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. 2023 Mar 18;101:skad084. doi: 10.1093/jas/skad084

Convergent changes in melanocortin receptor 1 gene are associated with black-headed coat color in sheep

Qian Zhou 1, Chunna Cao 2, Huanhuan Zhang 3, Yilin Liang 4, Xinyue Zhang 5, Yuxin Kang 6, Wenwen Fang 7, Xianyong Lan 8, Ran Li 9, Chuanying Pan 10,✉
PMCID: PMC10100648  PMID: 36933185

Abstract

As one of the most obvious phenotypic traits, the coat color of sheep is an ideal model to study the genetic mechanisms underlying coat color varieties of mammals. One distinguishable coat color is the black-headed type, such as the famous black-headed Dorper sheep from Africa and Bayinbuluke sheep from Asia. In this study, we compared the genome sequences of black-headed and all-white sheep to identify causative genes for the black-headed sheep, including black-headed Dorper vs. white-headed Dorper, as well as Bayinbuluke (black-headed) vs. Small-tailed Han (all-white). The most differentiating region between black-headed sheep and all-white sheep was found to harbor a haplotype covering melanocortin receptor 1 (MC1R) gene. The share of this haplotype by the black-headed sheep from Africa and Asia suggested that the convergent change in the MC1R region is likely to determine this unique coat color. Two missense mutations (g. 14251947T > A and g. 14252090G > A) within this haplotype of MC1R gene were found. We further analyzed whole genome sequence data of 460 worldwide sheep with diverse coat colors and confirmed the association between the MC1R haplotype with pigmentation variations. Our study provides novel insights into coat color genetics in sheep and expands our knowledge of the link between MC1R gene and varying pigmentation patterns in sheep.

Keywords: black-headed sheep, coat color, melanocortin receptor 1, missense mutations, sheep

This study provides new insights into the inheritance of coat color traits in sheep and expands the understanding of the association between the melanocortin receptor 1 gene and different pigmentation patterns in sheep.

Introduction

Coat color is the most distinguishable phenotype of domestic animals as recognized by Darwin (Darwin, 1868). Domestication, adaptation, and artificial selection have produced a large variety of coat colors that become the most noticeable traits of diverse breeds (Cieslak et al., 2011). In modern animal farm animal breeding, the coat color could be used to discriminate between breeds and varieties. Furthermore, coat color becomes an important economic trait for sheep which are raised for skins and wool (Sun et al., 2020). The ancestral coat color of sheep is mainly brown, but domesticated sheep displayed various colors, patterns, and white markings (Lundie, 2011). Therefore, the diverse sheep breeds provide a suitable animal model to study the genetic background of coat color diversity in animals.

Coat color patterns often abide by the Mendelian mode of inheritance and are among the first traits to be studied by a molecular geneticist (Rieder, 2009). Classical candidate genes for the coat color of mammals that have been reported include the agouti signaling protein (ASIP) gene, melanocortin 1 receptor (MC1R) gene, tyrosinase-related protein 1 gene, melanocyte-inducing transcription factor gene, and tyrosine-protein kinase gene. These five genes play key roles in melanin synthesis, differentiation, and migration of melanocytes and thus represent the most widely studied pigmentation genes (Nazari-Ghadikolaei et al., 2018; Yao et al., 2019; Gebreselassie et al., 2020; Jiang et al., 2021; Liang et al., 2021; Patterson et al., 2021). Mutations in the MC1R gene have been found to determine the black phenotype of Chinese sheep (Yang et al., 2013). The black skin and hairs of Masai sheep were also found to be associated with MC1R mutations (Fontanesi et al., 2011).

Of the diverse coat colors in sheep, pigmentation type in head is most distinguishable. The black-headed Dorper from Africa and Bayinbuluke sheep from Asia are two unique breeds that demonstrate similar black-headed patterns where the pigmentation expands from the face to the neck. ­Meanwhile, a white Dorper breed have also been developed by modern breeding, which could be used as a control to study the black-headed coat color. In this study, we aimed to identify genes and loci affecting pigmentation in head of sheep by analyzing genome sequences of black-headed sheep with other breeds. The results will expand our knowledge of the genetic background and convergent evolution underlying coat color diversities in domestic animals.

Materials and Methods

Ethics statement

All animal experiments were approved by the International Animal Care and Use Committee of the Northwest A&F University (IACUC-NWAFU) in accordance with the regulations of the Administration of Affairs Concerning Experimental Animals of China.

