西藏班戈绒山羊高海拔环境适应性的遗传分析
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摘要
高原哺乳类动物的高海拔环境适应性分子机制一直是各国科研工作者热衷研究的课题之一，其对于优良畜禽资源的保护和利用、发展高原畜牧养殖事业及高原疾病的诊治和预防等都具有重要的意义。西藏班戈绒山羊是在高海拔地区经过长期自然选择和人工驯养的我国特有地方品种，对高海拔地区低压、低氧、严寒等恶劣气候环境有良好的适应能力，已形成在高海拔环境下稳定遗传的能力，而其高海拔环境适应性的分子机制尚不明确。本文分别从不同海拔地区山羊血液生理特性分析、转录组研究、低氧诱导因子HIF1A基因特性分析及山羊外显子捕获等方面研究探讨西藏班戈绒山羊的高海拔环境适应性分子遗传机制，主要研究内容如下：
通过对不同海拔地区的西藏班戈绒山羊和辽宁绒山羊的血液生理生化指标的测定，发现西藏班戈绒山羊的平均血红蛋白含量（MCH）、血清白蛋白（ALB）、尿氮素（BUN）和谷草转氨酶（AST）与辽宁绒山羊的相应指标差异极显著（P<0.01）；白细胞（WBC）和平均血红蛋白浓度（MCHC）与辽宁绒山羊的相应指标差异显著（P<0.05）。这些血液指标的表型特征反映了西藏班戈绒山羊通过调节血液中多种成分含量来适应高海拔环境。这些表型特征的差异必然与基因组适应性进化相关，为从分子进化角度揭示西藏班戈绒山羊适应高海拔环境的分子机制研究提供基础。
利用转录组测序技术（RNA sequencing, RNA-Seq），在Illumina Hiseq2000测序平台上对西藏班戈绒山羊和辽宁绒山羊的大脑皮层、呼吸道、皮肤毛囊、心脏、肺、肝、胆囊、脾、肾、骨髓、骨骼肌11个不同组织转录组进行混池测序，筛选品种内和品种间SNP位点。在与山羊基因组比对后，共筛选出53,800个班戈绒山羊品种内转录组SNPs位点，60,738个辽宁绒山羊品种内转录组SNP位点以及5,391个品种间转录组SNPs位点。此外，以de novo拼接方式组装转录组，将转录组测序结果中未与山羊基因组比对上的reads与之比对，挖掘出可能由于可变剪切的存在而被过滤的有效的8,178和7,727品种内转录组SNP位点。经GO分类和KEGG分析，筛选出包括FGF12、FGF14、BMPR-IA、MTR、MT2、BMP2K、GHR、GH2等与山羊绒生长相关的基因和EPAS1、PTEN、CDH13、GNPAT、FOXO1、HLA-DRA和RHOB等与高海拔环境适应性相关的基因以及在HIF-1信号通路中的11个基因（HIF1A、EGLN1、PTEN、PIK3CA、PIK3C2A、PIK3CB、PIK3CG、PIK3R1、CPKC、CAMK2和IL6R）。
西藏班戈绒山羊HIF1A基因与山羊基因组中该基因比较发现，存在4个同义突变（G1074A,T1467C, C1738T和G1989A）和2个引起155和793位氨基酸改变的突变（A463G和G2377A）。其中A793T突变没有影响到蛋白质空间结构的改变。而I155V突变处在PAS结构域中，该突变不但引起西藏班戈绒山羊HIF1A二级结构改变，更使79位和155位、80位和158位氨基酸的空间距离变大（26.583→31.205、17.396→23.566），推测这种改变使其更容易与HIF1B相结合，从而在低氧条件下，促进一系列与氧运输、生长和新陈代谢相关基因的转录。
在以上研究基础上，选取其它4个生活在不同海拔地区和生态环境中的绒山羊群体：西藏日土白绒山羊（海拔4750米）、柴达木山羊（海拔2980米）、新疆南疆绒山羊（海拔1700米）、内蒙古绒山羊（海拔1500米），利用外显子捕获和DNA池测序技术，进行基因组编码区大量SNP位点的扫描，在西藏班戈绒山羊、日土白绒山羊、柴达木山羊、新疆南疆绒山羊、内蒙古绒山羊中和辽宁绒山羊中分别筛选到45470、46501、53971、48704、57444和39180个有效SNPs位点；经中性检验分析，共检测得到1260个西藏班戈绒山羊特有的基因，这些基因显著富集于多细胞组织进程（GO:0032501）、感知光刺激（GO:0050953）、离子转运（GO:0006811）、氧自由基反应（GO:0000305）、铁离子平衡（GO:0055072）和核因子-κB调控（GO:0043122和GO:0043123）的GO分类中。结果表明，在自然选择和人工选择压力下，西藏班戈绒山羊为了应对低氧环境和高原强紫外线照射在基因组上产生了适应性变化，这些基因发生适应性突变以提高其对环境的适应能力。
Molecular mechanism of high altitude adaptation for plateau mammals has been one of the hotresearch topics for researchers all over the world. It is of significant importance in the protection andutilization of the excellent livestock and poultry resources, the development of livestock farming, andthe diagnosis and treatment of plateau diseases. Bange Cashmere goat (BG) is the unique local varietiesat high altitudes after long-term natural selection and artificial domestication, having the good ability toadapt to low pressure, low oxygen, and cold weather in high altitude area, also forming a stable geneticability in high altitude environments. However, the molecular mechanism for high altitude adaptation isunclear. This study investigated the molecular genetic mechanism for high altitude adaptation of BangeCashmere goat from several aspects, the blood physiological characteristics of the goats from differentaltitudes, the transcriptome research, HIF-1gene characteristics, and exons capture research of the goats.The main content is as follows:
Blood physiological and biochemical values from Bange Cashmere goat and Liaoning Cashmere goatat different altitudes were determined. The results showed that the mean corpuscular hemoglobin(MCH), serum albumin (ALB), blood urine nitrogen (BUN), and aspartate transaminase (AST) ofBange Cashmere goat were significantly higher than those in Liaoning Cashmere goat (P<0.01). Thewhite blood cell (WBC) and mean corpuscular hemoglobin concerntration (MCHC) of Bange Cashmeregoat were higher than those in Liaoning Cashmere goat (P<0.05). These phenotypic characteristics ofblood reflect that the contents of several components in the blood were regulated by Bange Cashmeregoat to adapt to high altitude. These phenotypic characteristics were closely associated with adaptivegenome evolution, laying the foundations for molecular mechanisms for high altitude adaptation ofBange Cashmere goat at the molecular evolution level.
The single nucleotide polymorphisms (SNPs) in transcriptomes of Bange Cashmere goat andLiaoning Cashmere goat were identified using RNA sequencing technology (RNA-Seq). Thetranscriptome sequencing was conducted on Illumina Hiseq2000platform for11pooled tissues,including cerebral cortex, bronchus, skin, heart muscle, lung, liver, gall-bladder, spleen, kidney, marrow, andskeletal muscle. After alignment with the goat genome,53,800intra-specific putative SNPs in the BangeCashmere goat sequence assembly,60,738intra-specific putative SNPs in the Liaoning Cashmere goatsequence assembly, and5,391inter-specific SNPs between Bange Cashmere goat and LiaoningCashmere goat were identified. In addition, transcriptomes were also assembled using de novo strategy.The reads unmapped to the goat genome were aligned to the contig sequence from the de novo assembly.The alignment showed that the hidden8,178intra-specific putative SNPs and7,727intra-specificputative SNPs, probably caused by alternative splicing, were found in Bange Cashmere goat contigsequence and Liaoning Cashmere goat contig sequence, respectively. Furthermore, several cashmeregrowth related genes (FGF12, FGF14, BMPR-IA, MTR, MT2, BMP2K, GHR, and GH2), high-altitudeadaptation related genes (EPAS1, PTEN, CDH13, GNPAT, FOXO1, HLA-DRA, and RHOB), and11HIF-1signal pathway related genes (HIF1A, EGLN1, PTEN, PIK3CA, PIK3C2A, PIK3CB, PIK3CG, PIK3R1, CPKC, CAMK2, and IL6R) were identified after GO classification and KEGG pathwayanalysis.
Comparison to the genome of Capra hircus, six SNPs were identified in HIF1A gene of Bangecashmere goat, including A463G, G1074A, T1467C, C1738T, G1989A, and G2377A. Of them, A463Gcaused an amino acid mutation, I155V, which made the secondary structure and spatial structure ofHIF1A of Bange Cashmere goat different from that of Capra hircus’s (JN897021). The increaseddistances between amino acids79and155(from26.583to31.205), amino acids80and158(from17.396to23.566) of HIF1A of Bange Cashmere goat make it easier to form a dimer with HIF1B toenhance the transcription of the genes involving in the oxygen transportation, growth, and metabolismunder the high altitude hypoxia environments.
On the basis of the above results, four additional breeds of goat living in the different altitude regions,which are Rutog goat (RT, altitude4750m), Chaidamu goat (CD, altitude2980m), Nanjiang Cashmeregoat (NJ, altitude1700m), and Inner Mongolia Cashmere Goat (IM, altitude1500m), were selected toscan coding SNPs (cSNPs) in the genome using exome capture and DNA pooling sequencingtechnology. The potential45470SNPs for BG,46501for RT,53971for CD,48704for NJ,57444forIM, and39180for LN were screened, respectively. After neutral test, the unique1,260genes for BGwere identified, which were mainly classified in the GO terms: multicellular organismal process(GO:0032501), sensory perception of light stimulus (GO:0050953), ion transport (GO:0006811),response to oxygen radical (GO:0000305), ion homeostasis (GO:0055072), and regulation of I-kappaBkinase/NF-kappaB cascade (GO:0043122and GO:0043123).These results demonstrated that under thenatural and artificial selection, Bange Cashmere goat accumulated mutations in the genome in responseto high altitude hypoxia and strong ultraviolet environments and the mutation of the the genome ofBange Cashmere goat increased its adaptability to the high altitude environments.
通过对不同海拔地区的西藏班戈绒山羊和辽宁绒山羊的血液生理生化指标的测定，发现西藏班戈绒山羊的平均血红蛋白含量（MCH）、血清白蛋白（ALB）、尿氮素（BUN）和谷草转氨酶（AST）与辽宁绒山羊的相应指标差异极显著（P<0.01）；白细胞（WBC）和平均血红蛋白浓度（MCHC）与辽宁绒山羊的相应指标差异显著（P<0.05）。这些血液指标的表型特征反映了西藏班戈绒山羊通过调节血液中多种成分含量来适应高海拔环境。这些表型特征的差异必然与基因组适应性进化相关，为从分子进化角度揭示西藏班戈绒山羊适应高海拔环境的分子机制研究提供基础。
利用转录组测序技术（RNA sequencing, RNA-Seq），在Illumina Hiseq2000测序平台上对西藏班戈绒山羊和辽宁绒山羊的大脑皮层、呼吸道、皮肤毛囊、心脏、肺、肝、胆囊、脾、肾、骨髓、骨骼肌11个不同组织转录组进行混池测序，筛选品种内和品种间SNP位点。在与山羊基因组比对后，共筛选出53,800个班戈绒山羊品种内转录组SNPs位点，60,738个辽宁绒山羊品种内转录组SNP位点以及5,391个品种间转录组SNPs位点。此外，以de novo拼接方式组装转录组，将转录组测序结果中未与山羊基因组比对上的reads与之比对，挖掘出可能由于可变剪切的存在而被过滤的有效的8,178和7,727品种内转录组SNP位点。经GO分类和KEGG分析，筛选出包括FGF12、FGF14、BMPR-IA、MTR、MT2、BMP2K、GHR、GH2等与山羊绒生长相关的基因和EPAS1、PTEN、CDH13、GNPAT、FOXO1、HLA-DRA和RHOB等与高海拔环境适应性相关的基因以及在HIF-1信号通路中的11个基因（HIF1A、EGLN1、PTEN、PIK3CA、PIK3C2A、PIK3CB、PIK3CG、PIK3R1、CPKC、CAMK2和IL6R）。
