荷斯坦牛生长与营养代谢相关基因表达及INSR基因遗传变异研究
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摘要
本研究包括以下两方面内容：
1营养水平对荷斯坦犊牛骨骼肌中mTOR、IGF和胰岛素信号通路相关基因表达的影响
本研究中以荷斯坦公犊牛为研究对象，通过考察两种蛋白水平日粮的采食量对犊牛生长、血液代谢指标和半腱肌中mTOR（Mammalian Target of Rapamycin）、IGF（Insulin-like Growth Factor）和胰岛素信号通路中15个与生长和细胞代谢相关基因mRNA表达的影响，以期更好地从分子水平理解营养水平对断奶前后犊牛肌肉生长和营养代谢调控机制。研究中对20头犊牛（2-3日龄）按照初始体重分为两组，并随机接受两种等能日粮处理：（1）CON：对照日粮组，传统代乳粉（20%粗蛋白，20%粗脂肪，4.90Mcal/kg ME；1.25%BW；干物质基础）+传统开食料（20%粗蛋白，3.16Mcal/kg ME；干物质基础）；（2）HIPRO：高蛋白日粮组，高蛋白代乳粉（28%粗蛋白，16%粗脂肪，4.84Mcal/kg ME；2%BW；干物质基础）+高蛋白开食料（25%粗蛋白，3.20Mcal/kg ME；干物质基础）。最后的分析结果比较两种日粮采食量对断奶前（0-5周龄）与断奶后（6-10周龄）生长、营养代谢与基因表达的不同影响。研究获得以下研究结果：
1.1营养水平对犊牛生长性能的影响
日粮与时间的交互作用不影响犊牛活体重、胴体重和胴体组成（蛋白质、脂肪和灰分）及总内脏重量和肝脏重。除胴体脂肪重（P=0.10）外，高蛋白组较对照组显著提高了犊牛活体重、胴体重和胴体蛋白质、灰分重及总内脏重量和肝脏重（P=0.01）。犊牛10周龄时的活体重、胴体重和胴体组成重（蛋白质、脂肪和灰分）及总内脏重和肝脏重均较5周龄时的犊牛有显著提高（P=0.01）。
1.2营养水平对犊牛营养代谢的影响
日粮与时间的交互作用显著影响犊牛血液葡萄糖浓度（P=0.01）。在犊牛5周龄时，血液葡萄糖浓度随日粮营养水平提高而显著上升（P=0.04）。而在10周龄时，日粮营养水平不影响犊牛血液葡萄糖浓度。此外，采食高蛋白组日粮的犊牛在10周龄时的血液葡萄糖浓度显著低于在5周龄时的血液葡萄糖浓度（P=0.01）。随着日粮营养水平提高，犊牛血液尿素浓度显著上升（P=0.01）。犊牛10周龄时的血液尿素浓度（P=0.01）和BHBA（β-hydroxybutyric acid，β-羟基丁酸，P=0.01）浓度均明显高于5周龄时的浓度。犊牛10周龄时的血液总蛋白浓度明显低于5周龄时的浓度（P=0.01）。日粮与时间的交互作用显著影响犊牛血液中NEFA（nonesterified fatty acid，非酯化脂肪酸）的浓度（P=0.01）。在犊牛5周龄时，随着日粮营养水平提高，NEFA浓度显著升高（P=0.01）。犊牛10周龄时的NEFA浓度显著低于5周龄时的浓度（P=0.01）。犊牛10周龄时的血液胰岛素浓度显著高于5周龄时的浓度（P=0.01），而且随着日粮营养水平提高，胰岛素浓度有上升的趋势（P=0.09）。
1.3营养水平对犊牛骨骼肌中mTOR、IGF和胰岛素信号通路中相关基因表达的影响
日粮与时间的交互作用显著影响犊牛肌肉中IGF1R基因的表达（P=0.04）。在5周龄时，犊牛肌肉中IGF1R的表达量随日粮营养水平提高而下调。日粮与时间的交互作用也对TSC2基因的表达有显著影响（P=0.02）。在5周龄时，日粮处理不影响犊牛肌肉中TSC2基因的表达，但在犊牛10周龄时，提高日粮营养水平能明显增加TSC2基因的表达。而且，仅在采食高蛋白日粮时，犊牛10周龄时TSC2基因的表达量才明显高于5周龄时的表达量。本研究中虽未观察到TSC1基因表达量的显著改变，但一直与TSC2基因表达量呈现相反的变化趋势。与采食低蛋白日粮的犊牛相比，采食高蛋白日粮的犊牛肌肉中RPS6KB1基因的表达在5周龄和10周龄时均明显下调（P=0.03），IRS1基因的表达明显上调（P=0.02），INSR基因的表达呈现下调趋势（P=0.10），PDPK1基因的表达呈现上调趋势（P=0.10）。与5周龄时犊牛肌肉中基因表达相比，10周龄时犊牛肌肉中FOXO1（P=0.04）和INSR基因（P=0.05）表达明显下调，TSC2基因表达明显增加（P=0.01）。与5周龄时犊牛肌肉中基因表达相比，10周龄时犊牛肌肉中FOXO1（P=0.04）和INSR（P=0.05）基因表达明显下调，TSC2基因表达明显增加（P=0.01），而RICTOR（P=0.07）、RPTOR（P=0.10）和TSC1（P=0.06）基因均呈下调趋势。
2中国荷斯坦牛INSR基因遗传变异分析
本研究基于营养生理学与遗传学的综合考虑，以INSR基因为候选基因，筛选通过影响奶牛正常采食信号接收、转导而影响奶牛产奶性能的分子标记。试验中以205头中国荷斯坦奶牛为研究对象，应用DNA测序、DNA序列分析和PCR-RFLP技术，分析牛INSR基因的遗传变异。此外，还分析了牛INSR基因的多态性与中国荷斯坦奶牛产奶性能（乳脂率、乳蛋白率、乳脂产量、乳蛋白产量和产奶量）的关系，期望为未来集约化生产条件下奶牛的生产和分子标记辅助选育提供有益的参考。研究得出以下结果：
2.1牛INSR基因SNPs的检测
试验中共设计27对引物，对牛INSR基因的所有CDS（Coding Sequence，编码序列）区共22个外显子进行双向测序和SNP（Single Nucleotide Polymorphism，单核苷酸多态性）扫描分析。利用DNA测序技术、DNA序列分析和PCR-RFLP技术在牛INSR基因上共发现13个突变位点，其中7个SNPs发生于编码区，并导致氨基酸发生改变，6个SNPs发生于非编码区。这些突变分别位于第8内含子、第11外显子、第16内含子、第20内含子和第21外显子。
（1）突变nt12689G>A发生于第8内含子，表现出Hinf I酶切多态性，本试验研究群体在该基因座的Hinf I PCR-RFLP分析中表现出三种基因型，分别为GG型（315bp+149bp+34bp+5bp）、GA型（315bp+218bp+149bp+97bp+34bp+5bp）和AA型（218bp+149bp+97bp+34bp+5bp）。
（2）突变nt26301G>A、nt26334G>C、nt26496A>G、nt26504C>T和nt26526A>G均发生于第11外显子，导致氨基酸的改变依次为Arg509His、Arg520Pro、Gln574Arg、Arg577Trp、His584Arg。测序结果显示这5个SNPs不连锁。
（3）突变nt44018G>A、nt44024A>G和nt44067C>T均发生于第16内含子，测序结果显示这3个SNPs连锁，并表现出Hha I酶切多态性。本试验研究群体在该基因座的Hha I PCR-RFLP分析中表现出三种基因型，分别为GG型（526bp+345bp）、GA型（871bp+526bp+345bp）和AA型（871bp）。
