Relating the disease mutation spectrum to the evolution of the cystic fibrosis transmembrane conductance regulator (CFTR).
Relating the disease mutation spectrum to the evolution of the cystic fibrosis transmembrane conductance regulator (CFTR).
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DOI：
10.1371/journal.pone.0042336
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
McCarty NA
中科院分区：
文献类型：
--
作者：
Rishishwar L;Varghese N;Tyagi E;Harvey SC;Jordan IK;McCarty NA
囊性纤维化（CF）是高加索人中最常见的遗传性疾病，因此囊性纤维化跨膜传导调节因子（CFTR）蛋白可能具有最佳表征的疾病突变谱，已经鉴定出超过1，500种致病突变。在这项研究中，我们利用丰富的突变信息，努力将位点特异性进化参数与CFTR致病突变的倾向和严重程度联系起来。为此，我们根据格兰瑟姆氨基酸化学差异矩阵设计了已知CFTR致病突变的评分方案。CFTR网站特定的进化约束值，然后计算7个不同的进化指标在一个范围内不断增加的进化深度。比较CFTR突变评分和各种位点特异性进化约束值，以评估哪些进化措施最能反映致病突变谱。来自广泛使用的比较方法PolyPhen 2的位点特异性进化约束值显示出与CFTR突变评分谱的最佳相关性，而更直接的基于保守性的测量（ConSurf和ScoreCons）显示出预测个体CFTR致病突变的最大能力。虽然远远大于仅凭偶然性所能预期的，但PolyPhen 2度量（3.6%）解释的突变评分变异性的比例，以及预测致病残基的最佳配对灵敏度（58%）和特异性（60%）值的沿着，是微不足道的。这些数据表明，进化的约束水平是信息，但远远没有决定性的致病突变CFTR。然而，这项工作表明，当结合额外的证据，信息的位点特异性进化保护可以而且应该用来指导定点诱变实验，更狭义地定义一组目标残基，从而可能节省时间和金钱。
Cystic fibrosis (CF) is the most common genetic disease among Caucasians, and accordingly the cystic fibrosis transmembrane conductance regulator (CFTR) protein has perhaps the best characterized disease mutation spectrum with more than 1,500 causative mutations having been identified. In this study, we took advantage of that wealth of mutational information in an effort to relate site-specific evolutionary parameters with the propensity and severity of CFTR disease-causing mutations. To do this, we devised a scoring scheme for known CFTR disease-causing mutations based on the Grantham amino acid chemical difference matrix. CFTR site-specific evolutionary constraint values were then computed for seven different evolutionary metrics across a range of increasing evolutionary depths. The CFTR mutational scores and the various site-specific evolutionary constraint values were compared in order to evaluate which evolutionary measures best reflect the disease-causing mutation spectrum. Site-specific evolutionary constraint values from the widely used comparative method PolyPhen2 show the best correlation with the CFTR mutation score spectrum, whereas more straightforward conservation based measures (ConSurf and ScoreCons) show the greatest ability to predict individual CFTR disease-causing mutations. While far greater than could be expected by chance alone, the fraction of the variability in mutation scores explained by the PolyPhen2 metric (3.6%), along with the best set of paired sensitivity (58%) and specificity (60%) values for the prediction of disease-causing residues, were marginal. These data indicate that evolutionary constraint levels are informative but far from determinant with respect to disease-causing mutations in CFTR. Nevertheless, this work shows that, when combined with additional lines of evidence, information on site-specific evolutionary conservation can and should be used to guide site-directed mutagenesis experiments by more narrowly defining the set of target residues, resulting in a potential savings of both time and money.
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影响因子：
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作者：
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