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A mutation in the MATP gene causes the cream coat color in the horse

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Abstract

In horses, basic colours such as bay or chestnut may be partially diluted to buckskin and palomino, or extremely diluted to cream, a nearly white colour with pink skin and blue eyes. This dilution is expected to be controlled by one gene and we used both candidate gene and positional cloning strategies to identify the "cream mutation". A horse panel including reference colours was established and typed for different markers within or in the neighbourhood of two candidate genes. Our data suggest that the causal mutation, a G to A transition, is localised in exon 2 of the MATP gene leading to an aspartic acid to asparagine substitution in the encoded protein. This conserved mutation was also described in mice and humans, but not in medaka.

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... While the eye color of most horses has been described as black or dark brown, horses with blue and amber eyes have also been described. Horses homozygous for the cream dilution allele, caused by a missense mutation in solute carrier family 45 member 2 (SLC45A2) have blue irises (Mariat et al. 2003). Also, several white coat pattern mutations (known as tobiano, overo, and splashed white) (Brooks et al. 2007, Hauswirth et al. 2012Santschi et al. 1998) have been implicated in blue iris pigmentation. ...
... Light Brown or Grey eye colors were excluded from the study because they were intermediary colors that could not be easily categorized as darker shades of the tiger-eye phenotype or lighter shades of the wild-type phenotype. Since blue eyes in horses have been associated with white spotting patterns and homozygosity for the cream dilution, these were also initially excluded from analysis (Mariat et al. 2003;Hauswirth et al. 2012). Additionally, because base coat color dilution genes affect iris pigmentation in horses, horses with a dilute coat color phenotype were also excluded from the study (Mariat et al. 2003). ...
... Since blue eyes in horses have been associated with white spotting patterns and homozygosity for the cream dilution, these were also initially excluded from analysis (Mariat et al. 2003;Hauswirth et al. 2012). Additionally, because base coat color dilution genes affect iris pigmentation in horses, horses with a dilute coat color phenotype were also excluded from the study (Mariat et al. 2003). Sixty-two horses were excluded based on this criteria. ...
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A unique eye color, called tiger-eye, segregates in the Puerto Rican Paso Fino Horse breed and is characterized by a bright yellow, amber, or orange iris. Pedigree analysis identified a simple autosomal recessive mode of inheritance for this trait. A genome-wide association study with 24 individuals identified a locus on ECA 1 reaching genome wide significance (Pcorrected =1.32 x 10(-5)). This ECA1 locus harbors the candidate gene, Solute Carrier Family 24 (Sodium/Potassium /Calcium Exchanger), Member 5 (SLC24A5), with known roles in pigmentation in humans, mice, and zebrafish. Humans with compound heterozygous mutations in SLC24A5 have oculocutaneous albinism type 6 (OCA6) which is characterized by dilute skin, hair, and eye pigmentation as well as ocular anomalies. Twenty tiger-eye horses were homozygous for a non-synonymous mutation in Exon 2 (p.Phe91Tyr) of SLC24A5 (called here Tiger-eye 1), which is predicted to be deleterious to protein function. Additionally, eight of the remaining 12 tiger-eye horses heterozygous for the p.Phe91Tyr variant were also heterozygous for a 628bp deletion encompassing all of Exon 7 of SLC24A5 (c.875-340_1081+82del) which we will call here the Tiger-eye 2 allele. None of the 122 brown-eyed horses were homozygous for either tiger-eye associated allele or were compound heterozygotes. Further, neither variant was detected in 196 horses from four related breeds, not known to have the tiger-eye phenotype. Here we propose that two mutations in SLC24A5 affect iris pigmentation in tiger-eye Puerto Rican Paso Fino horses. Further, unlike OCA6 in humans, the Tiger-eye 1 mutation in its homozygous state or as a compound heterozygote (Tiger-eye 1/ Tiger-eye 2), do not appear to cause ocular anomalies or change in coat color in the Puerto Rican Paso Fino horse.
... Six alleles (cream, pearl, sunshine, champagne, dun, silver) have been described in the horse that dilute either pheomelanin, eumelanin or both. Three of these alleles are caused by variants in SLC45A2; cream (Cr) c.457G>A, pearl (Prl) c.985G>A, sunshine (Sun) c.586G>A are thought to disrupt protein function and subsequent trafficking of molecules to the melanosomes resulting in a reduction of pigment production [3][4][5]. Both Prl and Sun follow a recessive mode of inheritance and dilute both eumelanin and pheomelanin, while Cr shows an incomplete dominant mode of inheritance and affects pheomelanin in a heterozygous state and both pheomelanin and eumelanin in a homozygous state [3]. ...
... Three of these alleles are caused by variants in SLC45A2; cream (Cr) c.457G>A, pearl (Prl) c.985G>A, sunshine (Sun) c.586G>A are thought to disrupt protein function and subsequent trafficking of molecules to the melanosomes resulting in a reduction of pigment production [3][4][5]. Both Prl and Sun follow a recessive mode of inheritance and dilute both eumelanin and pheomelanin, while Cr shows an incomplete dominant mode of inheritance and affects pheomelanin in a heterozygous state and both pheomelanin and eumelanin in a homozygous state [3]. The champagne (Ch) coat color dilution caused by (SLC36A1 c.188C>G) is a completely dominant allele that dilutes both pheomelanin and eumelanin. ...
... Presented are results for the phenotyped sample set of Shetland Ponies (mushroom and chestnut) and the p-value for the mushroom associated variant. Mu denotes the mushroom allele. 2 Mushroom Shetland Pony.3 Chestnut Shetland Pony. ...
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Mushroom is a unique coat color phenotype in Shetland Ponies characterized by the dilution of the chestnut coat color to a sepia tone and is hypothesized to be a recessive trait. A genome wide association study (GWAS), utilizing the Affymetrix 670K array (MNEc670k) and a single locus mixed linear model analysis (EMMAX), identified a locus on ECA7 for further investigation (Pcorrected = 2.08 × 10−10). This locus contained a 3 Mb run of homozygosity in the 12 mushroom ponies tested. Analysis of high throughput Illumina sequencing data from one mushroom Shetland pony compared to 87 genomes from horses of various breeds, uncovered a frameshift variant, p.Asp201fs, in the MFSD12 gene encoding the major facilitator superfamily domain containing 12 protein. This variant was perfectly concordant with phenotype in 96 Shetland Ponies (P = 1.15 × 10−22), was identified in the closely related Miniature Horse for which the mushroom phenotype is suspected to occur (fmu = 0.02), and was absent in 252 individuals from seven additional breeds not reported to have the mushroom phenotype. MFSD12 is highly expressed in melanocytes and variants in this gene in humans, mice, and dogs impact pigmentation. Given the role of MFSD12 in melanogenesis, we propose that p.Asp201fs is causal for the dilution observed in mushroom ponies.
... Normal allele N participate in the production of pigments. A mutation leads to formation of allele Cr which causes the dilution of the colour called cream coat colour (Mariat et al., 2003;Georgescu et al. 2007). The authors revealed a mutation in position 72 on exon 2, where GAT codon is replaced by AAT codon. ...
... We analysed two single nucleotide polymorphisms and one deletion -C to T substitution in the codon 83 of the MC1R gene (Marklund et al., 1996), G72A substitution in exon 2 of the MATP gene (Mariat et al., 2003) and a 11 bp deletion in exon 2 of ASIP gene (Rieder et al., 2001). ...
... When Cream allele occurred in genotype, base colour was diluted to palomino, buckskin or smoky black. This finding has been confirmed by Mariat et al. (2003), Brooks et al. (2005) and Georgescu et al. (2007). Horses with two Cream alleles were diluted to pseudoalbinos. ...
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The basic colour in horses, such as black, brown and chestnut is affected by only two genes MC1R and ASIP. Other colours in horses are affected by modifying genes, such as dilution gene MATP. In this paper genotypes of 133 horses were determined using PCR-RFLP for MATP (membrane-associated transporter protein) gene and duplex PCR-RFLP for MC1R (melanocortin 1 receptor) and ASIP (agouti signaling protein) genes. The allele and genotype frequencies were detected in a group of horses of 6 different breeds. In animals, which was not influenced by modification allele of another colour gene, we found the concordance between detected genotypes and phenotypes observed in summer and in winter. But in some animals, it was difficult to derive genotypes from their colour and therefore DNA analysis could be necessary.
... Genotyping for the DDB2 c.1013C>T risk variant was performed via the commercially available assay, Ocular Squamous Cell Carcinoma Test e , for all included horses. All horses were also genotyped for the known equine coat colour loci routinely tested at the Veterinary Genetics Laboratory, University of California-Davis, including agouti [17], extension (chestnut) [18], grey [19], cream/pearl [20], champagne [21], silver [22], dun [23], leopard complex [24], pattern 1 [25], frame [26], tobiano [27], sabino 1 [28], dominant white 5, 10 and 20 [29] and splashed white 1-4 [30,31] (Supplementary Item 1) to use in testing for an association between known coat colour alleles and disease status (ocular SCC phenotype). ...
... The median age at diagnosis of ocular SCC or carcinoma in situ in this sample was 11 years (range: 5-27 years). The median age at the time of examination of the control group was 15 years (range: [13][14][15][16][17][18][19][20][21][22][23][24][25]. The median age of the affected group was significantly younger than that of the control group (U = 101, P = 0.002). ...
... The median age of the affected group was significantly younger than that of the control group (U = 101, P = 0.002). There were significantly more males than females included in this study (31 males, 12 females; P = 0.002), and there were significantly more affected males (20) than unaffected males (11; P = 0.04). There was no significant difference between the number of affected females (5) and unaffected females (7; ...
Article
Background Belgian horses are commonly affected with ocular squamous cell carcinoma (SCC), the most common cancer of the equine eye. A missense mutation in damage‐specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) has been established as a recessive genetic risk factor for ocular SCC in the Haflinger breed. A sample of Belgian horses with unknown SCC phenotype was shown to possess this variant at a similar frequency to the Haflinger breed. Retrospective studies indicate chestnut coat colour may predispose to the development of SCC. Objectives To determine if DDB2 c.1013C>T is a risk factor for ocular SCC in a strictly‐phenotyped sample of Belgian horses. To investigate associations between coat colour loci genotypes and ocular SCC. Study design Retrospective and prospective case identification, genetic investigation. Methods Genomic DNA was isolated from blood, hair, or formalin‐fixed paraffin‐embedded tissue from 25 Belgian horses with histologically‐confirmed ocular SCC and 18 unaffected Belgian horses. Association testing of 34 single nucleotide variants from 11 genomic loci and genotyping for DDB2 c.1013C>T and coat colour alleles were performed. Exons of DDB2 were sequenced in four cases and two controls. Associations were analysed by Chi‐square or Fisher's Exact tests and relative risk was calculated. Results Homozygosity for DDB2 c.1013C>T was significantly associated with ocular SCC (P = 7.4 x 10‐7). Seventy‐six percent of affected horses were homozygous for the variant. Relative risk for homozygous horses developing SCC was 4.0 (P = 1.0x10‐4). Sequencing DDB2 did not identify a variant more concordant with disease phenotype. An association between disease and coat colour loci was not identified. Main limitations Phenotyping was determined at a single timepoint. Each included horse genotyped as chestnut so association with this MC1R variant could not be investigated. Conclusions A missense variant, DDB2 c.1013C>T, p.Thr338Met, is a risk factor for ocular SCC in Belgian horses. A genetic risk test is commercially available. This article is protected by copyright. All rights reserved.
... The homozygote C Cr allele dilutes all basic colour phenotypes and is characterized by rosy-pink skin, cream-coloured coats that can appear almost white and pale blue eyes. Mariat et al. (2003) located a single base substitution in exon 2 of the solute carrier family 45, member 2 (SLC45A2) gene, also known as membraneassociated transporter protein (MATP), fully associated with the phenotypes segregating with C Cr . ...
... Among the analysed samples, one horse exhibiting a chestnut/sorrel coat colour and another with black coat were found to be carriers for the C prl allele. This new allele may also explain the very light palomino coat colour of one horse carrying only one C Cr copy described by Mariat et al. (2003), with it probably being a SLC45A2 compound heterozygote. ...
Article
Four loci seem responsible for the dilution of the basic coat colours in horse: Dun (D), Silver Dapple (Z), Champagne (CH) and Cream (C). Apart from the current phenotypes ascribed to these loci, pearl has been described as yet another diluted coat colour in this species. To date, this coat colour seems to segregate only in the Iberian breeds Purebred Spanish horse and Lusitano and has also been described in breeds of Iberian origin, such as Quarter Horses and Paint Horse, where it is referred to as the ‘Barlink Factor’. This phenotype segregates in an autosomal recessive manner and resembles some of the coat colours produced by the champagne CHCH and cream CCr alleles, sometimes being difficult to distinguish among them. The interaction between compound heterozygous for the pearl Cprl and cream CCr alleles makes SLC45A2 the most plausible candidate gene for the pearl phenotype in horses. Our results provide documented evidence for the missense variation in exon 4 [SLC45A2:c.985G>A; SLC45A2:p.(Ala329Thr)] as the causative mutation for the pearl coat colour. In addition, it is most likely involved as well in the cremello, perlino and smoky cream like phenotypes associated with the compound CCr and Cprl heterozygous genotypes (known as cream pearl in the Purebred Spanish horse breed). The characterization of the pearl mutation allows breeders to identify carriers of the Cprl allele and to select this specific coat colour according to personal preferences, market demands or studbook requirements as well as to verify segregation within particular pedigrees.
... PMEL (SILV), a gene on chromosome 6, is responsible for the dilution of black pigment and causes the silver dapple phenotype seen in horses with black and bay base coat color (Brunberg et al. 2006). The cream (C) locus (SLC45A2, solute carrier family 45 member 2, also known as MATP) is located on equine chromosome 21 and is the allelic location for the variant responsible for cream dilution (C Cr ) (Mariat et al. 2003). Cream is expressed in an incomplete dominant fashion. ...