（4）突变nt121892A>G和nt121877A>G发生于第20内含子；突变nt122326T>C和nt122362T>C均发生于第21外显子，导致氨基酸发生的改变依次为Val1231Ala和Leu1243Pro。测序结果显示，突变nt121877A>G、nt122326T>C和nt122362T>C这3个SNPs连锁，并且表现出Hha I酶切多态性，本试验研究群体在该基因座的HhaIPCR-RFLP分析中表现出三种基因型，分别为GG型（621bp）、 GA型（621bp+517bp+104bp）和AA型（517bp+104bp）。突变nt121877A>G引起的多态性通过引入酶切位点后，在Pvu IIPCR-RFLP分析中表现出三种基因型，分别为AA型（577bp）、AG型（577bp+542bp+35bp）和GG型（542bp+35bp）。
2.2牛INSR基因的群体遗传结构分析
（1）牛INSR基因所有基因座均检测到三种不同基因型。由He（Heterozygosity，杂合度）和PIC（Polymorphism Information Content，多态信息含量）数据可见，INSR基因的所有基因座在本试验研究群体内的多态性不是很丰富。与He（0.4085-0.4971）的数据一致，基因座GT2、GT4、GT5和GT9的PIC值较高（0.3250-0.3735），具有较高的遗传多态性。
（2）经群体平衡性检验，在本试验研究群体内，牛INSR基因的所有基因座均处于Hardy-Weinberg非平衡状态（P<0.05）。
（3）在本研究奶牛群体中，INSR基因不同基因座间的D’值均大于0，表明各不同基因座之间存在着不同程度的连锁不平衡关系（0 2.3牛INSR基因多态性对中国荷斯坦奶牛产奶性能的影响
将牛INSR基因的9个多态性基因座与205头中国荷斯坦奶牛的产奶性能进行相关分析后发现：
（1）基因座GT1、GT3、GT5、GT7和GT8对各生产指标均无影响（P>0.05）。
（2）基因座GT2可能是影响中国荷斯坦奶牛乳脂率、乳蛋白产量和产奶量的重要基因座。基因座GT2中AA型个体的乳脂率显著高于GG型和GA型个体（P=0.022），分别高出3.7%（GG型）和3.9%（GA型），GG型个体与GA型个体间的乳脂率无显著差异。胎次与GT2间的交互作用显著影响乳蛋白产量（P=0.015）和产奶量（P=0.008），第一胎的GG型个体明显比AA型个体生产更多的奶和乳蛋白质。胎次与GT2间的交互作用也有影响乳脂产量的趋势（P=0.078）。
（3）基因座GT4可能是影响乳脂率、乳脂产量、乳蛋白产量和产奶量的重要基因座。基因座GT4中GG型个体的乳脂率比AG型个体高出3.7%；产犊季节与GT4间的交互作用显著影响乳脂率（P=0.018），对于AG型个体，6-8月产犊的个体比9-11月和12-2月产犊的个体乳脂率要低。基因座GT4中AA型个体乳脂产量明显比GG型个体高出11.58%。基因座GT4的不同基因型有影响乳蛋白产量（P=0.081）和产奶量的趋势（P=0.053）。
（4）基因座GT6可能是影响乳脂率和乳蛋白率的重要基因座。基因座GT6中GG型个体的乳脂率比AG型个体高出4.7%。GG型个体的乳蛋白率比AG型个体高出0.6%。
（5）基因座GT9的不同基因型不会影响乳脂率、乳脂产量、乳蛋白产量和产奶量，但是有影响乳蛋白率的趋势（P=0.085）。这个结果提示，GT9可能是影响中国荷斯坦奶牛乳蛋白率的重要基因座之一。
In present study, two parts were included:
1The effects of level of nutrition on expression of genes involved in pathways of mTOR,IGF and insulin signaling in skeletal muscle of Holstein calf
In present study, we explored the molecular mechanism,by which level of nutritionaffected growth of skeletal muscle and nutrition metabolism of calf by measuring calfperformance, blood metabolites and the expression of15genes in volved inpathways ofmTOR, IGF and insulin signaling in semitendinosus tissue of Holstein calves via quantitativePCR. Twenty calves were assigned randomly to two diets based on block-design by bodyweight:(1) CON: a control diet, constituted by conventional milk replacer (20%CP,20%fat,4.90Mcal/kg ME;1.25%BW; DM basis) and conventional starter (20%CP,3.16Mcal/kg ME,DM basis);(2)HIPRO: a high-protein diet, constituted by high-protein milk replacer (28%CP,16%fat,4.84Mcal/kg ME;2%BW; DM basis) and high-protein starter (25%CP,3.20Mcal/kgME, DM basis). The final results were focused to compare the dietary differences duringpreweaning (0-5wk) and postweaning (5-10wk), respectively. The results were in thefollowings:
1.1The effects of level of nutrition on calf performance
Interaction of diet and time did not significantly affect calf live BW, carcass weight,carcass composition (including protein, fat, and ash), total viscera weight, and liver weight.Except for fat weight, significant increases (P=0.01) were observed for final live BW, carcassweight, carcass composition (including protein and ash), total viscera weight and liver weightin calves fed high-protein diet vs. control diet. Greater live BW, carcass weight, carcasscomposition (including protein, fat and ash), and total viscera weight and liver weight wereobserved for calves at10wk vs.5wk.
