牛8个基因的克隆、表达特征、原核表达、SNPs检测及其与部分性状的关联分析
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摘要
牛育种工作的最终目的是提高牛生产的经济效益。因此,在确定育种目标时,应该充分考虑长久影响牛群经济效益的所有性状。出于这点考虑,在牛育种中不仅要考虑直接作用牛生产经济效益的主生产性状,而且要考虑诸如繁殖力、使用年限、产犊行为、抗病力等间接作用牛生产经济效益的所谓次级性状。但次级性状本身受到环境、遗传以及营养条件等多种因素的影响,难于度量,且其遗传力较低,所以利用常规育种的方法选择次级性状的准确性低,遗传进展慢。为揭示次级性状的遗传规律提供方法论,本研究采用现代分子数量联合育种方法,针对影响牛只健康和生产效率性状中与使用年限关联的一些基因,应用EST拼接、RT-PCR、GenScan、直接测序、RFLP、荧光定量PCR、原核表达等技术以及生物信息学和关联分析方法,进行了基础的分子遗传学探索,获得如下结果:
1.得到了牛AKAP10、MBL2、PON1、P53、PON2、SIRT2、SIRT3和WARS2共8个候选基因完整的CDS区序列并进行了生物信息学分析。向GenBank数据库提交了AKAP10、PON1、PON2和SIRT2等4个基因的cDNA序列,获取的登录号分别为:EU239246、EU289337、EF522785和EU562194。
2.对所研究候选基因中的AKAP10、PON1、PON2、MBL2和WARS2等5个基因在卵巢、肝脏、肌肉、小肠、脂肪、子宫、肾脏、心脏、肺、淋巴、瘤胃、睾丸和乳腺共13个组织中的表达进行了表达特性研究,结果表明,除AKAP10基因是在睾丸中表达量最高外,其它4个基因均表现为肝脏中表达量最高。与NCBI数据库中的电子表达谱比较分析表明,两者之间有着很明显的差异。
3.对牛的PON1和PON2两个新基因外显子进行SNPs的检测,发现在PON1基因第6外显子A147G和G162A;PON2基因第5外显子A73G和A110G、第6外显子T76C、第9外显子T98C共6个SNPs,并对其中的PON1基因的第6外显子A147G和G162A3,以及PON2基因的第9外显子T98C共3个位点进行了PCR-RFLP和PCR-SSCP多态性遗传特性分析。分析了它们在12个牛群体中的基因型频率,及等位基因的分布差异。
4.对PON1和PON2基因的多态基因型与体尺体重及部分生长和胴体性状进行了关联分析,结果发现:(1)鲁西牛6种体尺体重性状间除体高与其它性状之间相关性不显著外,体重、体长、胸围、管围和腹围之间都表现出显著的相关(P<0.05);(2)PON1基因第6外显子多态性中,AA基因型个体可能为短期肥育类型;GG型个体则应在选择过程中加以淘汰;GA型个体有可能具有比较合理的体型结构和生长发育模式,A162G位点可尝试用于家畜生产年限的预测;(3)PON1基因双酶切位点分析表明,专门化的肉用品种比兼用牛品种有着更为明显的生长特性。胴体性状方面,西门塔尔牛除背膘厚、嫩度、总骨重、眼肌面积和肉色性状外,其它性状存在相对劣势。同时,牛实验期初始重的差异对于某种单体型个体可能源自潜在的生长势,并表明PON1基因的AeAeGaGa基因型可能直接影响牛的背膘厚(P<0.01);(4)在与7个品种关联分析中,PON1基因EcoRⅤ-RFLP位点BB基因型个体的眼肌面积显著高于AA和AB基因型(P=0.0302);(5)PON2基因第9外显子三种基因型频率在7个牛品种间存在极显著的差异(P < 0.01),而各品种中各种基因型间与各品种间差异不显著(P > 0.05),在鲁西牛不同年龄组间无显著差异(P > 0.05)。而三种基因型频率之间则存在极显著的差异(P < 0.01),且三种基因型频率均有随着年龄增加而降低的趋势,但AA型和BB型个体在一定的年龄之后,(约为7岁)又均有数量增加的现象。
5.构建了牛PON1和PON2基因的pET28a+原核表达载体,并成功地在BL21表达菌种中实现了对氧磷酶1(PON1)和对氧磷酶2(PON2)两种蛋白的融合表达,为进一步纯化和应用提供依据。
Obtainning larger economic benefit is the final purpose in cattle breeding. So all the traits should be thought thoroughly, which may influence the economic benefit of cattle for a long time. Based on this idea, it is not only the major production traits, directly to the benefits, but also the secondary traits like productivity, lifespan, calf behavior and resistence of disease, which influences the benefits indirectly, should be taken attention on. For these traits are influenced by the conditions, heredity, and nutrition and so on, and difficult to measurement, the secondary traits selection plannings become so complecity and difficulty. And because the heritability of the secondary traits is very low, it results in slower progression of breeding with common methods. In order to provide certain methodology, what could it reveal the genetics roles of the secondary traits? This article focused on the molecule genetics of some lifespan traits genes, which influence the health and efficency, to provide elementary genetic information to cattle breeding by modern molecule and quantitative combination breeding methods, such as ESTs, RT-PCR, GenScan, direct sequencing, RFLP, Q-PCR, prokaryotic expression, bioinfermtics methods and association analysis. And the results were showed below:
