Review Article

Cytochrome-P450 (CYP11B1 Gene) Polymorphism and its Role in Bovine Milk Producing Traits

Faheen Riaz1, Sarfraz Mehmmod1, Aatka Jamil1, Khansa Jamil1, Imran Riaz Malik2, Muhammad Naeem Riaz1* and Ghulam Muhammad Ali1

1Animal Biotechnology Program, National Agriculture Center, Islamabad, Pakistan; 2University of Sargodha, Sargodha, Pakistan.

Received | October 20, 2023; Accepted | July 25, 2024; Published | November 29, 2024

*Correspondence | Muhammad Naeem Riaz, Animal Biotechnology Program, National Agriculture Center Islamabad, Pakistan; Email: [email protected]

Citation | Riaz, F., S. Mehmmod, A. Jamil, K. Jamil, I.R. Malik, M.N. Riaz and G.M. Ali. 2024. Cytochrome-P450 (CYP11B1 gene) polymorphism and its role in bovine milk producing traits. Sarhad Journal of Agriculture, 40(4): 1522-1532.

DOI | https://dx.doi.org/10.17582/journal.sja/2024/40.4.1522.1532

Keywords | BTA14, CYP11B1, milk composition, QTL, Bovine

Copyright: 2024 by the authors. Licensee ResearchersLinks Ltd, England, UK.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Introduction

In the recent 40 years of development and progress the primary focus of animal biotechnology is to improve the milk and milk component yield. The untiring effort has been put into improving the nutritional value of milk’s component profile. The improvement of milk quality has always been a subject of concern because of its economic importance (Kale et al., 2021). The most significant and valuable livestock species for dairy production are thought to be cattle and buffalo. Many different livestock breeds are currently being utilized for value-added goods in the dairy sector. The adoption of the prevalent breed in each region of the world is prioritized to sustainably produce milk in that location (Kale et al., 2021) . To better understand molecular processes underlying the phenotypic manifestation of the milk production trait and to enhance the genomic assessment of milk-related traits, it is essential to identify genomic areas and candidate genes linked with the trait. The current review article focuses on the genetic processes underlying milk composition and production features, particularly concerning CYP11B1 gene polymorphism investigations. The most significant component of milk’s nutritional value is thought to be its fat content (Lock and Bauman, 2004). Raising the quality of milk is a goal of cattle breeding, in addition to boosting milk fat and protein levels (Kale et al., 2021). The most significant and energizing component of milk is milk fat, and its content and composition are crucial benchmarks for assessing milk quality. The identification of useful candidate genes controlling milk fat is currently limited, though (Mu et al., 2022).

It is critical to review genetic studies on dairy cattle to improve milk quality. Numerous genes have been investigated and discovered to be cooperatively involved in milk production features in dairy cattle, including GAPD, RPS9, OXT, ACTB, GTP, ITGB4BP, Prolactin (PRL), RPS23, POU1F1, RPS15, UXT, RAB11FIP1, DGAT1, SCD1, STATA5, ACSS2, AGPAT6, CYP11B1, PPARGC1A, CYP2U1, MRPS30, NIM1K, ZNF131, SLC4A4 ARHGAP39, PPP1R16A, FOXH1, KIFC2, CYHR1, and TONSL etc. have been identified to play a role in milk production features (Wang et al., 2020; Clancey et al., 2019; Cai et al., 2020; Jiang et al., 2014).

The cytochrome P450 11 beta-hydroxylase 1 (CYP11B1) gene in cattle is the subject of our current review article. Due to CYP11B1’s function in steroid hormone synthesis in mammals, it is the significant candidate gene that affects the fat content of milk. The main goal of molecular genetics is to identify DNA polymorphisms that have an impact on the characteristics that are being bred in animals (Bionaz and Loor, 2008). The ability to conduct genome-wide association analyses employing PCR-RFLP and single nucleotide polymorphism (SNP) markers to find quantitative trait loci (QTL) relating to milk production traits has been made possible by recent advances in molecular genetics (Bouwman et al., 2012). Identification of SNPs in the candidate genes for milk characteristics is crucial given the advantages of genomic selection (Rahayu et al., 2019). It’s critical to maintain a balance between molecular genetic methods and traditional methods of animal breeding (Kale et al., 2021).

The current study was also a modest attempt to investigate the genetic mechanism behind milk production traits with special reference to CYP11B1 gene polymorphism studies around the world which is a highly desired and demanded attribute in the Asian region.

CYP11B1 gene structure and function

The CYP11B1 gene was discovered and studied in humans, cattle, chickens, and rats (Amy et al., 1990; Chirala et al., 1997; Jayakumar et al., 1994). By combining somatic cell hybrid (Cruz et al. 2019) analysis and fluorescence in-situ hybridization, the bovine CYP11B1 gene was originally identified on chromosome BTA14q14 (Payne and Hales, 2004). The bovine CYP11B1 gene has a 7716 base pair and has 9 exons and 8 introns (Figure 1) (GenBank Acc. No. NC_037341). (http://www.ncbi.nlm.nih.gov/gene/282422).

 

The inner mitochondrial membrane contains the CYP11B1 enzyme. The CYP11B1 enzyme which is also regarded as aldosterone synthase can catalyze three consecutive processes that all require one NADPH molecule, and one oxygen molecule in addition to the mitochondrial electron transport system to produce aldosterone from 11-deoxycorticosterone. The following are the three successive reactions: Aldosterone is created through the 11-hydroxylation of the 11-deoxycorticosterone via carbon 18 hydroxylation and the subsequent hydroxyl group oxidation of carbon 18 to produce the 18-C aldehyde group (Figure 3) (Boleckova et al., 2012; Lisurek and Bernhardt, 2004).

 

 

The CYPIIBI gene greatly influences cortisol synthesis, androgen activity, and the number of milk gland cells that proliferate (Javed et al., 2013). The major hormone that is involved in lipolysis and lipogenesis is still cortisol. The CYP11B1 locus is now a prime target for association research and is of particular interest. In several breeds, the CYPIIBI gene has been linked to milk production, energy metabolism, somatic cell score, and reproduction (Manzoor et al., 2018).

CYP11B1 gene polymorphism studies using molecular techniques

Das et al. (2019) examined the Deoni cattle breed and revealed two genotypes, VV and VA, for the putative exon 1 of the CYP11B1 gene that were digested with the restriction enzyme PstI. Three band patterns mean VV genotypes, while four band patterns indicated VA genotypes. The observed frequencies of the VV and VA genotypes were 0.23 and 0.77, respectively, while the allelic frequencies for the V and A types were 0.62 and 0.38. In putative exon 1 of CYP11B1, sequence analysis discovered sixteen single nucleotide polymorphisms. The CYP11B1 gene sequence was uploaded online to the NCBI gene bank and given the accession number KF471016 (Das et al., 2019).

To better understand the biology behind milk production and give breeders the ability to alter milk fat content via genetic selection, Cruz et al. (2019) worked on the identification of genomic areas and potential genes related to milk fatty acids. They use a high-density (777K) SNP panel to undertake genome-wide association studies for five groups of milk fatty acids in Holstein cattle and suggest that the CYP11B1 gene, a CYHR1 paralogous that is related to milk fat in buffalo. Furthermore, according to Boleckova, a functional gene for traits associated with milk production in cattle is CYP11B1. However, the majority of genes with substantial impacts were found in the BTA14, adjacent to the DGAT1 gene. This suggests that the DGAT1 gene’s effect may be influenced by a strong linkage disequilibrium with polymorphisms in the DGAT1 gene which has been proven to be linked to milk fat content (Cruz et al., 2019).

The bovine CYP11B1 locus has a high level of overall sequence diversity, and 13 new polymorphisms were found. Seven of these were located in the coding region, while the other six were discovered in its intronic region. Genomic frequencies and allele distribution patterns were calculated for each SNP and HWE. SNPs that obey Hardy-Weinberg equilibrium were taken into account for linkage analysis. In this study, it was concluded that important polymorphisms in the CYP11B1 gene, including V340L, T372D, T401M, and A415T, change the amino acids, and that polymorphism g.1305935 (T401M), which was discovered to be related with milk fat % (Manzoor et al., 2018).

Another analysis by Javed et al. (2013) reported that the CYP11B1 gene in Pakistani riverine buffalo breeds was sequenced to determine the genomic causes of phenotypic diversity in dairy buffalo populations, particularly for milk yield traits. By analyzing the sequences of different buffalo groups having greater and lower fat contents, seven new SNPs were found (via an 8 % threshold value). Out of these versions of SNPs, only one was intronic. All of the remaining mutations, which caused amino acid alterations, were exonic and non-synonymous. These locations could be used to identify the causative mutation or neighboring QTL. However, breed-specificity was identified in polymorphic regions (Javed, 2016).

Javed (2016) aimed to predict protein-protein interactions in-silico for genes that are candidates for milk fat content in bovines. The prediction of a biological gene network was done followed by calculating the network interaction scores and determining the three-dimensional structure by applying PDB. Ten functional partners were identified through analysis of the CYP11B1 network: CYP11B2, CYP17A1, CYP19A1, HSD3B2, HSD17B6, HSD3B1, HSD17B3, and ENSG00000232414 (Figure 4). It was a network of closely linked nodes, and all of the associations were significant with high interaction score values. Along with this knowledge, 34 % homology of CYP11B1 protein’s three-dimensional structure was also estimated (Figure 2) (Javed, 2016).

