Computational analysis of functional single nucleotide polymorphisms associated with the CYP11B2 gene.

Minyue Jia,Huiling Shen,Zhongyi Li,Xiaoxiao Song,Boyun Yang,Wei Gu,Junwen Wang

doi:10.1371/journal.pone.0104311

Abstract

Single nucleotide polymorphisms (SNPs) are the most common type of genetic variations in humans and play a major role in the genetics of human phenotype variation and the genetic basis of human complex diseases. Recently, there is considerable interest in understanding the possible role of the CYP11B2 gene with corticosterone methyl oxidase deficiency, primary aldosteronism, and cardio-cerebro-vascular diseases. Hence, the elucidation of the function and molecular dynamic behavior of CYP11B2 mutations is crucial in current genomics. In this study, we investigated the pathogenic effect of 51 nsSNPs and 26 UTR SNPs in the CYP11B2 gene through computational platforms. Using a combination of SIFT, PolyPhen, I-Mutant Suite, and ConSurf server, four nsSNPs (F487V, V129M, T498A, and V403E) were identified to potentially affect the structure, function, and activity of the CYP11B2 protein. Furthermore, molecular dynamics simulation and structure analyses also confirmed the impact of these nsSNPs on the stability and secondary properties of the CYP11B2 protein. Additionally, utilizing the UTRscan, MirSNP, PolymiRTS and miRNASNP, three SNPs in the 3′UTR region were predicted to exhibit a pattern change in the upstream open reading frames (uORF), and eight microRNA binding sites were found to be highly affected due to 3′UTR SNPs. This cataloguing of deleterious SNPs is essential for narrowing down the number of CYP11B2 mutations to be screened in genetic association studies and for a better understanding of the functional and structural aspects of the CYP11B2 protein.

Highlights

Single nucleotide polymorphisms (SNPs) are the most abundant class of genetic variations in the human genome with a frequency of approximately every 100 to 300 base pairs [1]
The trajectory files were produced after the molecular dynamics simulation, and we investigated the root-mean square deviation (RMSD), radius of gyration (Rg), and solvent-accessible surface area (SASA) variations between the native and the four mutant structures
The principal objective of studies in molecular biology and population genetics is to identify and characterize SNPs that are functionally deleterious from neutral SNPs

Summary

Introduction

Single nucleotide polymorphisms (SNPs) are the most abundant class of genetic variations in the human genome with a frequency of approximately every 100 to 300 base pairs [1]. Experimental techniques will provide the strongest evidence for the functional role of a genetic variant [3], it is not feasible to perform laboratory experiments for all SNPs in the human genome or even in a single gene. Theoretical and/ or computational methods are becoming indispensable for the identification and prioritization of SNPs with functional significance from an enormous number of non-risk alleles [4]. Computational methods are sufficiently fast and flexible to provide reliable predictions of functionally significant SNPs with a high accuracy of 80–85% [5,6,7,8,9] when combined with sequence, structure, and phylogenetic relationships

Methods

Results

Conclusion