1.2The effects of level of nutrition on nutrition metabolism of calf
Interaction of diet and time (P=0.01) significantly affect blood glucose concentration ofcalves (P=0.01). Rise in blood glucose concentration were observed as nutrition levelincreased for calves at5wk (P=0.04). But no alteration was found for blood glucoseconcentration as nutrition level increased for calves at10wk. In addition, decreasedconcentration of blood glucose was demonstrated for calves fed high-protein diet at10wk vs. 5wk (P=0.01).Blood urea concentration was significantly higher for calves fed high-proteindiet compared to that of calves fed control diet (P=0.01). Urea concentration (P=0.01) andBHBA (β-hydroxybutyric acid, P=0.01) concentration for calves at10wk were significantlyhigher than those for calves at5wk. Total protein concentrationfor calves at10wk weresignificantly lower than that for calves at5wk (P=0.01). Interaction of diet and time (P=0.01)had significant effects on blood NEFA (nonesterified fatty acid) concentration of calves(P=0.01).NEFA concentration increased markedly as nutrition level elevated (P=0.01). Calvesat10wk possessed lower NEFA concentration compared calves at5wk (P=0.01). There wasan overall increase between wk5and wk10for blood insulin concentration (P <0.01), andthere was an increased tendency of insulin by elevated nutrion level (P=0.09).
1.3The effects of nutrion level on expression of genes involved in pathways of mTOR,IGF and insulin signaling in skeletal muscle of calf
The interaction of diet and time had significant effects on expression of IGF1R(P=0.04)in semitendinosus tissue of calf. For calves at5wk, expression of IGF1R decreased withelevated nutrition level. The interaction of diet and time also affected expression of TSC2(P=0.02). No change of expression of TSC2by nutrition level was observed for calves at5wk.But for calves at10wk, expression of TSC2was greater for calves fed high-protein dietcompared to that for calves fed control diet. Moreover, higher expression of TSC2for calvesat10wk than that for calves at5wk only occurred for calves fed high-protein diet. Nosignificant changes were found for expression of TSC1, which displayed opposite tendency tothe changes of expression of TSC2. Compared to the gene expression of calves fed controldiet, expression of RPS6KB1for calves fed high-protein diet was markedly downregulatedboth at5wk and10wk (P=0.03), that of IRS1was upregulated (P=0.02), that of INSR tendedto be downregulated (P=0.10), and that of PDPK1tended to be upregulated (P=0.10).Compared to the gene expression of calves at5wk, expression of FOXO1(P=0.04) and INSR(P=0.05) significantly downregulated, that of TSC2was significantly upregulated (P=0.01),and expression of RICTOR (P=0.07), RPTOR (P=0.10) and TSC1(P=0.06) tended to bedownregulated.