西藏班戈绒山羊HIF1A基因与山羊基因组中该基因比较发现，存在4个同义突变（G1074A,T1467C, C1738T和G1989A）和2个引起155和793位氨基酸改变的突变（A463G和G2377A）。其中A793T突变没有影响到蛋白质空间结构的改变。而I155V突变处在PAS结构域中，该突变不但引起西藏班戈绒山羊HIF1A二级结构改变，更使79位和155位、80位和158位氨基酸的空间距离变大（26.583→31.205、17.396→23.566），推测这种改变使其更容易与HIF1B相结合，从而在低氧条件下，促进一系列与氧运输、生长和新陈代谢相关基因的转录。
在以上研究基础上，选取其它4个生活在不同海拔地区和生态环境中的绒山羊群体：西藏日土白绒山羊（海拔4750米）、柴达木山羊（海拔2980米）、新疆南疆绒山羊（海拔1700米）、内蒙古绒山羊（海拔1500米），利用外显子捕获和DNA池测序技术，进行基因组编码区大量SNP位点的扫描，在西藏班戈绒山羊、日土白绒山羊、柴达木山羊、新疆南疆绒山羊、内蒙古绒山羊中和辽宁绒山羊中分别筛选到45470、46501、53971、48704、57444和39180个有效SNPs位点；经中性检验分析，共检测得到1260个西藏班戈绒山羊特有的基因，这些基因显著富集于多细胞组织进程（GO:0032501）、感知光刺激（GO:0050953）、离子转运（GO:0006811）、氧自由基反应（GO:0000305）、铁离子平衡（GO:0055072）和核因子-κB调控（GO:0043122和GO:0043123）的GO分类中。结果表明，在自然选择和人工选择压力下，西藏班戈绒山羊为了应对低氧环境和高原强紫外线照射在基因组上产生了适应性变化，这些基因发生适应性突变以提高其对环境的适应能力。
Molecular mechanism of high altitude adaptation for plateau mammals has been one of the hotresearch topics for researchers all over the world. It is of significant importance in the protection andutilization of the excellent livestock and poultry resources, the development of livestock farming, andthe diagnosis and treatment of plateau diseases. Bange Cashmere goat (BG) is the unique local varietiesat high altitudes after long-term natural selection and artificial domestication, having the good ability toadapt to low pressure, low oxygen, and cold weather in high altitude area, also forming a stable geneticability in high altitude environments. However, the molecular mechanism for high altitude adaptation isunclear. This study investigated the molecular genetic mechanism for high altitude adaptation of BangeCashmere goat from several aspects, the blood physiological characteristics of the goats from differentaltitudes, the transcriptome research, HIF-1gene characteristics, and exons capture research of the goats.The main content is as follows:
Blood physiological and biochemical values from Bange Cashmere goat and Liaoning Cashmere goatat different altitudes were determined. The results showed that the mean corpuscular hemoglobin(MCH), serum albumin (ALB), blood urine nitrogen (BUN), and aspartate transaminase (AST) ofBange Cashmere goat were significantly higher than those in Liaoning Cashmere goat (P<0.01). Thewhite blood cell (WBC) and mean corpuscular hemoglobin concerntration (MCHC) of Bange Cashmeregoat were higher than those in Liaoning Cashmere goat (P<0.05). These phenotypic characteristics ofblood reflect that the contents of several components in the blood were regulated by Bange Cashmeregoat to adapt to high altitude. These phenotypic characteristics were closely associated with adaptivegenome evolution, laying the foundations for molecular mechanisms for high altitude adaptation ofBange Cashmere goat at the molecular evolution level.
