Barenboim Maxim, Jamison D Curtis, Vaisman Iosif I
School of Computational Sciences, George Mason University, Manassas, Virginia.
Hum Mutat. 2005 Nov;26(5):471-6. doi: 10.1002/humu.20238.
The ability to predict the effect of nonsynonymous SNPs (nsSNPs) on protein function is important for the success of genetic disease association studies. Here we present a statistical geometry approach to nsSNP classification based on Delaunay tessellation, whereby the impact of nsSNPs on protein function is correlated with the change in the four-body statistical potential (DeltaQ) of the protein caused by the amino acid substitution. We observed that the DeltaQ of polymorphic proteins with disease-associated nsSNPs (daSNPs) was on average significantly lower than the DeltaQ of the proteins with neutral SNPs (ntSNPs). Clustering amino acid substitutions into conservative and nonconservative groups, and using a three-letter alphabet based on side-chain polarity showed significantly lower DeltaQ in nonconservative changes to daSNPs and when hydrophobic residues were substituted by charged or by polar residues. We also found that the daSNPs in the protein core caused much lower DeltaQ than surface daSNPs. This approach demonstrates a strong correlation between the computed DeltaQ and SNP classification. Integration of our approach with the existing models will help achieve a more precise recognition of nsSNPs that underlie polygenic diseases. All of the programs were written in Java and are available from the authors upon request.
预测非同义单核苷酸多态性（nsSNPs）对蛋白质功能的影响，对于遗传疾病关联研究的成功至关重要。在此，我们提出一种基于德劳内三角剖分的统计几何方法用于nsSNP分类，据此，nsSNPs对蛋白质功能的影响与氨基酸替换导致的蛋白质四体统计势（DeltaQ）的变化相关。我们观察到，具有疾病相关nsSNPs（daSNPs）的多态性蛋白质的DeltaQ平均显著低于具有中性SNP（ntSNPs）的蛋白质的DeltaQ。将氨基酸替换聚类为保守和非保守组，并基于侧链极性使用三字母字母表，结果显示，daSNPs的非保守变化以及疏水残基被带电或极性残基取代时，DeltaQ显著更低。我们还发现，蛋白质核心中的daSNPs导致的DeltaQ比表面daSNPs低得多。该方法证明了计算得到的DeltaQ与SNP分类之间存在强相关性。将我们的方法与现有模型相结合，将有助于更精确地识别多基因疾病潜在的nsSNPs。所有程序均用Java编写，可应作者要求提供。
