title: Distribution of single-nucleotide variants on protein-protein interaction sites and its relationship with minor allele frequency.
abstract: Recent advances in DNA sequencing techniques have identified rare single-nucleotide variants with less than 1% minor allele frequency. Despite the growing interest and physiological importance of rare variants in genome sciences, less attention has been paid to the allele frequency of variants in protein sciences. To elucidate the characteristics of genetic variants on protein interaction sites, from the viewpoints of the allele frequency and the structural position of variants, we mapped about 20,000 human SNVs onto protein complexes. We found that variants are less abundant in protein interfaces, and specifically the core regions of interfaces. The tendency to "avoid" the interfacial core is stronger among common variants than rare variants. As amino acid substitutions, the trend of mutating amino acids among rare variants is consistent in different interfacial regions, reflecting the fact that rare variants result from random mutations in DNA sequences, whereas amino acid changes of common variants vary between the interfacial core and rim regions, possibly due to functional constraints on proteins. This study illustrated how the allele frequency of variants relates to the protein structural regions and the functional sites in general and will lead to deeper understanding of the potential deleteriousness of rare variants at the structural level. Exceptional cases of the observed trends will shed light on the limitations of structural approaches to evaluate the functional impacts of variants.
authors.affiliation: Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Miyagi, 980-8597, Japan.
authors.forename: Hafumi
authors.initials: H
authors.lastname: Nishi
authors.affiliation: Tohoku Medical Megabank Organization, Tohoku University, Miyagi, 980-8573, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nakata
authors.affiliation: Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Miyagi, 980-8597, Japan.|Tohoku Medical Megabank Organization, Tohoku University, Miyagi, 980-8573, Japan.|Institute of Development, Aging, and Cancer, Tohoku University, Miyagi, 980-8575, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Kinoshita
mesh_terms: D019943:Amino Acid Substitution; D004851:Epoxide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D006801:Humans; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps
chemical_list: D004851:Epoxide Hydrolases
keywords: 3D structure; nonsynonymous mutations; protein complex; protein-protein interface; rare variants