荣昌猪BPI基因全长cDNA克隆及SNP分析
摘要
杀菌通透性增强蛋白(bactericidal／permeability-increasing protein，BPI)是人和哺乳动物内源性阳离子蛋白质，主要存在于多形核白细胞的嗜苯胺蓝颗粒中。它具有很强的杀菌(主要指革兰氏阴性细菌)活性、中和内毒素或脂多糖(lipopolysaccharide，LPS)活性和调理功能，在动物机体天然防御中起到很重要的作用。目前，人、牛、鼠的BPI基因序列都已清楚，但猪BPI基因全长cDNA序列未知。此外，人BPI基因外显子3和4区域存在多态性，猪BPI基因第4和10外显子的RFLP多态性与沙门氏菌的易感性有关，并被确定为抗病育种的候选基因。而被联合国粮农组织列为重点保护猪种的荣昌猪，其BPI基因外显子3和4区域的多态性还有待研究。
本试验拟克隆出荣昌猪BPI基因的全长cDNA序列，并应用聚合酶链式反应-单链构象多态性(polymerase chain reaction-single strand conformation polymorphism，PCR-SSCP)技术，检测其第3和4外显子的单核苷酸多态性(single nucleotide polymorphism，SNP)位点。这些结果的获得，不仅可以为猪BPI功能研究、荣昌猪BPI基因多态性提供基础数据，而且对进一步寻找到合适的抗病育种或相关分子标记、分析BPI基因多态性与荣昌猪抗病力的相关性利荣昌猪的保种选育等研究具有基础贡献意义。
试验的方法及技术路线：
(1)荣昌猪BPI基因全长cDNA克隆及生物信息学分析：
首先选取一头100日龄左右健康的荣昌猪，提取其前腔静脉血总RNA，然后进行RT-PCR得到cDNA第一链；再根据同源性克隆方法，结合3′-和5′-cDNA末端快速扩增(Rapid amlification of cDNA ends，RACE)技术，分别克隆出荣昌猪BPI序列的中间编码区序列、3′-非编码区序列(untranslated region，UTR)和5′-UTR；拼接出全长cDNA序列，并进行序列比对、结构功能预测等生物信息学分析鉴定。
(2)荣昌猪BPI基因第3和4外显子序列SNP位点分析：
随机选取120头健康的荣昌猪，提取其耳组织基因组DNA，再以其为模板扩增出第3和4外显子序列；PCR产物经12％聚丙烯酰胺凝胶电泳(polyacrylamide gel electrophoresis，PAGE)，120V，4℃持续14h，然后银染显带；统计不同带型出现的频率(即基因型频率)和等位基因频率，并将显示不同带型的PCR扩增产物克隆测序；最后根据测序结果比对分析出外显子3和4区段存在的SNP位点，并根据这些SNP位点在等位基因中的分布和等位基因频率，计算出各SNP位点的优势碱基频率。
试验结果与结论：
(1)本试验首次克隆得到了荣昌猪BPI基因全长cDNA序列，也是猪BPI基因全长cDNA序列的首次报道，其Genebank登录号为：EF436278。序列比对和结构功能预测显示，荣昌猪BPI同人、牛等物种BPI具有相似的结构和功能。
(2)本试验应用PCR-SSCP分析方法，在荣昌猪BPI基因外显子3区段检测到一个新的SNP位点，即第397位的G→A突变，引起氨基酸由Arg替换为Gln，且产生带正电荷的Arg的碱基G为该位点的优势碱基，频率为0.7417。该位点的突变可能对荣昌猪BPI蛋白功能及机体天然免疫力有重要影响。外显子4区段共检测到4个SNP位点，它们是T512C，G551T，C563T，G599A。其中T512C，G551T，C563T为首次报道，G551T突变还产生了一个新的限制性内切酶MscⅠ或BalⅠ酶切位点(TGG／CCA)。第512、551、563、599位的优势碱基分别为C、G、C、G，出现的频率分别为0.6334，0.725，0.725，0.7501。此外，通过荣昌猪外显子4序列与猪EST序列比对分析，还发现了一个第479位的T→C突变。荣昌猪BPI基因外显子4区段的高度多态性，表明该区段有较大的遗传选择潜力。
通过分析推断，本试验检测到的外显子3和4区段的某些SNP位点，可能成为猪机体抗某些革兰氏阴性病原菌或其引起的疾病的分子标记。
Bactericidal/permeability-increasing protein (BPI) is a highly cationic protein which is located mainly in the primary granules of polymorphonuclear leucocyte (PMN). BPI has a high affinity for LPS of Gram-negative bacteria. Binding of BPI to susceptible bacteria is followed by increasing outer membrane permeability, inhibition of growth and ultimately, irreversible loss of viability. In addition, BPI also possesses an opsonic function. Because of these important functions, BPI plays an important role in host initial defense. At present, the full-length cDNA sequences of BPI gene has been elucidated in several species, including human, bovine, brown rat and mouse, but not in pig. In addition, several polymorphic sites were found in exons 3 and 4 of human BPI gene. It has been shown that the restriction fragment length polymorphism (RFLP) sites in exons 4 and 10 of porcine BPI gene are related to the susceptibility of Salmonella cholerasuis in several pig breeds. The porcine BPI gene was considered as a candidate gene of breeding for disease resistance. However, the polymorphism of exons 3 and 4 in Rongchang pig BPI gene, a stress preserving pig breed by Food and Agriculture Organization of United Nations, is unclear.
