ABC转运蛋白超家族中致病性SNPs的研究

发布时间：2018-05-03 09:01

本文选题：转运 + 蛋白　；参考：《中国科学院研究生院（大连化学物理研究所）》2007年博士论文

【摘要】： 目前认为,致病性(或功能性)SNPs往往因改变蛋白质结构、功能或蛋白质表达量而最终导致疾病的发生。ABC(ATP-Binding Cassette)转运蛋白在生物体内发挥着极其重要的生理功能,其基因水平上发生的SNPs若引起相应蛋白结构变化或功能缺陷,将产生一系列严重疾病。本论文基于ABC转运蛋白的特点,首次从理论和实验两方面就ABC转运蛋白中SNPs的特征进行了研究。在理论研究方面,主要研究成果有:I、采用岭偏最小二乘法(rPLS)和线性判别法(LDA)构建了以转运蛋白中致病性nsSNPs为研究对象的预测模型,两种模型的预测精度均大于84%(训练集762nsSNPs),同时预测出在ABCB亚家族中有28个nsSNPs可能具有致病性。II、采用rPLS及交叉验证,以ABC家族中的错义突变为研究对象,构建了包含5286个错义突变且蛋白质分子量大的理论预测模型。本模型对致病性错义突变的预测精度分别是:训练集82.2%(4098个nsSNPs),测试集81.4%(752个nsSNPs);同时预测出在ABC家族中有234个错义突变可能具有致病性。在实验研究方面,从2836位大连地区健康体检受试者中精选出265个汉族样本作为研究对象,采用PCR-RFLP方法确定了MDR1/ABCB1基因中功能性SNP位点3435CT的分布特征,其中基因型分别是:CC 32%(n=85),CT 48% (n=127)和TT 20%(n=53),为国内首次报道。综上,本研究首次将转运蛋白的序列保守性特征值与二级结构参数结合作为预测模型的基本参数;此外,因ABC转运蛋白为跨膜糖蛋白、分子量大和预测难度大的特性,本论文不但以转运蛋白的nsSNPs构建数据集,还以非ABC转运蛋白中大分子蛋白质中nsSNPs构建数据集,获得具有高精确度的预测ABC转运蛋白中致病性nsSNPs的理论模型。在实验方面,获得中国汉族健康人群中MDR1/ABCB1基因中3435CT位点分布特征的相关数据,填补了国内相关研究的空白。以上研究为今后开展理论模型结果的验证及探究由ABC蛋白引发疾病的机制、疾病防治,特别是为提高我国个体化医疗水平进行了探索性的尝试。
[Abstract]:At present, it is believed that the pathogenicity (or functional SNPs) may result in the development of disease by changing the protein structure, function or protein expression, and that the ATP-Binding Cassette-based transporter plays an extremely important physiological function in organisms. If the SNPs at the gene level causes the corresponding protein structural changes or functional defects, it will lead to a series of serious diseases. Based on the characteristics of ABC transporter, the characteristics of SNPs in ABC transporter were studied theoretically and experimentally for the first time. In the theoretical research, the main research results are: I, using the Ridge partial least Square method (rPLS) and the linear discriminant method (LDA) to construct a prediction model of pathogenicity nsSNPs in the transporter. The prediction accuracy of the two models was greater than 84 (training set 762 ns SNPs). At the same time, it was predicted that 28 nsSNPs in the ABCB subfamily might be pathogenicity. RPLS and cross-validation were used to study the missense mutation in the ABC family. A theoretical prediction model with 5286 missense mutations and high molecular weight of protein was constructed. The prediction accuracy of this model for pathogenicity missense mutations is as follows: training set 82.2and 4098 nsSNPs, test set 81.4 / 752 nsSNPs, and 234 missense mutations may be pathogenicity in ABC family. In the experimental study, 265 Han nationality samples were selected from 2836 healthy volunteers in Dalian as the study subjects. The distribution characteristics of functional SNP site 3435CT in the MDR1/ABCB1 gene were determined by PCR-RFLP method. The genotypes of TT20 and TT20 were reported for the first time in China. In conclusion, the conserved eigenvalues of transporter sequences and secondary structural parameters were used as the basic parameters of the prediction model for the first time, in addition, because ABC transporter was transmembrane glycoprotein, its molecular weight was high and the prediction was difficult. In this paper, the data set was constructed not only by nsSNPs of transporter, but also by nsSNPs of macromolecular protein in non-ABC transporter. The theoretical model of predicting pathogenicity nsSNPs in ABC transporter with high accuracy was obtained. In the aspect of experiment, the data about the distribution of 3435CT loci in the MDR1/ABCB1 gene in healthy Chinese Han population were obtained, which filled the gaps in the relevant research in China. These studies are an exploratory attempt to verify the results of theoretical models and explore the mechanism of disease caused by ABC protein, disease prevention and treatment, especially to improve the level of individualized medical treatment in China.
【学位授予单位】：中国科学院研究生院（大连化学物理研究所）
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R341

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