 

It was hypothesized that the gene responsible for the QTL associated with fat metabolism was located in the centromeric region of BTA14 (de Roos et al., 2007). It was found that the CYP11B1 gene was positively correlated with fat content but negatively correlated with milk yield and protein yield. CYP11B1 gene which has evolved into different isoforms in various species (Buelow et al., 1996; Mellon et al., 1995), although functional unity is retained in pigs, sheep, and cattle (Buelow et al., 1996). There are CYP11B1 pseudo genes in all animals (Mellon et al., 1995) . The CYP11B1 gene can be regarded as a positional candidate gene because it has been localized to BTA14q12 and HSA8q21–23 (Kaupe et al., 2004). They suggest that CYP11B1 is a potential candidate gene for milk yield as it’s also involved in energy metabolism reported by (Mohammed et al., 2014).

Several additional genes, including CYP11B1, MAPK15, VPS28, GPIHBP1, KCNK9, TRAPPC9, and CYHR1, were also reported by Jiang et al. (2014) in addition to the DGAT1 gene, which was verified in practically all association studies to have substantial connection with several milk production features. All of these genes were verified in their analysis, which also found that BAT14 has a considerable number of SNPs. It is thus highly likely that part of the effects are caused by linkage disequilibrium (LD) with the actual causal variations. We examined the levels of LD between each important SNP. On chromosomal BAT14, they reported SNPs in the CYP11B1 gene at positions 2705205, 2708768, and 2706012 (Jiang et al., 2014).

Singh along with colleagues has reported the CYP11B1 a potential gene for milk and milk production features. They found that there are 14 major milk proteins in cattle (Farrell et al., 2004), and they hypothesize that these proteins exhibit DNA-level variability, perpetuating a chemical change in the protein. However, the effects of each allele differ depending on the individual’s genetic background and the experimental model (single locus vs. multi-locus effects). Several of them, including casein (Navani et al., 2002) and CYP11B1 (Kaupe et al., 2007), have been demonstrated to be useful in determining the milk quality and lactation of dairy cattle and are commercially relevant (Singh et al., 2014).

BLAST was used to discover five polymorphic sites in the local Sahiwal breed. According to data, the exon one chromosomal locations 1310397, 1310450, 1310462, 1310487, and 1310519 had nucleotide changes in the following order: A>G, G>A, G>A, and A>G. The CYP11B1 gene product has an Alanine (A) to Valine (V) polymorphism (V30A), which was discovered by a nucleotide substitution at position P1310487. Using the BioEdit translate tool, a link between the amino acid makeup of the reference and subject proteins was identified. Although the majority of identified SNPs do not change the sequence of amino acids, these sites may be linked to surrounding QTLs and cause variants. The Sahiwal breed’s allele distribution pattern and frequency patterns were found at specific polymorphic sites which depict breed specificity that is directly linked to milk yield traits (Manzoor et al., 2013).

An experiment conducted by Javed et al. (2013) found 7 SNPs at the CYP11B1 gene in the Pakistani Nili Ravi Buffalo breed. DNA was extracted from a variety of buffalo to look for polymorphism sites in the gene. Seven SNP were found in an exonic region using the sequencing method. One of these SNPs was found to be silent, which didn’t alter the amino acid. The remaining are significant in a way that they can change the amino acid sequence, which in turn can have an impact on the protein’s structure and function (Javed et al., 2013).

Boleckova and colleagues investigated allelic and genotypic frequencies of 5 DNA markers in Czech Fleckvieh cattle which are positional as well as functional candidates for the milk production traits. The CYP11B1 gene has one of these markers. They assessed LD i.e. linkage disequilibrium between the 2 markers within the PRL (prolactin) gene and analyzed the correlation of the identified markers with breeding values associated with milk and milk production traits. 505 Czech Fleckvieh cows were genotyped in this investigation. In their investigation, segregation was confirmed by markers in PPARGC1A, SPP1, CYP11B1, and two polymorphisms in the PRL gene. They looked into the p.Val30Ala polymorphism in the CYP11B1 first exon. CYP11B1 gene polymorphism is positively associated with milk and milk production traits (Boleckova et al. 2012).

