Li Shuyan, Iakoucheva Lilia M, Mooney Sean D, Radivojac Predrag
School of Informatics and Computing, Indiana University, Bloomington, IN 47408, USA.
Pac Symp Biocomput. 2010:337-47. doi: 10.1142/9789814295291_0036.
Understanding and predicting molecular cause of disease is one of the major challenges for biology and medicine. One particular area of interest continues to be computational analyses of disease-associated amino acid substitutions. To this end, various studies have been performed to identify molecular functions disrupted by disease-causing mutations. Here, we investigate the influence of disease-associated mutations on post-translational modifications. In particular, we study the loss of modification target sites as a consequence of disease mutation. We find that about 5% of disease-associated mutations may affect known modification sites, either partially (4%) of fully (1%), compared to about 2% of putatively neutral polymorphisms. Most of the fifteen post-translational modification types analyzed were found to be disrupted at levels higher than expected by chance. Molecular functions and physiochemical properties at sites of disease mutation were also compared to those of neutral polymorphisms involved in the process of post-translational modification site disruption. Disease-associated mutations in the neighborhood of post-translationally modified sites were found to be enriched in mutations that change polarity, charge, and hydrophobicity of the wild-type amino acids. Overall, these results further suggest that disruption of modification sites is an important but not the major cause of human genetic disease.
理解和预测疾病的分子病因是生物学和医学面临的主要挑战之一。一个特别受关注的领域仍然是对疾病相关氨基酸替换的计算分析。为此，已经进行了各种研究来确定由致病突变破坏的分子功能。在这里，我们研究疾病相关突变对翻译后修饰的影响。特别是，我们研究疾病突变导致的修饰靶点的丧失。我们发现，与约2%的假定中性多态性相比，约5%的疾病相关突变可能影响已知的修饰位点，其中部分影响（4%）或完全影响（1%）。在所分析的15种翻译后修饰类型中，大多数被发现以高于偶然预期的水平被破坏。还将疾病突变位点的分子功能和物理化学性质与参与翻译后修饰位点破坏过程的中性多态性的分子功能和物理化学性质进行了比较。发现在翻译后修饰位点附近的疾病相关突变富含改变野生型氨基酸极性、电荷和疏水性的突变。总体而言，这些结果进一步表明修饰位点的破坏是人类遗传疾病的一个重要但不是主要原因。