2Analysis of genetic variation of bovine INSR gene in China Holstein dairy cattle
Taken into account of the importance of nutritional physiology and genetics, INSR genewas selected as a candidate to find potential molecular markers, which controlled dairy cattleperformance by modulating feeding signals reception and transduction. A population of205China Holstein dairy cattle was investigated to study the genetic variation of bovine INSR viaDNA sequencing, DNA sequence analysis and PCR-RFLP techniques. We also conductedassociation analysis between the polymorphism of bovine INSR gene and milk performance (i.e., milk protein content, milk fat content, milk protein yield, milk fat yield and milk yield)of China Holstein dairy cattle, expecting to improve the future productionof dairy cattle in thecondition of intensive production and the application of MAS (marker-assist-selection). Theresults were in the followings:
2.1Detection of SNPs within bovine INSR gene
Sequencing from two direction and SNP scanning were conducted for CDS (codingsequence) region (including22exons) in the bovine INSR gene using27pairs of primers.Thirteen mutations were revealed within bovine INSR gene via DNA sequencing, DNAsequence analysis and PCR-RFLP techniques, including7SNPs, which occurred in codingregion and resulted alterations of amino acids, and6SNPs, which occurred in non-codingregion. The mutations were observed at intron8, exon11, intron16, intron20and exon21.
(1) Mutation nt12689G>A occurred at intron8, resulting Hinf I polymorphism. Threegenotypes were observed via Hinf I PCR-RFLP analysis: genotype GG(315bp+149bp+34bp+5bp), genotype GA (315bp+218bp+149bp+97bp+34bp+5bp) andgenotype AA (218bp+149bp+97bp+34bp+5bp).
(2) Mutation nt26301G>A, nt26334G>C, nt26496A>G, nt26504C>T and nt26526A>Goccurred at exon11, resulting alterations of amino acids as followings: Arg509His、Arg520Pro、Gln574Arg、Arg577Trp、His584Arg. No linkage was observed among the5SNPs.
(3) Mutations nt44018G>A, nt44024A>G and nt44067C>T, which were linked together,occurred at intron16, resulting Hha I polymorphism, and three genotypes were observed:genotype GG (526bp+345bp), genotype GA (871bp+526bp+345bp) and genotype AA(871bp).
(4) Mutations nt121892A>G and nt121877A>G occurred at intron20; Mutationsnt122326T>C and nt122362T>C occurred at exon21，resulting alterations of amino acids asfollowings: Val1231Ala and Leu1243Pro. Linkage among mutations nt121877A>G,nt122326T>C and nt122362T>C possessed Hha I polymorphism: genotype GG (621bp),genotype GA (621bp+517bp+104bp) and genotype AA (517bp+104bp). Three genotypeswere observed via forced Pvu II PCR-RFLP for mutation nt121877A>G: genotype AA(577bp), genotype AG (577bp+542bp+35bp) and genotype GG (542bp+35bp).
2.2Genetic parameters of population for bovine INSR gene
(1) Three genotypes were observed for all loci of bovine INSR. Data of He(Heterozygosity) and PIC (Polymorphism Information Content) suggested that polymorphismof INSR gene was not rich in the investigated population. Consistent with values ofHe(0.4085-0.4971), values of PIC at locus GT2, GT4, GT5and GT9implied a higher genetic polymorphism.
(2) All loci in bovine INSR gene were not in Hardy-Weinberg balance in presentinvestigated population (P<0.05).
(3) In present population, values of D’between two loci within INSR gene were higherthan0, suggesting linkage disequilibrium between two loci (0 2.3The effects of polymorphism of bovine INSR on milk performance in ChinaHolstein dairy cattle
Association analysis between9loci of bovine INSR gene and milk performance (milkprotein content, milk fat content, milk protein yield, milk fat yield and milk yield) of205China Holstein dairy cattle revealed the followings:
(1) There was no effect of polymorphisms of locus GT1、GT3、GT5、GT7and GT8onmilk performance, respectively (P>0.05).
(2) Locus GT2might be important for milk fat content, milk protein yield and milk yield.Individuals with genotype AA had higher milk fat content than those with genotype GG(3.7%)and GA(3.9%), and no difference were observed for milk fat content between individuals withgenotype GG and GA. The interaction of lactation and GT2significantly influenced milkprotein yield (P=0.015),milk yield (P=0.008), with more milk protein yield and milk yield forindividuals with genotype GG than those with genotype AA at first lactation. The interactionof lactation and GT2tended to influenc milk fat yield (P=0.078).
(3) Locus GT4might be important for milk fat content, milk fat yield, milk protein yieldand milk yield. Individuals with genotype GG had higher milk fat content than those withgenotype AG (3.7%). The interaction of season and GT4significantly influenced milk fatcontent (P=0.018), individuals with genotype AG had less milk fat content when deliveryoccurred from June to Augast than those from September to November and those fromDecember to Febrary. Interaction of lactation and GT2tended to influenc milk fat yield(P=0.078). Individuals with genotype AA had11.58%higher milk fat yield than those withgenotype GG at locus GT4. Genotype of locus GT4tended to affect milk protein yield(P=0.081) and milk yield (P=0.053).
(4) Locus GT6might be important for milk fat content and milk protein content.Individuals with genotype GG had higher milk fat content than those with genotype AG (4.7%) at locus GT6. Individuals with genotype GG possessed higher milk protein contentthan those with genotype AG (0.6%).
