脊椎动物Hoxall基因进化分析与研究
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摘要
Hox基因具高度保守的180 bp的同源异型框(homeobox),它编码具螺旋—转角—螺旋结构的转录因子,能与特定区域的DNA结合,从而调节动物个体发育过程中体轴的形态建成。在动物进化过程中,形态特征的改变与控制发育的基因演化有关。Hoxa-11基因在鱼类鳍和四足动物肢发育过程中起着重要作用。因此,对Hoxa-11基因的研究不仅有利于我们了解动物个体发育过程中的遗传控制,也有助于我们从分子水平上解释脊椎动物从水生到陆生进化过程中鳍到肢的转变。
根据已报道的人和鼠的Hoxa-11基因序列,设计了简并引物,用PCR法扩增和克隆了斑马鱼、大黄鱼、花鲈、罗非鱼、红鳍东方鲀、乌鳢、矛尾鱼、热带爪蟾、绿背树蜥和家鸡等动物的Hoxa-11基因。克隆的基因与从GenBank中获取的人、小家鼠、黄牛、匙吻白鲟、角虎鲨Hoxa11基因及青鳉Hoxa11a基因进行比较分析,这些动物代表了有颌类的三个谱系:软骨鱼类谱系(角虎鲨)、辐鳍鱼类谱系(斑马鱼、大黄鱼、花鲈、罗非鱼、红鳍东方鲀、乌鳢、青鳉和匙吻白鲟)和肉鳍鱼类谱系(矛尾鱼、热带爪蟾、绿背树蜥、家鸡、人、小家鼠和黄牛)。无论在核苷酸水平还是在氨基酸水平,三个不同谱系动物间的Hoxa11基因都表现出了很高的相似性。
在核苷酸水平上,不但编码序列具有较高的保守性,而且内含子的5'端也是非常保守的。在内含子的5'端发现了两个高度保守的序列——进化印记(phylogenetic footprints),长度分别为35 bp和17 bp,35 bp的核苷酸片段能与HeLa细胞和鸡胚细胞抽提物中的蛋白结合,可能是一种调节元件。采用Tajima试验分析脊椎动物Hoxa11基因的核苷酸进化相对速率,结果表明Hoxa11基因编码序列的进化速率在角虎鲨谱系与匙吻白鲟谱系之间没有明显差异,而高等硬骨鱼类谱系的进化速率明显高于角虎鲨谱系和匙吻白鲟谱系;在高等硬骨鱼类之中斑马鱼谱系的进化速率不同于其它鱼类谱系,存在明显加速现象。且发现在硬骨鱼类,基因进化速率的差异是基因特异的,而非谱系特异的。高等硬骨鱼类高的进化速率可能与进化过程中硬骨鱼类Hox基因簇经历一次额外的复制有关。内含子序列的进化速率在不同的谱系之间存在差异,在硬骨鱼类谱系和哺乳动物谱系,Hoxa11基因的内含子与外显子组成了一个共进化单位(co-evolutionary unit);而在绿背树蜥谱系和热带爪蟾谱系,Hoxa11
Hox genes, containing a 180 bp homeobox, encode helix-turn-helix transcription factors. Hox proteins can bind DNA, and regulate the axial patterning during embryonic development of animals. The evolution of morphological characters is thought to be mediated through the evolution of genes controlling embryonic development in animal phylogenesis. Hoxa-11gene plays an important role in the development of fish fins and tetrapod limbs. Therefore, studies on Hoxall gene can help us to understand both the genetic control in animal development and the fin-limb transition in vertebrate evolution.Degenerate primers for PCR, based on reported Hoxall genes from human and mouse, were designed to amplify fragments of Hoxall genes from ten vertebrates, Danio rerio, Pseudosciaena crocea, Lateolabrax japonicus, Oreochromis niloticus, Fugu rubripes, Ophiocephalus argus, Latimeria chalumnae, Xenopus tropicalis, Calotes jerdoni and Gallus gallus. Hoxall genes from 16 vertebrates were analyzed, containing 10 cloned Hoxall genes mentioned above and 6 Hoxall genes from GenBank, Homo sapiens, Mus musculus, Bos taurus, Polyodon spathula, Heterodontus francisci, and Oryzias latipes, in representatives of the three major gnathostome lineages: cartilaginous fish, ray-finned fish and lobe-finned fish. Hoxall genes from the three lineages have high similarity in both nucleotide and amino acid sequences.In nucleotide level, both the coding sequence and 5' intron sequence are very conservative. Two phylogenetic footprints, 35 bp and 17 bp in length respectively, were found in 5' intron sequence. 35 bp nucleotide fragment can bind proteins from HeLa cell extract and chicken embryonic cell extract, which means that the 35 bp nucleotide fragment may be a regulatory element. Relative rates of Hoxall coding sequences among vertebrates were analyzed by Tajima test. The results showed that there was no significant different between horn shark (Heterodontus francisci) and Mississippi paddlefish (Polyodon spathula) lineages. However, the evolutionary rate in higher teleost lineages was significantly higher than that in horn shark and Mississippi paddlefish lineages. Among higher teleost sampled, the zebrafish (Danio rerio) lineage had the highest rate. The difference of relative rates among teleost was a gene-, and not lineage-, specific phenomenon. The high
