Functional impacts of non-synonymous single nucleotide polymorphisms: Selective constraint and structural environments

In this work, we studied the correlations between selective constraint, structural environments and functional impacts of non-synonymous single nucleotide polymorphisms (nsSNPs). We found that the relation between solvent accessibility and functional impacts of nsSNPs is not as simple as generally thought. Finer structural classifications need to be taken into account to reveal the complex relations between the characteristics of a structure environment and its influence on the functional impacts of nsSNPs. We introduced two parameters for each structural environment, consensus residue percentage and residue distribution distance, to characterize the selective constraint imposed by the environment. Both parameters significantly correlate with the functional bias of nsSNPs across the structural environments. This result shows that selective constraint underlies the bias of a structural environment towards a certain type of nsSNPs (disease-associated or benign).