... The SLC45A2:c.601G>A variant is the previously described cream allele, C CR (Mariat et al. 2003 deleterious). The genotype agreed with the expected phenotype for all tested horses with a P-value of 6.5 9 10 À41 (Table S2). ...
Article
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Variations in the SLC45A2 gene are responsible for the dilution phenotypes cream and pearl in domestic horses. Cream dilution is inherited in an incomplete dominant manner, diluting only red in the heterozygous state but both red and black pigments when two alleles are present. The pearl dilution is recessive and dilutes only the red and black pigment in the homozygous state or when paired with a cream allele. Horses that inherit one copy of pearl (Cprl) and one copy of the dominant cream allele (CCr) display a dilution phenotype similar to that of homozygous cream, suggesting that pearl is the result of a different variation in the same gene responsible for cream. We sequenced SLC45A2 in two ‘false double dilute’ horses that appeared phenotypically homozygous cream but tested as possessing only a single CCr allele. We also sequenced one known pearl carrier to screen for putative causal variants. The missense variant ECA21:SLC45A2:c.985G>A; p.Ala329Thr (Cprl) was present in one false double dilute and the pearl carrier and was also genotyped in an additional 126 horses for statistical evaluation. The genotype matched the expected phenotype in all horses (P‐value = 6.5 × 10−41) and is identical to a pearl variant found previously. The second false double dilute horse and one non‐dilute offspring genotyped as heterozygous for a novel missense variant ECA21:SLC45A2:c.568G>A (p.Gly190Arg), the proposed Csun variant (for the name of the horse). This variant produces a recessive dilution similar to pearl and indicates that multiple alleles of SLC45A2 result in dilution phenotypes in the domestic horse.
... Solute carrier family 45, member 2 (SLC45A2) is one of the recently identified genes involved in the pigmentation pathway, and it has been found that mutations in SLC45A2 are associated with reduction of melanin synthesis in varying degrees, resulting in phenotypes such as oculocutaneous albinism type 4 (OCA 4) in humans (Newton et al. (2001), underwhite in mice (Du and Fisher 2002), palomino in horses (Mariat et al. 2003), white/pale cream in white tigers (Xu et al. 2013) and Western Lowland Gorillas (Prado-Martinez et al. 2013), gold color in lower vertebrates such as Medaka fish (Fukamachi et al. 2001) and silver in chicken (Gunnarsson et al. 2007). ...
... All the albino dogs were also genotyped for MC1R for the E alleles (Newton et al. 2000;Schmutz and Berryere 2007b) because in the horse, the shades of "white" caused by SLC45A2 mutations are slightly different depending on the MC1R genotype (Mariat et al. 2003). The mixed breed dog was e/e, the Lhasa Apso was E M /E M , and the others were E/E at this locus suggesting that the albino genotype at SLC45A2 in these dogs was epistatic to the E M , E, and e alleles of MC1R. ...
Article
Homozygosity for a large deletion in the solute carrier family 45, member 2 (SLC45A2) gene causes oculocutaneous albinism (OCA) in the Doberman Pinscher breed. An albino Lhasa Apso did not have this g.27141_31223del (CanFam2) deletion in her SLC45A2 sequence. Therefore, SLC45A2 was investigated in this female Lhasa Apso to search for other possible variants that caused her albinism. The albino Lhasa Apso was homozygous for a nonsynonymous substitution in the seventh exon, a c.1478G>A base change that resulted in a glycine to aspartic acid substitution (p.G493D). This mutation was not found in a wolf, a coyote, or any of the 15 other Lhasa Apso dogs or 32 other dogs of breeds related to the Lhasa Apso. However, an albino Pekingese, 2 albino Pomeranians, and an albino mixed breed dog that was small and long haired were also homozygous for the 493D allele. The colored puppies of the albino Lhasa Apso and the colored dam of the 2 albino Pomeranians were heterozygous for this allele. However, an albino Pug was homozygous for the 493G allele and therefore although we suggest the 493D allele causes albinism when homozygous in several small, long haired dog breeds, it does not explain all albinism in dogs. A variant effect prediction for the albino Lhasa Apso confirms that p.G493D is a deleterious substitution, and a topology prediction for SLC45A2 suggests that the 11th transmembrane domain where the 493rd amino acid was located, has an altered structure. © The American Genetic Association 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
... It plays a significant role in animal social behavior, such as communication, camouflage, enemy avoidance, and selective mating (Kelsh 2004;Protas and Patel 2008;Rodgers et al. 2010). Body color phenotypic variation and the mechanism of pigment formation have been studied in terms of the evolution of pigmentation and pigmentation patterns (Kelsh 2004;Protas and Patel 2008;Braasch et al. 2009), the molecular mechanism of body coloration, and the genetic changes causing phenotypic variation (Mariat et al. 2003;Xu et al. 2013). It is essential to determine the molecular mechanism of body coloration involved in biological, ecological, and evolutionary processes (Katasonov 1978;Parichy and Johnson 2001;David et al. 2004;Wang et al. 2008). ...
... Amelanism in corn snakes was likely contributed to an LTR-retrotransposon insertion in the OCA2 gene (Suzame et al. 2015). A "G" to "A" transition in exon 2 of the MATP gene resulted in cream coat color in horse (Mariat et al. 2003). It is very likely that the mechanism of red and white color formation lies in the mutation of pigmentation genes, rather than the difference at the expression level of pigmentation genes. ...
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Body color variation has long been a hot research topic in evolutionary and functional biology. Oujiang color common carp (Cyprinus carpio var. color) is a well-known economical and ornamental fish. Three main types of pigments and four distinct color patterns are typical characters of Oujiang color common carp, which makes it an excellent fish model to study body coloration. In this study, skin transcriptome assembly and comparisons were conducted in two Oujiang color common carp varieties: whole red and whole white. Transcriptome comparison revealed that more differentially expressed energy metabolism genes were upregulated in whole white compared to whole red. The results indicated that energy metabolism genes might be strongly associated with environmental adaption and growth performance and likely affect the red and white color formation in Oujiang color common carp. Our study provided direct guidance for the aquaculture industrials of Oujiang color common carp and presented valuable genetic resources for body color research in fish.
... Additionally, Case 2 genotyped as a bay horse with two copies of the cream color dilution mutation, demonstrating a perlino coat phenotype. The mutation responsible for the cream pigment dilution is in the gene membrane associated transport protein (MATP) and is thought to disrupt pigmentation by impairing normal trafficking of pigment granules within the developing melanocyte [28]. Horses homozygous for the cream dilution typically have a very dilute coat, lack pigment in their skin, and have blue irises, as presented in Case 2 [28]. ...
... The mutation responsible for the cream pigment dilution is in the gene membrane associated transport protein (MATP) and is thought to disrupt pigmentation by impairing normal trafficking of pigment granules within the developing melanocyte [28]. Horses homozygous for the cream dilution typically have a very dilute coat, lack pigment in their skin, and have blue irises, as presented in Case 2 [28]. Thus, a combination of reduced photoprotective pigment and loss of functional DDB2 could have contributed to the younger age and bilateral nature of SCC development, and aggressive clinical course that necessitated exenteration. ...
Article
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Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye. A missense variant within the gene damage-specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) was previously identified as a causal recessive genetic risk factor for the development of ocular SCC within Haflingers, Belgian Draft horses, and Rocky Mountain Horses, but not in the Appaloosa or Arabian breeds. This study aimed to evaluate three cases of ocular SCC in additional breeds and determine if DNA testing for the DDB2 variant in warmblood horses and Connemara ponies is warranted. Histopathology confirmed ocular SCC in all three cases and DNA testing confirmed each horse was homozygous for the DDB2 risk factor. The DDB2 risk allele frequency was estimated to be 0.0043 for Holsteiners (N = 115), 0.014 for Belgian Warmbloods (N = 71), and 0.22 for Connemara Ponies (N = 86). Taken together these data support using DNA testing for DDB2 in Connemara Ponies to assist in mate selection and clinical management. Given the low observed allele frequencies in both the Holsteiner and Belgian Warmblood breeds and that the case under investigation was a warmblood cross-bred, evaluating additional SCC affected warmbloods is warranted to fully determine the importance of DDB2 genotyping as a risk factor in warmblood breeds.
... In total, 229 SLC genes have been identified in the chicken genome . SLC24A5, SLC24A4, and SLC45A2 have been identified as major determinants of pigmentation in humans and in other vertebrates (fish, mice, birds, horses, and Xenopus laevis) (Mariat, et al., 2003;Gunnarsson et al., 2007;Ginger et al., 2008;Sturm, 2009). Sequence variation in these 3 genes was found to be associated with diluted coat colors or hypopigmentation. ...
Article
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Melanin-based coloration in the meat of black-boned chicken is a major economic issue in China. Variation in the pigmentation (hypopigmentation) of chicken muscle causes direct economic losses every year. To determine the molecular mechanisms involved in the melanogenesis of muscle tissue, this study used high-throughput sequencing to compare differences in the transcriptome between black (BM) and white (WM) chicken breast muscles. We constructed 6 cDNA libraries from BM and WM groups in Muchuan black-boned chickens. A comparison between the BM and WM groups revealed 264 differentially expressed genes, of which 152 were upregulated, whereas 112 were downregulated in black muscle. Gene ontology and a Kyoto Encyclopedia of Genes and Genomes pathway analysis identified several differentially enriched biological functions and processes of the 2 muscles. Seven promising candidate genes [PMEL, Ras-related protein RAB29, and 5 solute carrier superfamily genes: SLC6A9, SLC38A4, SLC22A5, SLC35F3, and SLC16A3] may play an important role in the melanogenesis of chicken muscle. Our data provide a valuable resource for identifying genes whose functions are critical for muscle melanogenesis, and will assist studies of the molecular mechanisms of melanogenesis regulation in chicken muscle.
... In all kingdoms of life, anomalous transport of pigments themselves or pigment-related substrates is another important pigmentation mechanism, which has been confirmed to be responsible for eye color in D.melanogaster [46] and silkworm [47]; shell color in pacific oyster [48]; and coat color in horse [49], tiger [50], and chicken [51]. A pigment transport mechanism responsible for bird BGEC has been proposed by Liu et al. [13] and Wang et al. [15]. ...
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Background In birds, blue-green eggshell color (BGEC) is caused by biliverdin, a bile pigment derived from the degradation of heme and secreted in the eggshell by the shell gland. Functionally, BGEC might promote the paternal investment of males in the nest and eggs. However, little is known about its formation mechanisms. Jinding ducks (Anas platyrhynchos) are an ideal breed for research into the mechanisms, in which major birds lay BGEC eggs with minor individuals laying white eggs. Using this breed, this study aimed to provide insight into the mechanisms via comparative transcriptome analysis. Results Blue-shelled ducks (BSD) and white-shelled ducks (WSD) were selected from two populations, forming 4 groups (3 ducks/group): BSD1 and WSD1 from population 1 and BSD2 and WSD2 from population 2. Twelve libraries from shell glands were sequenced using the Illumina RNA-seq platform, generating an average of 41 million clean reads per library, of which 55.9% were mapped to the duck reference genome and assembled into 31,542 transcripts. Expression levels of 11,698 genes were successfully compared between all pairs of 4 groups. Of these, 464 candidate genes were differentially expressed between cross-phenotype groups, but not for between same-phenotype groups. Gene Ontology (GO) annotation showed that 390 candidate genes were annotated with 2234 GO terms. No candidate genes were directly involved in biosynthesis or transport of biliverdin. However, the integral components of membrane, metal ion transport, cholesterol biosynthesis, signal transduction, skeletal system development, and chemotaxis were significantly (P < 0.05) overrepresented by candidate genes. Conclusions This study identified 464 candidate genes associated with duck BGEC, providing valuable information for a better understanding of the mechanisms underlying this trait. Given the involvement of membrane cholesterol contents, ions and ATP levels in modulating the transport activity of bile pigment transporters, the data suggest a potential association between duck BGEC and the transport activity of the related transporters. Electronic supplementary material The online version of this article (10.1186/s12864-017-4135-2) contains supplementary material, which is available to authorized users.
... Variants that impact base coat color have been identified in agouti signaling protein (ASIP) and melanocortin 1 receptor (MC1R) [5][6][7]. Six variants in five genes have been shown to dilute pigment, and these are known as cream (Cr), pearl (Prl), champagne (Ch), dun (D), mushroom (Mu), and silver (Z) [8][9][10][11][12][13]. Variants in seven genes (KIT, EDNRB, TRPM1, MITF, PAX3, RFWD3, STX17) have been documented to cause white patterning in domestic horses . ...
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Coat color is a trait of economic significance in horses. Variants in seven genes have been documented to cause white patterning in horses. Of the 34 variants that have been identified in KIT proto-oncogene, receptor tyrosine kinase (KIT), 27 have only been reported in a single individual or family and thus not all are routinely offered for genetic testing. Therefore, to enable proper use of marker-assisted selection, determining breed specificity for these alleles is warranted. Screening 19 unregistered all-white Shetland ponies for 16 white patterning markers identified 14 individuals whose phenotype could not be explained by testing results. In evaluating other known dominant white variants, 14 horses were heterozygous for W13. W13 was previously only reported in two quarter horses and a family of Australian miniature horses. Genotyping known white spotting variants in 30 owner-reported white animals (25 Miniature Horses and five Shetland ponies) identified two additional W13/N American Miniature Horses. The estimated allele frequency of W13 in the American Miniature Horse was 0.0063 (79 N/N, 1 W13/N) and the allele was not detected in a random sample (n = 59) of Shetland ponies. No homozygous W13 individuals were identified and W13/N ponies had a similar all-white coat with pink skin phenotype, regardless of the other white spotting variants present, demonstrating that W13 results in a Mendelian inherited dominant white phenotype and homozygosity is likely lethal. These findings document the presence of W13 in the American Miniature Horse and Shetland pony populations at a low frequency and illustrate the importance of testing for this variant in additional breeds.