1. The complete CDS sequences of AKAP10、MBL2、PON1、P53、PON2、SIRT2、SIRT3 and WARS2 cDNA were cloned. And the cDNA sequences of AKAP10, PON1, PON2 and SIRT2 genes were submitted to GenBank, the accession numbers were EU239246, EU289337, EF522785 and EU562194, respectively.
2. Five candidate genes (AKAP10、PON1、PON2、MBL2 and WARS2) were detected in ovary, liver, skeleton muscle, small intestine, fat, uterus, kidney, heart, lung, lymph, rumen, testis and galactophore by RT-PCR and Real-time PCR, and the results showed that 4 candidate genes are higher expression in liver except that AKAP10 gene is highly expressed in testis specially. Comparing with the database of electron expression in NCBI website, there were obviously differences between the database and the results.
3. PON1 and PON2 genes’exons sequences were detected for SNPs and 6 SNPs were identified: A147G and G162A in exon6 of PON1 gene; A73G and A110G in exon5, T76C in exon6, T98C in exon9 of PON2 gene. Among these SNPs, the hereditary capacities of A147G, G162A in PON1 gene and T98C in PON2 gene were analyzed by PCR-RFLP and PCR-SSCP in 12 bovine breeds, respectively.
4. Association analysis between PON1 and PON2 genes SNPs and body size, growth and parts carcass traits were carried out. (1) It is significant difference between body size and stem length, and chest measurement, and circumference of cannon bone and abdomen circumference (P<0.05), except for height at withers. (2) Individuals of AA genotype at A162G in exon6 of PON1 gene may act as short term cram group, and GG type should be eliminated through selection or competition. Individuals of GA types possess line fitting follow the ages, this type may have reasonable three-dimensional structure, and growth and development pattern in reproduction group. So A162G locus should be tasted to predict cattle lifespan. (3) The results of two enzymes digesting analysis shown that the specialized beef breed grow fast than dual purpose breeds. Simmental is in inferior position in the carcass traits, except for backfat thickness, tendness, total bone weight, rib eye area and carnation traits. At the same time, the beginning weight difference of any haplotype individuals maybe from some growth potential. The AeAeGaGa genotype of PON1 gene may influence the backfat thickness directly (P<0.01). (4) The results of association anlysis in 7 breeds shown that the rib eye area is higher in the individuals of BB genotype than those in AA and AB types significantly (P=0.0302). (5) There were significant differences of three genotypes in exon9 of PON2 gene among 7 breeds (P<0.01), and no difference in or between breeds and in various age groups (P>0.05). However, there are significant differences among three genotypes (P<0.01). And three genotype frequencies present a kind of reducing tendency following ages, but AA and BB genotype frequencies emerge supernumerary phenomenon about at 7 years old.
