Color Inheritance in the English Mastiff

NEWS FLASH: Bull's DNA was submitted for genetic testing. He is aY and will soon be 'published'.

(December 17, 2005)
update 09/07/04: Recent data (to be submitted for publication) indicate that a brindle can be born from two phenotypic fawns, at least in French Bulldogs (see Brindle / K locus). Apparently, in order to phenotypically show brindling the French Bulldog must have the E or Em allele. How this relates to Mastiffs, is unknown.
update 12/31/03: Since the last scientific literature update (Sept. 2003), the page has changed to focus more specifically on those color genes phenotypically expressed in the Mastiff. I have added some photos, chromosomal locations and conclusions from two recent publications; Schmutz et al. [24] "MC1R Studies in dogs with melanistic mask or brindle patterns" and Kerns et al. [17]"Exclusion of melanocortin-1 receptor (Mc1r) and agouti as candidates for dominant black in dogs"

First, let it be known that this is a work in progress which started circa November 1999. Also, I am not a genetics expert. Trying to understand color inheritance in the English Mastiff is merely a hobby for me. I don't claim to have all the answers and judging from some of the inconsistencies within the literature, I feel relatively safe in saying that nobody does. Consequently, if anybody has either data to refute what has been written here or constructive criticism please send me an e:mail me and I will make the necessary changes. For this page, I have received some extremely valuable input from Dr. Schmutz whose web page can be visited here (Genetics of Coat Color in Dogs).

The photo below
(I know it's poor. I really am working on a better one.) shows what generated my initial interest. It's a picture of Bull, my fawn male, with what appears to be faint black stripes on his leg. Is this brindling ? He is from an apricot x fawn mating. Some contend that you cannot have a brindle pup without a brindle parent. This may be true and these markings may not be brindling. I don't know. Yet, these are clearly stripes and neither of his parents were a registered brindle. Regardless, his markings are responsible for my interest and I am writing this article because I have yet to find any source which sufficiently addresses Mastiff color inheritance. His phenotype has also raised the question - What gene locus combination (A, C, D, E or some other) is responsible for the color apricot ? Are there two genotypes of apricot mastiffs, one which can carry brindle without expressing it while the other ('ay_') must show brindle ? Recently a study by Newton et al. [1] has described the MC1R variation (see below, E locus) in several breeds which may contribute to some of the apricot color.

stripes on foreleg

With the excellent help and painstaking effort of Deb Jones and the DeVine Farms Pedigree program (money from it's purchase goes towards Mastiff Rescue), the following numbers have been generated. The table below (includes stats through December 2001) shows the color and number of all the pups that resulted from the matings described in the first two columns. The number in parenthesis indicates the percent of that color pup of total pups within that mating.


Mating
Number of pups that are the color (%)
Sire color
Dam color
Fawn
Apricot
Brindle
apricot
apricot
197 (30)
450 (69)
2 (0.3)
apricot
fawn
998 (52)
898 (47)
22 (1)
apricot
brindle
186 (23)
206 (26)
412 (51)
fawn
apricot
946 (50)
929 (49)
11 (0.6)
fawn
fawn
6865 (95)
279 (4)
69 (1)
fawn
brindle
1172 (42)
197 (7)
1412 (51)
brindle
apricot
239 (26)
213 (23)
477 (51)
brindle
fawn
1163 (42)
152 (5)
1477 (53)
brindle
brindle
141 (19)
47 (6)
558 (75)


These data show that there were 104 brindle pups (2+22+11+69) that did not have a registered brindle parent. Those who believe a brindle pup must have a brindle parent could argue that the Mastiffs (parent or pup) were registered incorrectly, either by accident or purposefully. This may be true. However, I'd ask, "Why are only the brindles misregistered ?" Shouldn't it be just as likely that the fawns and apricots be misregistered so that these could then 'make up' for the incorrect brindle registrations ? I don't have the answer, wish I did - I'm only posing the question.