rate in higher teleost might be relative to an additional Hox cluster duplication during teolest evolution. In addition to the coding sequence, relative rates of intron sequences also had significant difference among vertebrate lineages. Exons and intron of Hoxall gene belonged to a co-evolutionary unit in teleost and mammalian lineages, and evolved independently in frog (Xenopus tropicalis) and lizard (Calotes jerdoni) lineages. The results of both Z test and Fisher exact test showed that Darwin's positive selection acted on Hoxall coding sequence, and the positive selection caused a large change to Hoxall N-terminal amino acid sequence.Hoxall protein was divided into three regions, N-terminal conservative region, intermediate changeable region and C-terminal conservative region according to Clustal W alignment. The similarity of Hoxall amino acid sequences from different vertebrates was very high in both N- and C-terminal conservative regions. The number of amino acids was nearly equal from horn shark to human in the two conservative regions. The similarity was low, and the number of amino acids was changeable in the intermediate changeable region. Therefore, the evolutionary model of different regions was various in Hoxall. Polyalanine and closely neighboring polyhistone were first found in the Hoxall changeable region in Percomorpha fishes.Hoxall proteins from all sampled vertebrates had an obvious hydrophilic region, and its position remained relatively stable. It contained the majority of the changeable region and the little minority of the C-terminal conservative region. In the hydrophilic region, the number of amino acids was gradually increased from fish to mammals, which reflected a lengthened tendency of the hydrophilic region in tetrapod lineage. In a similar way, alanine content was also gradually increased in the hydrophilic region from fish to mammals. Horn shark had the lowest alanine content, about 3.03%;the next was coelacanth (Latimeria chalumnae), about 4.55%;other teleosts ranged from 5.88% to 8.82%;frog {Xenopus tropicalis), lizard (Calotes jerdoni) and chick (Gallus gallus) were 10.81%, 15.38% and 17.50% respectively;mammals were more than 20%.
根据已报道的人和鼠的Hoxa-11基因序列,设计了简并引物,用PCR法扩增和克隆了斑马鱼、大黄鱼、花鲈、罗非鱼、红鳍东方鲀、乌鳢、矛尾鱼、热带爪蟾、绿背树蜥和家鸡等动物的Hoxa-11基因。克隆的基因与从GenBank中获取的人、小家鼠、黄牛、匙吻白鲟、角虎鲨Hoxa11基因及青鳉Hoxa11a基因进行比较分析,这些动物代表了有颌类的三个谱系:软骨鱼类谱系(角虎鲨)、辐鳍鱼类谱系(斑马鱼、大黄鱼、花鲈、罗非鱼、红鳍东方鲀、乌鳢、青鳉和匙吻白鲟)和肉鳍鱼类谱系(矛尾鱼、热带爪蟾、绿背树蜥、家鸡、人、小家鼠和黄牛)。无论在核苷酸水平还是在氨基酸水平,三个不同谱系动物间的Hoxa11基因都表现出了很高的相似性。
在核苷酸水平上,不但编码序列具有较高的保守性,而且内含子的5'端也是非常保守的。在内含子的5'端发现了两个高度保守的序列——进化印记(phylogenetic footprints),长度分别为35 bp和17 bp,35 bp的核苷酸片段能与HeLa细胞和鸡胚细胞抽提物中的蛋白结合,可能是一种调节元件。采用Tajima试验分析脊椎动物Hoxa11基因的核苷酸进化相对速率,结果表明Hoxa11基因编码序列的进化速率在角虎鲨谱系与匙吻白鲟谱系之间没有明显差异,而高等硬骨鱼类谱系的进化速率明显高于角虎鲨谱系和匙吻白鲟谱系;在高等硬骨鱼类之中斑马鱼谱系的进化速率不同于其它鱼类谱系,存在明显加速现象。且发现在硬骨鱼类,基因进化速率的差异是基因特异的,而非谱系特异的。高等硬骨鱼类高的进化速率可能与进化过程中硬骨鱼类Hox基因簇经历一次额外的复制有关。内含子序列的进化速率在不同的谱系之间存在差异,在硬骨鱼类谱系和哺乳动物谱系,Hoxa11基因的内含子与外显子组成了一个共进化单位(co-evolutionary unit);而在绿背树蜥谱系和热带爪蟾谱系,Hoxa11
Hox genes, containing a 180 bp homeobox, encode helix-turn-helix transcription factors. Hox proteins can bind DNA, and regulate the axial patterning during embryonic development of animals. The evolution of morphological characters is thought to be mediated through the evolution of genes controlling embryonic development in animal phylogenesis. Hoxa-11gene plays an important role in the development of fish fins and tetrapod limbs. Therefore, studies on Hoxall gene can help us to understand both the genetic control in animal development and the fin-limb transition in vertebrate evolution.Degenerate primers for PCR, based on reported Hoxall genes from human and mouse, were designed to amplify fragments of Hoxall genes from ten vertebrates, Danio rerio, Pseudosciaena crocea, Lateolabrax japonicus, Oreochromis niloticus, Fugu rubripes, Ophiocephalus argus, Latimeria chalumnae, Xenopus tropicalis, Calotes jerdoni and Gallus