Abstract
IN SILICO ANALYSIS OF CODING NON-SYNONYMOUS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPs) OF HUMAN NQO1 GENE AND THEIR IMPACT ON BENZENE INDUCED HAEMATOTOXICITY

Dr. Mahdi H. A. Abdalla and Dr. Mohamed M. Babeker*

ABSTRACT

Occupational exposure to benzene can cause blood disorders including aplastic anemia and acute myelogenous leukemia. Significant decreases in the number of white blood cells and platelets have been reported in workers exposed to benzene. NQO1 protein is an enzyme that has attracted considerable attention because of its ability to detoxify a number of natural and synthetic compounds. It plays a necessary role in the protection of benzene workers against benzene toxicity by catalyzing two and four electron reduction of benzoquinone. In this study we utilized computational analyses tools to identify functionally important coding non-synonymous (ns) SNPs in human NQO1gene. nsSNPs were analyzed by different bioinformatics tools to predict their functional effects. 12 SNPS, out of 159 nsSNPs were found to be deleterious with double positive prediction by SIFT software and polyphen-2 server. Two out of these 12 deleterious SNPs were classified as high risk SNPs with common positive prediction by PROVEAN, PhD-SNP and SNPs&GO algorithmic tools. I- mutant detected an alteration in protein stability due to these two SNPs which further potentiates their functional impact. Analysis of these SNPs by Project Hope indicated that the two SNPS were found to be expressed in conserved regions, so variations in these regions may lead to potential functional changes. Bioinformatics algorithmic tools that were used in this study failed to classify the SNP (rs1800566) within the NQO1 gene at position 609 in exon6 (C- T) (the most reported SNP within NQO1 gene) as pathological SNP, this limitation draw an attention to improve the prediction capacity of these tools. In conclusion, our results suggest that the application of computational tools like SIFT, PolyPhen-2, PROVEAN, PhD-SNP, SNPs&GO, I-Mutant and Project Hope may provide an alternative approach for selecting target SNPs. Our results showed that the amino acid residue substitutions which had the greatest impact on the function of the NQO1 protein were R119P (rs11555215) and L7R (rs368942932). Failures to classify the most reported SNP, with its pathological effects, as pathological SNP by the used bioinformatics tools highlighted a clear limitation and draw an attention to improve the prediction capacity of these tools.

Keywords: In silico analysis, Single nucleotide polymorphism (SNP), NQO1 gene, Benzene induced haematotoxicity.


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