Prediction of the damage-associated non-synonymous single nucleotide polymorphisms in the human MC1R gene.

Diego Hepp,Thales Renato Ochotorena De Freitas,Gislene Lopes Gonçalves,Shenying Fang

doi:10.1371/journal.pone.0121812

Abstract

The melanocortin 1 receptor (MC1R) is involved in the control of melanogenesis. Polymorphisms in this gene have been associated with variation in skin and hair color and with elevated risk for the development of melanoma. Here we used 11 computational tools based on different approaches to predict the damage-associated non-synonymous single nucleotide polymorphisms (nsSNPs) in the coding region of the human MC1R gene. Among the 92 nsSNPs arranged according to the predictions 62% were classified as damaging in more than five tools. The classification was significantly correlated with the scores of two consensus programs. Alleles associated with the red hair color (RHC) phenotype and with the risk of melanoma were examined. The R variants D84E, R142H, R151C, I155T, R160W and D294H were classified as damaging by the majority of the tools while the r variants V60L, V92M and R163Q have been predicted as neutral in most of the programs The combination of the prediction tools results in 14 nsSNPs indicated as the most damaging mutations in MC1R (L48P, R67W, H70Y, P72L, S83P, R151H, S172I, L206P, T242I, G255R, P256S, C273Y, C289R and R306H); C273Y showed to be highly damaging in SIFT, Polyphen-2, MutPred, PANTHER and PROVEAN scores. The computational analysis proved capable of identifying the potentially damaging nsSNPs in MC1R, which are candidates for further laboratory studies of the functional and pharmacological significance of the alterations in the receptor and the phenotypic outcomes.

Highlights

The melanocortin 1 receptor (MC1R) gene encodes for a G protein-coupled receptor (GPCR) with seven transmembrane domains involved in the control of melanogenesis
We used 11 computational tools based on different approaches to predict the damage-associated non-synonymous single nucleotide polymorphisms in the coding region of the human MC1R gene
The R variants D84E, R142H, R151C, I155T, R160W and D294H were classified as damaging by the majority of the tools while the r variants V60L, V92M and R163Q have been predicted as neutral in most of the programs The combination of the prediction tools results in 14 non-synonymous single nucleotide polymorphisms (nsSNPs) indicated as the most damaging mutations in MC1R (L48P, R67W, H70Y, P72L, S83P, R151H, S172I, L206P, T242I, G255R, P256S, C273Y, C289R and R306H); C273Y showed to be highly damaging in SIFT, Polyphen-2, MutPred, PANTHER and PROVEAN scores

Summary

Introduction

The melanocortin 1 receptor (MC1R) gene encodes for a G protein-coupled receptor (GPCR) with seven transmembrane domains involved in the control of melanogenesis. The human MC1R protein contains 317 amino acids encoded in a single exon, and shows many polymorphisms that have been described in different populations [2]. The non-synonymous single nucleotide polymorphisms (nsSNPs) in the coding region alter the corresponding proteins. These changes may affect the protein functions in many different ways, for instance by altering the catalytic or ligand binding sites, leading to improper protein folding, incorrect intracellular transportation, or decrease in the stability or loss of function of the gene product [10] [11] [12] [13] [14] [15] [16] [17] [18]. While in vitro tests can assess the effect of specific variations, it is laborious and time-consuming to evaluate the large amount of variation in the human genome [28]

Methods

Results

Discussion

Conclusion