... A 78-kb haplotype around SLC24A5, which is in linkage disequilibrium with rs1426654, was also identified to accumulate in Europeans [22]. A similar pattern can be observed at rs16891982 in SLC45A2 [23], which has been reported to be associated with pigmentation in several species, e.g., mice, fish, birds, and horses [24][25][26]. Other variants in this gene, including rs26722, rs2287949, and rs40132, were also shown to be coloration-associated in Europeans [23,27,28]. ...
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Background Skin color is a well-recognized adaptive trait and has been studied extensively in humans. Understanding the genetic basis of adaptation of skin color in various populations has many implications in human evolution and medicine. Discussion Impressive progress has been made recently to identify genes associated with skin color variation in a wide range of geographical and temporal populations. In this review, we discuss what is currently known about the genetics of skin color variation. We enumerated several cases of skin color adaptation in global modern humans and archaic hominins, and illustrated why, when, and how skin color adaptation occurred in different populations. Finally, we provided a summary of the candidate loci associated with pigmentation, which could be a valuable reference for further evolutionary and medical studies. Conclusion Previous studies generally indicated a complex genetic mechanism underlying the skin color variation, expanding our understanding of the role of population demographic history and natural selection in shaping genetic and phenotypic diversity in humans. Future work is needed to dissect the genetic architecture of skin color adaptation in numerous ethnic minority groups around the world, which remains relatively obscure compared with that of major continental groups, and to unravel the exact genetic basis of skin color adaptation.
... The cream coat of hypopigmented fur seals is most likely the result of a dilution of pheomelanin, as has been suggested for the hypopigmented Kermode bear and the Labrador breed of domestic dogs (Newton et al. 2000;Ritland et al. 2001). Variants of genes associated with pheomelanin dilution responsible for several different phenotypes have been identified in multiple mammal species (Mariat et al. 2003;Chintala et al. 2005). None of these, however, give rise to the cream-colored coat observed in several dog and some cattle breeds (Guibert et al. 2004;Schmutz and Berryere 2007), which is also most similar to that of hypopigmented fur seals. ...
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Although the genetic basis of color variation has been extensively studied in humans and domestic animals, the genetic polymorphisms responsible for different color morphs remain to be elucidated in many wild vertebrate species. For example, hypopigmentation has been observed in numerous marine mammal species but the underlying mutations have not been identified. A particularly compelling candidate gene for explaining color polymorphism is the melanocortin 1 receptor (MC1R), which plays a key role in the regulation of pigment production. We therefore used Antarctic fur seals (Arctocephalus gazella) as a highly tractable marine mammal system with which to test for an association between nucleotide variation at the MC1R and melanin-based coat color phenotypes. By sequencing 70 wild-type individuals with dark-colored coats and 26 hypopigmented individuals with cream-colored coats, we identified a nonsynonymous mutation that results in the substitution of serine with phenylalanine at an evolutionarily highly conserved structural domain. All of the hypopigmented individuals were homozygous for the allele coding for phenylalanine, consistent with a recessive loss-of-function allele. In order to test for cryptic population structure, which can generate artefactual associations, and to evaluate whether homozygosity at the MC1R could be indicative of low genome-wide heterozygosity, we also genotyped all of the individuals at 50 polymorphic microsatellite loci. We were unable to detect any population structure and also found that wild-type and hypopigmented individuals did not differ significantly in their standardized multilocus heterozygosity. Such a lack of association implies that hypopigmented individuals are unlikely to suffer disproportionately from inbreeding depression, and hence, we have no reason to believe that they are at a selective disadvantage in the wider population.
... Samples were tested for the basic colours bay, chestnut and black via the MC1R-and ASIP-loci (Marklund et al., 1996;Rieder et al., 2001). Epistatic dilutions Cream (Mariat et al., 2003) and Silver (Reissmann et al., 2007) and spottings Overo (Santschi et al., 1998), Tobiano (Brooks et al., 2002) and Sabino (Brooks and Bailey, 2005) were examined. In addition, the grey-locus, resulting in a complete white coat in adult horses regardless of original colour, was investigated. ...
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In the Celtic world, horses enjoyed a prominent position as status symbols and objects of veneration, yet little is known about these Celtic horses except that they were rather small. The Late Iron Age was a time defined by increasing inter-cultural contact between Celtic peoples and the Romans. This is, amongst other features, observable in the phenotypes of domestic livestock such as horses. Amongst the usually small animals, larger ones are rarely but regularly encountered in the archaeological record. We have investigated mitochondrial (mt) DNA d-loop diversity, sex and coat colour using bones from 34 horses of different size from three Swiss sites (Mormont, Basel-Gasfabrik, Aventicum) most of them dating from 150 to 50BCE. The aim was to characterise the diversity of matrilineages and coat colourations of Iron Age horses, and to identify molecular sex. We detected eleven mt haplotypes clustering into six haplogroups (B, D, F, I, X2, X3) in the ancient dataset (n=19). Large individuals were all male, but smaller stallions were also identified; molecular sexing confirmed and augmented to morphological results. The horses were bay, chestnut and black in colour, and spottings or dilutions were absent in all animals. With a simplified primer system to detect premature greying, white coats can be excluded as well. The limited colour range proposes selection for monochrome animals. Additionally, ancient matrilineages were compared to modern horses from regions appertaining to the Late Roman Republic and to European pony breeds. Based on Principal Component Analysis (haplotype frequencies) and FST-values (genetic distances) the mtDNA variation of the Iron Age horses investigated here has survived in modern European breeds, particularly in northern European ponies.
... CNVs and Nonsynonymous Mutations. We identified Yakutian-specific CNVs by detecting regions showing an excess of reads mapping to the genome of the Thoroughbred horse (Twilight), in which duplications were masked beforehand using mrCaNaVaR version 0.31 and mrFAST version 2.0.0.5 (77). Potential Yakutian horse-specific markers were collected based on criteria described by Baye et al. (78). ...
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Yakutia, Sakha Republic, in the Siberian Far East, represents one of the coldest places on Earth, with winter record temperatures dropping below -70 °C. Nevertheless, Yakutian horses survive all year round in the open air due to striking phenotypic adaptations, including compact body conformations, extremely hairy winter coats, and acute seasonal differences in metabolic activities. The evolutionary origins of Yakutian horses and the genetic basis of their adaptations remain, however, contentious. Here, we present the complete genomes of nine present-day Yakutian horses and two ancient specimens dating from the early 19th century and ∼5,200 y ago. By comparing these genomes with the genomes of two Late Pleistocene, 27 domesticated, and three wild Przewalski's horses, we find that contemporary Yakutian horses do not descend from the native horses that populated the region until the mid-Holocene, but were most likely introduced following the migration of the Yakut people a few centuries ago. Thus, they represent one of the fastest cases of adaptation to the extreme temperatures of the Arctic. We find cis-regulatory mutations to have contributed more than nonsynonymous changes to their adaptation, likely due to the comparatively limited standing variation within gene bodies at the time the population was founded. Genes involved in hair development, body size, and metabolic and hormone signaling pathways represent an essential part of the Yakutian horse adaptive genetic toolkit. Finally, we find evidence for convergent evolution with native human populations and woolly mammoths, suggesting that only a few evolutionary strategies are compatible with survival in extremely cold environments.
... The causative mutations of many patterns remain unknown. The missense G457A mutation in MATP causes the incomplete dominant cream dilution (C cr allele) [8]. All Thoroughbred horses are homozygous non-cream (genotype C/C), so this gene was used as a control invariant site. ...
... Polymorphisms in SLC45A2 produce similar effects in other animals. In horse, D153N in the SLC45A2 homolog MATP is associated with a cream coat color (31). In mouse, an SLC45A2 homolog is encoded by the uw gene (6,17), while mutations in the corresponding gene b in medaka fish reduce melanin content (7) and in birds, plumage color is also controlled by alleles of the gene encoding MATP (32). ...
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Solute carrier family 45 member 2 encodes the melanosomal membrane protein, membrane‑associated transporter protein (MATP), of unknown function, that is required for normal melanin synthesis. The present study analyzed the effects of two human MATP mutations, D93N, which causes oculocutaneous albinism 4 (OCA4), and L374F, which is correlated with light pigmentation in European populations. Corresponding mutations were produced in the related and well‑characterized sucrose transporter from rice, OsSUT1, and transport activity was measured by heterologous expression in Xenopus laevis oocytes, in addition to 14C‑sucrose uptake in yeast. The mutation corresponding to D93N resulted in a complete loss of transport activity. The mutation corresponding to L374F resulted in a 90% decrease in transport activity, although the substrate affinity was unaffected. The results indicated that the D93N mutation causes OCA4 as a result of loss of MATP transport activity, and that the F374 allele confers significantly lower transport activity than L374.
... The molecular background of the remaining basic coat colors (black and bay) was discovered in 2001 when causative 11 bp deletion in exon 2 of the ASIP (agouti signaling protein) gene was found by Rieder et al. [2001]. Till date, the molecular basis of many other coat colors in horses was identified, including cream and silver dilutions as an effect of the 153 Asp→Asn mutation in the MATP (solute carrier family 45, member 2) and 618 Arg→Cys substitution in the PMEL17 (melanocyte protein 17 precursor) proteins, respectively [Mariat et al. 2003, Brunberg et al. 2006. ...
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Equine coat color is an important phenotypic trait, predominantly within the context of correct animal identification. Due to the increased import of horses to Poland during the last years, uncommon coat colors seem to occur more often. In this study, we have analyzed the genotypes of cold-blooded horses representing four breeds (Polish Cold-blooded Horse, Belgian Draft Horse, Percheron Horse and Ardennes Horse) for genes determining basic coat colors (MC1R and ASIP) as well as silver and cream dilutions (PMEL17 and MATP). We have also compared the results of our molecular study with the coat color of each horse listed in the breeding documents. Uneven distribution of genotypes between the investigated groups was observed. Moreover, we have identified several mistakes in coat color descriptions of horses, which justifies the necessity for genetic testing, particularly in case of coat colors difficult to categorize "by eye". We also suggest to extend the list of horse coat colors recognized by the Polish Horse Breeders Association.
... Researchers have determined that mutations in SLC45A2 can abrogate the processing and trafficking of tyrosinase at the Golgi level, leading to oculocutaneous albinism type IV, a low pigment disorder with autosomal recessive inheritance [3,7,8]. These mutations not only alter the pigmentation of medaka fish [9], mice [2,10], horses [11], chicken and quail [12] but are also correlated with abnormal eye and skin color development in humans [13][14][15]. The membrane-associated transporter protein encoded by the SLC45A2 gene has been recognized as a sodium-hydrogen exchanger that functions in melanosomes to regulate the activity of tyrosinase in human melanocytes [16]. ...
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Introduction: To investigate whether the membrane-associated transporter protein SLC45A2 is differentially expressed in the skin of sheep with different coat colors and to determine its correlation with coat color establishment in sheep. Material and methods: The expression of SLC45A2 in sheep skin samples with different coat colors was qualitatively and quantitatively analyzed by PCR amplification, RT-PCR, immunohistochemical staining and Western blotting. Results: A 193-bp SLC45A2 CDS sequence was successfully amplified from sheep skin samples with diverse coat colors. RT-PCR analysis revealed that SLC45A2 mRNA was expressed in all sheep skin samples tested, with relative expression levels of 512.74 ± 121.51 in black skin, 143.38 ± 119.31 and 1.36 ± 0.09 in black dots and white dots of piebald skin, respectively, and 1.02 ± 0.23 in white skin (p < 0.01**). Positive SLC45A2 protein bands were also detected in all skin samples by Western blot analysis, with relative expression levels of 0.85 ± ± 0.17** in black skin, 0.60 ± 0.05** and 0.34 ± 0.07 in black dots and white dots of piebald skin, respectively, and 0.20 ± 0.05 in white skin (p < 0.01**). Immunohistochemical assays revealed that SLC45A2 was expressed in the hair follicle matrix, the inner and outer root sheath, and the dermal papilla in the skin tissues with different coat colors. These patterns were quantified by optical density (OD) analysis, which yielded relative expression levels of 0.23 ± 0.11 in black skin, 0.19 ± 0.09 and 0.10 ± 0.03 in black dots and white dots of piebald skin, respectively, and 0.08 ± 0.01 in white skin (p < 0.05*). Conclusion: SLC45A2 is detectably expressed in sheep skin of all coat colors, though at significantly different levels. SLC45A2 may participate in the establishment of coat color by regulating the synthesis and trafficking of melanin.
... Mutations in SLC45A2 (also known as membrane-associated transporter protein, MATP, or antigen isolated from immunoselected melanoma 1, AIM1 [30]) are known to cause a wide range of phenotypes that are characterized by reduced levels or complete absence of melanin synthesis in a variety of species, e.g. white tigers [31], cream-colored horses [32], hypopigmented medaka fish [33], mice with the underwhite (uw) phenotype [34,35], and chicken and Japanese quail with silver or cinnamon plumage color or imperfect albinism [36]. Furthermore, OCA in a Western lowland gorilla [37], white Doberman pinscher dogs [38] and several long-haired dog breeds [39] was also traced back to mutations in SLC45A2. ...
