Forecasting most deleterious nsSNPs in human TLR9 gene and their cumulative impact on biophysical features of the protein using in silico approaches

Abstract

In women, the uterine cervix and corpus uteri are two main suspects, playing a major role in cancer-associated-mortality. Immunologically, Toll-like receptors (TLRs) associated with the innate immune system, can recognize pathogens and induce immune responses against pathogens. Cellularly, TLR9 expression occurs in immune system cells including macrophages, natural killer cells, dendritic cells, and other antigen-presenting cells. TLR9 recognizes and interacts with viral and bacterial DNA comprising cytosine-phosphate-guanine (CpG) dideoxynucleotide motif. The current study is designed to identify the most deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) in the TLR9 gene and to delineate their deleterious effect on the structural and functional features of proteins at the molecular level. Based on the implementation of various computational tools and algorithms eight most deleterious nsSNPs (P139H, R257C, C265Y, L283P, G514D, L544Q, H566Y, and W670R) have been identified in the human TLR9 gene as potentially damaging SNPs. Further, our study suggests highly conserved patterns at deleterious nsSNPs sites could influence protein stability and its functional features. Additionally, this study identifies two nsSNPs (G514D and W670R) associated with the severity of Uterine corpus endometrial carcinoma. In support of our computational findings, the validation of key results using polymerase chain reaction and other experimental methods is warranted in the Indian population. In general, this study might be able to delineate the guideline for identifying the most damaging SNPs and enhances the understating of the risk factors for cancer and disease susceptibilities.