(5) Although there was no effect of polymorphism of locus GT9on milk fat content,milk fat yield, milk protein yield and milk yield (P>0.05), it showed tendency for milk proteincontent (P=0.085)，suggesting that locus GT9probably was important for milk proteincontent.
1营养水平对荷斯坦犊牛骨骼肌中mTOR、IGF和胰岛素信号通路相关基因表达的影响
本研究中以荷斯坦公犊牛为研究对象，通过考察两种蛋白水平日粮的采食量对犊牛生长、血液代谢指标和半腱肌中mTOR（Mammalian Target of Rapamycin）、IGF（Insulin-like Growth Factor）和胰岛素信号通路中15个与生长和细胞代谢相关基因mRNA表达的影响，以期更好地从分子水平理解营养水平对断奶前后犊牛肌肉生长和营养代谢调控机制。研究中对20头犊牛（2-3日龄）按照初始体重分为两组，并随机接受两种等能日粮处理：（1）CON：对照日粮组，传统代乳粉（20%粗蛋白，20%粗脂肪，4.90Mcal/kg ME；1.25%BW；干物质基础）+传统开食料（20%粗蛋白，3.16Mcal/kg ME；干物质基础）；（2）HIPRO：高蛋白日粮组，高蛋白代乳粉（28%粗蛋白，16%粗脂肪，4.84Mcal/kg ME；2%BW；干物质基础）+高蛋白开食料（25%粗蛋白，3.20Mcal/kg ME；干物质基础）。最后的分析结果比较两种日粮采食量对断奶前（0-5周龄）与断奶后（6-10周龄）生长、营养代谢与基因表达的不同影响。研究获得以下研究结果：
1.1营养水平对犊牛生长性能的影响
日粮与时间的交互作用不影响犊牛活体重、胴体重和胴体组成（蛋白质、脂肪和灰分）及总内脏重量和肝脏重。除胴体脂肪重（P=0.10）外，高蛋白组较对照组显著提高了犊牛活体重、胴体重和胴体蛋白质、灰分重及总内脏重量和肝脏重（P=0.01）。犊牛10周龄时的活体重、胴体重和胴体组成重（蛋白质、脂肪和灰分）及总内脏重和肝脏重均较5周龄时的犊牛有显著提高（P=0.01）。
1.2营养水平对犊牛营养代谢的影响
日粮与时间的交互作用显著影响犊牛血液葡萄糖浓度（P=0.01）。在犊牛5周龄时，血液葡萄糖浓度随日粮营养水平提高而显著上升（P=0.04）。而在10周龄时，日粮营养水平不影响犊牛血液葡萄糖浓度。此外，采食高蛋白组日粮的犊牛在10周龄时的血液葡萄糖浓度显著低于在5周龄时的血液葡萄糖浓度（P=0.01）。随着日粮营养水平提高，犊牛血液尿素浓度显著上升（P=0.01）。犊牛10周龄时的血液尿素浓度（P=0.01）和BHBA（β-hydroxybutyric acid，β-羟基丁酸，P=0.01）浓度均明显高于5周龄时的浓度。犊牛10周龄时的血液总蛋白浓度明显低于5周龄时的浓度（P=0.01）。日粮与时间的交互作用显著影响犊牛血液中NEFA（nonesterified fatty acid，非酯化脂肪酸）的浓度（P=0.01）。在犊牛5周龄时，随着日粮营养水平提高，NEFA浓度显著升高（P=0.01）。犊牛10周龄时的NEFA浓度显著低于5周龄时的浓度（P=0.01）。犊牛10周龄时的血液胰岛素浓度显著高于5周龄时的浓度（P=0.01），而且随着日粮营养水平提高，胰岛素浓度有上升的趋势（P=0.09）。
1.3营养水平对犊牛骨骼肌中mTOR、IGF和胰岛素信号通路中相关基因表达的影响
日粮与时间的交互作用显著影响犊牛肌肉中IGF1R基因的表达（P=0.04）。在5周龄时，犊牛肌肉中IGF1R的表达量随日粮营养水平提高而下调。日粮与时间的交互作用也对TSC2基因的表达有显著影响（P=0.02）。在5周龄时，日粮处理不影响犊牛肌肉中TSC2基因的表达，但在犊牛10周龄时，提高日粮营养水平能明显增加TSC2基因的表达。而且，仅在采食高蛋白日粮时，犊牛10周龄时TSC2基因的表达量才明显高于5周龄时的表达量。本研究中虽未观察到TSC1基因表达量的显著改变，但一直与TSC2基因表达量呈现相反的变化趋势。与采食低蛋白日粮的犊牛相比，采食高蛋白日粮的犊牛肌肉中RPS6KB1基因的表达在5周龄和10周龄时均明显下调（P=0.03），IRS1基因的表达明显上调（P=0.02），INSR基因的表达呈现下调趋势（P=0.10），PDPK1基因的表达呈现上调趋势（P=0.10）。与5周龄时犊牛肌肉中基因表达相比，10周龄时犊牛肌肉中FOXO1（P=0.04）和INSR基因（P=0.05）表达明显下调，TSC2基因表达明显增加（P=0.01）。与5周龄时犊牛肌肉中基因表达相比，10周龄时犊牛肌肉中FOXO1（P=0.04）和INSR（P=0.05）基因表达明显下调，TSC2基因表达明显增加（P=0.01），而RICTOR（P=0.07）、RPTOR（P=0.10）和TSC1（P=0.06）基因均呈下调趋势。
2中国荷斯坦牛INSR基因遗传变异分析
本研究基于营养生理学与遗传学的综合考虑，以INSR基因为候选基因，筛选通过影响奶牛正常采食信号接收、转导而影响奶牛产奶性能的分子标记。试验中以205头中国荷斯坦奶牛为研究对象，应用DNA测序、DNA序列分析和PCR-RFLP技术，分析牛INSR基因的遗传变异。此外，还分析了牛INSR基因的多态性与中国荷斯坦奶牛产奶性能（乳脂率、乳蛋白率、乳脂产量、乳蛋白产量和产奶量）的关系，期望为未来集约化生产条件下奶牛的生产和分子标记辅助选育提供有益的参考。研究得出以下结果：
2.1牛INSR基因SNPs的检测
试验中共设计27对引物，对牛INSR基因的所有CDS（Coding Sequence，编码序列）区共22个外显子进行双向测序和SNP（Single Nucleotide Polymorphism，单核苷酸多态性）扫描分析。利用DNA测序技术、DNA序列分析和PCR-RFLP技术在牛INSR基因上共发现13个突变位点，其中7个SNPs发生于编码区，并导致氨基酸发生改变，6个SNPs发生于非编码区。这些突变分别位于第8内含子、第11外显子、第16内含子、第20内含子和第21外显子。
（1）突变nt12689G>A发生于第8内含子，表现出Hinf I酶切多态性，本试验研究群体在该基因座的Hinf I PCR-RFLP分析中表现出三种基因型，分别为GG型（315bp+149bp+34bp+5bp）、GA型（315bp+218bp+149bp+97bp+34bp+5bp）和AA型（218bp+149bp+97bp+34bp+5bp）。
（2）突变nt26301G>A、nt26334G>C、nt26496A>G、nt26504C>T和nt26526A>G均发生于第11外显子，导致氨基酸的改变依次为Arg509His、Arg520Pro、Gln574Arg、Arg577Trp、His584Arg。测序结果显示这5个SNPs不连锁。