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Background Cases of albinism have been reported in several species including cattle. So far, research has identified many genes that are involved in this eye-catching phenotype. Thus, when two paternal Braunvieh half-sibs with oculocutaneous albinism were detected on a private farm, we were interested in knowing whether their phenotype was caused by an already known gene/mutation. Results Analysis of genotyping data (50K) of the two albino individuals, their mothers and five other relatives identified a 47.61-Mb candidate haplotype on Bos taurus chromosome BTA20. Subsequent comparisons of the sequence of this haplotype with sequence data from four Braunvieh sires and the Aurochs genome identified two possible candidate causal mutations at positions 39,829,806 bp (G/A; R45Q) and 39,864,148 bp (C/T; T444I) that were absent in 1682 animals from various bovine breeds included in the 1000 bull genomes project. Both polymorphisms represent coding variants in the SLC45A2 gene, for which the human equivalent harbors numerous variants associated with oculocutaneous albinism type 4. We demonstrate an association of R45Q and T444I with the albino phenotype by targeted genotyping. Conclusions Although the candidate gene SLC45A2 is known to be involved in albinism in different species, to date in cattle only mutations in the TYR and MITF genes were reported to be associated with albinism or albinism-like phenotypes. Thus, our study extends the list of genes that are associated with bovine albinism. However, further research and more samples from related animals are needed to elucidate if only one of these two single nucleotide polymorphisms or the combination of both is the actual causal variant. Electronic supplementary material The online version of this article (doi:10.1186/s12711-017-0349-7) contains supplementary material, which is available to authorized users.
... Hence, appearance of bay dun and blue dun horses implicates the appearance of red duns which, however, were not registered in the studbook. Similarly, when the MATP (C cr ) gene occurs, not only palomino horses (_ _eeC cr C) should be present, but also buckskins (A_E_C cr C), smokies (aaE_C cr C), and various kinds of cremellos (_ _ _ _C cr C cr ) (Adalsteinsson 1974;Mariat et al. 2003). We suspect that possible red duns were classified as chestnuts, buckskins as bay duns, and smokies as blacks, whereas cremellos, if they appeared at all, were not registered. ...
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The objective of this study was to estimate the frequencies of alleles which produce coat colour in Polish Coldblood horse population, and to verify the hypothesis that coat colour is not considered in its selection. The analysis included 35 928 horses and their parents having been registered in the studbook over a half-century. Allele frequencies in Agouti (A), Extension (E), Dun (D), Roan (Rn), and Grey (G) loci, in parental and offspring generations, were estimated according to test matings and the square root of recessive phenotype frequency. The population structure is in Hardy–Weinberg equilibrium only at E locus and coat colour is regarded by breeders. Black horses are favoured. Higher E locus homozygosity in blacks than in bays makes it easier to obtain black foals. Dun-diluted, roan and grey coat colours are undesirable and the population has come to consist almost uniformly of basic coat colours. These results show the importance of studies on population genetic structure, which despite no formal criteria for breeding for colour, can considerably change through generations.
... membrane associated transporter protein, MATP or antigen isolated from immuno-selected melanoma-1, AIM1) . Mutations in the homologous gene underlie pigment dilution in a number of vertebrate species, including gorilla, several breeds of dog, tigers, horses, mice, shrew, chickens, pigeons, quail, frogs, fish and perhaps cattle (Caduff et al., 2017;DeLay et al., 2018;Domyan et al., 2014;Dooley et al., 2013;Fukamachi et al., 2001;Gunnarsson et al., 2007;Mariat et al., 2003;Minvielle et al., 2009;Newton et al., 2001;Prado-Martinez et al., 2013;Rothammer et al., 2017;Tsetskhladze et al., 2012;Tsuboi et al., 2009;Wijesena and Schmutz, 2015;Winkler et al., 2014;Xu et al., 2013), and polymorphisms at the SLC45A2 locus are associated with skin tone differences and skin aging in several human population studies (Adhikari et al., 2019a;Branicki et al., 2008;Cerqueira et al., 2014;Fracasso et al., 2017;Han et al., 2008;Jonnalagadda et al., 2016;Law et al., 2017;Liu et al., 2015;Lopez et al., 2014;Soejima and Koda, 2007;Stokowski et al., 2007;Yuasa et al., 2006). OCA4 patients have very low levels of pigmentation and phenotypically resemble OCA2 patients who lack the melanosomal chloride channel, OCA2 (Bellono et al., 2014), suggesting that SLC45A2 plays an important role in melanogenesis (Montoliu et al., 2014). ...
Article
Melanin synthesis is required for proper development and function of the visual system and for protection against ultraviolet radiation. Defects in melanin synthesis result in albinism, which is characterized by visual defects and increased skin cancer risk. Melanin is synthesized in pigment cells within specialized subcellular organelles called melanosomes. Some forms of albinism result from defects in melanosome maturation, but the underlying molecular mechanisms are incompletely understood. Melanosome maturation requires the trafficking of melanogenic cargoes to melanosome precursors and an increase in melanosome pH, thereby supporting activity of the enzyme tyrosinase to promote melanin synthesis. In this work, we investigate melanosome biogenesis and maturation in melanocytes derived from mouse models of two forms of albinism, (1) oculocutaneous albinism type 4 (OCA4) due to loss of function of SLC45A2, and (2) the Hermansky-Pudlak syndrome mouse model buff that has a missense mutation in VPS33A. (1) Here we show that SLC45A2, a putative sugar/proton symporter, localizes to melanosomes and increases organellar pH at its sites of localization. Further, we show that SLC45A2 likely functions at a later stage of melanosome maturation than the ion channel OCA2, which is also necessary to raise melanosomal pH and is defective in another subtype of OCA. Additionally, we show that a common SLC45A2-L374F variant associated with lighter pigmentation in humans is degraded more rapidly than the dark skin-associated L374 variant, indicating that decreased pigmentation reflects reduced proton export from melanosomes. (2) VPS33A, an SM protein that mediates fusion, is required in the endolysosomal and autophagosomal pathways, but whether it plays a direct role in melanosomal trafficking is unknown. Contrary to a previous report, we show that a VPS33A-D251E mutation in melan-bf cells does not prohibit pigmentation; instead, buff melanocytes cells contain enlarged, mature melanosomes despite partial mistrafficking of the mature melanosomal marker TYRP1. Replacement of wild-type VPS33A in wild-type melanocytes by VPS33A-D251E does not phenocopy buff melanocytes, suggesting that an additional mutation may be responsible for our observed buff phenotype. Our analyses of mouse albinism models have thus yielded significant insights into mechanisms of melanosome maturation.
... One of the wellknown genes involved in the repeated evolution of light and dark color polymorphisms is the melanocortin-1 receptor (MC1R) that modulates the activity of the melanin synthesis pathways in the fur, plumage, scales and skin of mammals, birds, reptiles, amphibians, and fish [2]. In other cases, similar coloration has independently evolved in multiple lineages via mutations in different genes (e.g., LYST and AIM1 in polar bears and KIT and MATP in horses with white coats) [3][4][5]. Understanding the genetic mechanisms of color variation and phenotypic convergence has shed light on how novel phenotypes evolve under similar selective forces (either natural or artificial). In addition, high conservation of melanogenesis pathways across vertebrates warrants transformative research in human genomics research, such as the case of MC1R that is strongly associated with increased risk for melanoma [6,7]. ...
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Structural variations (SVs) represent a large fraction of all genetic diversity, but how this genetic diversity is translated into phenotypic and organismal diversity is unclear. Explosive diversification of dog coat color and patterns after domestication can provide a unique opportunity to explore this question; however, the major obstacle is to efficiently collect a sufficient number of individuals with known phenotypes and genotypes of hundreds of thousands of markers. Using customer-provided information about coat color and patterns of dogs tested on a commercial canine genotyping platform, we identified a genomic region on chromosome 38 that is strongly associated with a mottled coat pattern (roaning) by genome-wide association study. We identified a putative causal variant in this region, an 11-kb tandem duplication (11,131,835–11,143,237) characterized by sequence read coverage and discordant reads of whole-genome sequence data, microarray probe intensity data, and a duplication-specific PCR assay. The tandem duplication is in an intronic region of usherin gene ( USH2A ), which was perfectly associated with roaning but absent in non-roaned dogs. We detected strong selection signals in this region characterized by reduced nucleotide diversity (π), increased runs of homozygosity, and extended haplotype homozygosity in Wirehaired Pointing Griffons and Australian Cattle Dogs (typically roaned breeds), as well as elevated genetic difference ( F ST ) between Wirehaired Pointing Griffon (roaned) and Labrador Retriever (non-roaned). Surprisingly, all Dalmatians (N = 262) carried the duplication embedded in identical or similar haplotypes with roaned dogs, indicating this region as a shared target of selection during the breed’s formation. We propose that the Dalmatian’s unique spots were a derived coat pattern by establishing a novel epistatic interaction between roaning “R-locus” on chromosome 38 and an uncharacterized modifier locus. These results highlight the utility of consumer-oriented genotype and phenotype data in the discovery of genomic regions contributing to phenotypic diversity in dogs.
... [1][2][3][4] In equines, mutations in the SLC45A2 gene, located on chromosome 21, are responsible for the cream, pearl and sunshine dilutions. 5,6 In this study, we focused on a Gypsy breed mare that appeared phenotypically cremello (light creamy white) but tested negative for any known dilution or spotting alleles, including sabino, W20, tobiano, PATN1 and SW1-4 ( Fig. 1). We obtained hair samples from 15 Gypsy horses, including the affected mare, her dam and sire, and three half siblings. ...
... In addition to these basic coat colors, cream dilution is caused by a mutation of the solute carrier family 45 member 2 (MATP) gene. A missense mutation of MATP results in a buckskin or palomino coat color in heterozygous horses and a doubledilute coat color in homozygous horses [20]. Since horses are mainly used because of their physical performance, breeds have been intensively selected for physical performance-related traits such as locomotion traits. ...
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The Kushum is a relatively new breed of horses in Kazakhstan that was established in the middle of the 20th century through a cross between mares of Kazakhstan local horses and stallions of Thoroughbred, Trotter, and Russian Don breeds to supply military horses. To reveal the genetic characteristics of this breed, we investigated haplotypes of mitochondrial DNA (mtDNA) and single-nucleotide polymorphisms of the Y chromosome, as well as genotypes of five functional genes associated with coat color, body composition, and locomotion traits. We detected 10 mtDNA haplotypes that fell into 8 of the 17 major haplogroups of horse mtDNA, indicating a unique haplotype composition with high genetic diversity. We also found two Y-chromosomal haplotypes in Kushum horses, which likely originated from Trotter and/or Don breeds. The findings regarding the mtDNA and Y-chromosomal haplotypes are concordant with the documented maternal and paternal origins of the Kushum horses. The allele frequencies of ASIP, MC1R, and MATP associated with coat color were consistent with the coat color variations of Kushum horses. The allele frequencies of MSTN associated with endurance performance and those of DMRT3 associated with gait suggested that the observed allele frequencies of these genes were the result of selective breeding for these traits. As a result of this study, we were able to obtain useful information for a better understanding of the origin and breeding history of the Kushum horse breed using molecular markers.
... membrane associated transporter protein, MATP or antigen isolated from immuno-selected melanoma-1, AIM1) (Newton et al, 2001). Mutations in the homologous gene underlie pigment dilution in a number of vertebrate species, including gorilla, several breeds of dog, tigers, horses, mice, shrew, chickens, pigeons, quail, frogs, fish and perhaps cattle (Caduff et al, 2017;DeLay et al, 2018;Domyan et al, 2014;Dooley et al, 2013;Fukamachi et al, 2001;Gunnarsson et al, 2007;Mariat et al, 2003;Minvielle et al, 2009;Newton et al., 2001;Prado-Martinez et al, 2013;Rothammer et al, 2017;Tsetskhladze et al, 2012;Tsuboi et al, 2009;Wijesena & Schmutz, 2015;Winkler et al, 2014;Xu et al, 2013), and polymorphisms at the SLC45A2 locus are associated with skin tone differences and skin aging in several human population studies (Adhikari et al., 2019;Branicki et al., 2008;Cerqueira et al, 2014;Fracasso et al, 2017;Han et al., 2008;Jonnalagadda et al, 2016;Law et al, 2017;Liu et al., 2015;Lopez et al, 2014;Soejima & Koda, 2007;Stokowski et al., 2007;Yuasa et al, 2006). OCA4 patients have very low levels of pigmentation and phenotypically resemble OCA2 patients who lack the melanosomal chloride channel, OCA2 (Bellono et al, 2014), suggesting that SLC45A2 plays an important role in melanogenesis (Montoliu et al., 2014). ...
Article
SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations cause oculocutaneous albinism type IV (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 localizes to a cohort of mature melanosomes that only partially overlaps with those expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that in melanocytes, SLC45A2 expression, like OCA2 expression, results in the deacidification of maturing melanosomes to support melanin synthesis. Interestingly, OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 likely functions later during melanosome maturation than OCA2. Moreover, the light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes due to rapid proteasome-dependent degradation resulting in lower protein expression levels in melanosomes than the dark skin-associated allelic variant. Our data suggest that SLC45A2 maintains melanosome neutralization initially orchestrated by transient OCA2 activity to support melanization at late stages of melanosome maturation, and that a common variant imparts reduced activity due to protein instability.
... Castanhos e homozigotos Creme são chamados perlino. Já de base preta (eumelanina) e homozigoto creme é conhecido como smoky cream (ou creme esfumaçado) 24 . ...
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The knowledge about horse coat color genetics has several applications, ranging from selection of desirable characteristics, understanding of the domestication process and as an auxiliary diagnosis in the clinic. It is essential for the veterinary professional to have a basic understanding of the genetic and functional mechanisms of the coatings, to better provide patient care and help breeders/owners of horses. However, currently the literature on coat genetics in Portuguese is out-of-date, and many unfounded prejudices continue to be disseminated due to the lack of scientific knowledge. This article covers the major topics on horse coat color genetics, addressing phenotypic characteristics, detrimental pleiotropies and physiological mechanisms related to the coat of domestic horses.
... Some missense mutations of SLC45A2 resulted in a dominant Silver locus that made yellow plumage undetectable, confirming the previous reported dilution effect on pheomelanin by this locus 9 . Similarly, dilution of pheomelanin with no effect on eumelanin, or with only a slight effect, has been observed in SLC45A2 mutation horses 41 . It is interesting feature also an enigma concerning the specific inhibition of pheomelanin in Table 1. ...
