的QTL连锁基因。
Infectious disease has major adverse effects both on the economics of livestockproduction and on animal welfare. Cow mastitis is a common disease in dairy industryworldwide，and has caused tremendous loss to the dairy production. A number oftherapeutic, prophylactic and management strategies have been proposed to minimizethis complex disease. Although these treatments have very good clinical outcome,emerge of drug-resistant strains and remaining antibiotics in milk have brought greatconcerns. Thus, an approach based on improving the host genetics in resistance toinfectious diseases through molecular marker selective breeding is becoming widelyaccepted. Mannose-binding lectin (MBL) are collagenous C-type lectins involved inthe innate immune response to various microbial pathogens. Antimicrobial functionsof MBL, including opsonization, neutralization, and complement activation. MBLselectively targets invading microorganisms for neutralization by its recognitiondomain’s binding to cell surface mannose, then activating MBL-associated serineproteases (MASPs).
By screening the genetic variation of MBL2exon in825individuals of ChinaHolstein, using PCR-SSCP techniques, four new SNPs were found in exon1, g.1164G>A, g.1197C>A, g.1198G>A,1207T>C. No SNPs were found in exon2, exon3andexon4in my research. Statistical analyses revealed correlation between both g.1164G>A, g.1197C>A and somatic cell score (SCS).
The effect of polymorphism g.1164G>A and g.1197C>A loci of MBL2gene oncomplement activity and serum MBL-C level was analyzed, the results indicated thatin the g.1164G>A and g.1197C>A loci, the different genotype had no significantinfluence on complement activity; in the g.1164G>A, the different genotype hadsignificant correlation on serum MBL-C level.
MBL2gene was amplified using reverse transcription-polymerase chain reaction(RT-PCR). The g.1164G>A loci of MBL2was mutation by rite-directed mutagenesis.The PCR product was inserted into vector pET32a(+) to construct plasmid pET32a (+)/MBL2and pET32a(+)/MBL2-TB, then the plasmid was expressed in E.coli BL21(DE3)cell that induced by IPTG. The diversity of antibacterial activity of wild-typeand mutant was assayed by agar whole diffusion-inhibition zone method and electronmicroscope using the purified recombination protein against Sta. aureu. The resultsanalysis showed the encoding a polypeptide. SDS-PAGE and Western blotting resultsshowed that the recombinant proteins were expressed in E. coli.The purified proteinMBLC had antibacterial activity, the wild-type had stronger antibacterial activity thanmutant by Scanning electron microscope and killed pathogenic bacteria by leaking thecontent out in vitro against Sta. aureus.
In this research, we cloned the2285bp DNA sequence of bovine MBL25′flanking region by LA-PCR method. The analysis of this2285bp fragment indicatedthat there were no canonical TATA boxes. No CpG island and two repetitive elementswithin promoter region were also found. Of particular interest is the fact that severalwell-documented transcription factor consensus motifs are precisely conserved in theregion immediately upstream of the MBL2exon1,including binding sites for GR、SP1,NF-1, NF-1/L, AP-1et al. Multiple of the sites for enhancer were also found. ThepEGFP-N1/2285plasmid has been constructed and transfetced into293T cells byLip2000, successful expression of EGFP gene was obtained. It implies that the2285bp of bovine MBL25′flanking region is promoter functional.
To further characterize the5′flanking region, we constructed a set of luciferasereporter gene constructs containing successive5′deletions of the bovine MBL2promoter. Promoter activity analysis was performed by dual-luciferase reporter assaysystem. The core promoter of the gene was located at the+52~-85bp. Some positiveregulatory elements are located at-1189～-562and-297～-85bp. And the results alsoshowed the presence of repressor elements in this region-562～-297bp and-2237～-1549bp.
In our study, three SNPs including g.905C>G, g.956C>T, g.895A>T wereexamined by sequencing and g.905C>G, g.956C>T were closely linked. Statisticalanalyses revealed correlation between both g.905C>G, g.956C>T and somatic cellscore (SCS). Based on the bioinformatics analysis, the SNPs were further surveyed.
FQ-PCR was used to detect mRNA expression of MBL2gene in different tissuesand the different genotype of g.905C>G and g.956C>T, the results indicated that MBL2mRNA were expressed in all tissues examined, including heart, liver, spleen,lung, kidney, mammary gland and thyroid, the expression of mRNA in the liver wassignificantly higher than other tissues, the different genotype of g.905C>G and g.956C>T had significant correlation on mRNA expression.
It could be preliminarily deduced that MBL2gene was probably a major gene ora QTL linked gene which associated with mastitis resistance traits in pig.