Within the 104 brindle pups, there were 71 different sires, 76 different dams
(three specific sets of parents were responsible for 14 of these brindle pups) and 273 different grandparents (of the possible 2x 71+76 = 294). Moreover, of the grandparents (five were of unknown color), there were 42 apricot (16%), 173 fawn (64%) and 53 brindle (20%) which closely mimics the color distribution within the general Mastiff database of 3371 apricot (17%), 11907 fawn (60%) and 4440 brindle (22%). Thus, there does not appear to be any specific color lineage associated with the 104 brindle pups from non-registered brindle parents. Moreover, do not be mistaken into believing that these brindle pups are merely ancient history because, since January of 1998, there have been 18 brindle pups born from non-brindle registered parents according to the Pedigree database. I have not contacted the owners of these pups to enquire as to their DNA certification.

Not withstanding, the results from this analysis are also internally consistent. That is, color inheritance, as shown in the table, is clearly not sex linked. For example, an apricot x fawn or a fawn x apricot mating produce nearly an identical percentage and number of fawn, apricot and brindle pups. Furthermore, this can be demonstrated with all matings between parents of dissimilar color.


As an aside, there are 4763 mastiffs listed that have no color assigned, and another 72 with some unusual designations including blue brindle (2), apricot fawn (7), fawn apricot (5), red (4), red fawn (6) and black (4).

The graphs below show the percentage of each color born within the total population (ie. listed) on a monthly and yearly basis since 1965. Note that there is no good reason to believe that color and month of birth should show any correlation. I was merely curious.

click for larger version click for larger version

Color and melanin
(The text immediately below may be difficult to follow, but allows the reader to more easily put the genes, and the proteins they encode, into the proper perspective as to how they may affect melanin and color formation.)

During embryogenesis specific cells (melanoblasts) migrate from the neural crest [2] into the basal epithelium of the epidermis, hair bulbs of the skin and specific areas of the eye, ear and brain. Migration tends to be directionally from head (rostral) to tail (caudal) and top (dorsal) to bottom (ventral) [3]. One only needs to look at the final color pattern in dogs to see this directional effect. For example, both the vertical stripes of the brindling pattern and the tips coloring pattern (e.g. tail, paws) which may be very different in color from the main body, are both reminiscent of the melanocyte precursor migration pathway. If, during embryogenesis, there is a shortage of melanocytes, particular areas of the body receive priority (e.g. eye, brain and ear). However, the specific survival, proliferation, migration and final differentiation of these melanoblasts into melanocytes is influenced by several paracrine factors, including basic fibroblast growth factor, steel factor [4](a.k.a. mast cell growth factor or stem cell factor or c-kit ligand) and endothelin-1 [5] which may be released by cells (e.g. keratinocytes and fibroblasts) in the epidermis. For color production, the melanocytes synthesize a chemical pigment, melanin, which is deposited onto the structural fibullar component gp100, located in subcellular organelles called melanosomes. However, the follicular microenvironment (i.e. hair bulb area) rather than the melanocyte genotype appear to regulate which type of melanin synthesis (i.e. eumelanogenesis or pheomelanogenesis) predominates [6]. Once the melanosomes are packed with either eumelanin or phaeomelanin, these melanosomes are translocated over the melanocyte cytoskeleton within the developing hair shaft using myosin V through dendritic processes to an area where the melanosomes maybe taken up by keratinocyte phagocytosis [7]. Each melanocyte may have as many as 36 keratinocytes associated with it. Slowly, the keratinocytes are pushed up the hair shaft as cells near the base of the hair fiber (i.e. dermal papilla) continue to multiply. This is a perpetual process employing an array of different proteins so that new melanosomes can be continuously produced and released into adjacent keratinocytes which are then pushed up the shaft. Consequently, color differences are effected, in part, by melanosome movements within the melanocyte. For some excellent figures and description of the developing hair shaft and melanocyte involvement visit the links at Hair Biology and Hair Color.

