MC1R studies in dogs with melanistic mask or brindle patterns

Black mask is a characteristic pattern in which red, yellow, tan, fawn, or brindle dogs exhibit a melanistic muzzle which may extend up onto the ears. Melanistic mask is inherited in several breeds as an autosomal dominant trait, and appears to be a fixed trait in a few breeds of dogs. A MC1R nonsense mutation, R306ter, has been shown to cause a completely red or yellow coat color in certain breeds such as Irish setters, yellow Labrador retrievers, and golden retrievers. The amino acid sequence for the melanocortin receptor 1 gene (MC1R) was examined in 17 dogs with melanistic masks from seven breeds, 19 dogs without melanistic masks, and 7 dogs in which their coat color made the mask difficult to distinguish. We also examined nine brindle dogs of four breeds, including three dogs who also had a black mask. No consistent amino acid change was observed in the brindle dogs. All dogs with a melanistic mask had at least one copy of a valine substitution for methionine at amino acid 264 (M264V) and none were homozygous for the premature stop codon (R306ter). These results suggest that black mask, but not brindle, is caused by a specific MC1R allele.     

Mutations in the melanocortin 1 receptor (MC1R) gene are associated with coat colours in the domestic rabbit (Oryctolagus cuniculus)

We sequenced almost the complete coding region of the MC1R gene in several domestic rabbits (Oryctolagus cuniculus) and identified four alleles: two wild-type alleles differing by two synonymous single nucleotide polymorphisms (c.333A>G;c.555T>C), one allele with a 30-nucleotide in-frame deletion (c.304_333del30) and one allele with a 6-nucleotide in-frame deletion (c.280_285del6). A polymerase chain reaction-based protocol was used to distinguish the wild-type alleles from the other two alleles in 263 rabbits belonging to 37 breeds or strains. All red/fawn/yellow rabbits were homozygous for the c.304_333del30 allele. This allele represents the recessive e allele at the extension locus identified through pioneering genetic studies in this species. All Californian, Checkered, Giant White and New Zealand White rabbits were homozygous for allele c.280_285del6, which was also observed in the heterozygous condition in a few other breeds. Black coat colour is part of the standard colour in Californian and Checkered breeds, in contrast to the two albino breeds, Giant White and New Zealand White. Following the nomenclature established for the rabbit extension locus, the c.280_285del6 allele, which is dominant over c.304_333del30, may be allele E(D) or allele E(S).     

The role of MC1R gene in buffalo coat color

Melanocortin-1 receptor (MC1R) plays a major role in pigmentation in many species. To investigate if the MC1R gene is associated with coat color in water buffalo, the coding region of MC1R gene of 216 buffalo samples was sequenced, which included 49 black river buffalo (Murrah and Nili-Ravi), 136 swamp buffalo (Dehong, Diandongnan, Dechang, Guizhou, and Xilin) with white and gray body, and 31 hybrid offspring of river buffalo Nili-Ravi (or Murrah) and swamp buffalo. Among the three variation sites found, SNP684 was synonymous, while SNP310 and SNP384 were nonsynonymous, leading to p.S104G and p.I128M changes, respectively. Only Individuals carrying homozygote EBR/EBR were black. The genotype and phenotype analysis of the hybrid offspring of black river buffalo and gray swamp buffalo further revealed that the river buffalo type allele EBR or the allele carrying the amino acid p.104S was important for the full function of MC1R. The in silico functional analysis showed that the amino acid substitutions p.G104S and p.M128I had significant impact on the function of MC1R. Above results indicate that the allele EBR or the allele carrying the amino acid p.104S was associated with the black coat color in buffalo.     

