The functional importance of disease-associated mutation
The functional importance of disease-associated mutation
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DOI：
10.1186/1471-2105-3-24
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发表时间：
2002-01-01
影响因子：
3
通讯作者：
Klein, TE
中科院分区：
文献类型：
--
作者：
Mooney, SD;Klein, TE
背景：多年来，科学家认为基因中的点突变是囊性纤维化、苯丙酮尿和癌症等躯体和遗传性疾病的遗传开关。其中一些突变可能以一种有害的方式改变蛋白质的功能，它们应该发生在基因蛋白质产物的功能重要区域。在这里，我们表明疾病相关的突变发生在保守的基因区域，并且可以识别可能的致病突变。结果：为了证明这一点，我们确定了231个基因中6185个非同义和遗传性疾病相关突变的保护模式。我们定义了一个参数，守恒比，作为基因序列中报告突变的可分析位置的平均负熵与每个可分析位置的平均负熵之比。我们发现231个基因中有84.0%的保守比小于1。139个基因有11个或更多的可分析突变，88.0%的基因保守比小于1。结论：这些结果表明，系统发育信息是研究疾病相关突变的有力工具。我们的校准和分析已经作为数据库的一部分在[http://cancer.stanford.edu/mut-paper/]]上提供。在这个数据集中，每个位置都有分析注释，因此可以识别出最可能的致病突变。
Background: For many years, scientists believed that point mutations in genes are the genetic switches for somatic and inherited diseases such as cystic fibrosis, phenylketonuria and cancer. Some of these mutations likely alter a protein's function in a manner that is deleterious, and they should occur in functionally important regions of the protein products of genes. Here we show that disease-associated mutations occur in regions of genes that are conserved, and can identify likely disease-causing mutations.Results: To show this, we have determined conservation patterns for 6185 non-synonymous and heritable disease-associated mutations in 231 genes. We define a parameter, the conservation ratio, as the ratio of average negative entropy of analyzable positions with reported mutations to that of every analyzable position in the gene sequence. We found that 84.0% of the 231 genes have conservation ratios less than one. 139 genes had eleven or more analyzable mutations and 88.0% of those had conservation ratios less than one.Conclusions: These results indicate that phylogenetic information is a powerful tool for the study of disease-associated mutations. Our alignments and analysis has been made available as part of the database at [http://cancer.stanford.edu/mut-paper/]. Within this dataset, each position is annotated with the analysis, so the most likely disease-causing mutations can be identified.