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Yellow plumage is common in chickens, especially in breeds such as the Huiyang Bearded chicken, which is indigenous to China. We evaluated plumage colour distribution in F1, F2, and F3 populations of an Huiyang Bearded chicken × White Leghorn chicken cross, the heredity of the yellow plumage trait was distinguished from that of the gold plumage and other known plumage colours. Microscopic analysis of the feather follicles indicated that pheomelanin particles were formed in yellow but not in white feathers. To screen genes related to formation of the pheomelanin particles, we generated transcriptome data from yellow and white feather follicles from 7- and 11-week-old F3 chickens using RNA-seq. We identified 27 differentially expressed genes (DEGs) when comparing the yellow and white feather follicles. These DEGs were enriched in the Gene Ontology classes ‘melanosome’ and ‘melanosome organization’ related to the pigmentation process. Down-regulation of TYRP1, DCT, PMEL, MLANA, and HPGDS, verified using quantitative reverse transcription PCR, may lead to reduced eumelanin and increased pheomelanin synthesis in yellow plumage. Owing to the presence of the Dominant white locus, both white and yellow plumage lack eumelanin, and white feathers showed no pigments. Our results provide an understanding of yellow plumage formation in chickens.
... The results showed that SLC18A3 had significantly lower expression levels in BS than in WS. In humans and other vertebrates (fish, mice, birds, horses, sheep, and Xenopus laevis), members of the SLC family such as SLC24A5, SLC24A4, SLC7A11, SLC2A11B, SLC36A1, and SLC45A2 have also been reported to be associated with melanin synthesis or pigmentation (Mariat et al. 2003;Gunnarsson et al. 2007;Ginger et al. 2008;Sturm Figure 3. Comparison of expression levels for 5 target mRNAs using qRT-PCR. ...
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MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that regulate gene expression in plants and animals. Skin colour is an important economic consideration in chicken production, and chickens with black skin have high market value. Nevertheless, little research has been conducted on miRNA regulation of melanogenesis in chicken skin. In this study, we sampled the dorsal skins of chickens with black (BS) and white (WS) skin to construct six small RNA libraries. High-throughput sequencing technology was then used to identify which miRNAs were expressed differentially between the BS and WS phenotypes. A total of 645 known and 64 novel miRNAs were identified from the six sequencing libraries. Additionally, the expression of 18 miRNAs was significantly different between the two phenotypes, including 9 miRNAs that were up-regulated, and 9 that were down-regulated. We identified 2 miRNAs, i.e. miR-204 and miR-6631-5p, that may be important for melanogenesis in chicken skin. Our data contribute to the understanding of the molecular mechanism, through miRNA regulation, of melanin formation in chicken skin. • Highlights • Differentially expressed miRNAs were identified in black skin (BS) and white skin (WS) of black-bone chickens • Eighteen DEMs were detected in BS and WS groups. • miR-204 and miR-6631-5p were potential candidates influencing skin melanogenesis in chicken.
... Deutlich von Vitiligo, einer progressiven Depigmentierung des Kopfes, Anus und der Perianalregion, abzugrenzen sind die Abzeichen, die durch das frühzeitige Ergrauen beim adulten Lipizzaner schwer zu identifizieren sind. Das Ziel der vorliegenden Arbeit war den Allelstatus und die Genotypenverteilungen einzelner bekannter Farbloci (MC1R (Marklund et al., 1996), ASIP (Rieder et al., 2001), STX17 (Pielberg et al., 2008), SLC45A2/MATP (Mariat et al., 2003), PMEL17/SILV (Brunberg et al., 2006), SLC36A1 (Cook et al., 2008), PAX C70Y (Hauswirth et al., 2012(Hauswirth et al., und 2013, SB1 (Brooks and Bailey, 2005)) in der aktuellen staatlichen Lipizzanerherde des Lipizzanergestütes Piber und der Spanischen Hofreitschule Wien zu erheben, die phänotypische Varianz der Abzeichen zu erfassen und eine Heritabilitätsschätzung für die Abzeichen durchzuführen. Damit soll eine Datengrundlage erstellt werden, die zukünftig für züchterische Maßnahmen in der Farbzucht beim Lipizzaner genutzt werden kann. ...
Article
Coat color represents one of the major selection criteria in horse breeding, and thus phenotypic color spectra directly correlate with the changes of breeding objectives and aesthetic attitudes. In this study we used the Austrian Lipizzan breeding herd of the stud farm Piber to illustrate this process by genotyping single coat color related loci ( MC1R, ASIP , STX17 , SLC45A2 / MATP , PMEL17/SILV, SLC36A1, PAXC70Y , SB1) , phenotypic analy ses of white markings and comparisons with historical records from the early 18th century. The majority of Lipizzans was gray (98,1%), whereas 80,6% were homozygous for the G -allele on the STX17 locus. Beyond the gray coat 81,1% of horses were bay, 18,9% were black, chestnut horses did not occur and three heterozygous buckskins were detected. Three Lipizzans were phenotypically spotted, which could be drawn back to the Dominant White locus (segregation of the W20 allele). Compared to the 18th century, it could be shown, that besides the drift on the gray locus towards homo zygosity, a shift from black color towards bay color occurred. Heritability estimates for white markings varied from 23% to 71%. The results of this study allow a precise breeding plan and selection strategy in favour of more phenotypic variability of coat color.
... OCA type 4 (OMIM #606574) represents 3-12% of total OCA patients in population studies (Gronskov et al., 2009;Wei et al., 2010Wei et al., , 2015Mauri et al., 2017;Lasseaux et al., 2018) and is due to mutations in the SLC45A2 gene encoding the putative transmembrane transporter SLC45A2 (aka membrane-associated transporter protein, MATP, or antigen isolated from immuno-selected melanoma-1, AIM1) (Newton et al., 2001). Mutations in the homologous gene underlie pigment dilution in a number of vertebrate species, including gorilla, several breeds of dog, tigers, horses, mice, shrew, chickens, pigeons, quail, frogs, fish, and perhaps cattle (Fukamachi et al., 2001;Newton et al., 2001;Mariat et al., 2003;Gunnarsson et al., 2007;Minvielle et al., 2009;Tsuboi et al., 2009;Tsetskhladze et al., 2012;Dooley et al., 2013;Prado-Martinez et al., 2013;Xu et al., 2013;Domyan et al., 2014;Winkler et al., 2014;Wijesena and Schmutz, 2015;Caduff et al., 2017;Rothammer et al., 2017;DeLay et al., 2018), and polymorphisms at the SLC45A2 locus are associated with skin tone differences and skin aging in several human population studies (Yuasa et al., 2006;Soejima and Koda, 2007;Stokowski et al., 2007;Branicki et al., 2008;Han et al., 2008;Cerqueira et al., 2014;Lopez et al., 2014;Liu et al., 2015;Jonnalagadda et al., 2016;Fracasso et al., 2017;Law et al., 2017;Adhikari et al., 2019). OCA4 patients have very low levels of pigmentation and phenotypically resemble OCA2 patients who lack the melanosomal chloride channel, OCA2 (Bellono et al., 2014), suggesting that SLC45A2 plays an important role in melanogenesis (Montoliu et al., 2014). ...
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SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations and polymorphisms cause oculocutaneous albinism (OCA) and pigmentation variation, but neither SLC45A2 localization and function nor how gene variants affect these properties are known. We show that SLC45A2 localizes to mature melanosomes that only partially overlap with a cohort expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that, like OCA2, SLC45A2 in melanocytes de-acidifies maturing melanosomes to support melanin synthesis. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 functions later during melanosome maturation than OCA2, and that OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. The light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes because of low level expression in melanosomes due to rapid proteasome-independent degradation. Our data indicate that SLC45A2 maintains melanosome neutralization – initially orchestrated by transient OCA2 activity – to support melanization at late stages of melanosome maturation, and that a common variant imparts reduced activity due to protein instability.
... In Europeans, a 78-kb haplotype around SLC24A5, which is in linkage disequilibrium with rs1426654, has been discovered to accumulate [95]. Many animals, including birds, horses, fish, and mice, have a similar pattern at rs16891982 in SLC45A2, associated with pigmentation [96,97]. In Europeans, other variants in this gene, such as rs40132, rs2287949 and rs26722, have also been associated with coloration [95,98]. ...
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Background: In the world scientific tradition, skin color is the primary physical characteristic used to divide humans into groups. Human skin has a wide range of tones and colors, which can be seen in a wide range of demographic populations. Many factors influence the color of people's skin, but the pigment melanin is by far the most important. Melanin is produced by cells called melanocytes in the skin and is the primary determinant of skin color in people with darker skin. Indeed, >150 genes have now been identified as having a direct or indirect effect on skin color. Vitamin D has recently been discovered to regulate cellular proliferation and differentiation in a variety of tissues, including the skin. The mechanisms through which the active vitamin D metabolite 1,25 dihydroxyvitamin D3 (or calcitriol) affects keratinocyte development are numerous and overlap with the mechanisms by which calcium influences keratinocyte differentiation. Ultraviolet (UV) is the most major modifiable risk factor for skin cancer and many other environmental-influenced skin disorders when it is abundant in the environment. Although the UV component of sunlight is known to cause skin damage, few researches have looked at the impact of non-UV solar radiation on skin physiology in terms of inflammation, and there is less information on the role of visible light in pigmentation. Summary: The quantity and quality of melanin are regulating by the expression of genes. The enzyme tyrosinase is primarily responsible for the genetic mechanism that controls human skin color. Genetics determines constitutive skin color, which is reinforced by facultative melanogenesis and tanning reactions. High quantities of melanin and melanogenic substances are typically accepted in darker skin to protect against UV radiation-induced molecular damage. Previous research has proposed that skin color variation is caused by a dynamic genetic mechanism, contributing to our understanding of how population demographic history and natural selection shape human genetic and phenotypic diversity. However, the most significant ethnic skin color difference is determined by melanin content. This current review aimed to assess the influence of skin color variations in skin structure and functions as well as difference in dermatological disease patterns. Also, this article reviewed several cases of skin color adaptation in different populations. Key Messages: Skin color impacts the composition and activity. Therefore, the contrast of dermatological ailments between distinct race-related categories is remarkable. Skin color adaptation is a challenging procedure. Refinement of skin color is an age-old craving of humans with ever-evolving drifts.
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Color morphs in ball pythons ( Python regius ) provide a unique and largely untapped resource for understanding the genetics of coloration in reptiles. Here we use a community-science approach to investigate the genetics of three color morphs affecting production of the pigment melanin. These morphs—Albino, Lavender Albino, and Ultramel—show a loss of melanin in the skin and eyes, ranging from severe (Albino) to moderate (Lavender Albino) to mild (Ultramel). To identify genetic variants causing each morph, we recruited shed skins of pet ball pythons via social media, extracted DNA from the skins, and searched for putative loss-of-function variants in homologs of genes controlling melanin production in other vertebrates. We report that the Albino morph is associated with missense and non-coding variants in the gene TYR . The Lavender Albino morph is associated with a deletion in the gene OCA2 . The Ultramel morph is associated with a missense variant and a putative deletion in the gene TYRP1 . Our study is one of the first to identify genetic variants associated with color morphs in ball pythons and shows that pet samples recruited from the community can provide a resource for genetic studies in this species.
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The horse (Equus ferus caballus) is one of the earliest domesticated species and has played an important role in the development of human societies over the past 5,000 years. In this study, we characterized the genome of the Marwari horse, a rare breed with unique phenotypic characteristics, including inwardly turned ear tips. It is thought to have originated from the crossbreeding of local Indian ponies with Arabian horses beginning in the 12th century. We generated 101 Gb (~30 × coverage) of whole genome sequences from a Marwari horse using the Illumina HiSeq2000 sequencer. The sequences were mapped to the horse reference genome at a mapping rate of ~98% and with ~95% of the genome having at least 10 × coverage. A total of 5.9 million single nucleotide variations, 0.6 million small insertions or deletions, and 2,569 copy number variation blocks were identified. We confirmed a strong Arabian and Mongolian component in the Marwari genome. Novel variants from the Marwari sequences were annotated, and were found to be enriched in olfactory functions. Additionally, we suggest a potential functional genetic variant in the TSHZ1 gene (p.Ala344>Val) associated with the inward-turning ear tip shape of the Marwari horses. Here, we present an analysis of the Marwari horse genome. This is the first genomic data for an Asian breed, and is an invaluable resource for future studies of genetic variation associated with phenotypes and diseases in horses.
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The Mangalitza lard‐type pig breed is well known for its fat appearance and curly hair, and it is mainly distributed in Eastern Europe. Four main lines were created in the nineteenth century by artificial selection: Blond Mangalitza, Black Mangalitza, Swallow‐Belly Mangalitza and Red Mangalitza. The Swallow‐Belly line has a black coat combined with yellow‐blond throat and underbelly. In the current work, we aimed to investigate if the colourations of Mangalitza pigs are genetically determined by one or a few loci whose frequencies have been modified by artificial selection. The results of selection scans, with HapFLK and BayeScan, and of a GWAS for coat colour highlighted the existence of one region on SSC16 (18–20 Mb) with potential effects on hair pigmentation (Red vs. Blond contrast). The analysis of the gene content of this region allowed us to detect the solute carrier family 45 member 2 (SLC45A2) locus as a candidate gene for this trait. The polymorphism of the SLC45A2 locus has been associated with reduced levels or the absence of melanin in several mammalian species. The genotyping of four missense polymorphisms evidenced that rs341599992:G > A and rs693695020:G > A SNPs are strongly but not fully associated with the red and blond coat colours of Mangalitza pigs, a result that was confirmed by performing a haplotype association test. The near fixation of alternative SLC45A2 genotypes in Red and Blond Mangalitza pigs provides a compelling example of the consequences of a divergent directional selection for coat colour in a domestic species.