In this study, the full-length cDNA of Rongchang pig BPI gene was cloned and the SNP sites in exons 3 and 4 of this gene were detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. There results will offer some basic data to the function studying of porcine BPI, the association research between BPI gene polymorphism and the disease resistance of Rongchang pig and the breeding and preservation of Rongchang pig. Some useful molecular markers of breeding for disease resistance are also expected to find in the possible SNP sites.
The main technical route and methods of this work were carried out as follows:
(1) Cloning and analysis of the full-length cDNA of BPI gene in Rongchang pig:
Firstly, about 5 ml anticoagulant peripheral blood was gained from a 100d healthy Rongchang pig, the total RNA from this blood was extracted using the RNA extraction kit. Then the RNA was taken to convert mRNAs into cDNA. Following, the coding sequence, 3'-UTR and 5'-UTR of Rongchang pig BPI were cloned using homology cloning approach combined with 3' and 5' RACE. Finally, the full-length cDNA of Rongchang pig BPI gene was obtained by overlapping the three sequences. Assessment and analysis of the full-length sequence were done by bioinformatics methods.
(2) SNP analysis of the exons 3 and 4 of Rongchang pig BPI gene:
Firstly, the genomic DNA was extracted from 120 healthy Rongchang pigs' ear tissues. And the exons 3 and 4 fragments were amplified using the genomic DNA templates. Then these PCR products were detected by polyacrylamide gel electrophoresis (PAGE) at 120 V for 14 h at 4℃, and gels were developed with silver staining. The PCR products showing different patterns were purified and cloned into pMD18T vector for sequencing. Finally, the frequencies of difference genotypes were accounted and the allelic genes frequencies were calculated according to the former result. Further more, the SNP sites in exons 3 and 4 were found by sequence alignment of different allelic genes. Frequencies of the bases with higher appearance frequency in these SNP sites were calculated according to the distribution of SNP sites in all the allelic genes.
The results and conclusions of this study were list as follows:
(1) The full-length cDNA of Rongchang pig BPI gene was cloned for the first time in this study and it was also the first time reporting the full-length cDNA of porcine BPI gene. Its GeneBank accession number is EF436278. The structure and function of Rongchang pig BPI were similar to those of human, bovine and other species' BPI by sequences alignment and structure and function prediction.
(2) There was one novel SNP (G397A) detected in the exon 3 of Rongchang pig BPI gene by PCR-SSCP. This mutation made Arg101Gln substitution and the base with higher appearance frequency in this SNP site is base G. Its appearance frequency is 0.7417. In the exon 4 fragment, three novel (T512C, G551T, C563T) of four SNPs (T512C, G551T, C563T, G599A) were detected and all of the SNPs were synonymous substitutions. The bases with higher appearance frequency in these SNP sites were base C, G, C and G and their appearance frequency were 0.6334, 0.725, 0.725 and 0.7501 respectively. In addition, another novel SNP (T479C) in exon 4 was found by aligning exon 4 sequence with porcine ESTs. The affluent polymorphism of exon 4 indicate its huge potentiality in genetic selection.
