蒙古马免疫相关基因表达研究及脾脏表达谱分析
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摘要
中国马业正处在从传统马业向现代马业转型的过程中，急需培育出适应我国自然环境的马匹新品种（系）。为此，对优良地方品种蒙古马免疫相关基因进行研究，不但可以进一步了解蒙古马抗病力强的原因，为揭示蒙古马抗病力遗传特性提供理论依据，而且可以对蒙古马种质资源的保护、利用和创新起到积极的作用，并指导地方品种马的杂交改良、品种（系）的培育。本研究以蒙古马为研究对象，以纯血马为对照，首先对蒙古马与纯血马血液生化、免疫和抗氧化指标进行测定分析，判断正常生理情况下，蒙古马与纯血马血液指标是否存在差异，从总体上掌握两个品种马抗病力的情况；其次，对马匹抗病候选基因TLR2、TLR4多态性进行研究，分析两个品种马基因型的差异性；再次，采用实时荧光定量RT-PCR（RT-qPCR）的相对定量方法对两个品种马不同组织中TLRs基因的表达量进行差异分析，同时对在脂多糖（LPS）诱导下的两个品种马单核细胞与免疫相关基因的差异表达进行研究，得到各基因的相对表达量，进而分析免疫相关基因对不同品种间抗性的影响；最后，利用高通量测序技术对蒙古马与纯血马脾脏表达谱文库进行测序，以寻找两个品种马脾脏组织中的差异表达基因。通过本研究的结果可以为揭示蒙古马抗病力遗传特性提供理论依据，并获得以下主要研究结果：
1．通过对血液生化、免疫和抗氧化指标的结果分析发现，纯血马血液中白蛋白和胆固醇的含量偏高，这与其饲料营养水平相一致；蒙古马血液中球蛋白、IgG和IgA的含量均显著高于纯血马（P＜0.05），推测与蒙古马的免疫力高有关。
2．采用PCR-SSCP技术对蒙古马与纯血马TLR2基因进行分型，两个群体都呈现出三种基因型（AA、AB和BB型）；经测序发现该基因外显子存在两处突变：编码区945bp位置G→C的同义突变和1070bp位置G→A的错义突变；由于密码子的摆动性，945bp位置并未导致精氨酸的突变；而1070bp位置由精氨酸突变为谷氨酰胺。对基因型统计分析，蒙古马与纯血马品种之间不同基因型分布存在显著差异（0.01≤P＜0.05）。
3．通过直接测序方法发现，蒙古马与纯血马TLR4基因第3外显子共发现11处碱基突变，其中8处（520bp位置T→G，668bp位置A→G，817bp位置C→T，1003bp位置C→T，1513bp位置T→C，1546bp位置G→A，1771bp位置T→C和1903bp位置T→C）为同义突变；其他3处，713bp位置C→A导致谷氨酰胺变为赖氨酸，1353bp位置T→C使甲硫氨酸变为苏氨酸，1673bp位置A→G导致甲硫氨酸变为缬氨酸，并且这3处不同基因型分布存在极显著差异（P＜0.01）。
4．采用RT-qPCR的2-△Ct方法对蒙古马与纯血马TLR1-9基因在肝脏、脾脏、肺脏、盲肠和骨髓组织进行了差异表达研究。结果表明各基因在5个组织中均有表达；TLRs基因在免疫器官（脾脏和骨髓）中的表达量为蒙古马高于纯血马；而在肝脏中为蒙古马低于纯血马。
5．马外周血单核细胞经LPS刺激后，无论是蒙古马还是纯血马TLR4、CD14、MD-2、TNF-α、INF-β、IL-1β、IL-6和IL-8基因表达量都有所增加（与对照组相比）；TLR4、CD14、IL-1β、IL-6和IL-8基因的表达量均是蒙古马低于纯血马，其中TLR4基因和IL-1β基因表达差异显著（P＜0.05）。单核细胞上清液中细胞因子（TNF-α、INF-β、IL-1β和IL-8）含量在两个品种之间差异不显著（P≥0.05）。
6．构建了蒙古马-脾脏和纯血马-脾脏组织表达谱文库，经Illumina Miseq高通量测序，分别获得了6811804和7744386有效reads；两个文库Map到8号和1号染色体的reads最多，而Map到29号、30号和31号染色体的reads最少；两个文库共筛出279个差异表达基因，其中与免疫相关的基因有45个。GO功能富集分析结果表明差异表达基因与生物学过程、细胞组分和分子功能有关；KEGG通路富集分析结果表明差异最大的显著富集KEGG条目为免疫系统。
China Horse Industry is transforming from the traditional horse industry to themodern form. Breeding of new horse lines (breeds) adapt to the natural environmentalconditions of China become an urgent demand. It is necessary to research immune relatedgenes of Mongolian Horse, the excellent local species. There are several reasons to supportthe view above: Firstly, it indicates why Mongolian Horse can strongly resist diseases, andprovides the theoretical proofs to revealing the genetic characteristics of disease resistance;Secondly, the research plays a positive role for protecting, utilizing and breedinginnovation of germplasm; also improves the techniques of the crossbreeding and new lines’cultivation. Mongolian Horse and Thoroughbred have been chosen to be the experientgroup and control group resepectively. First of all, to figure out whether there wassignificant difference between the two species regarding to disease resistance ability, thefollowing blood analysis including biochemical, immune and antioxidant indices at theirnormal biophysical state had been done. Secondly, the study on polymorphism of bothTLR2and TLR4were used to analyze the differences of genotype between the two horsespecies. Thirdly, a differential expression assay of TLRs in different tissues of the twospecies by real-time reverse transcription quantitative