Melanin is not a simple molecule but actually a polymer synthesized within the melanosome using two different types of 'building blocks'. One, eumelanin, responsible for the black to brown coloration and another, phaeomelanin, responsible for the yellow to red coloration. Both eumelanin and phaeomelanin are formed from the precursors dihydroxyphenylalanine (DOPA) and tyrosine. These precursors are enacted upon by tyrosinase (see C locus), the first enzyme and the rate limiting enzyme in the melanin synthesis pathway, which catalyzes the formation of dopaquinone. Whether, dopaquinone proceeds toward eumelanin (black) or phaeomelanin (red) appears to be dependent upon both the level of tyrosinase activity and the presence of thiols (e.g. cysteine and glutathione) [8]. If tyrosinase activity is low relative to cysteine levels, then phaeomelanogenesis proceeds; if tyrosinase activity is high, or cysteine levels low, then eumelanogenesis. Tyrosinase variants tend to be less active than the native form and lessen the depth of black or red color. For an excellent review of pheomelanogenesis see Wolff [9].
Two other enzymes besides tyrosinase have been described specifically in the eumelanogenesis pathway, tyrosinase-related protein-1 (TRP-1, see B locus) [10] and tyrosinase-related protein-2 [11] (TRP-2; a.k.a. dopachrome tautomerase). These enzymes may help to stabilize tyrosinase by forming a multi-enzyme complex in the melanosome [12]. Thus if any of these proteins are not in their 'wild-type' or native form, production and depth of black pigment will suffer. This has been shown in a study by Beermann et al [28] in which mice devoid of TRP-2 resulted in a phenotype similar to the slaty mutation (i.e. greyish).

Melanin synthesis (or melanogenesis) can be modulated primarily by the opposite action of two intercellular signaling molecules, alpha-melanocyte stimulating hormone (MSH) and agouti protein (see A locus)[13]. MSH and adrenocorticotropin hormone (ACTH) [14], whose from a family of related molecules cleaved from the precursor pro-hormone pro-opiomelanocortin, can up-regulate melanin synthesis by its interaction (i.e. binding) with the melanocortin 1 receptor (MC1R, see E locus) located on melanocytes. The MC1R is a G-protein coupled receptor such that the binding of MSH (or ACTH) triggers a cAMP dependent signal cascade leading to an increase in the activity of tyrosinase. As discussed above, an increase in tyrosinase activity results in a preferential increase in the synthesis of eumelanin and an increase in the eumelanin:phaeomelanin ratio. So, a wild type MC1R would allow full color development. On the other hand, the switch from eumelanin to phaeomelanin biosynthesis can be stimulated by the second intercellular molecule, agouti protein, which is secreted from dermal papilla cells and produced by neighboring keratinocytes. In the hair follicle, agouti protein inhibits the binding of MSH to MC1R, thereby decreasing tyrosinase activity and in effect, increasing the redich pigment. Agouti protein has also been shown to down-regulate genes necessary for eumelanin synthesis [15].
click for larger version

In the mouse, more than 100 (~127) different genes have been shown to affect coat color (see The Coat Colors of Mice). The proteins encoded by these genes include DNA transcription factors which regulate the rate at which specific genes produce their proteins (e.g. MITF locus, microphthalmia transcription factor which plays a role in melanocyte survival and differentiation), receptors and their ligands (e.g. MSH and MC1R or steel factor and cKIT), structural proteins (e.g. lysosome associated membrane protein), transport proteins (e.g. myosin V) and enzymes. For example, there is a protein which is necessary for the transport of cysteine into the melanosome. Since cysteine is necessary for phaeomelanogenesis, this transport protein would be required for red pigmentation. Yet, up to now, no one has been able to identify the gene locus responsible for this transport protein. Consequently, those proteins described above are an attempt to simplify melanogenesis (though it might not seem that way) and to allow the reader to more easily put the genes (described below), and the proteins they encode, into the proper perspective as to how they may affect color formation. Generally speaking, in order of phenotypic expression, proteins which control melanocyte distribution (e.g. S, T and W loci) will have a more visible effect than those proteins which control melanin synthesis (e.g. E and C loci) and its regulation (e.g. A locus) which will, in turn, have a more visible effect than those proteins effecting melanosome structure and transport (e.g. D locus ?). Thus, different colors and patterns can be achieved by genes controlling the distribution of melanocytes, the activity of melanin synthesis and the transport of melanosomes to the keratinocytes.

Gene locus
For the entire dog genome visit the Dog Genome Project . But for color specifics, there are some very good web pages by Dr. Sheila Schmutz (Genetics of Coat Color in Dogs) and Sue Ann Bowling (Animal Genetics) which discuss many of the alleles in depth. For more breed specific canine color inheritance visit the excellent list at Canine Color Genetics Links by Liisa Sarakontu where there are close to 80 different breeds listed. Here, the journey begins for the English Mastiff. I have seen as few as 9 and as many as 15 gene loci primarily used to describe the inheritance of color in the canine.