Some of the SNP sites detected in this study may be important molecular markers of porcine disease resistance, specifically resistant to Gram-negative bacterias and its caused diseseses.
本试验拟克隆出荣昌猪BPI基因的全长cDNA序列，并应用聚合酶链式反应-单链构象多态性(polymerase chain reaction-single strand conformation polymorphism，PCR-SSCP)技术，检测其第3和4外显子的单核苷酸多态性(single nucleotide polymorphism，SNP)位点。这些结果的获得，不仅可以为猪BPI功能研究、荣昌猪BPI基因多态性提供基础数据，而且对进一步寻找到合适的抗病育种或相关分子标记、分析BPI基因多态性与荣昌猪抗病力的相关性利荣昌猪的保种选育等研究具有基础贡献意义。
试验的方法及技术路线：
(1)荣昌猪BPI基因全长cDNA克隆及生物信息学分析：
首先选取一头100日龄左右健康的荣昌猪，提取其前腔静脉血总RNA，然后进行RT-PCR得到cDNA第一链；再根据同源性克隆方法，结合3′-和5′-cDNA末端快速扩增(Rapid amlification of cDNA ends，RACE)技术，分别克隆出荣昌猪BPI序列的中间编码区序列、3′-非编码区序列(untranslated region，UTR)和5′-UTR；拼接出全长cDNA序列，并进行序列比对、结构功能预测等生物信息学分析鉴定。
(2)荣昌猪BPI基因第3和4外显子序列SNP位点分析：
随机选取120头健康的荣昌猪，提取其耳组织基因组DNA，再以其为模板扩增出第3和4外显子序列；PCR产物经12％聚丙烯酰胺凝胶电泳(polyacrylamide gel electrophoresis，PAGE)，120V，4℃持续14h，然后银染显带；统计不同带型出现的频率(即基因型频率)和等位基因频率，并将显示不同带型的PCR扩增产物克隆测序；最后根据测序结果比对分析出外显子3和4区段存在的SNP位点，并根据这些SNP位点在等位基因中的分布和等位基因频率，计算出各SNP位点的优势碱基频率。
试验结果与结论：
(1)本试验首次克隆得到了荣昌猪BPI基因全长cDNA序列，也是猪BPI基因全长cDNA序列的首次报道，其Genebank登录号为：EF436278。序列比对和结构功能预测显示，荣昌猪BPI同人、牛等物种BPI具有相似的结构和功能。
(2)本试验应用PCR-SSCP分析方法，在荣昌猪BPI基因外显子3区段检测到一个新的SNP位点，即第397位的G→A突变，引起氨基酸由Arg替换为Gln，且产生带正电荷的Arg的碱基G为该位点的优势碱基，频率为0.7417。该位点的突变可能对荣昌猪BPI蛋白功能及机体天然免疫力有重要影响。外显子4区段共检测到4个SNP位点，它们是T512C，G551T，C563T，G599A。其中T512C，G551T，C563T为首次报道，G551T突变还产生了一个新的限制性内切酶MscⅠ或BalⅠ酶切位点(TGG／CCA)。第512、551、563、599位的优势碱基分别为C、G、C、G，出现的频率分别为0.6334，0.725，0.725，0.7501。此外，通过荣昌猪外显子4序列与猪EST序列比对分析，还发现了一个第479位的T→C突变。荣昌猪BPI基因外显子4区段的高度多态性，表明该区段有较大的遗传选择潜力。
通过分析推断，本试验检测到的外显子3和4区段的某些SNP位点，可能成为猪机体抗某些革兰氏阴性病原菌或其引起的疾病的分子标记。
Bactericidal/permeability-increasing protein (BPI) is a highly cationic protein which is located mainly in the primary granules of polymorphonuclear leucocyte (PMN). BPI has a high affinity for LPS of Gram-negative bacteria. Binding of BPI to susceptible bacteria is followed by increasing outer membrane permeability, inhibition of growth and ultimately, irreversible loss of viability. In addition, BPI also possesses an opsonic function. Because of these important functions, BPI plays an important role in host initial defense. At present, the full-length cDNA sequences of BPI gene has been elucidated in several species, including human, bovine, brown rat and mouse, but not in pig. In addition, several polymorphic sites were found in exons 3 and 4 of human BPI gene. It has been shown that the restriction fragment length polymorphism (RFLP) sites in exons 4 and 10 of porcine BPI gene are related to the susceptibility of Salmonella cholerasuis in several pig breeds. The porcine BPI gene was considered as a candidate gene of breeding for disease resistance. However, the polymorphism of exons 3 and 4 in Rongchang pig BPI gene, a stress preserving pig breed by Food and Agriculture Organization of United Nations, is unclear.
