A comprehensive in silico prediction of the most deleterious missense variants in the bovine LEP gene

Abstract

Leptin is a versatile hormone involved in many biological functions, including controlling body weight, energy homeostasis, reproduction, and immune function. Though exhaustive studies were performed on the bovine LEP gene, no efforts have been made to comprehensively and systematically analyze single nucleotide polymorphisms (SNPs) in its coding sequence. The present study was conducted to identify the most deleterious nonsynonymous SNPs (nsSNPs) of the bovine LEP gene. SNPs retrieved from the dbSNP database were investigated using various computational tools, including SIFT, PolyPhen-2, PANTHER, PROVEAN, SNAP2, I-Mutant2, mCSM, SDM, DUET, Cobalt, SPPIDER, ConSurf, and MutPred. A total of 28 nsSNPs were considered for the present study. Only 4 nsSNPs, namely, R66M, D186G, C191S, and C191G were found to be deleterious by all the used common nsSNP prediction tools and affected leptin protein structure, function, and biological stability. These variants were located in very highly conserved positions, and thus mutations in these amino acid positions have deleterious evolutionary consequences. The findings of the present study proved that R66M, D186G, C191S, and C191G nsSNPs have the most deleterious consequences on both the structure and the function of bovine leptin, with a special emphasis on the remarkable effects of the last two nsSNPs on the breakage of the disulfide linkage which may lead to a variety of deleterious consequences of this disturbed three-dimensional structure on bovine life and performance. This study provides the first comprehensive computation of the damaging effects of nsSNPs on leptin in bovines.