（3）突变nt44018G>A、nt44024A>G和nt44067C>T均发生于第16内含子，测序结果显示这3个SNPs连锁，并表现出Hha I酶切多态性。本试验研究群体在该基因座的Hha I PCR-RFLP分析中表现出三种基因型，分别为GG型（526bp+345bp）、GA型（871bp+526bp+345bp）和AA型（871bp）。
（4）突变nt121892A>G和nt121877A>G发生于第20内含子；突变nt122326T>C和nt122362T>C均发生于第21外显子，导致氨基酸发生的改变依次为Val1231Ala和Leu1243Pro。测序结果显示，突变nt121877A>G、nt122326T>C和nt122362T>C这3个SNPs连锁，并且表现出Hha I酶切多态性，本试验研究群体在该基因座的HhaIPCR-RFLP分析中表现出三种基因型，分别为GG型（621bp）、 GA型（621bp+517bp+104bp）和AA型（517bp+104bp）。突变nt121877A>G引起的多态性通过引入酶切位点后，在Pvu IIPCR-RFLP分析中表现出三种基因型，分别为AA型（577bp）、AG型（577bp+542bp+35bp）和GG型（542bp+35bp）。
2.2牛INSR基因的群体遗传结构分析
（1）牛INSR基因所有基因座均检测到三种不同基因型。由He（Heterozygosity，杂合度）和PIC（Polymorphism Information Content，多态信息含量）数据可见，INSR基因的所有基因座在本试验研究群体内的多态性不是很丰富。与He（0.4085-0.4971）的数据一致，基因座GT2、GT4、GT5和GT9的PIC值较高（0.3250-0.3735），具有较高的遗传多态性。
（2）经群体平衡性检验，在本试验研究群体内，牛INSR基因的所有基因座均处于Hardy-Weinberg非平衡状态（P<0.05）。
（3）在本研究奶牛群体中，INSR基因不同基因座间的D’值均大于0，表明各不同基因座之间存在着不同程度的连锁不平衡关系（0
将牛INSR基因的9个多态性基因座与205头中国荷斯坦奶牛的产奶性能进行相关分析后发现：
（1）基因座GT1、GT3、GT5、GT7和GT8对各生产指标均无影响（P>0.05）。
（2）基因座GT2可能是影响中国荷斯坦奶牛乳脂率、乳蛋白产量和产奶量的重要基因座。基因座GT2中AA型个体的乳脂率显著高于GG型和GA型个体（P=0.022），分别高出3.7%（GG型）和3.9%（GA型），GG型个体与GA型个体间的乳脂率无显著差异。胎次与GT2间的交互作用显著影响乳蛋白产量（P=0.015）和产奶量（P=0.008），第一胎的GG型个体明显比AA型个体生产更多的奶和乳蛋白质。胎次与GT2间的交互作用也有影响乳脂产量的趋势（P=0.078）。
（3）基因座GT4可能是影响乳脂率、乳脂产量、乳蛋白产量和产奶量的重要基因座。基因座GT4中GG型个体的乳脂率比AG型个体高出3.7%；产犊季节与GT4间的交互作用显著影响乳脂率（P=0.018），对于AG型个体，6-8月产犊的个体比9-11月和12-2月产犊的个体乳脂率要低。基因座GT4中AA型个体乳脂产量明显比GG型个体高出11.58%。基因座GT4的不同基因型有影响乳蛋白产量（P=0.081）和产奶量的趋势（P=0.053）。
（4）基因座GT6可能是影响乳脂率和乳蛋白率的重要基因座。基因座GT6中GG型个体的乳脂率比AG型个体高出4.7%。GG型个体的乳蛋白率比AG型个体高出0.6%。
（5）基因座GT9的不同基因型不会影响乳脂率、乳脂产量、乳蛋白产量和产奶量，但是有影响乳蛋白率的趋势（P=0.085）。这个结果提示，GT9可能是影响中国荷斯坦奶牛乳蛋白率的重要基因座之一。
In present study, two parts were included:
1The effects of level of nutrition on expression of genes involved in pathways of mTOR,IGF and insulin signaling in skeletal muscle of Holstein calf
In present study, we explored the molecular mechanism,by which level of nutritionaffected growth of skeletal muscle and nutrition metabolism of calf by measuring calfperformance, blood metabolites and the expression of15genes in volved inpathways ofmTOR, IGF and insulin signaling in semitendinosus tissue of Holstein calves via quantitativePCR. Twenty calves were assigned randomly to two diets based on block-design by bodyweight:(1) CON: a control diet, constituted by conventional milk replacer (20%CP,20%fat,4.90Mcal/kg ME;1.25%BW; DM basis) and conventional starter (20%CP,3.16Mcal/kg ME,DM basis);(2)HIPRO: a high-protein diet, constituted by high-protein milk replacer (28%CP,16%fat,4.84Mcal/kg ME;2%BW; DM basis) and high-protein starter (25%CP,3.20Mcal/kgME, DM basis). The final results were focused to compare the dietary differences duringpreweaning (0-5wk) and postweaning (5-10wk), respectively. The results were in thefollowings:
1.1The effects of level of nutrition on calf performance
Interaction of diet and time did not significantly affect calf live BW, carcass weight,carcass composition (including protein, fat, and ash), total viscera weight, and liver weight.Except for fat weight, significant increases (P=0.01) were observed for final live BW, carcassweight, carcass composition (including protein and ash), total viscera weight and liver weightin calves fed high-protein diet vs. control diet. Greater live BW, carcass weight, carcasscomposition (including protein, fat and ash), and total viscera weight and liver weight wereobserved for calves at10wk vs.5wk.