In this study, the full-length cDNA of Rongchang pig BPI gene was cloned and the SNP sites in exons 3 and 4 of this gene were detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. There results will offer some basic data to the function studying of porcine BPI, the association research between BPI gene polymorphism and the disease resistance of Rongchang pig and the breeding and preservation of Rongchang pig. Some useful molecular markers of breeding for disease resistance are also expected to find in the possible SNP sites.
The main technical route and methods of this work were carried out as follows:
(1) Cloning and analysis of the full-length cDNA of BPI gene in Rongchang pig:
Firstly, about 5 ml anticoagulant peripheral blood was gained from a 100d healthy Rongchang pig, the total RNA from this blood was extracted using the RNA extraction kit. Then the RNA was taken to convert mRNAs into cDNA. Following, the coding sequence, 3'-UTR and 5'-UTR of Rongchang pig BPI were cloned using homology cloning approach combined with 3' and 5' RACE. Finally, the full-length cDNA of Rongchang pig BPI gene was obtained by overlapping the three sequences. Assessment and analysis of the full-length sequence were done by bioinformatics methods.
(2) SNP analysis of the exons 3 and 4 of Rongchang pig BPI gene:
Firstly, the genomic DNA was extracted from 120 healthy Rongchang pigs' ear tissues. And the exons 3 and 4 fragments were amplified using the genomic DNA templates. Then these PCR products were detected by polyacrylamide gel electrophoresis (PAGE) at 120 V for 14 h at 4℃, and gels were developed with silver staining. The PCR products showing different patterns were purified and cloned into pMD18T vector for sequencing. Finally, the frequencies of difference genotypes were accounted and the allelic genes frequencies were calculated according to the former result. Further more, the SNP sites in exons 3 and 4 were found by sequence alignment of different allelic genes. Frequencies of the bases with higher appearance frequency in these SNP sites were calculated according to the distribution of SNP sites in all the allelic genes.
The results and conclusions of this study were list as follows:
(1) The full-length cDNA of Rongchang pig BPI gene was cloned for the first time in this study and it was also the first time reporting the full-length cDNA of porcine BPI gene. Its GeneBank accession number is EF436278. The structure and function of Rongchang pig BPI were similar to those of human, bovine and other species' BPI by sequences alignment and structure and function prediction.
(2) There was one novel SNP (G397A) detected in the exon 3 of Rongchang pig BPI gene by PCR-SSCP. This mutation made Arg101Gln substitution and the base with higher appearance frequency in this SNP site is base G. Its appearance frequency is 0.7417. In the exon 4 fragment, three novel (T512C, G551T, C563T) of four SNPs (T512C, G551T, C563T, G599A) were detected and all of the SNPs were synonymous substitutions. The bases with higher appearance frequency in these SNP sites were base C, G, C and G and their appearance frequency were 0.6334, 0.725, 0.725 and 0.7501 respectively. In addition, another novel SNP (T479C) in exon 4 was found by aligning exon 4 sequence with porcine ESTs. The affluent polymorphism of exon 4 indicate its huge potentiality in genetic selection.
Some of the SNP sites detected in this study may be important molecular markers of porcine disease resistance, specifically resistant to Gram-negative bacterias and its caused diseseses.
引文
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