Differential expression of MC1R gene in Liaoning Cashmere goats with different coat colors

Melanocyte stimulating hormone receptor (MC1R) has been known as a regulator of eumelanin and phaeomelanin production in the melanocytes, and MC1R mutations causing coat color changes are known in many vertebrates; however, there are no research reports about the differentially expression of MC1R gene and its coding protein in Cashmere goats with different coat color. We examined the presence of MC1R distribution and MC1R protein and gene expression in the white Cashmere goats and black Cashmere goats, respectively; q-PCR, Western blot and immunhistochemical analysis showed that the expression of the MC1R gene in the black Cashmere goats was 3.39 fold more than the white ones (p?<?0.01), and Cashmere goats with black genotype had significantly higher (2.03, p?<?0.01) MC1R protein expression than white genotype in the all investigated samples. Moreover, all Cashmere goats with different coat color available for immunhistochemical analysis showed either lower (white Cashmere goats) or higher (black Cashmere goats) expression of the MC1R protein; these findings suggested that it had a relationship between the MC1R and the coat color of Cashmere goats. That could lay the foundation for the further research of the MC1R and coat color controllability regulation of the Cashmere goats.     

FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ² = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism.     

Melanocortin 1-receptor (MC1R) mutations are associated with plumage colour in chicken

The co-segregation of plumage colour and sequence polymorphism in the melanocortin 1-receptor gene (MC1R) was investigated using an intercross between the red junglefowl and White Leghorn chickens. The results provided compelling evidence that the Extended black (E) locus controlling plumage colour is equivalent to MC1R. E/MC1R was assigned to chromosome 11 with overwhelming statistical support. Sequence analysis indicated that the E92K substitution, causing a constitutively active receptor in the sombre mouse, is the most likely causative mutation for the Extended black allele carried by the White Leghorn founders in this intercross. The MC1R sequence associated with the recessive buttercup (ebc) allele indicated that this allele evolved from a dominant Extended black allele as it shared the E92K and M71T substitutions with some E alleles. It also carried a third missense mutation H215P which thus may interfere with the constitutive activation of the receptor caused by E92K (and possibly M71T).     

Two missense mutations in melanocortin 1 receptor (MC1R) are strongly associated with dark ventral coat color in reindeer (Rangifer tarandus)

The protein‐coding region of melanocortin 1 receptor (MC1R) was sequenced to identify potential variation affecting coat color in reindeer (Rangifer tarandus). A T→C sequence variation at nucleotide position 218 (c.218T>C) causing an amino acid (aa) change from methionine to threonine at aa position 73 (p.Met73Thr) was identified. In addition, a T→G sequence variation was found at nucleotide position 839 (c.839T>G), causing phenylalanine to be exchanged by cysteine at aa position 280 (p.Phe280Cys). The two sequence variants (c.218C and c.839G) were found to be closely associated with a darker belly coat compared with animals not having any of these two variants. The aa acid change p.Met73Thr affects the same position as p.Met73Lys previously reported to give constitutive activation of MC1R in black sheep (Ovis aries), whereas p.Phe280Cys is identical to one of two variants previously reported to be associated with dark coat color in Arctic fox (Alopex lagopus), supporting that the two variants found in reindeer are functional. The complete absence of Thr73 and Cys280 among the 51 wild reindeer analyzed provides some evidence that these variants are more common in the domestic herds.     

牛黑素皮质素受体1(MC1R)基因与毛色表形的研究

牛MC1R基因不仅与毛色有关, 而且与牛乳中乳蛋白的含量有关。利用PCR-RFLP和DNA测序技术分析了中国荷斯坦黑白花牛, 中国荷斯坦红白花牛, 鲁西黄牛和渤海黑牛共4个品种的MC1R基因。共检测出3种等位基因(E^D, E⁺, e)。中国荷斯坦黑白花牛主要是E^D和E⁺等位基因(E^D=0.12、E⁴=0.80); 渤海黑牛也主要是E^D和E⁺等位基因(E^D=0.52、E⁺=0.47); 中国荷斯坦红白花牛和鲁西黄牛大多为e等位基因(e=0.95)。中国荷斯坦红白花牛和鲁西黄牛还存在E⁺/e基因型。由此推测E^D和E⁺等位基因导致黑色素合成。另外发现牛MC1R基因编码区725处存在一重要的SNP(单核苷酸多态性)。     

Common variants in the obesity-associated genes FTO and MC4R are not associated with risk of colorectal cancer