Samples collection, DNA extraction, and SNP calling

Whole-blood samples were collected from the Yulin Shanghe Hu Sheep Breeding Base in black-headed Dorper (n = 10) and white-headed Dorper sheep (n = 5). DNA was extracted using the standard phenol-chloroform method (Köchl et al., 2005). Paired-end sequence data for all individuals were generated using the DNBSEQ T7 platform. The whole genome sequence data generated in this study have been deposited in NCBI SRA database with Project number PRJNA904424. Besides, we collected whole genome sequencing data of 110 individual sheep. Samples were selected to obtain the optimum representation of global sheep diversity, and Supplementary Table S1 provides sample information. All sequences were downloaded from NCBI. After quality filtering of the original FASTQ files, the whole genome sequence was compared with slat (v1.0.3) to obtain the Binary Alignment MAP (.bam) files. Then, slct (1.0.3) was used to construct the gvcf file of each sample and the vcf file was merged by slmgvcf_gpu (v2.0.7) (Zhang et al., 2021). Finally, we used the bcftools-1.13 view module of “QD < 2.0, QUAL < 30.0, SOR > 3.0, FS > 60.0, MQ < 40.0, MQRankSum < -12.5 and ReadPosRankSum <-8.0” to remove SNP sequencing and alignment errors. And we used bcftools-1.13 to filter out variants with a call rate > 80% and minor allele frequency < 0.05 for further analysis.

Population structure and phylogenetic analysis

We used PLINK for principal component analysis (PCA) and ADMIXTURE analysis, and PCA used smartPCA program in EIGENSOFT v5.0 package (Patterson et al., 2006). Population structure analysis was carried out using ADMIXTURE v1.3 (Alexander and Lange, 2011). Neighbor-Joining tree was constructed for the whole-genome SNP, and the MEGA v5.0 (Tamura et al., 2011) and exhibited FigTree v1.4.3 visualization.

Exploration of selective sweep regions

To identify the genomic signatures of selection, we calculated the averaged the fixed index (FST) values (Weir and Cockerham, 1984) across each 10-kb window using the VCFtools v0.1.16 between Bayinbuluke and Small-tailed Han sheep, as well as black-headed Dorper and white-headed Dorper. Besides, we then estimated nucleotide diversity θπ using VCFtools v0.1.16 (--window-pi 10000).To identify the population structure across all sheep populations, we performed a haplotype-based approach across all individuals using ChromoPainter and fineSTRUCTURE to explore haplotype-sharing patterns (Lawson et al., 2012). LDBlockShow software with default parameters was used to reconstructed patterns of linkage disequilibrium between different sheep breeds from a single vcf files (Dong et al., 2021).

Annotation

SnpEff V4.2 annotated SNP based on sheep reference genome Oar_rambouillet_v2.0. It can be divided into intron regions, exonic regions, intergenic regions, splicing sites, upstream, and downstream regions. Those SNPs in exons are further divided into synonymous or non-synonymous SNPs (Lv et al., 2022). Finally, the allele frequencies of SNPs variants in different varieties were calculated by VCFtools v0.1.16, and compared allelic variations of the genes in diverse breeds.

Results

Population structure and relationships

We generated complete genomes from black-headed Dorper (n = 10) and white-headed Dorper (n = 5) with an average sequencing depth of 21.5×. We also downloaded publicly available data from black-headed Dorper (BDP), white-headed Dorper (WDP), Bayinbuluke sheep (BYK), and Small-tailed Han sheep (STH) (supplementary Table S1). In this way, we were able to compare black-headed Dorper (n = 15) and white-headed Dorper (n = 14), Small-tailed Han sheep (n = 23), and Bayinbuluke sheep (n = 34) to identify selection signals associated with black-headed coat color (Figure 1). The Small-tailed Han sheep was used here for comparison with Bayinbuluke sheep as they two shares the same ancestry of Mongolian sheep lineage.

Figure 1.

Figure 1.

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Experimental design to study the genetics of black-headed sheep.

PCA analysis on whole genome sequencing data showed three geographic clusters including African breeds (BDP and WDP), Asian breeds (BYK and STH), and wild (Figure 2A and B). The neighbor-Joining tree generally agrees with the PCA analysis and showed that the black-headed Dorper and white-headed Dorper were mixed in one cluster indicating their relatively low genetic differentiation (Figure 2B). In the ADMIXTURE analysis, when K = 2, the sheep breeds were genetically divided into domestic sheep and Mouflon ancestry; when K = 3, the white-headed Dorper sheep showed clear evidence of shared genome ancestry with black-headed Dorper sheep (Figure 2C).

Figure 2.

Figure 2.

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Phylogenetic relationships among five sheep populations. (A) PCA of 5 sheep breeds (B)Neighbor-joining tree of the relationships between the five sheep breeds (110 animals).(C) ADMIXTURE results for K = 2 and K = 3, showing low cross-validation error.

Screening genes associated with black-headed sheep

To identify genes related to black-headed sheep, we performed two independent comprisons using the full genome sequences of black-headed Dorper vs. white-headed Dorper, and Bayinbuluke (black-headed sheep) vs. Small-tailed Han (all-white sheep) by calculating the average FST values. The most noticeable signal of FST that segregated in black and white-headed sheep is located in the region of 15.25 to 15.26 Mbp on chromosome 14 (Figure 3A and B). The high FST and low π ratio indicated that this region was subjected to selection in Bayinbuluke and black-headed Dorper sheep (Figure 3C–F). Notably, this region harbors the MC1R gene, which is a well-known genes controlling the switch between eumelanin and phaeomelanin production (Marklund et al., 1996; Bellone, 2010).

Figure 3.

Figure 3.

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Identification of genes associated with Bayinbuluke and Dorper black-headed traits. (A–B) Manhattan plot of selective sweeps in black-headed Dorper and Bayinbuluke sheep. (C–D) FST at the MC1R gene region. The gray bar spans the MC1R gene model under the strongest selection. (E–F) Nucleotide diversity at the MC1R gene region. (G) SNPs with minor allele frequencies > 0.1 are used to construct haplotype patterns (Chr 14:15.47-15.49 Mb). Two mutations of MC1R gene (g. 14251947T > A and g. 14252090G > A) were both located in the exon region. (H) Haplotype block analysis at the MC1R loci.

Within the selection regions, we found two missense mutations in the protein-coding region of MC1R, namely g.14251947T > A (p.M73K) and g.14252090G > A (p.D121N) residing in the haplotype (Figure 3G). These two variants in MC1R might represent the functional variants affecting the black-headed trait in Bayinbuluke and Dorper sheep. We examined the allele frequencies of two missense mutations (g.14251947T > A and g.14252090G > A) of MC1R gene in many breeds. As these two mutations are linked in one haplotype block (Figure 3H), we mainly analyzed the A allele frequency of g. 14251947T > A. The A allele was highest in Bayinbuluke (BYK, frequency = 64.71%), Sunite (frequency = 62.50%) and black-headed Dorper (BDP, frequency = 100%) (Supplementary Figure S1). In addition, the derived allele A was absent in wild Mouflons, Bighorn sheep, and Argali sheep (Supplementary Figure S1), suggesting that the putative causative mutations emerged after domestication.

MC1R haplotypes in sheep with diverse pigmentation patterns

The classic sheep coat color associated with pigmentation, included black-headed, black-spotted, all-black, all-white, and brown pigment types. We collected 460 resequencing data from 29 sheep breeds each corresponding to one of the five coat colors. Interestingly, our study found that the MC1R gene haplotype indeed had a certain association with different patterns. According to results from haplotype, the white coat color and brown breeds were clustered together, while black-headed, black-spotted, and all-black sheep shared similar haplotypes. As expected, the black-headed Dorper and Bayinbuluke have a unique haplotype (Figure 4). However, it is worth noting that all-black sheep and black spotted sheep also share this cluster with blackheads, suggesting that other loci are also involved to affect the extent and location of melanin deposition, resulting in these different pigmentation patterns.

Figure 4.

Figure 4.

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Haplotype network based on pairwise differences within MC1R gene. Each circle represents a haplotype, and the size of the circle indicates the number of samples contained in that haplotype. Green represents all-white sheep, yellow for spotted sheep (with black spots on the head or body), blue for black-headed sheep (with black only the head), orange for all-black sheep, and rusty red represents wild Mouflon sheep (brown).

Discussion

Sheep are one of the earliest domesticated animals in the world. It is not only an important source of human meat, but also an important textile material (Rochus et al., 2018). In addition, coat color is an important economic trait for the sheep breeds which are kept for skins and wool, and can also be used for species identification and characterization (Fontanesi et al., 2010). Therefore, it is important to identify genomic regions and genetic variations associated with sheep coat color traits.

We analyzed the genetic basis of the divergence of different head colors in sheep by selective signal and haplotype analysis. Most interestingly, we found the same haplotype in African and Asian sheep with similar black-headed phenotypes, both containing MC1R gene. Black-headed Dorper in African and Bayinbuluke sheep in Asia were raised and selected independently, suggesting that converging changes in the MC1R gene range led to this common phenotype. The MC1R is a seven-transmembrane domain G-protein-coupled receptor, which mainly exists in melanocytes and can be used as a switch to control the synthesis of melanin types for deposition in tissues (Mountjoy et al., 1992; Gebreselassie et al., 2020). When MC1R was activated by melanocyte-stimulating hormone from pituitary, MC1R initiated a downstream signal cascade, resulting in melanin eumelanin production by melanocytes (Swope et al., 2018; Jiang et al., 2021). The MC1R gene was reported to be a potential candidate gene that plays an important role in melanin production and wool pigmentation, and is associated with black fur color in mammals (Våge et al., 1999; Mao et al., 2010; Li et al., 2013; Switonski et al., 2013; Matsumoto et al., 2020). Hepp et al. found that MC1R was involved in the control of dark wool color in Brazilian Creole sheep, where the dominant allele (ED) was only found in colored animals, and the recessive allele (E+) was only homozygous in white individuals (Hepp et al., 2012). In our study, the selective signal and the long haplotype of the selected regions have come from the black-headed sheep breeds. Meanwhile, we also found two missense mutations in the MC1R gene, and hypothesized that the missense mutations may disrupt the melanic pigmentation receptor of MC1R, consequently preventing normal pigmentation of coat color.

A notable example is the conserved role of the MC1R in mammalian pigmentation which could affect the degree and region of melanosis (Andersson, 2003; Yang et al., 2013). We studied the relationship between MC1R haplotypes and coat color using resequencing data from black-headed, black-spotted, all-black, all-white, and Mouflon sheep in 460 sheep. Indeed, we found an obvious haplotype, cluster pattern in which individuals with different degrees of pigmentation clustered together, and white individuals clustered together. Studies have shown that MC1R interacts with other genes to regulate a variety of coat colors, such as ASIP gene (Fontanesi et al., 2011; Hepp et al., 2016). Besides, animal skin pigmentation is a complex trait controlled by multiple genes and may be influenced by different types of multi-gene interactions (Barsh, 1996; Hubbard et al., 2010; Rochus et al., 2019; Shi et al., 2021). Therefore, we speculated that in addition to the influence of MC1R haplotype on black-headed sheep, the coat color of other breeds with black faces, all-black, and black spotted may also be jointly regulated by other coat color genes.

Conclusions

In this study, we found that MC1R is likely to control the black-headed coat color in sheep. We further analyzed MC1R haplotypes using whole genome sequence data available and confirmed the association between MC1R haplotypes and pigmentation patterns in sheep providing novel insights into the coat color genetics of sheep.

Supplementary Material

skad084_suppl_Supplementary_Figure_S1
Click here for additional data file. (81.6KB, docx)
skad084_suppl_Supplementary_Table_S1
Click here for additional data file. (38.3KB, xlsx)

Acknowledgments

This work was funded by the National Key R&D Program of China (2022YFF1000100 & 2022YFD1300200) and Shaanxi Livestock and Poultry Breeding Double-chain Fusion Key Project (2022GD-TSLD-46-0401). We also thank the National Supercomputing Center in Xi’an for providing computing resources.

Glossary

Abbreviations

ASIP

agouti signaling protein

BDP

black-headed Dorper

BYK

Bayinbuluke

F ST

fixed index

MC1R

melanocortin receptor 1

PCA

principal component analysis

STH

Small-tailed Han

WDP

white-headed Dorper

Contributor Information

Qian Zhou, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Chunna Cao, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Huanhuan Zhang, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Yilin Liang, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Xinyue Zhang, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Yuxin Kang, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Wenwen Fang, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Xianyong Lan, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Ran Li, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Chuanying Pan, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

Conflict of Interest Statement

The authors declare no real or perceived conflicts of interest.

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