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Introduction Base Colors (Black, Chestnut, Bay, and Seal Brown) Dilutions (Cream, Pearl, Champagne, Silver, Dun, and Lavender Foal) White Spotting and Depigmentation Patterns (Frame, Tobiano, Sabino, Dominant White, Leopard Complex, Gray, Roan, and White face and leg markings) References
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Horse breeding and husbandry has a large economic impact in Germany. Using the new developments in equine genome analysis, more breeding traits can be analysed by means of molecular genetic tools. Equine linkage and radiation hybrid maps are dense enough to allow whole genome scans. Fine-mapping requires development of new markers, particularly by employing comparative genomics. In the near future however, much progress in respect of development of SNPs and horse genome sequence is expected through the ongoing horse genome project. The horse genome project will provide the first complete genome sequence of a horse. In horses, five monogenetic defects have been described and for some colour loci, such as agouti, extension, cream und sabino mutations associated with phenotypic colour variants have been found. QTL for osteochondrosis (OC) and radiological changes of navicular bones have been reported. A marker in population-wide linkage disequilibrium was shown for OC. It might be expected that important traits in horse breeding will be characterized by QTL and these QTL will be fine mapped using the tools provided by the horse genome project.
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The mane and tail colour can differ drastically from the colour of the body caused by the effect of several genes. This effect can be seen in blacks and bays as well as chestnuts. There are several different causes for mane and tail dilutions in horses. Mane and tail of chestnuts can be diluted by the flaxen allele (f) affecting only phaeomelanin. Another allele diluting exclusively mane and tail seems to be the reason for silver mane and tail in blacks and bays with Arabian blood. Independently of the basic colour, dun horses can show a white case around the fully pigmented mane. Sometimes in buckskins, cream dilution leads to mottled mane and tail. On the basis of cream dilution and a possible combination with the flaxen allele, palominos show almost always white mane and tail. All horses with double cream dilution have white to cream coloured mane and tail. Silver dappling in blacks and bays leads to a strong dilution of mane and tail hairs. That is often the reason of false breeding registration. Independently of these main gene effects on mane and tail dilution, many modifying genes exist that produce different nuances of mane and tail colours. A clear knowledge of different colour dilutions supports the colour breeding, avoids mistakes in colour registration and creates conditions for molecular analysis.
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The aim of this study was to determine the allele frequency of the glycogen synthase 1 (GYS1) mutation associated with polysaccharide storage myopathy type 1 in the Austrian Noriker horse. Furthermore, we examined the influence of population substructures on the allele distribution. The study was based upon a comprehensive population sample (208 breeding stallions and 309 mares) and a complete cohort of unselected offspring from the year 2014 (1553 foals). The mean proportion of GYS1 carrier animals in the foal cohort was 33%, ranging from 15% to 50% according to population substructures based on coat colours. In 517 mature breeding horses the mutation carrier frequency reached 34%, ranging on a wider scale from 4% to 62% within genetic substructures. We could show that the occurrence of the mutated GYS1 allele is influenced by coat colour; genetic bottlenecks; and assortative, rotating and random mating strategies. Highest GYS1 carrier frequencies were observed in the chestnut sample comprising 50% in foals, 54% in mares and 62% in breeding stallions. The mean inbreeding of homozygous carrier animals reached 4.10%, whereas non-carrier horses were characterized by an inbreeding coefficient of 3.48%. Lowest GYS1 carrier frequencies were observed in the leopard spotted Noriker subpopulation. Here the mean carrier frequency reached 15% in foals, 17% in mares and 4% in stallions and inbreeding decreased from 3.28% in homozygous non-carrier horses to 2.70% in heterozygous horses and 0.94% in homozygous carriers. This study illustrates that lineage breeding and specified mating strategies result in genetic substructures, which affect the frequencies of the GYS1 gene mutation.
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The genomic changes underlying both early and late stages of horse domestication remain largely unknown. We examined the genomes of 14 early domestic horses from the Bronze and Iron Ages, dating to between ∼4.1 and 2.3 thousand years before present. We find early domestication selection patterns supporting the neural crest hypothesis, which provides a unified developmental origin for common domestic traits. Within the past 2.3 thousand years, horses lost genetic diversity and archaic DNA tracts introgressed from a now-extinct lineage. They accumulated deleterious mutations later than expected under the cost-ofdomestication hypothesis, probably because of breeding from limited numbers of stallions. We also reveal that Iron Age Scythian steppe nomads implemented breeding strategies involving no detectable inbreeding and selection for coat-color variation and robust forelimbs. Copyright © 2016 by the American Association for the Advancement of Science; All rights reserved.
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Our understanding of canine coat colour genetics and the associated health implications is developing rapidly. To date, there are 15 genes with known roles in canine coat colour phenotypes. Many coat phenotypes result from complex and/or epistatic genetic interactions among variants within and between loci, some of which remain unidentified. Some genes involved in canine pigmentation have been linked to aural, visual and neurological impairments. Consequently, coat pigmentation in the domestic dog retains considerable ethical and economic interest. In this paper we discuss coat colour phenotypes in the domestic dog, the genes and variants responsible for these phenotypes and any proven coat colour‐associated health effects.
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The Eneolithic Botai culture of the Central Asian steppes provides the earliest archaeological evidence for horse husbandry, ~5,500 ya, but the exact nature of early horse domestication remains controversial. We generated 42 ancient horse genomes, including 20 from Botai. Compared to 46 published ancient and modern horse genomes, our data indicate that Przewalski’s horses are the feral descendants of horses herded at Botai and not truly wild horses. All domestic horses dated from ~4,000 ya to present only show ~2.7% of Botai-related ancestry. This indicates that a massive genomic turnover underpins the expansion of the horse stock that gave rise to modern domesticates, which coincides with large-scale human population expansions during the Early Bronze Age.
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The roan coat color in horses is characterized by dispersed white hair and dark points. This phenotype segregates in a broad range of horse breeds, while the underlying genetic background is still unknown. Previous studies mapped the roan locus to the KIT gene on equine chromosome 3 (ECA3). However, this association could not be validated across different horse breeds. Performing a genome-wide association analysis (GWAS) in Noriker horses, we identified a single nucleotide polymorphism (SNP) (ECA3:g.79,543.439 A > G) in the intron 17 of the KIT gene. The G -allele of the top associated SNP was present in other roan horses, namely Quarter Horse, Murgese, Slovenian, and Belgian draught horse, while it was absent in a panel of 15 breeds, including 657 non-roan horses. In further 379 gray Lipizzan horses, eight animals exhibited a heterozygous genotype (A/G). Comparative whole-genome sequence analysis of the KIT region revealed two deletions in the downstream region (ECA3:79,533,217_79,533,224delTCGTCTTC; ECA3:79,533,282_79,533,285delTTCT) and a 3 bp deletion combined with 17 bp insertion in intron 20 of KIT (ECA3:79,588,128_79,588,130delinsTTATCTCTATAGTAGTT). Within the Noriker sample, these loci were in complete linkage disequilibrium (LD) with the identified top SNP. Based upon pedigree information and historical records, we were able to trace back the genetic origin of roan coat color to a baroque gene pool. Furthermore, our data suggest allelic heterogeneity and the existence of additional roan alleles in ponies and breeds related to the English Thoroughbred. In order to study the roan phenotype segregating in those breeds, further association and verification studies are required.
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Through the last century there has been a steady progression in our understanding of the biology of melanin biosynthesis. Much of this work includes the analysis of coat color mutations of the mouse and albinism in man. Our understanding has been greatly enhanced in the last 10 years, as the molecular pathogenesis of albinism has been better understood. Different mutations of the tyrosinase gene (TYR) , and their association with oculocutaneous albinism type 1 (OCA1) has provided insight into the biology of tyrosinase, including protein trafficking and structure/function analysis. Several questions still remain, including cryptic mutations that affect tyrosinase activity and the minimum amount of pigment required for normal optic development. The next 10 years should prove just as exciting as the last.
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Screening of a lambda gt11 human melanocyte cDNA library with antibodies against hamster tyrosinase (monophenol, L-dopa:oxygen oxidoreductase, EC 1.14.18.1) resulted in the isolation of 16 clones. The cDNA inserts from 13 of the 16 clones cross-hybridized with each other, indicating that they were from related mRNA species. One of the cDNA clones, Pmel34, detected one mRNA species with an approximate length of 2.4 kilobases that was expressed preferentially in normal and malignant melanocytes but not in other cell types. The amino acid sequence deduced from the nucleotide sequence showed that the putative human tyrosinase is composed of 548 amino acids with a molecular weight of 62,610. The deduced protein contains glycosylation sites and histidine-rich sites that could be used for copper binding. Southern blot analysis of DNA derived from newborn mice carrying lethal albino deletion mutations revealed that Pmel34 maps near or at the c-albino locus, the position of the structural gene for tyrosinase.
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The pink-eyed dilution (p) locus in the mouse is critical to melanogenesis; mutations in the homologous locus in humans, P, are a cause of type II oculocutaneous albinism. Although a cDNA encoded by the p gene has recently been identified, nothing is known about the protein product of this gene. To characterize the protein encoded by the p gene, we performed immunoblot analysis of extracts of melanocytes cultured from wild-type mice with an antiserum from rabbits immunized with a peptide corresponding to amino acids 285-298 of the predicted protein product of the murine p gene. This antiserum recognized a 110-kDa protein. The protein was absent from extracts of melanocytes cultured from mice with two mutations (pcp and p) in which transcripts of the p gene are absent or greatly reduced. Introduction of the cDNA for the p gene into pcp melanocytes by electroporation resulted in expression of the 3.3-kb mRNA and the 110-kDa protein. Upon subcellular fractionation of cultured melanocytes, the 110-kDa protein was found to be present in melanosomes but absent from the vesicular fraction; phase separation performed with the nonionic detergent Triton X-114 confirmed the predicted hydrophobic nature of the protein. These results demonstrate that the p gene encodes a 110-kDa integral melanosomal membrane protein and establish a framework by which mutations at this locus, which diminish pigmentation, can be analyzed at the cellular and biochemical levels.
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Thirty-six new horse microsatellites (11 from plasmid libraries and 25 from a cosmid library) were isolated and characterized on a panel of four horse breeds. Thirty were found to be polymorphic with heterozygosity levels ranging between 0.20 and 0.87. Twenty-two of the cosmids were physically mapped to R-banded single horse Chromosomes (Chrs) 1, 3, 4, 9, 11, 12, 13, 15, 18, 19, 21, 22, 23 and three to pericentromeric regions. Furthermore, linkage analysis between a selection of 42 DNA markers, including those presented in this study, and 16 conventional markers of the horse hemotype was performed on six paternal half-sib horse families. Five linkage groups were detected, of which four were assigned to Chr 10, 11, 15, and 18. This work increased by one-third the number of published polymorphic DNA markers suitable for horse mapping and approximately doubled the number of known linkage groups. Our cosmids labeled 14 out of the 31 horse autosomes. Moreover, the physical anchoring of part of these markers will orient linkage and synteny groups on the chromosomes and will contribute to their assignment.
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A primary male autosomal linkage map of the domestic horse (Equus caballus) has been developed by segregation analysis of 140 genetic markers within eight half-sib families. The family material comprised four Standardbred trotters and four Icelandic horses, with a total of 263 offspring. The marker set included 121 microsatellite markers, eight protein polymorphisms, five RFLPs, three blood group polymorphisms, two PCR-RFLPs, and one single strand conformation polymorphism (SSCP). One hundred markers were arranged into 25 linkage groups, 22 of which could be assigned physically to 18 different chromosomes (ECA1, ECA2, ECA3, ECA4, ECA5, ECA6, ECA7, ECA9, ECA10, ECA11, ECA13, ECA15, ECA16, ECA18, ECA19, ECA21, ECA22, and ECA30). The average distance between linked markers was 12.6 cM and the longest linkage group measured 103 cM. The total map distance contained within linkage groups was 679 cM. If the distances covered outside the ends of linkage groups and by unlinked markers were included, it was estimated that the marker set covered at least 1500 cM, that is, at least 50% of the genome. A comparison of the relationship between genetic and physical distances in anchored linkage groups gave ratios of 0.5-0.8 cM per Mb of DNA. This would suggest that the total male recombinational distance in the horse is 2000 cM; this value is lower than that suggested by chiasma counts. The present map should provide an important framework for future genome mapping in the horse.
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Myosin-X is the founding member of a novel class of unconventional myosins characterized by a tail domain containing multiple pleckstrin homology domains. We report here the full-length cDNA sequences of human and bovine myosin-X as well as the first characterization of this protein's distribution and biochemical properties. The 235 kDa myosin-X contains a head domain with <45% protein sequence identity to other myosins, three IQ motifs, and a predicted stalk of coiled coil. Like several other unconventional myosins and a plant kinesin, myosin-X contains both a myosin tail homology 4 (MyTH4) domain and a FERM (band 4.1/ezrin/radixin/moesin) domain. The unique tail domain also includes three pleckstrin homology domains, which have been implicated in phosphatidylinositol phospholipid signaling, and three PEST sites, which may allow cleavage of the myosin tail. Most intriguingly, myosin-X in cultured cells is present at the edges of lamellipodia, membrane ruffles, and the tips of filopodial actin bundles. The tail domain structure, biochemical features, and localization of myosin-X suggest that this novel unconventional myosin plays a role in regions of dynamic actin.
