摘要
本文基于公共数据库资源,以人类组织特异性基因为对象,利用生物信息学的理论和方法,对处于调控通路不同阶段的人类组织特异性基因的进化特征进行比较研究,揭示人类组织特异性基因和非组织特异性基因在特定进化特征上的差异,以及处于信号通路不同阶段的人类组织特异性基因之间存在的进化特征异同,进而对相应的潜在机制进行探索。另外,本文从共进化的角度揭示了导致编码区进化速率差异的可能原因,为深入研究此类基因的进化机制提供新的思路。主要研究结果如下:
(1)通过系统分析人类组织特异性基因及其在小鼠中的同源基因,计算多种进化选择压力(如同义替代率(Ks)、非同义替代率(Ka)和进化速率)。结果显示调控通路中不同阶段的组织特异性基因具有不同的进化速率。和其他组织特异性基因相比,组织特异性的转录因子(包括Hox基因,non-Hox homeobox基因, HLH基因以及Zinger finger基因)具有相对较低的进化速率,而细胞外信号、膜结合的信号受体以及神经递质基因具有明显高的进化速率。
(2)对不同种类组织特异性基因的非同义替代率进行比较分析,发现突变率的不同并不是造成进化速率不同的真正原因,而组织特异性转录因子处于较强选择压力以及功能和表达方式的差异才可能是潜在原因。
(3)通过与非组织特异性基因比较发现并非所有的人类组织特异性基因均进化较快;和细胞信号及细胞分化相关的非组织特异基因相比,除神经递质和膜结合的细胞信号受体基因以外,其他所有的组织特异性基因的进化速率均显著较低。
(4)进一步识别并分析了不同基因内含子区的可转移元件,发现编码区具有较低进化速率的基因在其相应内含子区便具有较低的可转移元件密度,表明编码区和其相应的内含子区之间可能存在协调进化。
通过对上述研究结果的综合分析,初步揭示了人类组织特异性基因的特定进化特性,即:相对于非组织特异性基因,并非所有的人类组织特异性基因均进化较快,而且不同种类的人类组织特异性基因具有不同的进化速率,而不同编码区和其相应的内含子区之间存在的协调进化可能是此现象的潜在驱动因素。本文的研究结果为更深入探索此类基因的进化机制提供了相应基础和启示。
Based on the public databases, we investigate systematically the evolution features of the human tissue-specific genes which are involved in different places on the regulatory pathway, utilizing theories and methods of bioinformatics and evolutionary genomics. The work indicates that there exist the distinct evolution characteristics between the tissue-specific genes and the control. Further, we explore the underlying factors which may be the potential dynamics of the divergence in evolution rates. The presented work provides insight to the evolution selection of human tissue-specific genes, as well as new scenario for elucidating the potential evolutionary mechanism of corresponding genes.
The main results are demonstrated as following:
1) We examined different types of selection pressures [e.g. against amino acid mutations (Ka/Ks), against mutations at synonymous sites (Ks), against mutations at nonsynonymous sites (Ka)] by systemic analyses of human tissue-specific genes and their homologous genes in mouse. The results indicate that different classes of human tissue-specific genes involved in the regulatory pathway have divergent evolutionary rates. Similar to other tissue-specific genes, including signal transducers, nuclear receptors and neuroreceptors, tissue-specific transcription factors(Hox genes, non-Hox homeobox genes, HLH genes, Zinger finger genes) have on average lower value of Ka/Ks. However, the genes, including extracellular signals, signal receptors (Membrane-bound), neurotransmitters and other effectors, have the higher value of Ka/Ks.
2) By calculating and comparing the values of Ks among all the classes of human tissue-specific genes, we find that the average synonymous rate does not exhibit the same magnitude of the average nonsynonymous substitution rate, illuminating that the mutation rate differences are not the main cause for the difference of selective constraints. The potential causes may underlie in the divergent function and expression.
3) Compared to the cell-signaling and cell-division related genes, not all types of human tissue-specific genes evolve quickly. Apart from the Neurotransmitters and Signal receptors (Membrane-bound) genes, all the other tissue-specific genes have statistically lower value of Ka/Ks.
4) We further identified and analyzed the transposable elements in the intronic regions of different genes. The results presented that the genes with lower evolution rates in coding regions have fewer density of transposable elements in intronic regions. It seems to imply that there exist potential correlation between the evolution of coding regions and corresponding intronic regions.
In conclusion, in the paper, the divergent features and potential dynamics in evolution of human tissue-specific gene are detected and analyzed. The study provides a base clue and novel orientation for more profound investigations on evolution and divergence of tissue-specific genes.
引文
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