1.2The effects of level of nutrition on nutrition metabolism of calf
Interaction of diet and time (P=0.01) significantly affect blood glucose concentration ofcalves (P=0.01). Rise in blood glucose concentration were observed as nutrition levelincreased for calves at5wk (P=0.04). But no alteration was found for blood glucoseconcentration as nutrition level increased for calves at10wk. In addition, decreasedconcentration of blood glucose was demonstrated for calves fed high-protein diet at10wk vs. 5wk (P=0.01).Blood urea concentration was significantly higher for calves fed high-proteindiet compared to that of calves fed control diet (P=0.01). Urea concentration (P=0.01) andBHBA (β-hydroxybutyric acid, P=0.01) concentration for calves at10wk were significantlyhigher than those for calves at5wk. Total protein concentrationfor calves at10wk weresignificantly lower than that for calves at5wk (P=0.01). Interaction of diet and time (P=0.01)had significant effects on blood NEFA (nonesterified fatty acid) concentration of calves(P=0.01).NEFA concentration increased markedly as nutrition level elevated (P=0.01). Calvesat10wk possessed lower NEFA concentration compared calves at5wk (P=0.01). There wasan overall increase between wk5and wk10for blood insulin concentration (P <0.01), andthere was an increased tendency of insulin by elevated nutrion level (P=0.09).
1.3The effects of nutrion level on expression of genes involved in pathways of mTOR,IGF and insulin signaling in skeletal muscle of calf
The interaction of diet and time had significant effects on expression of IGF1R(P=0.04)in semitendinosus tissue of calf. For calves at5wk, expression of IGF1R decreased withelevated nutrition level. The interaction of diet and time also affected expression of TSC2(P=0.02). No change of expression of TSC2by nutrition level was observed for calves at5wk.But for calves at10wk, expression of TSC2was greater for calves fed high-protein dietcompared to that for calves fed control diet. Moreover, higher expression of TSC2for calvesat10wk than that for calves at5wk only occurred for calves fed high-protein diet. Nosignificant changes were found for expression of TSC1, which displayed opposite tendency tothe changes of expression of TSC2. Compared to the gene expression of calves fed controldiet, expression of RPS6KB1for calves fed high-protein diet was markedly downregulatedboth at5wk and10wk (P=0.03), that of IRS1was upregulated (P=0.02), that of INSR tendedto be downregulated (P=0.10), and that of PDPK1tended to be upregulated (P=0.10).Compared to the gene expression of calves at5wk, expression of FOXO1(P=0.04) and INSR(P=0.05) significantly downregulated, that of TSC2was significantly upregulated (P=0.01),and expression of RICTOR (P=0.07), RPTOR (P=0.10) and TSC1(P=0.06) tended to bedownregulated.
