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.
Highlights
Single-nucleotide variants (SNVs) are nucleotide differences in DNA sequences among individual genomes, which may cause phenotypic variations and potentially some diseases
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
Interfacial location and minor allele frequency of SNVs We found 20,305 variants on 1,343 protein complexes by mapping all of the variants in the NHLBI Exome Sequencing Project[14] onto protein complex structures via the RefSeq[15] protein sequences by using BLAST,[16] where the protein complexes were obtained from PDBePISA.[17]
Summary
Single-nucleotide variants (SNVs) are nucleotide differences in DNA sequences among individual genomes, which may cause phenotypic variations and potentially some diseases. Genome-wide association studies (GWAS) have successfully identified disease-related variants in a statistical manner, and some were subsequently verified as disease-causing variants by biochemical and cell biological experiments.[1,2] recent advances in DNA sequencing techniques allow large-scale genome analyses, which can identify rare variants with less than 1% minor allele frequency (MAF).[3,4] According to the vast accumulation of genomic data, variants with high MAFs (common variants) are not considered to cause severe effects, and rare variants will often have larger impacts for diseases than common variants.[5] GWAS analyses are based on the statistical association between genomic differences and phenotypic changes, and they are not effective for rare genomic variations, unless a vast number of samples are available. We observed the relationship between DNA-level random mutation patterns and biased patterns at the protein level
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