A - agoutiF - rufus P - pink eye
B - brown/black SE - super extension, black mask R - roan
C - concentration K - brindle (?) S (or W ?) - spotting; distribution of color
D - dilution G - graying T - ticking
E - extension M - merle W - proposed, white


The three AKC standard acceptable Mastiff colors, fawn, brindle and apricot are shown below. The middle brindle photo below was kindly provided by Gatehouse Mastiffs (Carrie K, copyright 2003).

FAWN BRINDLE APRICOT

Variations within these colors go by many names. For example, within fawn some descriptions include honey/golden fawn and silver fawn. For brindles, there may be fawn (silver), apricot and what is commonly referred to as 'reverse'. The photo showing two brindles and fawn was kindly provided by Gatehouse Mastiffs (Carrie K, copyright 2003).
comparison of golden fawn with no black tipped hairs on 
main body and fawn covered with black tipped hairs silver fawn fawn brindle on the left and 
apricot brindle on the right typically called a reverse brindle


The table below describes the different gene loci with emphasis on those genes that are phenotypically most influential in the Mastiff and produce fawn, apricot, brindle and black mask. Some alleles (designated with *)which produce 'non-standard' color in the mastiff are taken from an article recently written by D. Collinson, Ph.D. in the OEMC newsletter [16] which can be found here . Finally, alleles are listed in order of dominance within the locus and the existence of some of the genes and lesser dominant alleles is speculative (as shown in red).


A - agouti; encodes the agouti protein which inhibits the interaction of alpha-MSH with MC1R and down regulates genes necessary for eumelanin production.
As---
Ayrestricts B series and produces phaeomelanin; incompletely dominant to at; ayay could be clear red, dependent upon modifiers while ayat would be, on the average, darker with more black hairs either tipped or interspersed and may darken with age; see A locus red tan, sable, fawnMastiff, Collie, Boxer, Great Dane
atrestricts tan (phaeomelanin) to certain points (e.g. muzzle, over the eyes, chest, all four boots) black & tandoberman, rottweiler, Bernese mountain dog
awindividual hair fibers are banded; wild type, wolf color salt & pepperNorwegian elkhounds, Afghan, shih-tzu
asa saddle tan; restricts dark color to saddle pattern--
arecessive black; either no agouti or inactive agouti protein may be produced -Shetland sheepdog, German shepherd
An all black coat* and the at* pattern has been seen in Mastiffs, though these are not approved by the modern standard. Recently, the agouti locus has been excluded as a possible site for 'dominant black' by Kerns et al. [17]


B - brown/black; encodes Tryp1, a 538 amino acid protein located on dog chromosome 11 [18], which helps to stabilize tyrosinase and thus the polymerization of melanin; possibly effects the structure of the melanosomes and the distribution of the eumelanin pigment; may regulate basal levels of melanin formation. Schmutz et al. [18] describe three main sequence variants; S41C, Q331ter and 345delP. Their suggested allele designation is shown in the table below.
Bwild type, large, densely packed melanosomesblackMastiff
bsQ331ter, stop codon brown/liverchocolate lab
bd345delP, proline deletion brown/liverchocolate lab
bcS41C, cysteine replaced by serine brown/liverchocolate lab
B or b can be told by the color of the points (i.e. nose leather, lips, eye rims and usually, foot pads). Tyrp1 can make a mask brown. All dogs are either black or liver, regardless of the coat color. Schmutz et al suggest that black dogs have no more than one of these variants and brown dogs have two or more. But, there is no obvious difference in shade of brown in relation to which variant is present. When variants are present melanin is significantly less polymerized and melanosomes are smaller, less densely packed. Can produce what may be described as reds in Australian shepherd, border collie, Doberman, pharaoh hound and Ibizian hound; atatbb = red Doberman; bbcchcch = dead grass color seen in Chesapeake Bay retriever; bb* appeared in Crown Prince.