2Analysis of genetic variation of bovine INSR gene in China Holstein dairy cattle
Taken into account of the importance of nutritional physiology and genetics, INSR genewas selected as a candidate to find potential molecular markers, which controlled dairy cattleperformance by modulating feeding signals reception and transduction. A population of205China Holstein dairy cattle was investigated to study the genetic variation of bovine INSR viaDNA sequencing, DNA sequence analysis and PCR-RFLP techniques. We also conductedassociation analysis between the polymorphism of bovine INSR gene and milk performance (i.e., milk protein content, milk fat content, milk protein yield, milk fat yield and milk yield)of China Holstein dairy cattle, expecting to improve the future productionof dairy cattle in thecondition of intensive production and the application of MAS (marker-assist-selection). Theresults were in the followings:
2.1Detection of SNPs within bovine INSR gene
Sequencing from two direction and SNP scanning were conducted for CDS (codingsequence) region (including22exons) in the bovine INSR gene using27pairs of primers.Thirteen mutations were revealed within bovine INSR gene via DNA sequencing, DNAsequence analysis and PCR-RFLP techniques, including7SNPs, which occurred in codingregion and resulted alterations of amino acids, and6SNPs, which occurred in non-codingregion. The mutations were observed at intron8, exon11, intron16, intron20and exon21.
(1) Mutation nt12689G>A occurred at intron8, resulting Hinf I polymorphism. Threegenotypes were observed via Hinf I PCR-RFLP analysis: genotype GG(315bp+149bp+34bp+5bp), genotype GA (315bp+218bp+149bp+97bp+34bp+5bp) andgenotype AA (218bp+149bp+97bp+34bp+5bp).
(2) Mutation nt26301G>A, nt26334G>C, nt26496A>G, nt26504C>T and nt26526A>Goccurred at exon11, resulting alterations of amino acids as followings: Arg509His、Arg520Pro、Gln574Arg、Arg577Trp、His584Arg. No linkage was observed among the5SNPs.
(3) Mutations nt44018G>A, nt44024A>G and nt44067C>T, which were linked together,occurred at intron16, resulting Hha I polymorphism, and three genotypes were observed:genotype GG (526bp+345bp), genotype GA (871bp+526bp+345bp) and genotype AA(871bp).
(4) Mutations nt121892A>G and nt121877A>G occurred at intron20; Mutationsnt122326T>C and nt122362T>C occurred at exon21，resulting alterations of amino acids asfollowings: Val1231Ala and Leu1243Pro. Linkage among mutations nt121877A>G,nt122326T>C and nt122362T>C possessed Hha I polymorphism: genotype GG (621bp),genotype GA (621bp+517bp+104bp) and genotype AA (517bp+104bp). Three genotypeswere observed via forced Pvu II PCR-RFLP for mutation nt121877A>G: genotype AA(577bp), genotype AG (577bp+542bp+35bp) and genotype GG (542bp+35bp).
2.2Genetic parameters of population for bovine INSR gene
(1) Three genotypes were observed for all loci of bovine INSR. Data of He(Heterozygosity) and PIC (Polymorphism Information Content) suggested that polymorphismof INSR gene was not rich in the investigated population. Consistent with values ofHe(0.4085-0.4971), values of PIC at locus GT2, GT4, GT5and GT9implied a higher genetic polymorphism.
(2) All loci in bovine INSR gene were not in Hardy-Weinberg balance in presentinvestigated population (P<0.05).
(3) In present population, values of D’between two loci within INSR gene were higherthan0, suggesting linkage disequilibrium between two loci (0
Association analysis between9loci of bovine INSR gene and milk performance (milkprotein content, milk fat content, milk protein yield, milk fat yield and milk yield) of205China Holstein dairy cattle revealed the followings:
(1) There was no effect of polymorphisms of locus GT1、GT3、GT5、GT7and GT8onmilk performance, respectively (P>0.05).
(2) Locus GT2might be important for milk fat content, milk protein yield and milk yield.Individuals with genotype AA had higher milk fat content than those with genotype GG(3.7%)and GA(3.9%), and no difference were observed for milk fat content between individuals withgenotype GG and GA. The interaction of lactation and GT2significantly influenced milkprotein yield (P=0.015),milk yield (P=0.008), with more milk protein yield and milk yield forindividuals with genotype GG than those with genotype AA at first lactation. The interactionof lactation and GT2tended to influenc milk fat yield (P=0.078).
(3) Locus GT4might be important for milk fat content, milk fat yield, milk protein yieldand milk yield. Individuals with genotype GG had higher milk fat content than those withgenotype AG (3.7%). The interaction of season and GT4significantly influenced milk fatcontent (P=0.018), individuals with genotype AG had less milk fat content when deliveryoccurred from June to Augast than those from September to November and those fromDecember to Febrary. Interaction of lactation and GT2tended to influenc milk fat yield(P=0.078). Individuals with genotype AA had11.58%higher milk fat yield than those withgenotype GG at locus GT4. Genotype of locus GT4tended to affect milk protein yield(P=0.081) and milk yield (P=0.053).
(4) Locus GT6might be important for milk fat content and milk protein content.Individuals with genotype GG had higher milk fat content than those with genotype AG (4.7%) at locus GT6. Individuals with genotype GG possessed higher milk protein contentthan those with genotype AG (0.6%).
(5) Although there was no effect of polymorphism of locus GT9on milk fat content,milk fat yield, milk protein yield and milk yield (P>0.05), it showed tendency for milk proteincontent (P=0.085)，suggesting that locus GT9probably was important for milk proteincontent.
引文
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