Some of the important economic traits like MY, FY, PY, FP, and PP major 10 SNP markers were selected for positional candidate gene searches within a flanking window of 1 Mb on either side of the marker. A semi-automated procedure that entailed acquiring and reviewing gene function predictions and publications for each gene and its orthologs in other species was used to choose functional candidate genes from the flanking areas. The genotyping data of GWAS related to milk yield from the BovineSNP50 Bead-Chip was used in this study. Over the entire genome, many potential and positional candidate genes for milk components were found. CYP11B1 gene, which is located on chromosome BTA14, and other previously identified genes having a significant influence on milk production traits (Li et al., 2010).

Steroid 11-hydroxylase (cytochrome P450, subfamily XI B, polypeptide 1 (CYP11B1)) is a gene that encodes a steroid 11-beta-hydroxylase that converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone, according to Boleckova et al. (2012). The ILSTS039 marker is close to the location of the CYP11B1 gene on bovine chromosome 14. This marker is linked to milk production characteristics. This makes the CYP11B1 gene, along with milk yield and milk component yield, a structural and positional candidate gene for milk traits. Ala/Ala, Ala/Val, and Val/Val genotype frequencies in the Czech Fleckvieh population were 0.07, 0.38, and 0.55, respectively. Hardy-Weinberg equilibrium existed in the CYP11B1 gene’s genotype distribution (P 0.05), and the gene variation CYP11B1A was substantially related to increased MYBV (P 0.001). Bovine CYP11B1 gene Ala/Val polymorphism has a significant impact on milk output, breeding values for milk yield, and fat and protein contents in Czech Fleckvieh cows (Boleckova et al., 2012).

Another study describes the CYP11B1 gene as a potential gene for attributes related to milk production on the bovine chromosome 14, which has been thoroughly investigated for quantitative trait loci (QTL). Wibowo and his colleagues found 126 QTL by reviewing more than 40 studies that could be linked to genome assembly i.e. Btau 4.0. They discovered the region spanning 0–10 Mb on chromosome BTA14 in dairy cattle that have the highest density quantitative trait loci (QTL) map with a total 56 number of QTL, mostly for milk composition traits (Wibowo et al. 2008).

Another study was conducted to investigate the link between milk production and CYP11B1 gene variants with the help of CYP11B1 gene sequencing and other genetic tools. The exonic region of the bovine CYP11B1 gene was amplified, sequenced, and genotyped by isolated genomic DNA samples and designing Primers of the targeted region. Less information is available about CYP11B1 as a molecular marker on the genetic map at chromosome 14 which is why Kaupe et al. (2007) described little association of respective genes. The targeted region at CYP11B1 gene product has an Alanine (A) to Valine (V) polymorphism (V30A), due to nucleotide substitution at position P1310487 in the 5’UTR and exon 1 of the CYP11B1 gene according to research results published by Kaupe et al. (2007). One of the genetic variability in the 5 UTR at exon 1 is strongly associated with the milk and milk components in German Holstein cattle (Kaupe et al., 2007).

The candidate gene approach is a powerful tool in genetic research and breeding programs and provides valuable insights into genes associated with specific traits based on prior knowledge of their biological function, to achieve a better understanding of the genetic basis of complex traits including milk production traits, livestock improvement, and disease management.

Conclusions and Recommendations

One of the probable candidate genes for milk production features and characteristic breeding values for MY, FY, FP, PY, and PP in various cattle breeds is the CYP11B1 gene. The CYP11B1 gene’s DNA polymorphism research employing different molecular markers can be used to enhance the milk quality of dairy cattle. A thorough investigation of the gene’s unstudied CYP11B1 locus may also result in the discovery of several innovative and economically advantageous SNPs that will support breeding and selection decisions for the genetic advancement of dairy cattle. In light of these findings, the CYP11B1 polymorphism has demonstrated favorable relationships with milk and milk composition traits such as MY (milk yield), PY (protein yield), and FY (fat yield) in several breeds of cattle (Kale et al., 2021). A possible marker for more productive and economical features can be employed with the identified polymorphism. A dependent evaluation of gene expression patterns will aid in our understanding of the biological mechanisms behind the CYP11B1 gene along with its function in dairy animal production features. As a result, functional validation of CYP11B1 gene polymorphisms should be carried out in the future (Manzoor et al., 2018).

Novelty Statement

This review explores the novel role of the CYP11B1 gene in the regulation of milk production in cattle, offering insights into the genetic influence on milk production and ultimately providing a fresh perspective on enhancing dairy productivity through genetic selection

Author’s Contribution

Faheen Riaz: Conceptualization, methodology, writing original draft.

Sarfraz Mehmood: Review & editing, data curation.Aatka Jamil and Khansa Jamil: Review & editing.

Imran Riaz Malik: Visualization, review & editing.

Muhammad Naeem Riaz: Supervision, project administration.

Ghulam Muhammad Ali: Resources.

Conflict of interest

The authors have declared no conflict of interest.

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