C - concentration; encodes tyrosinase, the critical enzyme in melanin synthesis; primarily noticeable by its affect on phaeomelanin; blacks become silvery gray and reds become cream to off-white. Has been linked to dog chromosome 21 [19].
Cthe structural gene for wild type tyrosinase; allows the full depth of pigment solid colormost breeds, Mastiff
cchreduces the red (phaeomelanin) pigment to cream with little effect on eumelanin. Very light tan dogs are probably cchcch. chinchillapale yellow lab
cdinhibits production of red pigment. white coat, black eyesSamoyed
ceextreme dilution or cb (Burmese) pale gray coat, pale blue eyesPekinese, Pomeranian
cainactive variant of tyrosinase, lack of melanin; albinism white coat, pink eyesnot known to occur in dogs
The gene for tyrosinase is very mutagenic. There is a temperature sensitive variant which is displayed in rabbits (Himalayan; equivalent to Siamese in the cat) such that the enzyme works at temperatures below the normal body temperature. ceceee maybe West Highland terrier

D - dilution; in mouse encodes the motor protein myosin V, but most likely not myosin V in dogs; responsible for transporting the melanin containing melanosome through the dendritic processes toward the keratinocytes; effects both eumelanin and phaeomelanin intensity of pigmentation
Dallows full dense pigmentationself color-
dclumping of melanosomes leading to reduced light absorption; flattening or dulling of color bluish gray or silverweimararner, blue Great Dane
This is probably the primary gene that will effect the coloration of the points. Though B, TYRP1, can also show some effects in the mask and BBdd will be bluish gray while bbdd will be silver. If black patterns are present they also will change to blue, e.g. blue mask, blue tipping, blue brindle. dd * may produce blue brindles in mastiffs.

The following phenotypes (i.e. brindle, black mask and dominant black) are among the most misunderstood as to which gene locus they reside. Early studies by Little [20], and even some present inheritance models, put brindle, black mask and recessive red all at E (extension locus). However, some recent investigators agree that black mask and brindle cannot be in the same series since, for example, a mating of two black masked, brindle mastiffs would produce 25% offspring without a mask, which doesn't happen. S. Pober postulates a K locus where dominant black, brindle and wild-type exist. Yet, other studies involving many other mammals put dominant black at the E locus. Kerns et al.[17] have recently excluded the E locus (MC1R) as a candidate for dominant black in dogs (e.g. black lab, Newfoundland). It's quite likely that there is some confusion with nomenclature and semantics. For 'simplicity' sake, I'll use two loci to describe these phenotypes - even though four maybe incorrect, since E (extension) is the only universally recognized locus at this time.

E - extension; encodes the expression of MC1 receptor in dog [21]; located on chromosome 5 [22];
Ewild type MC1R (317 residues, sequence in ref. 23), allowing eumelanin over the entire body as the A locus dictates self coloring-
EM melanistic mask, color dependent upon other genes effecting eumelanin; all dogs with mask have at least one copy of a valine substitution for methionine at amino acid 264 (M264V) [24]; demonstrates that a MC1R mutant may be spatially restricted (also seen with Etob, dorsal restriction, in mice) - mechanism unknown brown or black maskMastiff, Boxer, Akita
erecessive red; encodes an inactive MC1R variant (R306ter); a small number of dark (i.e. eumelanin) hairs can be found dorsally and eumelanin can be found in the skin [21]; dark hairs my occur due to high basal (i.e. unstimulated) activity of eumelanogenesis, thus precluding the need for a functional MC1R ;red, orange, yellowIrish setter, Golden retriever, yellow lab
In some breeds (e.g. Great Dane, cocker spaniel, Red chow, Samoyed) reds may be either ayay or ee In general, the ay produces more yellow-tan while the e more reddish tones. The ee will not change as much from birth as the sable. There is also an S90G variant but this is merely a polymorphism and has no known effect on color. In addition to black mask and Etob, two recessive alleles have been postulated which yield a partially distributed pigmentation with the appearance of brindle or tortoiseshell patterns (eb in guinea pig and et in rabbit) by Ibsen in 1919 [25], Chase in 1939 [26] and Punnet in 1924 [27].