5. The prokaryotic expression vector of PON1 and PON2 genes were structured using RT-PCR and pET28a+ vector, and the PON1 and PON2 and 6 His fusion proteins were expressed in the BL21 strain. These results will provid the bases for the purifying and application of these two fusion proteins.
1.得到了牛AKAP10、MBL2、PON1、P53、PON2、SIRT2、SIRT3和WARS2共8个候选基因完整的CDS区序列并进行了生物信息学分析。向GenBank数据库提交了AKAP10、PON1、PON2和SIRT2等4个基因的cDNA序列,获取的登录号分别为:EU239246、EU289337、EF522785和EU562194。
2.对所研究候选基因中的AKAP10、PON1、PON2、MBL2和WARS2等5个基因在卵巢、肝脏、肌肉、小肠、脂肪、子宫、肾脏、心脏、肺、淋巴、瘤胃、睾丸和乳腺共13个组织中的表达进行了表达特性研究,结果表明,除AKAP10基因是在睾丸中表达量最高外,其它4个基因均表现为肝脏中表达量最高。与NCBI数据库中的电子表达谱比较分析表明,两者之间有着很明显的差异。
3.对牛的PON1和PON2两个新基因外显子进行SNPs的检测,发现在PON1基因第6外显子A147G和G162A;PON2基因第5外显子A73G和A110G、第6外显子T76C、第9外显子T98C共6个SNPs,并对其中的PON1基因的第6外显子A147G和G162A3,以及PON2基因的第9外显子T98C共3个位点进行了PCR-RFLP和PCR-SSCP多态性遗传特性分析。分析了它们在12个牛群体中的基因型频率,及等位基因的分布差异。
4.对PON1和PON2基因的多态基因型与体尺体重及部分生长和胴体性状进行了关联分析,结果发现:(1)鲁西牛6种体尺体重性状间除体高与其它性状之间相关性不显著外,体重、体长、胸围、管围和腹围之间都表现出显著的相关(P<0.05);(2)PON1基因第6外显子多态性中,AA基因型个体可能为短期肥育类型;GG型个体则应在选择过程中加以淘汰;GA型个体有可能具有比较合理的体型结构和生长发育模式,A162G位点可尝试用于家畜生产年限的预测;(3)PON1基因双酶切位点分析表明,专门化的肉用品种比兼用牛品种有着更为明显的生长特性。胴体性状方面,西门塔尔牛除背膘厚、嫩度、总骨重、眼肌面积和肉色性状外,其它性状存在相对劣势。同时,牛实验期初始重的差异对于某种单体型个体可能源自潜在的生长势,并表明PON1基因的AeAeGaGa基因型可能直接影响牛的背膘厚(P<0.01);(4)在与7个品种关联分析中,PON1基因EcoRⅤ-RFLP位点BB基因型个体的眼肌面积显著高于AA和AB基因型(P=0.0302);(5)PON2基因第9外显子三种基因型频率在7个牛品种间存在极显著的差异(P < 0.01),而各品种中各种基因型间与各品种间差异不显著(P > 0.05),在鲁西牛不同年龄组间无显著差异(P > 0.05)。而三种基因型频率之间则存在极显著的差异(P < 0.01),且三种基因型频率均有随着年龄增加而降低的趋势,但AA型和BB型个体在一定的年龄之后,(约为7岁)又均有数量增加的现象。
5.构建了牛PON1和PON2基因的pET28a+原核表达载体,并成功地在BL21表达菌种中实现了对氧磷酶1(PON1)和对氧磷酶2(PON2)两种蛋白的融合表达,为进一步纯化和应用提供依据。
Obtainning larger economic benefit is the final purpose in cattle breeding. So all the traits should be thought thoroughly, which may influence the economic benefit of cattle for a long time. Based on this idea, it is not only the major production traits, directly to the benefits, but also the secondary traits like productivity, lifespan, calf behavior and resistence of disease, which influences the benefits indirectly, should be taken attention on. For these traits are influenced by the conditions, heredity, and nutrition and so on, and difficult to measurement, the secondary traits selection plannings become so complecity and difficulty. And because the heritability of the secondary traits is very low, it results in slower progression of breeding with common methods. In order to provide certain methodology, what could it reveal the genetics roles of the secondary traits? This article focused on the molecule genetics of some lifespan traits genes, which influence the health and efficency, to provide elementary genetic information to cattle breeding by modern molecule and quantitative combination breeding methods, such as ESTs, RT-PCR, GenScan, direct sequencing, RFLP, Q-PCR, prokaryotic expression, bioinfermtics methods and association analysis. And the results were showed below:
1. The complete CDS sequences of AKAP10、MBL2、PON1、P53、PON2、SIRT2、SIRT3 and WARS2 cDNA were cloned. And the cDNA sequences of AKAP10, PON1, PON2 and SIRT2 genes were submitted to GenBank, the accession numbers were EU239246, EU289337, EF522785 and EU562194, respectively.