BackgroundObesity is a convincing risk factor for colorectal cancer. Genetic variants in or near FTO and MC4R are consistently associated with body mass index and other body size measures, but whether they are also associated with colorectal cancer risk is unclear.MethodsIn the discovery stage, we tested associations of 677 FTO and 323 MC4R single nucleotide polymorphisms (SNPs) 100 kb upstream and 300 kb downstream from each respective locus with risk of colorectal cancer in data from the Colon Cancer Family Registry (CCFR: 1960 cases; 1777 controls). Next, all SNPs that were nominally statistically significant (p < 0.05) in the discovery stage were included in replication analyses in data from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO: 9716 cases; 9844 controls).ResultsIn the discovery stage, 43 FTO variants and 18 MC4R variants were associated with colorectal cancer risk (p < 0.05). No SNPs remained statistically significant in the replication analysis after accounting for multiple comparisons.ConclusionWe found no evidence that individual variants in or near the obesity-related genes FTO and MC4R are associated with risk of colorectal cancer.     

Non‐synonymous SNPs in MC1R gene are associated with the extended black variant in domestic ducks (Anas platyrhynchos)

In this study, we performed a sequence characterization of the duck melanocortin 1 receptor (alpha‐melanocyte stimulating hormone receptor) (MC1R) gene to analyze the relationship between MC1R polymorphism and the extended black variant in domestic ducks based on the extended black (E) and non‐extended black (e⁺) allele hypothesis of the duck MC1R gene. Both c.52G>A and c.376G>A substitutions are highly associated with the duck extended black variant (P < 0.01), but the novel c.52G>A substitution is more of a fit for the allele hypothesis of the duck MC1R gene.     

Two SNPs in the SILV gene are associated with silver coat colour in ponies

In horses, a pigment dilution acting only on black eumelanin is the so-called silver coat colour, which is characterized by a chocolate-to-reddish body with a white mane and tail. Using information from other species, we focused our study on SILV as a possible candidate gene for the equine silver phenotype. A 1559-bp genomic fragment was sequenced in 24 horses, and five SNPs were detected. Two of the five SNPs (DQ665301:g.697A>T and DQ665301:g.1457C>T) were genotyped in 112 horses representing eight colour phenotypes. Both mutations were completely associated with the silver phenotype: all eumelanin-producing horses (blacks and bays) with atypical white mane and tail were carriers of the [g.697T; g.1457T] haplotype. We identified this haplotype as well as the silver phenotype only in Shetland ponies and Icelandic horses. Horses without eumelanin (chestnuts) were carriers of the [g.697T; g.1457T] haplotype, but they showed no phenotypic effect. The white or flaxen mane often detected in chestnuts is presumably based on another SILV mutation or on polymorphisms in other genes.     

TYRP1 and MC1R genotypes and their effects on coat color in dogs

We used PCR amplification of cDNA prepared from skin biopsies to determine the nearly full-length, protein-coding sequence of dog TYRP1, and to define sequence variants potentially responsible for the B locus. One common variant contained a premature stop codon in exon 5 (Q331ter), and the other deleted a proline residue in exon 5 (345delP). A third variant in exon 2 (S41C) occurred less frequently. We genotyped 43 brown (including brown and white) and 34 black (including tricolor, black-and-tan, and black and white) dogs. All 43 of the brown group carried two or more of these sequence variants likely to interfere with TYRP1 function, whereas 0 of 34 in the black group carried two or more of these variants (10 carried one variant). We also genotyped 13 black-nosed and 10 brown-nosed dogs whose coat color was described as red, yellow, gold, apricot, or orange (including various degrees of white). All these dogs were homozygous for a R306X MC1R variant shown to be associated with these coat color phenotypes. The black or brown nose correlated perfectly with the absence or presence of the same three TYRP1 variants described above. TYRP1 was linkage mapped to dog chromosome 11, with a SNP in exon 7.     

Melanocortin receptor 1 (MC1R) mutations and coat color in pigs.

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.     

