AbstractLeptin is a versatile hormone that regulates several metabolic pathways, such as controlling body weight, feed intake, energy expenditure, immune function, and reproduction. In spite of exhaustively studies that performed on the bovine LEP gene, no attempt has been made to comprehensively and systematically analyze its entire coding SNPs. The present study was carried out to identify the most deleterious non-synonymous SNPs (nsSNPs) of bovine LEP gene.

To predict the possible impact of missense mutations on leptin structure and function, SNPs data that obtained from dbSNP database were analyzed using various bioinformatics tools. The total nsSNPs that considered for the present study were 28. It was found that 9 nsSNPs, including R66M, H91N, H91P, A104V, S162P, D186Y, D186G, C191S, and C191G, in 6 amino acid positions were found to be deleterious and damaging by four common nsSNPs prediction tools and thus affecting leptin protein structure and biological activity. I-Mutant-2 eliminated two nsSNPs including S12P and D16Y since they increase protein stability upon mutation. Further information regarding the residual deleterious nsSNPs showed that three of these variants including R66M, C191S, and C191G were confirmed that they were located in very high conserved positions, and thus the mutations in these amino acids positions have deleterious evolutionary consequences.

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The findings of the present study proved that R66M, C191S, and C191G nsSNPs have the most considerable deleterious consequences on both structure and function of bovine leptin. The present study provides the first comprehensive computation about the effect of the most damaging nsSNPs on both structure and function of bovine leptin. Exploration of these mutations may provide novel perspectives for various production traits associated features.  Keywords: bovine, computational analysis, leptin, non-synonymous SNPs IntroductionOne of the most prominent hormones that provide hotspot indicators for numerous metabolic traits of cattle is leptin. Leptin is a hormone that regulates the body weight by maintaining the balance between food intake and energy expenditure through signaling to the brain to change the stored energy levels (Zhou et al.

, 2009). It plays a crucial role in the regulation of feed and energy metabolism of cattle (Liefers et al., 2005).

In addition to the obvious role of leptin in controlling appetite, it has other noticeable roles in regulating growth, reproduction, body composition and immunity.  Leptin is encoded by a LEP gene, which is accommodated a size of about 20kb. It consists of three exons separated by two introns, and the exons for the LEP gene cover about 15kb of the bovine genome. Actually, the first exon is truncated in the mature blood circulating hormone. Meanwhile, the rest two exons produce the fully mature 167 residues by excising the first 24 signal amino acid residues to produce 16kd of blood circulating leptin (Liefers, 2004). Leptin contains a distinctive three-dimensional (3-D) four-?-helix bundle structure of A-B-C-D pattern (Kline et al.

, 1997). This structure is arranged in a four sequentially similar anti-parallel left-hand twisted ?-helices bundle that are connected by two crossover links, along with one short loop (Gutierrez et al., 2009). In addition to the four main helices, an extra fragment that known as helix E, which is a distorted short helix, is also presented on the structure.

The helix E is found in the loop linking between both helices C and D. Leptin contains a single disulfide bond that links two cysteine residues (Cys141 and Cys191) within the C and D helices to form a unique kink. This kinked helix that connects the last turn of the ?-helix D to a loop that extends from the C to D helix has been proven to be very crucial for the structural integrity and stability of leptin (Rock et al., 1996). Hence, any missense mutation that changes this highly organized 3D structure of leptin may have deleterious outcomes on many critical metabolic pathways this hormone is involved in. On the other hand, it was obviously demonstrated that many SNPs have functional effects on their corresponding protein structure either by a single change in the amino acid (Al-Shuhaib et al.

, 2017) or by substituting the transcription factors (Liao and Lee, 2010), or by other means. Synonymous, or silent, mutations are now widely acknowledged to be able to cause changes in protein expression, conformation, and function (Sauna and Kimchi-Sarfaty, 2011). However, mutations in introns and other non-coding regions do not alter amino acid sequences. Conversely, a non-synonymous single nucleotide polymorphism (nsSNP), which is present within the exon of a gene, is responsible for the incorporation of an alternative amino acid and known to be one of the main causes of the possible alterations of the leptin mode of action.

However, each amino acid alteration has its own consequences regarding its position and identity in the 3D structure of leptin. Accordingly, it is important to differentiate these consequences computationally. Through more than a decade, several missense mutations have been discovered in this highly studied leptin protein (Liefers et al., 2003; De Matteis et al., 2012), no comprehensive study were presented to predict the final consequences of the whole nsSNPs in this bovine hormone.

Therefore, this study is designed to provide the first comprehensive computational prediction for the most deleterious missense mutations in the bovine leptin.


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