PCR (RT-qPCR) had been taken.Meanwhile, stimulating horse monocytes by lipopolysaccharide (LPS), we got the relativeexpression data of immune related genes by the differential expression assay; furtherly, theinfluence of disease resistance genes had been analyzed on the resistance between differentspecies. Finally, expression profile analysis of spleen tissues of Mongolian Horse andThoroughbred by high-throughput sequencing was used to searche the differential genes.This thesis tried to provide the theoretical proofs to revealing the disease resistance geneticcharacteristics of Mongolian horses. The main results showed as following:
1. The results of the blood biochemical, immune and antioxidant indices showed thatthe Thoroughbred had high levels of albumin and cholesterol content in Mongolian Horse,which was consistent with the nutrition level of feed; The globulin, IgG and IgA contentsof Mongolian Horse were significantly higher than Thoroughbred (P＜0.05), whichsuggested it may be associated with the high immunity of Mongolian Horse.
2. The TLR2gene was categorized into three genotypes (AA, AB and BB) byPCR-SSCP in the two Horse species. The sequencing found that there were two deletionmutations in the exon: G→C synonymous mutation at945bp and G→A missense mutation at1070bp. Arg at945bp didn't alter due to the swing of the codon, but Arg was substitutedto Gln at1070bp. For the genotypes analysis, the distribution of genotypes had significantdifference between Mongolian Horse and Thoroughbred (0.01≤P＜0.05).
3. By direct sequencing, it was found there were11base mutations in exon3of TLR4gene in both species, which included8synonymous mutations (T→G at520bp, A→G at668bp, C→T at8171bp, C→T at1003bp, T→C at1513bp, G→A at1546bp, T→C at1771bp, and T→C at1903bp). The left3mutation sites were: i) C→A missense mutationat713bp leading to the Gln→Lys amino acid substitution; ii) T→C missense mutation at1353bp leading to the Met→Thr amino acid substitution; iii) A→G missense mutation at1673bp leading to the Met→Val amino acid substitution. And the genotype of these3sitesshowed a significant difference between Mongolian Horse and Thoroughbred（P＜0.01).
4. The differential expression of TLR1-9gene in liver, spleen, lung, caecum and bonemarrow of two species were analyzed by RT-qPCR with2-△Ctmethod. The results showedthat the genes mentioned above were detected in all tested tissues. The genes relativeexpression levels of Mongolian Horse were higher than Thoroughbred in immune organs(spleen and bone marrow), but lower in lung.
5. In vitro treatment of equine peripheral blood monocytes with LPS increasedtranscription level of all TLR4, CD14, MD-2, TNF-α, INF-β, IL-1β, IL-6and IL-8fromboth Mongolian Horse and Thoroughbred compared with the control groups. The mRNAlevel of TLR4, CD14, IL-1β, IL-6and IL-8in Mongolian Horse was lower thanThoroughbred, and the difference of TLR4and IL-1β expression was significant (P＜0.05).The levels of the cytokines (TNF-α, INF-β, IL-1β and IL-8) in the supernatant ofperipheral blood monocytes were no difference (P≥0.05) between the horse species.