Xp deletions associated with autism in three females

We report eight females with small deletions of the short arm of the X chromosome, three of whom showed features of autism. Our results suggest that there may be a critical region for autism in females with Xp deletions between the pseudoautosomal boundary and DXS7103. We hypothesise that this effect might be due either to the loss of function of a specific gene within the deleted region or to functional nullisomy resulting from X inactivation of the normal X chromosome. Received: 6 April 1998 / Accepted: 4 November 1998     

MC1R polymorphism associated with plumage color variations in Coturnix chinensis

The melanocortin 1 receptor (MC1R) gene was investigated as a candidate for plumage variations in Chinese painted quail, Coturnix chinensis. Four silent and two missense nucleotide polymorphisms were identified. The correspondent amino acid changes, p.Glu92Lys and p.Pro292Leu, were found in Blue Face and Red Breasted animals respectively. Blue Face is a melanic phenotype similar to the co‐dominant Extended Brown of Japanese quail, and both share the p.Glu92Lys mutation. The association of p.Pro292Leu with the recessive Red Breasted was confirmed in 23 animals from an experimental F2 cross.     

Not another type of potato: MC1R and the russet coloration of Burmese cats

The Burmese is a breed of domestic cat that originated in Southeast Asia and was further developed in the United States. Variants in melanocortin 1 receptor (MC1R) causes common coat colour phenotypes in a variety of mammalian species but only limited colour variation in the domestic cat. Known as the extension (E) locus, melanocortin 1 receptor (MC1R) interacts with the agouti locus to produce the eumelanin and pheomelanin pigments. Recently, a novel reddish coloration, which is termed russet, was identified in the Burmese cat breed. Because this russet Burmese coloration changes with aging, MC1R was suggested as candidate gene. The similar colouration in specific lineages of Norwegian Forest cat known as amber (e) (c.250G>A; p.Asp84Asn) was excluded for this Burmese phenotype. The complete 954‐bp coding region of MC1R was directly sequenced in russet Burmese and suspected carriers. A 3‐bp deletion (c.439_441del) associated with the deletion of a phenyalanine (p.Phe146del) in the protein sequence was identified. All russet coloured cats were homozygous for the variant, and all obligate carriers were heterozygous, confirming that the deletion segregated concordantly with colouring in Burmese cats from the New Zealand foundation lineage. The variant was not identified in 442 cats from 26 different breeds and random‐bred cats. Twenty‐six Burmese from the USA did not have the variant. This MC1R variant defines a unique coloration and the second breed‐specific MC1R variant in cats. The interactions of the two recessive feline MC1R alleles (E  >  e, e^r) is unknown.     

Missense SNP of the MC1R gene is associated with plumage variation in the Gyrfalcon (Falco rusticolus)

A single nucleotide polymorphism (MC1R: c.376A>G) in the MC1R gene was found to be highly correlated with pigment phenotype in the Gyrfalcon. Homozygous genotypes c.376GG and c.376AA were found to dominate the extreme white and dark plumage types respectively, and heterozygotes occurred mainly in intermediate phenotypes. However, some heterozygotes were associated with extreme phenotypes, indicating that melanism/albinism might also involve other loci.     

Deletions in the COL10A1 gene are not associated with skeletal changes in dogs

Type 10 collagen alpha 1 (COL10A1) is a short-chain collagen of cartilage synthesized by chondrocytes during the growth of long bones. COL10A1 mutations, which frequently result in COL10A1 haploinsufficiency, have been identified in patients with Schmid metaphyseal chondrodysplasia (SMCD), a cartilage disorder characterized by short-limbed short stature and bowed legs. Similarities between SMCD and short stature in various dog breeds suggested COL10A1 as a candidate for canine skeletal dysplasia. We report the sequencing of the exons and promoter region of the COL10A1 gene in dog breeds fixed for a specific type of skeletal dysplasia known as chondrodysplasia, breeds that segregate the skeletal dysplasia phenotype, and control dogs of normal stature. Thirteen single nucleotide polymorphisms (SNPs), one insertion, and two deletions, one of which introduces a premature stop codon and likely results in nonsense-mediated decay and the degradation of the mutant allele product, were identified in the coding region. There appear to be no causal relationships between the polymorphisms identified in this study and short stature in dogs. Although COL10A1 haploinsufficiency is an important cause of SMCD in humans, it does not seem to be responsible for the skeletal dysplasia phenotype in these dog breeds. In addition, homozygosity for the nonsense allele does not result in the observed canine skeletal dysplasia phenotype. Electronic Supplementary Material Electronic Supplementary material is available for this article at and accessible for authorised users.