中国荷斯坦牛MBL2基因外显子上存在单核苷酸多态性（g.1164G>A，g.1197C>A，g.1198G>A，1207T>C）与奶牛生产性状、奶牛血清补体活性和血清MBL-C蛋白含量相关分析表明，g.1164G>A，g.1197C>A位点的突变与体细胞评分有显著相关（P<0.01），与血清补体活性没有明显相关，g.1164G>A位点与血清MBL-C蛋白含量显著相关。实验成功突变了MBL2g.1164G>A位点，并体外表达了牛MBL-C野生型和突变型重组蛋白，证明重组蛋白对金黄色葡萄球菌有抑菌效果；扫描电镜观察发现野生型的抗菌能力要强于突变型。
克隆了牛MBL25’调控区2285bp的DNA序列，用EGFP报告基因瞬时转染技术鉴定了该区域具有启动子功能。通过双荧光素酶报告基因检测系统筛选到牛MBL2基础启动子和调控组件，发现牛MBL2基因5′调控区的-85～+52bp区域具有基本的启动子功能，结合序列分析发现牛MBL2基因上存在多个正调控和负调控组件。通过对牛MBL2基因5’调控区的SNPs分析，首次发现了3个SNPs位点：g.905C>G，g.956C>T，g.895A>T，分析发现这三个位点位于HNF-1、C-Myb、TATA box转录组件，可能具有重要的功能。通过荧光定量RT-PCR方法表明牛MBL2mRNA在肝脏、甲状腺、心脏、脾脏、乳腺、肺脏、肾脏组织均有表达，在肝脏组织中表达量最高；对应g.905C>G和g.956C>T位点不同基因型间乳腺组织mRNA表达没有明显差异。可以初步推断MBL2基因可能是影响奶牛乳腺炎抗性的主效基因或是与乳腺炎抗性相关的QTL连锁基因。
Infectious disease has major adverse effects both on the economics of livestockproduction and on animal welfare. Cow mastitis is a common disease in dairy industryworldwide，and has caused tremendous loss to the dairy production. A number oftherapeutic, prophylactic and management strategies have been proposed to minimizethis complex disease. Although these treatments have very good clinical outcome,emerge of drug-resistant strains and remaining antibiotics in milk have brought greatconcerns. Thus, an approach based on improving the host genetics in resistance toinfectious diseases through molecular marker selective breeding is becoming widelyaccepted. Mannose-binding lectin (MBL) are collagenous C-type lectins involved inthe innate immune response to various microbial pathogens. Antimicrobial functionsof MBL, including opsonization, neutralization, and complement activation. MBLselectively targets invading microorganisms for neutralization by its recognitiondomain’s binding to cell surface mannose, then activating MBL-associated serineproteases (MASPs).
By screening the genetic variation of MBL2exon in825individuals of ChinaHolstein, using PCR-SSCP techniques, four new SNPs were found in exon1, g.1164G>A, g.1197C>A, g.1198G>A,1207T>C. No SNPs were found in exon2, exon3andexon4in my research. Statistical analyses revealed correlation between both g.1164G>A, g.1197C>A and somatic cell score (SCS).
The effect of polymorphism g.1164G>A and g.1197C>A loci of MBL2gene oncomplement activity and serum MBL-C level was analyzed, the results indicated thatin the g.1164G>A and g.1197C>A loci, the different genotype had no significantinfluence on complement activity; in the g.1164G>A, the different genotype hadsignificant correlation on serum MBL-C level.
MBL2gene was amplified using reverse transcription-polymerase chain reaction(RT-PCR). The g.1164G>A loci of MBL2was mutation by rite-directed mutagenesis.The PCR product was inserted into vector pET32a(+) to construct plasmid pET32a (+)/MBL2and pET32a(+)/MBL2-TB, then the plasmid was expressed in E.coli BL21(DE3)cell that induced by IPTG. The diversity of antibacterial activity of wild-typeand mutant was assayed by agar whole diffusion-inhibition zone method and electronmicroscope using the purified recombination protein against Sta. aureu. The resultsanalysis showed the encoding a polypeptide. SDS-PAGE and Western blotting resultsshowed that the recombinant proteins were expressed in E. coli.The purified proteinMBLC had antibacterial activity, the wild-type had stronger antibacterial activity thanmutant by Scanning electron microscope and killed pathogenic bacteria by leaking thecontent out in vitro against Sta. aureus.
In this research, we cloned the2285bp DNA sequence of bovine MBL25′flanking region by LA-PCR method. The analysis of this2285bp fragment indicatedthat there were no canonical TATA boxes. No CpG island and two repetitive elementswithin promoter region were also found. Of particular interest is the fact that severalwell-documented transcription factor consensus motifs are precisely conserved in theregion immediately upstream of the MBL2exon1,including binding sites for GR、SP1,NF-1, NF-1/L, AP-1et al. Multiple of the sites for enhancer were also found. ThepEGFP-N1/2285plasmid has been constructed and transfetced into293T cells byLip2000, successful expression of EGFP gene was obtained. It implies that the2285bp of bovine MBL25′flanking region is promoter functional.
To further characterize the5′flanking region, we constructed a set of luciferasereporter gene constructs containing successive5′deletions of the bovine MBL2promoter. Promoter activity analysis was performed by dual-luciferase reporter assaysystem. The core promoter of the gene was located at the+52~-85bp. Some positiveregulatory elements are located at-1189～-562and-297～-85bp. And the results alsoshowed the presence of repressor elements in this region-562～-297bp and-2237～-1549bp.
In our study, three SNPs including g.905C>G, g.956C>T, g.895A>T wereexamined by sequencing and g.905C>G, g.956C>T were closely linked. Statisticalanalyses revealed correlation between both g.905C>G, g.956C>T and somatic cellscore (SCS). Based on the bioinformatics analysis, the SNPs were further surveyed.
FQ-PCR was used to detect mRNA expression of MBL2gene in different tissuesand the different genotype of g.905C>G and g.956C>T, the results indicated that MBL2mRNA were expressed in all tissues examined, including heart, liver, spleen,lung, kidney, mammary gland and thyroid, the expression of mRNA in the liver wassignificantly higher than other tissues, the different genotype of g.905C>G and g.956C>T had significant correlation on mRNA expression.
It could be preliminarily deduced that MBL2gene was probably a major gene ora QTL linked gene which associated with mastitis resistance traits in pig.
引文
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