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Coat color genetics, when successfully adapted and applied to different mammalian species, provides a good demonstration of the powerful concept of comparative genetics. Using cross-species techniques, we have cloned, sequenced, and characterized equine melanocortin-1-receptor (MC1R) and agouti-signaling-protein (ASIP), and completed a partial sequence of tyrosinase-related protein 1 (TYRP1). The coding sequences and parts of the flanking regions of those genes were systematically analyzed in 40 horses and mutations typed in a total of 120 horses. Our panel represented 22 different horse breeds, including 11 different coat colors of Equus caballus. The comparison of a 1721-bp genomic fragment of MC1R among the 11 coat color phenotypes revealed no sequence difference apart from the known chestnut allele (C901T). In particular, no dominant black (E D) mutation was found. In a 4994-bp genomic fragment covering the three putative exons, two introns and parts of the 5′- and 3′-UTRs of ASIP, two intronic base substitutions (SNP-A845G and C2374A), a point mutation in the 3′-UTRs (A4734G), and an 11-bp deletion in exon 2 (ADEx2) were detected. The deletion was found to be homozygous and completely associated with horse recessive black coat color (A a /A a ) in 24 black horses out of 9 different breeds from our panel. The frameshift initiated by ADEx2 is believed to alter the regular coding sequence, acting as a loss-of-function ASIP mutation. In TYRP1 a base substitution was detected in exon 2 (C189T), causing a threonine to methionine change of yet unknown function, and an SNP (A1188G) was found in intron 2.
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Myosin X is a member of the diverse myosin superfamily that is ubiquitously expressed in various mammalian tissues. Although its association with actin in cells has been shown, little is known about its biochemical and mechanoenzymatic function at the molecular level. We expressed bovine myosin X containing the entire head, neck, and coiled-coil domain and purified bovine myosin X in Sf9 cells. The Mg(2+)-ATPase activity of myosin X was significantly activated by actin with low K(ATP). The actin-activated ATPase activity was reduced at Ca(2+) concentrations above pCa 5 in which 1 mol of calmodulin light chain dissociates from the heavy chain. Myosin X translocates F-actin filaments with the velocity of 0.3 microm/s with the direction toward the barbed end. The actin translocating activity was inhibited at concentrations of Ca(2+) at pCa 6 in which no calmodulin dissociation takes place, suggesting that the calmodulin dissociation is not required for the inhibition of the motility. Unlike class V myosin, which shows a high affinity for F-actin in the presence of ATP, the K(actin) of the myosin X ATPase was much higher than that of myosin V. Consistently nearly all actin dissociated from myosin X in the presence of ATP. ADP did not significantly inhibit the actin-activated ATPase activity of myosin X, suggesting that the ADP release step is not rate-limiting. These results suggest that myosin X is a nonprocessive motor. Consistently myosin X failed to support the actin translocation at low density in an in vitro motility assay where myosin V, a processive motor, supports the actin filament movement.
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Pigmentation of the skin is of great social, clinical and cosmetic significance. Several genes that, when mutated, give rise to altered coat color in mice have been identified; their analysis has provided some insight into melanogenesis and human pigmentation diseases. Such analyses do not, however, fully inform on the pigmentation of lower vertebrates because mammals have only one kind of chromatophore, the melanocyte. In contrast, the medaka (a small, freshwater teleost) is a suitable model of the lower vertebrates because it has all kinds of chromatophores. The basic molecular genetics of fish are known and approximately 70 spontaneous pigmentation mutants have been isolated. One of these, an orange-red variant, is a homozygote of a well-known and common allele, b, and has been bred for hundreds of years by the Japanese. Here, we report the first successful positional cloning of a medaka gene (AIM1): one that encodes a transporter that mediates melanin synthesis. The protein is predicted to consist of 12 transmembrane domains and is 55% identical to a human EST of unknown function isolated from melanocytes and melanoma cells. We also isolated a highly homologous gene from the mouse, indicating a conserved function of vertebrate melanogenesis. Intriguingly, these proteins have sequence and structural similarities to plant sucrose transporters, suggesting a relevance of sucrose in melanin synthesis. Analysis of AIM1 orthologs should provide new insights into the regulation of melanogenesis in both teleosts and mammals.
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Animal pigmentation mutants have provided rich models for the identification of genes modulating pathways from melanocyte development to melanoma. One mouse model is theunderwhite locus, alleles of which manifest altered pigmentation of both eye and fur, sometimes in an age-dependent fashion. Here we show that the mouse homolog of a recently identified gene whose mutation produces Japanese gold-colored fish, medaka b, maps to the mouseunderwhite locus. We identify distinct mutations of this gene, known as Aim-1, in three underwhite mouse alleles and find that structure/function differences correlate with recessive versus dominant inheritance. The human ortholog of AIM-1 was originally identified as a melanocyte-restricted antigen that is recognized by autologous T cells from a patient with melanoma. We also provide evidence that AIM-1 is transcriptionally modulated by MITF, a melanocyte-specific transcription factor essential to pigmentation and a clinical diagnostic marker in human melanoma. Although AIM-1 appears to reside downstream of MITF, chromatin immunoprecipitations do not reveal binding of MITF to a 5′-flanking region containing histone 3 acetylation, indicating that MITF either acts indirectly on AIM-1 or it binds to a remote regulatory sequence. Nevertheless, MITF links AIM-1 expression and theunderwhite phenotype to a transcriptional network central to pigmentation in mammals.
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The aim of this study was to increase the number of type I markers on the horse cytogenetic map and to improve comparison with maps of other species, thus facilitating positional candidate cloning studies. BAC clones from two different sources were FISH mapped: homologous horse BAC clones selected from our newly extended BAC library using consensus primer sequences and heterologous goat BAC clones. We report the localization of 136 genes on the horse cytogenetic map, almost doubling the number of cytogenetically mapped genes with 48 localizations from horse BAC clones and 88 from goat BAC clones. For the first time, genes were mapped to ECA13p, ECA29, and probably ECA30. A total of 284 genes are now FISH mapped on the horse chromosomes. Comparison with the human map defines 113 conserved segments that include new homologous segments not identified by Zoo-FISH on ECA7 and ECA13p.
Article
This book is an excellent, well researched and comprehensive reference work for all areas of equine genetic. It covers topics from phylogeny to the measure of performance traits and will be a useful source of information for years to come. It is written in a style that is straight forward, easy to read and never superfluous. The layout of each chapter is very clear and the chapters are organized well in relation to each other according to subject area. The list of references at the end of each chapter is very thorough. In the early chapters, photographs of the various examples of the Equus subgenera and the not so familiar horse breeds, such as the 'Yakut', would have been a welcome addition to the written descriptions, which tend be tedious at the best of times. In addition, a picture of the skeleton and musculature of the horse at the beginning would have been helpful in those chapters that include descriptions of research on particular muscle areas, etc. The chapter on 'Genetic Resources and their Conservation' was particularly relevant, as breeders often do not consider the implications of their present breeding goals in the context of their use of only a few selected families in the production of sport horses. Perhaps this should have been the concluding chapter, as it summarizes the types of constraints and challenges that are facing horse breeders world-wide.
Article
The mouse pink eyed dilution locus, p, located on chromosome 7, mediates coat and eye color. The human correlate of this gene may underlie some forms of tyrosinase-positive oculocutaneous albinism. Mutations at the p locus result in a reduction in pigmentation of the eyes and coat. Although most mutant p alleles (including all spontaneous mutations) affect only pigmentation, several mutant alleles (all radiation induced) are also associated with a variety of other phenotypes. We have focused our attention on the pun mutant allele, a spontaneous mutation, exhibiting one of the highest reversion frequencies reported for a mammalian mutation. Using a new technique, genome scanning, we have cloned fragments of genomic DNA from the p locus that are associated with a DNA duplication in pun DNA. These fragments can now be used to locate the p gene-encoding sequences and aid in the molecular characterization of complex mutant p alleles.
Article
The mouse has provided several significant models for hypopigmentation disorders, including the major forms of albinism. Mutations at the mouse underwhite locus confer one of the most severe hypopigmentation phenotypes, similar to mutations at the pink-eyed dilution locus that is a model for type 2 oculocutaneous albinism. A melanocyte cell line established from underwhite mutant mice failed to pigment under conditions that support pigment production in wild-type melanocytes and melanoblasts from underwhite skin graft transplants failed to produce melanin in normal skin, demonstrating that the action of the gene encoded by the underwhite locus is intrinsic to melanocytes. Mice with mutations at the underwhite locus and either the pink-eyed dilution locus or the melanocortin receptor 1 locus exhibited more severe hypopigmentation than either mutation alone, suggesting that the actions of these genes are independent. These results demonstrate that the underwhite locus is a major determinant of mammalian pigmentation.Keywords: melanocyte, mouse mutations, pigmentation
Article
Overo lethal white syndrome (OLWS) is an inherited syndrome of foals born to American Paint Horse parents of the overo coat-pattern lineage. Affected foals are totally or almost totally white and die within days from complications due to intestinal aganglionosis. Related conditions occur in humans and rodents in which mutations in the endothelin receptor B (EDNRB) gene are responsible. EDNRB is known to be involved in the developmental regulation of neural crest cells that become enteric ganglia and melanocytes. In this report we identify a polymorphism in the equine EDNRB gene closely associated with OLWS. This Ile to Lys substitution at codon 118 is located within the first transmembrane domain of this seven-transmembrane domain G-protein-coupled receptor protein. All 22 OLWS-affected foals examined were homozygous for the Lys118 EDNRB allele, while all available parents of affected foals were heterozygous. All but one of the parents also had an overo white body-spot phenotype. Solid-colored control horses of other breeds were homozygous for the Ile118 EDNRB allele. Molecular definition of the basis for OLWS in Paint Horses provides a genetic test for the presence of the Lys118 EDNRB allele and adds to our understanding of the basis for coat color patterns in the horse.
Article
The mouse pink-eyed dilution locus, p, located on chromosome 7, mediates coat and eye color. The human correlate of this gene may underlie some forms of tyrosinase-positive oculocutaneous albinism. Mutations at the p locus result in a reduction in pigmentation of the eyes and coat. Although most mutant p alleles (including all spontaneous mutations) affect only pigmentation, several mutant alleles (all radiation induced) are also associated with a variety of other phenotypes. We have focused our attention on the p(un) mutant allele, a spontaneous mutation, exhibiting one of the highest reversion frequencies reported for a mammalian mutation. Using a new technique, genome scanning, we have cloned fragments of genomic DNA from the p locus that are associated with a DNA duplication in p(un) DNA. These fragments can now be used to locate the p gene-encoding sequences and aid in the molecular characterization of complex mutant p alleles.
Article
We have isolated and sequenced the gene encoding human tyrosinase, the key enzyme in pigment biosynthesis. The human tyrosinase gene contains five exons and spans more than 50 kb of DNA on chromosome segment 11q14----q21. We have also isolated a second segment in the human genome that is closely related to tyrosinase. The tyrosinase-related segment, located on 11p11.2----cen, contains only exons 4 and 5 plus adjacent noncoding regions. This segment is present in all human ethnic groups analyzed, and the noncoding nucleotide sequences shared by the 11q tyrosinase gene and the 11p tyrosinase-related segment differ by only 2.6%. This suggests that this segment of the tyrosinase gene was duplicated approximately 24 million years ago.
Article
Hundreds of murine dilute mutations have been identified and analysed, making dilute one of the best genetically characterized of all mammalian loci. The recessive dilute (d) coat colour mutation carried by many inbred strains of mice produces a lightening of coat colour, caused by an abnormal adendritic melanocyte morphology that results in an uneven release of pigment granules into the developing hair shaft. Most dilute alleles (dilute-lethal) also produce a neurological defect, characterized by convulsions and opisthotonus, apparent at 8-10 days of age and continuing until the death of the animal at 2-3 weeks of age. The discovery that the original dilute allele (now termed dilute-viral or dV) is the result of the integration of an ecotropic murine leukaemia provirus has allowed the cloning of genomic DNA and in this study complementary DNA, from the dilute locus. The predicted dilute amino-acid sequence indicates that dilute encodes a novel type of myosin heavy chain, with a tail, or C-terminal, region that has elements of both type II (alpha-helical coiled-coil) and type I (non-coiled-coil) myosin heavy chains. Dilute transcripts are differentially expressed in both embryonic and adult tissues and are very abundant in neurons of the central nervous system, cephalic ganglia, and spinal ganglia. These results suggest an important role for the dilute gene product in the elaboration, maintenance, or function of cellular processes of melanocytes and neurons.
Article
Eye tissues of tan-hooded, pink-eyed rats were shown in a previous report to become pigmented in short-term tissue cultures, and the phenomenon has now been analyzed in more detail. The rats, inbred and named the RCS strain, are homozygous for the recessive gene pink-eyed dilution, p, or an allele with similar properties. Eye tissues of postnatal rats and , , and mice are minimally pigmented in vivo, and made little pigment when cultured in synthetic media lacking tyrosine. Pigmentation was strong when tyrosine was present in the medium, and the pigment was identified as melanin on the basis of color, staining properties, intracellular location, appearance in electron micrographs, and restriction to the cells of the iris, ciliary body, pigment epithelium, and choroid that contain melanin in pigmented animals. Pigmentation was obtained in primary cultures on collagen-coated coverslips and in organ cultures, in room air and in an atmosphere of 95% O2-5% CO2. An inductive mechanism for the response is unlikely because tyrosine-mediated pigmentation was not prevented by puromycin (up to 150 μg/ml) or actinomycin D (up to 10 μg/ml) in the culture medium. Failure of melanin-synthesizing enzyme activity because of membrane disarray within mutant melanosomes was ruled out because disordered granules, like the regular ones, appeared pigmented in electron micrographs. Competitive inhibition by excess phenylalanine was ruled out by phenylalanine measurements in vivo and by varying phenylalanine: tyrosine ratios in culture. Tyrosinase contains copper, and a gene-controlled copper deficit might be corrected in vitro by copper in ordinary culture media; however, tyrosine-mediated pigmentation was undiminished by the use of copper-free media. The p genes reduce pigmentation despite the presence of an apparently appropriate melanin-synthesizing machinery, possibly by causing tyrosine to be shunted to other pathways; exogenous tyrosine in vitro restored the normal phenotype.