The single nucleotide polymorphisms (SNPs) in transcriptomes of Bange Cashmere goat andLiaoning Cashmere goat were identified using RNA sequencing technology (RNA-Seq). Thetranscriptome sequencing was conducted on Illumina Hiseq2000platform for11pooled tissues,including cerebral cortex, bronchus, skin, heart muscle, lung, liver, gall-bladder, spleen, kidney, marrow, andskeletal muscle. After alignment with the goat genome,53,800intra-specific putative SNPs in the BangeCashmere goat sequence assembly,60,738intra-specific putative SNPs in the Liaoning Cashmere goatsequence assembly, and5,391inter-specific SNPs between Bange Cashmere goat and LiaoningCashmere goat were identified. In addition, transcriptomes were also assembled using de novo strategy.The reads unmapped to the goat genome were aligned to the contig sequence from the de novo assembly.The alignment showed that the hidden8,178intra-specific putative SNPs and7,727intra-specificputative SNPs, probably caused by alternative splicing, were found in Bange Cashmere goat contigsequence and Liaoning Cashmere goat contig sequence, respectively. Furthermore, several cashmeregrowth related genes (FGF12, FGF14, BMPR-IA, MTR, MT2, BMP2K, GHR, and GH2), high-altitudeadaptation related genes (EPAS1, PTEN, CDH13, GNPAT, FOXO1, HLA-DRA, and RHOB), and11HIF-1signal pathway related genes (HIF1A, EGLN1, PTEN, PIK3CA, PIK3C2A, PIK3CB, PIK3CG, PIK3R1, CPKC, CAMK2, and IL6R) were identified after GO classification and KEGG pathwayanalysis.
Comparison to the genome of Capra hircus, six SNPs were identified in HIF1A gene of Bangecashmere goat, including A463G, G1074A, T1467C, C1738T, G1989A, and G2377A. Of them, A463Gcaused an amino acid mutation, I155V, which made the secondary structure and spatial structure ofHIF1A of Bange Cashmere goat different from that of Capra hircus’s (JN897021). The increaseddistances between amino acids79and155(from26.583to31.205), amino acids80and158(from17.396to23.566) of HIF1A of Bange Cashmere goat make it easier to form a dimer with HIF1B toenhance the transcription of the genes involving in the oxygen transportation, growth, and metabolismunder the high altitude hypoxia environments.
On the basis of the above results, four additional breeds of goat living in the different altitude regions,which are Rutog goat (RT, altitude4750m), Chaidamu goat (CD, altitude2980m), Nanjiang Cashmeregoat (NJ, altitude1700m), and Inner Mongolia Cashmere Goat (IM, altitude1500m), were selected toscan coding SNPs (cSNPs) in the genome using exome capture and DNA pooling sequencingtechnology. The potential45470SNPs for BG,46501for RT,53971for CD,48704for NJ,57444forIM, and39180for LN were screened, respectively. After neutral test, the unique1,260genes for BGwere identified, which were mainly classified in the GO terms: multicellular organismal process(GO:0032501), sensory perception of light stimulus (GO:0050953), ion transport (GO:0006811),response to oxygen radical (GO:0000305), ion homeostasis (GO:0055072), and regulation of I-kappaBkinase/NF-kappaB cascade (GO:0043122and GO:0043123).These results demonstrated that under thenatural and artificial selection, Bange Cashmere goat accumulated mutations in the genome in responseto high altitude hypoxia and strong ultraviolet environments and the mutation of the the genome ofBange Cashmere goat increased its adaptability to the high altitude environments.
引文
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