6. Expression profiling libraries of Mongolian Horse-spleen and Thoroughbred-spleen were constructed, and we obtained6811804and7744386useful reads by theIllumina Miseq sequencing respectively. Most reads of two expression profiling librarieswere maped on Chromosome8and Chromosome1, and least of reads were maped onChromosome29, Chromosome30and Chromosome31.279differential genes were foundbetween two expression profiling libraries, including45immune-related genes. The GeneOntology analysis showed that differentially expressed genes were related with biologicalprocess, cellular component and molecular function. The Kyoto Encyclopedia of Genesand Genomes analysis indicated that immune system was the greatest different KEGGterm.
1．通过对血液生化、免疫和抗氧化指标的结果分析发现，纯血马血液中白蛋白和胆固醇的含量偏高，这与其饲料营养水平相一致；蒙古马血液中球蛋白、IgG和IgA的含量均显著高于纯血马（P＜0.05），推测与蒙古马的免疫力高有关。
2．采用PCR-SSCP技术对蒙古马与纯血马TLR2基因进行分型，两个群体都呈现出三种基因型（AA、AB和BB型）；经测序发现该基因外显子存在两处突变：编码区945bp位置G→C的同义突变和1070bp位置G→A的错义突变；由于密码子的摆动性，945bp位置并未导致精氨酸的突变；而1070bp位置由精氨酸突变为谷氨酰胺。对基因型统计分析，蒙古马与纯血马品种之间不同基因型分布存在显著差异（0.01≤P＜0.05）。
3．通过直接测序方法发现，蒙古马与纯血马TLR4基因第3外显子共发现11处碱基突变，其中8处（520bp位置T→G，668bp位置A→G，817bp位置C→T，1003bp位置C→T，1513bp位置T→C，1546bp位置G→A，1771bp位置T→C和1903bp位置T→C）为同义突变；其他3处，713bp位置C→A导致谷氨酰胺变为赖氨酸，1353bp位置T→C使甲硫氨酸变为苏氨酸，1673bp位置A→G导致甲硫氨酸变为缬氨酸，并且这3处不同基因型分布存在极显著差异（P＜0.01）。
4．采用RT-qPCR的2-△Ct方法对蒙古马与纯血马TLR1-9基因在肝脏、脾脏、肺脏、盲肠和骨髓组织进行了差异表达研究。结果表明各基因在5个组织中均有表达；TLRs基因在免疫器官（脾脏和骨髓）中的表达量为蒙古马高于纯血马；而在肝脏中为蒙古马低于纯血马。
5．马外周血单核细胞经LPS刺激后，无论是蒙古马还是纯血马TLR4、CD14、MD-2、TNF-α、INF-β、IL-1β、IL-6和IL-8基因表达量都有所增加（与对照组相比）；TLR4、CD14、IL-1β、IL-6和IL-8基因的表达量均是蒙古马低于纯血马，其中TLR4基因和IL-1β基因表达差异显著（P＜0.05）。单核细胞上清液中细胞因子（TNF-α、INF-β、IL-1β和IL-8）含量在两个品种之间差异不显著（P≥0.05）。
6．构建了蒙古马-脾脏和纯血马-脾脏组织表达谱文库，经Illumina Miseq高通量测序，分别获得了6811804和7744386有效reads；两个文库Map到8号和1号染色体的reads最多，而Map到29号、30号和31号染色体的reads最少；两个文库共筛出279个差异表达基因，其中与免疫相关的基因有45个。GO功能富集分析结果表明差异表达基因与生物学过程、细胞组分和分子功能有关；KEGG通路富集分析结果表明差异最大的显著富集KEGG条目为免疫系统。
China Horse Industry is transforming from the traditional horse industry to themodern form. Breeding of new horse lines (breeds) adapt to the natural environmentalconditions of China become an urgent demand. It is necessary to research immune relatedgenes of Mongolian Horse, the excellent local species. There are several reasons to supportthe view above: Firstly, it indicates why Mongolian Horse can strongly resist diseases, andprovides the theoretical proofs to revealing the genetic characteristics of disease resistance;Secondly, the research plays a positive role for protecting, utilizing and breedinginnovation of germplasm; also improves the techniques of the crossbreeding and new lines’cultivation. Mongolian Horse and Thoroughbred have been chosen to be the experientgroup and control group resepectively. First of all, to figure out whether there wassignificant difference between the two species regarding to disease resistance ability, thefollowing blood analysis including biochemical, immune and antioxidant indices at theirnormal biophysical state had been done. Secondly, the study on polymorphism of bothTLR2and TLR4were used to analyze the differences of genotype between the two horsespecies. Thirdly, a differential expression assay of TLRs in different tissues of the twospecies by real-time reverse transcription quantitative PCR (RT-qPCR) had been taken.Meanwhile, stimulating horse monocytes by lipopolysaccharide (LPS), we got the relativeexpression data of immune related genes by the differential expression assay; furtherly, theinfluence of disease resistance genes had been analyzed on the resistance between differentspecies. Finally, expression profile analysis of spleen tissues of Mongolian Horse andThoroughbred by high-throughput sequencing was used to searche the differential genes.This thesis tried to provide the theoretical proofs to revealing the disease resistance geneticcharacteristics of Mongolian horses. The main results showed as following:
1. The results of the blood biochemical, immune and antioxidant indices showed thatthe Thoroughbred had high levels of albumin and cholesterol content in Mongolian Horse,which was consistent with the nutrition level of feed; The globulin, IgG and IgA contentsof Mongolian Horse were significantly higher than Thoroughbred (P＜0.05), whichsuggested it may be associated with the high immunity of Mongolian Horse.
2. The TLR2gene was categorized into three genotypes (AA, AB and BB) byPCR-SSCP in the two Horse species. The sequencing found that there were two deletionmutations in the exon: G→C synonymous mutation at945bp and G→A missense mutation at1070bp. Arg at945bp didn't alter due to the swing of the codon, but Arg was substitutedto Gln at1070bp. For the genotypes analysis, the distribution of genotypes had significantdifference between Mongolian Horse and Thoroughbred (0.01≤P＜0.05).
3. By direct sequencing, it was found there were11base mutations in exon3of TLR4gene in both species, which included8synonymous mutations (T→G at520bp, A→G at668bp, C→T at8171bp, C→T at1003bp, T→C at1513bp, G→A at1546bp, T→C at1771bp, and T→C at1903bp). The left3mutation sites were: i) C→A missense mutationat713bp leading to the Gln→Lys amino acid substitution; ii) T→C missense mutation at1353bp leading to the Met→Thr amino acid substitution; iii) A→G missense mutation at1673bp leading to the Met→Val amino acid substitution. And the genotype of these3sitesshowed a significant difference between Mongolian Horse and Thoroughbred（P＜0.01).
4. The differential expression of TLR1-9gene in liver, spleen, lung, caecum and bonemarrow of two species were analyzed by RT-qPCR with2-△Ctmethod. The results showedthat the genes mentioned above were detected in all tested tissues. The genes relativeexpression levels of Mongolian Horse were higher than Thoroughbred in immune organs(spleen and bone marrow), but lower in lung.
5. In vitro treatment of equine peripheral blood monocytes with LPS increasedtranscription level of all TLR4, CD14, MD-2, TNF-α, INF-β, IL-1β, IL-6and IL-8fromboth Mongolian Horse and Thoroughbred compared with the control groups. The mRNAlevel of TLR4, CD14, IL-1β, IL-6and IL-8in Mongolian Horse was lower thanThoroughbred, and the difference of TLR4and IL-1β expression was significant (P＜0.05).The levels of the cytokines (TNF-α, INF-β, IL-1β and IL-8) in the supernatant ofperipheral blood monocytes were no difference (P≥0.05) between the horse species.
6. Expression profiling libraries of Mongolian Horse-spleen and Thoroughbred-spleen were constructed, and we obtained6811804and7744386useful reads by theIllumina Miseq sequencing respectively. Most reads of two expression profiling librarieswere maped on Chromosome8and Chromosome1, and least of reads were maped onChromosome29, Chromosome30and Chromosome31.279differential genes were foundbetween two expression profiling libraries, including45immune-related genes. The GeneOntology analysis showed that differentially expressed genes were related with biologicalprocess, cellular component and molecular function. The Kyoto Encyclopedia of Genesand Genomes analysis indicated that immune system was the greatest different KEGGterm.
引文
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