Scrutinizing Deleterious Nonsynonymous SNPs and Their Effect on Human POLD1 Gene

Abstract

POLD1 (DNA polymerase delta 1, catalytic subunit) is a protein-coding gene that encodes the large catalytic subunit (POLD1/p125) of the DNA polymerase delta (Polδ) complex. The consequence of missense or nonsynonymous SNPs (nsSNPs), which occur in the coding region of a specific gene, is the replacement of single amino acid. It may also change the structure, stability, and/or functions of the protein. Mutation in the POLD1 gene is associated with autosomal dominant predisposition to colonic adenomatous polyps, colon cancer, endometrial cancer (EDMC), breast cancer, and brain tumors. These de novo mutations in the POLD1 gene also result in autosomal dominant MDPL syndrome (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy). In this study, genetic variations of POLD1 which may affect the structure and/or function were analyzed using different types of bioinformatics tools. A total of 17038 nsSNPs for POLD1 were collected from the NCBI database, among which 1317 were missense variants. Out of all missense nsSNPs, 28 were found to be deleterious functionally and structurally. Among these deleterious nsSNPs, 23 showed a conservation scale of >5, 2 were predicted to be associated with binding site formation, and one acted as a posttranslational modification site. All of them were involved in coil, extracellular structures, or helix formation, and some cause the change in size, charge, and hydrophobicity.

Prediction and assessment of deleterious and disease causing nonsynonymous single nucleotide polymorphisms (nsSNPs) in human FOXP4 gene: An in-silico study

“…2 A). The conserved residue encounters mutation, it is more destructive compared to the less conserved one [ 45 ].…”

In silico functional, structural and pathogenicity analysis of missense single nucleotide polymorphisms in human MCM6 gene

“…Although having a potential impact on the splicing process, these synonymous SNPs (sSNPs) are considered functionally inactive and have negligible impact on evolutionary processes 4 . Indeed, among the nsSNPs, missense SNPs mainly change the structure, stability, and functions of the corresponding protein 5 . Since intronic regions do not participate in translation, the SNPs in the region have the least contribution to disease pathogenesis.…”

An In silico Approach towards Finding the Cancer-Causing Mutations in Human MET Gene

“…The major intents of this research work are to identify and analyze the most deleterious nsSNPs of MET gene. Earlier the effects of oncogenic mutation on isocitrate dehydrogenase 1 [ 13 ], the impact of point mutation P29S in RAS-related C3 botulinum toxin substrate 1 [ 14 ], the role of T315I in BCR-ABL1 protein [ 15 ], effects of point mutation (R482W) in lamin A/C protein for laminopathy [ 16 ], and the impact of deleterious nsSNPs on human POLD1 gene [ 17 ] have been revealed using computational analysis. Bioinformatics analysis is not merely utilized in the deleterious mutation prediction rather it can further be expanded to the screening of suitable anticancer drugs [ 18 , 19 ].…”