Identification of deleterious non-synonymous single nucleotide polymorphisms using sequence-derived information.
BACKGROUND
As the number of non-synonymous single nucleotide polymorphisms (nsSNPs), also known as single amino acid polymorphisms (SAPs), increases rapidly, computational methods that can distinguish disease-causing SAPs from neutral SAPs are needed. Many methods have been developed to distinguish disease-causing SAPs based on both structural and sequence features of the mutation point. One limitation of these methods is that they are not applicable to the cases where protein structures are not available. In this study, we explore the feasibility of classifying SAPs into disease-causing and neutral mutations using only information derived from protein sequence.


RESULTS
We compiled a set of 686 features that were derived from protein sequence. For each feature, the distance between the wild-type residue and mutant-type residue was computed. Then a greedy approach was used to select the features that were useful for the classification of SAPs. 10 features were selected. Using the selected features, a decision tree method can achieve 82.6% overall accuracy with 0.607 Matthews Correlation Coefficient (MCC) in cross-validation. When tested on an independent set that was not seen by the method during the training and feature selection, the decision tree method achieves 82.6% overall accuracy with 0.604 MCC. We also evaluated the proposed method on all SAPs obtained from the Swiss-Prot, the method achieves 0.42 MCC with 73.2% overall accuracy. This method allows users to make reliable predictions when protein structures are not available. Different from previous studies, in which only a small set of features were arbitrarily chosen and considered, here we used an automated method to systematically discover useful features from a large set of features well-annotated in public databases.


CONCLUSIONS
The proposed method is a useful tool for the classification of SAPs, especially, when the structure of the protein is not available.
Hu
Jing
J
Department of Computer Science, Utah State University, Logan, UT 84322, USA. jinghu@cc.usu.edu
Yan
Changhui
C
D000818:Animals; D019295:Computational Biology / Q000379:methods*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein