Comprehensive genetic testing combined with citizen science reveals a recently characterized ancient MC1R mutation associated with partial recessive red phenotypes in dog

Abstract Background: The Melanocortin 1 Receptor (MC1R) plays a central role in regulation of coat color determination in various species and is commonly referred to as the “E (extension) Locus”. Allelic variation of the MC1R gene is associated with coat color phenotypes EM (melanistic mask), EG (grizzle/domino) and e1-3 (recessive red) in dogs. In addition, a previous study of archeological dog specimens over 10,000 years of age identified a variant p.R301C in the MC1R gene that may have influenced coat color of early dogs.Results: Commercial genotyping of 11,750 dog samples showed the R301C variant of the MC1R gene was present in 35 breeds or breed varieties, at an allele frequency of 1.5% in the tested population. We detected no linkage disequilibrium between R301C and other tested alleles of the E locus. Based on current convention we propose that R301C should be considered a novel allele of the E locus, which we have termed eA for “e ancient red”. Phenotype analysis of owner-provided dog pictures reveals that the eA allele has an impact on coat color and is recessive to wild type E and dominant to the e alleles. In dominant black (KB/*) dogs it can prevent the phenotypic expression of the K locus, and the expressed coat color is solely determined by the A locus. In the absence of dominant black, eA/eA and eA/e genotypes result in the coat color patterns referred to in their respective breed communities as domino in Alaskan Malamute and other Spitz breeds, grizzle in Chihuahua, and pied in Beagle.Conclusions: This study demonstrates a large genotype screening effort to identify the frequency and distribution of the MC1R R301C variant, one of the earliest mutations captured by canine domestication, and citizen science empowered characterization of its impact on coat color.

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Comprehensive genetic testing combined with citizen science reveals a recently characterized ancient MC1R mutation associated with partial recessive red phenotypes in dog

Canine Medicine and Genetics ◽

10.1186/s40575-020-00095-7 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Heidi Anderson ◽

Leena Honkanen ◽

Päivi Ruotanen ◽

Julia Mathlin ◽

Jonas Donner

Keyword(s):

Citizen Science ◽

Coat Color ◽

Allelic Variation ◽

Phenotypic Expression ◽

Wild Type ◽

Melanocortin 1 Receptor ◽

Phenotype Analysis ◽

Genotype Screening ◽

Dominant Black

Abstract Background The Melanocortin 1 Receptor (MC1R) plays a central role in regulation of coat color determination in various species and is commonly referred to as the “E (extension) Locus”. Allelic variation of the MC1R gene is associated with coat color phenotypes EM (melanistic mask), EG (grizzle/domino) and e1–3 (recessive red) in dogs. In addition, a previous study of archeological dog specimens over 10,000 years of age identified a variant p.R301C in the MC1R gene that may have influenced coat color of early dogs. Results Commercial genotyping of 11,750 dog samples showed the R301C variant of the MC1R gene was present in 35 breeds or breed varieties, at an allele frequency of 1.5% in the tested population. We detected no linkage disequilibrium between R301C and other tested alleles of the E locus. Based on current convention we propose that R301C should be considered a novel allele of the E locus, which we have termed eA for “e ancient red”. Phenotype analysis of owner-provided dog pictures reveals that the eA allele has an impact on coat color and is recessive to wild type E and dominant to the e alleles. In dominant black (KB/*) dogs it can prevent the phenotypic expression of the K locus, and the expressed coat color is solely determined by the A locus. In the absence of dominant black, eA/eA and eA/e genotypes result in the coat color patterns referred to in their respective breed communities as domino in Alaskan Malamute and other Spitz breeds, grizzle in Chihuahua, and pied in Beagle. Conclusions This study demonstrates a large genotype screening effort to identify the frequency and distribution of the MC1R R301C variant, one of the earliest mutations captured by canine domestication, and citizen science empowered characterization of its impact on coat color.

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Comprehensive genetic testing combined with citizen science reveals a recently characterized ancient MC1R mutation is associated with partial recessive red phenotypes in dog

10.21203/rs.3.rs-36023/v1 ◽

2020 ◽

Author(s):

Heidi Anderson ◽

Leena Honkanen ◽

Päivi Ruotanen ◽

Julia Mathlin ◽

Jonas Donner

Keyword(s):

Citizen Science ◽

Coat Color ◽

Allelic Variation ◽

Wild Type ◽

Melanocortin 1 Receptor ◽

Phenotype Analysis ◽

Genotype Screening ◽

Dominant Black ◽

Novel Allele

Abstract Background The Melanocortin 1 Receptor (MC1R) plays a central role in regulation of coat color determination in dogs and is commonly referred to as the “E (extension) Locus”. Allelic variation of the MC1R gene is associated with coat color phenotypes EM (melanistic mask), EG (grizzle/domino) and e1–3 (recessive red) in dogs. In addition, a previous study of archeological dog specimens over 10,000 years of age identified a variant p.R301C in the MC1R gene that may have influenced coat color of early dogs. Results Commercial genotyping of 11,726 dog samples showed the R301C variant of the MC1R gene was present in 34 breeds or breed varieties, at an allele frequency of 1.48% in the tested population. We detected no linkage disequilibrium between R301C and other tested alleles of the E locus. Based on current convention we propose that R301C should be considered a novel allele of the E locus, which we have termed eA for “e ancient”. Phenotype analysis of owner-provided dog pictures reveals eA allele has an impact on coat color and is recessive to wild type E and dominant to the e alleles. In dominant black (KB/*) dogs it can prevent the expression of the K locus, and the expressed coat color is solely determined by the A locus. In the absence of dominant black, eA/eA and eA/e genotypes result in the coat color patterns referred to in their respective breed communities as domino in Alaskan Malamute and other Spitz breeds, grizzle in Chihuahua, and pied in Beagle. Conclusions This study demonstrates a large genotype screening effort to identify the frequency and distribution of the MC1R R301C variant, one of the earliest mutations captured by canine domestication, and citizen science empowered characterization of its impact on coat color.

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Comprehensive genetic testing combined with citizen science reveals a recently characterized ancient MC1R mutation is associated with partial recessive red phenotypes in dog

10.21203/rs.3.rs-36023/v2 ◽

2020 ◽

Author(s):

Heidi Anderson ◽

Leena Honkanen ◽

Päivi Ruotanen ◽

Julia Mathlin ◽

Jonas Donner

Keyword(s):

Citizen Science ◽

Coat Color ◽

Allelic Variation ◽

Wild Type ◽

Melanocortin 1 Receptor ◽

Phenotype Analysis ◽

Genotype Screening ◽

Dominant Black ◽

Novel Allele

Abstract Background: The Melanocortin 1 Receptor (MC1R) plays a central role in regulation of coat color determination in dogs and is commonly referred to as the “E (extension) Locus”. Allelic variation of the MC1R gene is associated with coat color phenotypes EM (melanistic mask), EG (grizzle/domino) and e1-3 (recessive red) in dogs. In addition, a previous study of archeological dog specimens over 10,000 years of age identified a variant p.R301C in the MC1R gene that may have influenced coat color of early dogs.Results: Commercial genotyping of 11,750 dog samples showed the R301C variant of the MC1R gene was present in 35 breeds or breed varieties, at an allele frequency of 1.5% in the tested population. We detected no linkage disequilibrium between R301C and other tested alleles of the E locus. Based on current convention we propose that R301C should be considered a novel allele of the E locus, which we have termed eA for “e ancient red”. Phenotype analysis of owner-provided dog pictures reveals that the eA allele has an impact on coat color and is recessive to wild type E and dominant to the e alleles. In dominant black (KB/*) dogs it can prevent the expression of the K locus, and the expressed coat color is solely determined by the A locus. In the absence of dominant black, eA/eA and eA/e genotypes result in the coat color patterns referred to in their respective breed communities as domino in Alaskan Malamute and other Spitz breeds, grizzle in Chihuahua, and pied in Beagle.Conclusions: This study demonstrates a large genotype screening effort to identify the frequency and distribution of the MC1R R301C variant, one of the earliest mutations captured by canine domestication, and citizen science empowered characterization of its impact on coat color.

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Sequence Characterization of theMC1RGene in Yak (Poephagus grunniens) Breeds with Different Coat Colors

Journal of Biomedicine and Biotechnology ◽

10.1155/2009/861046 ◽

2009 ◽

Vol 2009 ◽

pp. 1-6 ◽

Cited By ~ 10

Author(s):

Shi-Yi Chen ◽

Yi Huang ◽

Qing Zhu ◽

Luca Fontanesi ◽

Yong-Gang Yao ◽

...

Keyword(s):

Coat Color ◽

Extracellular Loop ◽

Wild Type ◽

Coding Region ◽

Functional Effect ◽

Nucleotide Substitutions ◽

Melanocortin 1 Receptor ◽

Sequence Characterization ◽

Potential Association

Melanocortin 1 receptor (MC1R) gene plays a key role in determining coat color in several species, including the cattle. However, up to now there is no report regarding theMC1Rgene and the potential association of its mutations with coat colors in yak (Poephagus grunniens). In this study, we sequenced the encoding region of theMC1Rgene in three yak breeds with completely white (Tianzhu breed) or black coat color (Jiulong and Maiwa breeds). The predicted coding region of the yakMC1Rgene resulted of 954 bp, the same to that of the wild-type cattle sequence, with >99% identity. None of the mutation events reported in cattle was found. Comparing the yak obtained sequences, five nucleotide substitutions were detected, which defined three haplotypes (EY1,EY2, andEY3). Of the five mutations, two, characterizing theEY1haplotype, were nonsynonymous substitutions (c.340C>A and c.871G>A) causing amino acid changes located in the first extracellular loop (p.Q114K) and in the seventh transmembrane region (p.A291T).In silicoprediction might indicate a functional effect of the latter substitution. However, all three haplotypes were present in the three yak breeds with relatively consistent frequency distribution, despite of their distinguished coat colors, which suggested that there was no across-breed association between haplotypes or genotypes and black/white phenotypes, at least in the investigated breeds. Other genes may be involved in affecting coat color in the analyzed yaks.

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Genetic characterization of coat color genes in Brazilian Crioula sheep from a conservation nucleus

Pesquisa Agropecuária Brasileira ◽

10.1590/s0100-204x2017000800007 ◽

2017 ◽

Vol 52 (8) ◽

pp. 615-622 ◽

Cited By ~ 4

Author(s):

Lilian Cristina Gomes Cavalcanti ◽

José Carlos Ferrugem Moraes ◽

Danielle Assis de Faria ◽

Concepta Margaret McManus ◽

Alcebiades Renato Nepomuceno ◽

...

Keyword(s):

Coat Color ◽

Color Variation ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Epistatic Interactions ◽

Low Frequencies ◽

Melanocortin 1 Receptor ◽

Tyrosinase Related Protein

Abstract: The objective of this work was to identify single nucleotide polymorphisms (SNPs) in resequencing data from MC1R, ASIP, and TYRP1 genes derived from Crioula sheep (Ovis aris) with different coat colors. Polymorphisms in the ASIP (agouti-signaling protein), MC1R (melanocortin 1 receptor), and TRYP1 (tyrosinase-related protein 1) genes were analyzed in 115 sheep from Embrapa’s conservation nucleus of crioula sheep, in Brazil. A total of 7,914 bp were sequenced per animal, and 14 SNPs were identified. Two additional assays were performed to detect duplications and deletions in the ASIP gene. Ninety-five percent of the coat color variation was explained by epistatic interactions observed between specific alleles in the MC1R and ASIP genes. Evidence suggests an important role of TYRP1 variants for wool color, despite their low frequencies. The marker panel was efficient enough in predicting coat color in the studied animals and, therefore, can be used to implement a marker-assisted selection program in the conservation nucleus of sheep of the crioula breed.

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Melanocortin Receptor 1 (MC1R) Mutations and Coat Color in Pigs

Genetics ◽

10.1093/genetics/150.3.1177 ◽

1998 ◽

Vol 150 (3) ◽

pp. 1177-1185 ◽

Cited By ~ 8

Author(s):

J M H Kijas ◽

R Wales ◽

A Törnsten ◽

P Chardon ◽

M Moller ◽

...

Keyword(s):

Coat Color ◽

Melanocortin Receptor ◽

Missense Mutations ◽

Wild Type ◽

Black Spots ◽

European Wild Boar ◽

Classical Extension ◽

Strong Candidate ◽

Dominant Black ◽

Black Color

Abstract The melanocortin receptor 1 (MC1R) plays a central role in regulation of eumelanin (black/brown) and phaeomelanin (red/yellow) synthesis within the mammalian melanocyte and is encoded by the classical Extension (E) coat color locus. Sequence analysis of MC1R from seven porcine breeds revealed a total of four allelic variants corresponding to five different E alleles. The European wild boar possessed a unique MC1R allele that we believe is required for the expression of a wild-type coat color. Two different MC1R alleles were associated with the dominant black color in pigs. MC1R*2 was found in European Large Black and Chinese Meishan pigs and exhibited two missense mutations compared with the wild-type sequence. Comparative data strongly suggest that one of these, L99P, may form a constitutively active receptor. MC1R*3 was associated with the black color in the Hampshire breed and involved a single missense mutation D121N. This same MC1R variant was also associated with EP, which results in black spots on a white or red background. Two different missense mutations were identified in recessive red (e/e) animals. One of these, A240T, occurs at a highly conserved position, making it a strong candidate for disruption of receptor function.

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Molecular characterization of coat color gene in Sahiwal versus Karan Fries bovine

Journal of Genetic Engineering and Biotechnology ◽

10.1186/s43141-021-00117-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Talla Sridhar Goud ◽

Ramesh Chandra Upadhyay ◽

Vijaya Bhaskar Reddy Pichili ◽

Suneel Kumar Onteru ◽

Kiranmai Chadipiralla

Keyword(s):

Molecular Characterization ◽

Coat Color ◽

Genomic Sequence ◽

Color Variation ◽

Single Amino Acid ◽

Sequence Length ◽

Melanocortin 1 Receptor ◽

Sahiwal Cattle ◽

Karan Fries

Abstract Background Melanocortin-1-receptor gene (MC1R) plays a significant role in signaling cascade of melanin production. In cattle, the coat colors, such as red and black, are an outcome of eumelanin and pheomelanin pigments, respectively. The coat colors have become critical factors in the animal selection process. This study is therefore aimed at the molecular characterization of reddish-brown coat-colored Sahiwal cattle in comparison to the black and white-colored Karan Fries. Results The Sequence length of the MC1R gene was 954 base pairs in Sahiwal cattle. The sequences were examined and submitted to GenBank Acc.No. MG373575 to MG373605. Alignment of both (Sahiwal and Karan Fries) protein sequences by applying ClustalO multiple sequence alignment programs revealed 99.8–96.8% sequence similarity within the bovine. MC1R gene phylogenetic studies were analyzed by MEGA X. The gene MC1R tree, protein confines, and hereditary difference of cattle were derived from Ensemble Asia Cow Genome Browser 97. One unique single-nucleotide polymorphism (c.844C>A) (SNP) was distinguished. Single amino acid changes were detected in the seventh transmembrane structural helix region, with SNP at p.281 T>N of MC1R gene in Karan Fries cattle. Conclusions In this current research, we first distinguished the genomic sequence of the MC1R gene regions that showed evidence of coat variation between Indian indigenous Sahiwal cattle breed correlated with crossbreed Karan Fries. These variations were found in the Melanocortin 1 receptor coding regions of the diverse SNPs. The conclusions of this research provide new insights into understanding the coat color variation in crossbreed compared to the Indian Sahiwal cattle. Graphical abstract

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Molecular and pharmacological characterization of dominant black coat color in sheep

Mammalian Genome ◽

10.1007/s003359900939 ◽

1999 ◽

Vol 10 (1) ◽

pp. 39-43 ◽

Cited By ~ 145

Author(s):

Dag Inge Våge ◽

Helge Klungland ◽

Dongsi Lu ◽

Roger D. Cone

Keyword(s):

Coat Color ◽

Pharmacological Characterization ◽

Dominant Black

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The melanocortin 1 receptor is the principal mediator of the effects of agouti signaling protein on mammalian melanocytes

Journal of Cell Science ◽

10.1242/jcs.114.5.1019 ◽

2001 ◽

Vol 114 (5) ◽

pp. 1019-1024 ◽

Cited By ~ 2

Author(s):

Z.A. Abdel-Malek ◽

M.C. Scott ◽

M. Furumura ◽

M.L. Lamoreux ◽

M. Ollmann ◽

...

Keyword(s):

Coat Color ◽

Wild Type Mouse ◽

Tyrosinase Activity ◽

Loss Of Function ◽

Wild Type ◽

Melanocortin 1 Receptor ◽

Signaling Protein ◽

Melanocyte Stimulating Hormone ◽

Related Proteins ◽

Stimulating Hormone

The agouti gene codes for agouti signaling protein (ASP), which is temporally expressed in wild-type mouse follicular melanocytes where it induces pheomelanin synthesis. Studies using purified full-length agouti signaling protein has shown that it competes with (α)-melanocyte stimulating hormone for binding to the melanocortin 1 receptor. We have investigated whether ASP binds exclusively to the melanocortin 1 receptor expressed on mouse melanocytes in primary culture, or additionally activates a receptor that has not been identified yet. We have compared the responses of congenic mouse melanocytes derived from C57 BL/6J-E(+)/E(+), e/e, or E(so)/E(so) mice to (alpha)-MSH and/or ASP. E(+)/E(+) melanocytes express the wild-type melanocortin 1 receptor, e/e melanocytes express a loss-of-function mutation in the melanocortin 1 receptor that results in a yellow coat color, and E(so)/E(so) is a mutation that causes constitutive activation of the melanocortin 1 receptor and renders melanocytes unresponsive to (alpha)-melanocyte stimulating hormone. Mouse E(+)/E(+) melanocytes, but not e/e or E(so)/E(so) melanocytes, respond to agouti signaling protein with decreased basal tyrosinase activity, and reduction in levels of tyrosinase and tyrosinase-related proteins 1 and 2. Only in E(+)/E(+) melanocytes does agouti signaling protein abrogate the stimulatory effects of (alpha)-melanocyte stimulating hormone on cAMP formation and tyrosinase activity. These results indicate that a functional melanocortin 1 receptor is obligatory for the response of mammalian melanocytes to agouti signaling protein.

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