gallus. Hoxall genes from 16 vertebrates were analyzed, containing 10 cloned Hoxall genes mentioned above and 6 Hoxall genes from GenBank, Homo sapiens, Mus musculus, Bos taurus, Polyodon spathula, Heterodontus francisci, and Oryzias latipes, in representatives of the three major gnathostome lineages: cartilaginous fish, ray-finned fish and lobe-finned fish. Hoxall genes from the three lineages have high similarity in both nucleotide and amino acid sequences.In nucleotide level, both the coding sequence and 5' intron sequence are very conservative. Two phylogenetic footprints, 35 bp and 17 bp in length respectively, were found in 5' intron sequence. 35 bp nucleotide fragment can bind proteins from HeLa cell extract and chicken embryonic cell extract, which means that the 35 bp nucleotide fragment may be a regulatory element. Relative rates of Hoxall coding sequences among vertebrates were analyzed by Tajima test. The results showed that there was no significant different between horn shark (Heterodontus francisci) and Mississippi paddlefish (Polyodon spathula) lineages. However, the evolutionary rate in higher teleost lineages was significantly higher than that in horn shark and Mississippi paddlefish lineages. Among higher teleost sampled, the zebrafish (Danio rerio) lineage had the highest rate. The difference of relative rates among teleost was a gene-, and not lineage-, specific phenomenon. The high
rate in higher teleost might be relative to an additional Hox cluster duplication during teolest evolution. In addition to the coding sequence, relative rates of intron sequences also had significant difference among vertebrate lineages. Exons and intron of Hoxall gene belonged to a co-evolutionary unit in teleost and mammalian lineages, and evolved independently in frog (Xenopus tropicalis) and lizard (Calotes jerdoni) lineages. The results of both Z test and Fisher exact test showed that Darwin's positive selection acted on Hoxall coding sequence, and the positive selection caused a large change to Hoxall N-terminal amino acid sequence.Hoxall protein was divided into three regions, N-terminal conservative region, intermediate changeable region and C-terminal conservative region according to Clustal W alignment. The similarity of Hoxall amino acid sequences from different vertebrates was very high in both N- and C-terminal conservative regions. The number of amino acids was nearly equal from horn shark to human in the two conservative regions. The similarity was low, and the number of amino acids was changeable in the intermediate changeable region. Therefore, the evolutionary model of different regions was various in Hoxall. Polyalanine and closely neighboring polyhistone were first found in the Hoxall changeable region in Percomorpha fishes.Hoxall proteins from all sampled vertebrates had an obvious hydrophilic region, and its position remained relatively stable. It contained the majority of the changeable region and the little minority of the C-terminal conservative region. In the hydrophilic region, the number of amino acids was gradually increased from fish to mammals, which reflected a lengthened tendency of the hydrophilic region in tetrapod lineage. In a similar way, alanine content was also gradually increased in the hydrophilic region from fish to mammals. Horn shark had the lowest alanine content, about 3.03%;the next was coelacanth (Latimeria chalumnae), about 4.55%;other teleosts ranged from 5.88% to 8.82%;frog {Xenopus tropicalis), lizard (Calotes jerdoni) and chick (Gallus gallus) were 10.81%, 15.38% and 17.50% respectively;mammals were more than 20%.
引文
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