2. Five candidate genes (AKAP10、PON1、PON2、MBL2 and WARS2) were detected in ovary, liver, skeleton muscle, small intestine, fat, uterus, kidney, heart, lung, lymph, rumen, testis and galactophore by RT-PCR and Real-time PCR, and the results showed that 4 candidate genes are higher expression in liver except that AKAP10 gene is highly expressed in testis specially. Comparing with the database of electron expression in NCBI website, there were obviously differences between the database and the results.
3. PON1 and PON2 genes’exons sequences were detected for SNPs and 6 SNPs were identified: A147G and G162A in exon6 of PON1 gene; A73G and A110G in exon5, T76C in exon6, T98C in exon9 of PON2 gene. Among these SNPs, the hereditary capacities of A147G, G162A in PON1 gene and T98C in PON2 gene were analyzed by PCR-RFLP and PCR-SSCP in 12 bovine breeds, respectively.
4. Association analysis between PON1 and PON2 genes SNPs and body size, growth and parts carcass traits were carried out. (1) It is significant difference between body size and stem length, and chest measurement, and circumference of cannon bone and abdomen circumference (P<0.05), except for height at withers. (2) Individuals of AA genotype at A162G in exon6 of PON1 gene may act as short term cram group, and GG type should be eliminated through selection or competition. Individuals of GA types possess line fitting follow the ages, this type may have reasonable three-dimensional structure, and growth and development pattern in reproduction group. So A162G locus should be tasted to predict cattle lifespan. (3) The results of two enzymes digesting analysis shown that the specialized beef breed grow fast than dual purpose breeds. Simmental is in inferior position in the carcass traits, except for backfat thickness, tendness, total bone weight, rib eye area and carnation traits. At the same time, the beginning weight difference of any haplotype individuals maybe from some growth potential. The AeAeGaGa genotype of PON1 gene may influence the backfat thickness directly (P<0.01). (4) The results of association anlysis in 7 breeds shown that the rib eye area is higher in the individuals of BB genotype than those in AA and AB types significantly (P=0.0302). (5) There were significant differences of three genotypes in exon9 of PON2 gene among 7 breeds (P<0.01), and no difference in or between breeds and in various age groups (P>0.05). However, there are significant differences among three genotypes (P<0.01). And three genotype frequencies present a kind of reducing tendency following ages, but AA and BB genotype frequencies emerge supernumerary phenomenon about at 7 years old.
5. The prokaryotic expression vector of PON1 and PON2 genes were structured using RT-PCR and pET28a+ vector, and the PON1 and PON2 and 6 His fusion proteins were expressed in the BL21 strain. These results will provid the bases for the purifying and application of these two fusion proteins.
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