Article
Historically, most methods for detecting linkage disequilibrium were designed for use with diallelic marker loci, for which the analysis is straightforward. With the advent of polymorphic markers with many alleles, the normal approach to their analysis has been either to extend the methodology for two-allele systems (leading to an increase in df and to a corresponding loss of power) or to select the allele believed to be associated and then collapse the other alleles, reducing, in a biased way, the locus to a diallelic system. I propose a likelihood-based approach to testing for linkage disequilibrium, an approach that becomes more conservative as the number of alleles increases, and as the number of markers considered jointly increases in a multipoint test for linkage disequilibrium, while maintaining high power. Properties of this method for detecting associations and fine mapping the location of disease traits are investigated. It is found to be, in general, more powerful than conventional methods, and it provides a tractable framework for the fine mapping of new disease loci. Application to the cystic fibrosis data of Kerem et al, is included to illustrate the method.
Article
The mouse pink-eyed dilution (p) locus on chromosome 7 is associated with defects of skin, eye and coat pigmentation. Mutations at p cause a reduction of eumelanin (black-brown) pigment and altered morphology of black pigment granules (eumelanosomes), but have little effect on pheomelanin (yellow-red) pigment. We show here that the human complementary DNA DN10, linked to the p locus in mice, identifies the human homologue (P) of the mouse p gene, and appears to encode an integral membrane transporter protein. The expression pattern of this gene in various p mutant mice correlates with the pigmentation phenotype; moreover, an abnormally sized messenger RNA is detected in one mutant, p(un), which reverts to the normal size in p(un) revertants. The human P gene corresponds to the D15S12 locus within the chromosome segment 15q11-q13, which is typically deleted in patients with Prader-Willi and Angelman syndrome (see ref. 5 for review). These disorders are phenotypically distinct, depending on the parent of origin of the deleted chromosome, but both syndromes are often associated with hypopigmentation of the skin, hair and eyes (see ref. 8 for review), and deletion of the P gene may be responsible for this hypopigmentation. In addition, we report a mutation in both copies of the human P gene in one case of tyrosinase-positive (type II) oculocutaneous albinism, recently linked to 15q11-q13 (ref. 9).
Article
We propose that at least two families of genes regulate the melanin biosynthesis. The first is the tyrosinase gene family, which is comprised of tyrosinase (c locus), gp75 (b locus) and DOPAchrome tautomerase (slt locus). The second is the pmel 17 gene family, which is composed of pmel 17 (putative si locus) and chicken melanosomal matrix protein (MMP) 115. It appears that the tyrosinase gene family regulates melanin synthesis in the proximal steps of the melanin biosynthetic pathway and the pmel 17 gene family might be important at distal steps of the pathway.
Article
Human chromosome specific libraries (CSLs) were individually applied to equine metaphase chromosomes using the fluorescence in situ hybridization (FISH) technique. All CSLs, except Y, showed painting signals on one or several horse chromosomes. In total 43 conserved chromosomal segments were painted. Homoeology could not, however, be detected for some segments of the equine genome. This is most likely related to the very weak signals displayed by some libraries, rather than to the absence of similarity with the human genome. In spite of divergence from the human genome, dated 70-80 million years ago, a fairly high degree of synteny conservation was observed. In seven cases, whole chromosome synteny was detected between the two species. The comparative painting results agreed completely with the limited gene mapping data available in horses, and also enabled us provisionally to assign one linkage group (U2) and one syntenic group (NP, MPI, IDH2) to specific equine chromosomes. Chromosomal assignments of three other syntenic groups are also proposed. The findings of this study will be of significant use in the expansion of the hitherto poorly developed equine gene map.
Article
Myosins are molecular motors that move along filamentous actin. Seven classes of myosin are expressed in vertebrates: conventional myosin, or myosin-II, as well as the 6 unconventional myosin classes-I, -V, -VI, -VII, -IX, and -X. We have mapped in mouse 22 probes encompassing all known unconventional myosins and, as a result, have identified 16 potential unconventional myosin genes. These genes include 7 myosins-I, 2 myosins-V, 1 myosin-VI, 3 myosins-VII, 2 myosins-IX, and 1 myosin-X. The map location of 5 of these genes was identified in human chromosomes by fluorescence in situ hybridization.
Article
The melanocyte-stimulating hormone receptor gene (MC1R) is the major candidate gene for the chestnut coat color in horses since it is assumed to be controlled by an allele at the extension locus. MC1R sequences were PCR amplified from chestnut (e/e) and non-chestnut (E/-) horses. A single-strand conformation polymorphism was found that showed a complete association to the chestnut coat color among 144 horses representing 12 breeds. Sequence analysis revealed a single missense mutation (83Ser-->Phe) in the MC1R allele associated with the chestnut color. The substitution occurs in the second transmembrane region, which apparently plays a key role in the molecule since substitutions associated with coat color variants in mice and cattle as well as red hair and fair skin in humans are found in this part of the molecule. We propose that the now reported mutation is likely to be the causative mutation for the chestnut coat color. The polymorphism can be detected with a simple PCR-RFLP test, since the mutation creates a TaqI restriction site in the chestnut allele.
Article
Mice with mutations at the dilute locus exhibit a 'washed out' or 'diluted' coat color. The pigments that are responsible for the coloration of mammalian hair are produced by melanocytes within a specialized organelle, the melanosome. Each melanocyte is responsible for delivering melanosomes via its extensive dendritic arbor to numerous keratinocytes, which go on to form the pigmented hair shaft. In this study, we show by light immunofluorescence microscopy and immunoelectron microscopy that the myosin V isoform encoded by the dilute locus associates with melanosomes. This association, which was seen in all mouse melanocyte cell lines examined and with two independent myosin V antibodies, was evident not only within completely melanized cells, but also within cells undergoing the process of melanosome biogenesis, where coordinate changes in the distributions of a melanosome marker and myosin V were seen. To determine where myosin V, a known actin-based motor, might play a role in melanosome transport, we also examined the cellular distribution of F-actin. The only region where myosin V and F-actin were both concentrated was in dendrites and dendritic tips, which represent the sole destination for melanosomes and where they accumulate in cultured melanocytes. These results support the idea that myosin V serves as the motor for the outward movement of melanosomes within dendritic extensions, and, together with the available information regarding the phenotype of mutant melanocytes in vitro, argue that coat color dilution is caused by the absense of this myosin V-dependent melanosome transport system.
Article
Lethal White Foal Syndrome is a disease associated with horse breeds that register white coat spotting patterns. Breedings between particular spotted horses, generally described as frame overo, produce some foals that, in contrast to their parents, are all white or nearly all white and die shortly after birth of severe intestinal blockage. These foals have aganglionosis characterized by a lack of submucosal and myenteric ganglia from the distal small intestine to the large intestine, similar to human Hirschsprung Disease. Some sporadic and familial cases of Hirschsprung Disease are due to mutations in the endothelin B receptor gene (EDNRB). In this study, we investigate the role of EDNRB in Lethal White Foal Syndrome. A cDNA for the wild-type horse endothelin-B receptor gene was cloned and sequenced. In three unrelated lethal white foals, the EDNRB gene contained a 2-bp nucleotide change leading to a missense mutation (I118K) in the first transmembrane domain of the receptor, a highly conserved region of this protein among different species. Seven additional unrelated lethal white foal samples were found to be homozygous for this mutation. No other homozygotes were identified in 138 samples analyzed, suggesting that homozygosity was restricted to lethal white foals. All (40/40) horses with the frame overo pattern (a distinct coat color pattern that is a subset of overo horses) that were tested were heterozygous for this allele, defining a heterozygous coat color phenotype for this mutation. Horses with tobiano markings included some carriers, indicating that tobiano is epistatic to frame overo. In addition, horses were identified that were carriers but had no recognized overo coat pattern phenotype, demonstrating the variable penetrance of the mutation. The test for this mutant allele can be utilized in all breeds where heterozygous animals may be unknowingly bred to each other including the Paint Horse, Pinto horse, Quarter Horse, Miniature Horse, and Thoroughbred.
Article
A horse BAC library was constructed with about 40,000 clones and mean insert size of 110 kb representing a 1.5 genome equivalent coverage and a probability of finding a single sequence of 0.75. It was characterized by PCR screening of about 130 sequences of horse microsatellites and exonic gene sequences retrieved from databases. BACs containing 8 microsatellites and 12 genes were subsequently localized by fluorescent in situ hybridization (FISH) on chromosomes. Two linkage groups were newly assigned to chromosomes: LG2 to ECA3 and LG5 to ECA24, and five linkage groups were also oriented--LG3, LG4, LG5, LG8, and LG12--leaving only three groups unassigned. This work showed how this library makes an integrated map a realistic objective for the near future and how it can make comparative mapping more efficient in a search for candidate genes of interest.
Article
The pink-eyed dilution phenotype in mice arises from mutations in the p gene; in humans, analogous mutations in the P gene result in oculocutaneous albinism type 2. Although the molecular mechanisms which underlie this phenotype remain obscure, it has been postulated that mutations in p result in defective tyrosine transport into murine melanosomes, resulting in hypopigmentation and diminished coat color. However, we previously reported no difference in melanosomal tyrosine transport in unpigmented, melanoblast-like pink-eyed dilution (pcp/pcp), and in pigmented (melan-a) murine melanocytes. In this study, we utilized melan-p1 cells, more differentiated pink-eyed dilution (pcp/p25H) melanocytes which can be induced to produce melanin, to characterize the melanogenic lesion(s) more definitively. Uptake of [3H]tyrosine into melan-a melanosomes did not differ significantly from uptake into melanosomes derived from melan-p1 melanocytes, further arguing against its critical role as a tyrosine transporter. Pink-eyed dilution melanocytes incubated in high tyrosine concentrations became extremely pigmented as they became confluent and secreted large amounts of black material into the medium. Total cellular tyrosinase activity in melan-p1 melanocytes was significantly higher than that in melan-a melanocytes (which are wild-type at the p locus), but the localization of tyrosinase to melanosomes was impaired in melan-p1 melanocytes compared to melan-a melanocytes. These results indicate that mechanisms other than deficient tyrosine transport are involved in the pink-eyed dilution phenotype and that this protein may serve a chaperone-like or stabilizing function in melanocytes.
Article
A new allelic series at the underwhite gene is described. Three of the alleles in the series--uw, uwd, and Uwdbr--arose as spontaneous mutations on different genetic backgrounds at The Jackson Laboratory. We report here the visible phenotypes and dominance hierarchy of these alleles, all of which are defined by a reduction of pigmentation in both eye and coat color. Electron microscopic analysis of retinal epithelium suggests that the primary defect is in the melanosome. The degree of severity of melanosome anomalies in the retina correlates with the degree of hypopigmentation in the coat. The perturbed gene and its gene product are unknown. We show that the uw locus is genetically distinct from Myo10, a suggested candidate gene for this mutation.
Article
In order to increase the number of markers on the horse cytogenetic map and expand the integration with the linkage map, an equine BAC library was screened for genes and for microsatellites. Eighty-nine intra-exon primers were designed from consensus gene sequences in documented species. After PCR screening, 38 clones containing identified genes were isolated and FISH mapped. These data allowed us to refine the available Zoo-FISH results, to define ten new conserved cytogenetic segments and expand two others, thus leading to the identification of a total of 26 conserved segments between horse and human. Interestingly, a new homeology segment was detected between ECA6p and HSA2q. Screening BAC clones for dinucleotide repeats led to the isolation of 33 microsatellites. Ten of the clones each contained at least a polymorphic microsatellite and one specific gene. The success of the approach in the production of integrative anchor loci and their potential use in localization and analysis of traits of interest by the candidate gene and positional cloning approach, are discussed.
Article
Oculocutaneous albinism (OCA) affects approximately 1/20,000 people worldwide. All forms of OCA exhibit generalized hypopigmentation. Reduced pigmentation during eye development results in misrouting of the optic nerves, nystagmus, alternating strabismus, and reduced visual acuity. Loss of pigmentation in the skin leads to an increased risk for skin cancer. Two common forms and one infrequent form of OCA have been described. OCA1 (MIM 203100) is associated with mutations of the TYR gene encoding tyrosinase (the rate-limiting enzyme in the production of melanin pigment) and accounts for approximately 40% of OCA worldwide. OCA2 (MIM 203200), the most common form of OCA, is associated with mutations of the P gene and accounts for approximately 50% of OCA worldwide. OCA3 (MIM 203290), a rare form of OCA and also known as "rufous/red albinism," is associated with mutations in TYRP1 (encoding tyrosinase-related protein 1). Analysis of the TYR and P genes in patients with OCA suggests that other genes may be associated with OCA. We have identified the mouse underwhite gene (uw) and its human orthologue, which underlies a new form of human OCA, termed "OCA4." The encoded protein, MATP (for "membrane-associated transporter protein") is predicted to span the membrane 12 times and likely functions as a transporter.
Article
The colour locus historically referred to as C in the horse is linked to microsatellites markers on horse chromosome 21. Preliminary results demonstrated linkage of Ccr, thought to be the cream dilution variant of the C locus, to HTG10. An analysis of horse chromosome 21 using additional families confirmed and established a group of markers linked to Ccr. This work also improved the resolution of previously reported linkage maps for this chromosome. Linkage analysis unambiguously produced the map order: SGCV16-(19.1 cM)-HTG10-(3.8 cM)-LEX60/COR73-(1.3 cM)-COR68-(4.5 cM)- Ccr-(11.9 cM)-LEX31. Comparative and synteny data suggested that the horse C locus is not tyrosinase (TYR).
Cytogenetic localization of 136 genes in the horse: comparative mapping with the human genome Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4
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Organizationandnucleotidesequencesof thehumantyrosinasegeneandatruncatedtyrosinase-relatedsegment
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Documentation for CRI-MAP, version 2.4
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The genetics of the horse
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Zoo-FISH delineates conserved chromosomal segments in horse and man
  • T Raudsepp