K - brindle ???
Kdominant black; same as As in agouti locus as postulated by C. Little --
kbr allows brindle-Mastiff, boxer
kwild type, no brindling -most breeds

I have removed the text dealing with the rufus, graying, merle, pink eye and roan loci since these are not readily displayed in the Mastiff and are not well characterized. On the other hand, since occassionally a Mastiff will show a light (or white)patch on their chest, the S, T and W loci will be discussed.


The next three series (S, T and W) appear to have some phenotypes which could appear to be similar. Also, trying to equate these loci and the genes they encode with the mouse (or dog) nomenclature has been difficult (or impossible).
For the sake of consistency, I try to continually refer to the mouse nomenclature. Mouse nomenclature may take precedence over the nomenclature suggested for dogs 40 years ago since most future molecular biology and gene identification will proceed in the mouse or human (my opinion). In the mouse, the following genes are described:

  • s - piebald; encodes the endothelin-B receptor
  • sl - steel; encodes steel factor (a.k.a. c-kit ligand or mast cell growth factor)
  • w - white spotting; encodes the steel factor receptor (cKIT)
  • Each of these genes and their encoded proteins (endothelin-B receptor, steel factor and cKIT) are required for proper melanocyte development and migration. Thus, mutant alleles at any of these loci could be responsible for depigmentation and white color patterns. To add more confusion, even though there is an 's - piebald' locus (endothelin-B receptor), most piebaldism in the mouse results from mutations at the loci encoding either steel factor or cKIT. Consequently, does the S locus (white spotting - described in dogs) encode cKIT or does W (in dogs) encode steel factor or does T encode endothelin-B receptor ?


    S - spotting (or W -white spotting ?) ; controls melanocyte distribution
    San even distribution of color with possible, very minor, white markings on the toes, tail tip and chest--
    siIrish spotting; some what symmetrical; limited to muzzle, neck, chest, feet, legs and tail; no white on rump-collie, Boston terrier
    sppiebald; large white spots, generally greater than 50% is white, may cross the back -cocker spaniel, shar-pei
    swextreme white piebald; nearly entire dog is white with only patches of color around the head, eyes and ears-white bull terrier, great pyrenees
    This series is not completely understood since it is unclear how many alleles occur. The series is greatly affected by other modifying genes. A more extensive discussion of this series can be found at Animal Genetics and Borzois.


    T - ticking; distribution of melanocytes to specific areas
    Tallows small areas of self coloring within white areas; ticking is not visible at birth -dalmation
    tno ticking--


    W - white; proposed to inhibit pigment production
    Wdilutes gray color of merle to white; lethal in the homozygous state -Great Dane
    wnon-clearing--


    Finally, since my investigation into the area of color inheritance in the English Mastiff is an ongoing dynamic project, I fully expect that some of the text here will eventually be proven incorrect. However, I feel that publicly displaying these data are imperative to receiving the feedback essential to altering this working model accordingly. With the recent advances made in the field of molecular biology, it's only a matter of time before we have the answers necessary for a definitive color inheritance model. For example, there are many other proteins and genes recognized that have yet to be fit into this model (e.g. TRP2 (slaty in mouse), MSH, silver locus protein, pink-eyed dilution locus, fibroblast growth factor, endothelin-B). Hopefully, in the not to distant future, we'll have the answers.

    Oh, and by the way (if you've read this far), I still don't have the answer for apricot Mastiffs. Furthermore, Bull's stripes seem to be less noticeable in the winter time. Could they possibly be due to a temperature sensitive variant of tyrosinase ? Does brindling tend to be lighter in the cold winter months ? - more food for thought. If you think Bull's stripes are odd, you should visit a web page which shows some more unusual coloring in the mastiff here .


    Genetics

    This is not the space to discuss the basics of genetics. There are many excellent web pages which can educate you about genetics. I suggest you visit a very good site, Genetic Science Learning Center. Moreover, let the reader beware that, even knowing the different loci for the genes cannot fully explain how they may interact. For example, there can be:
    incomplete (intermediate) dominance - if allele A is 'completely' dominant, AA and Aa individuals are alike phenotypically; but if AA produced a more extreme or differential expression than Aa, the inheritance is 'intermediate'
    modifiers - genes which can alter or modify, by suppressing or enhancing, the visible effects of other genes
    epistasis - any gene or gene pair that masks the expression of another, nonallelic gene, is epistatic to that gene; the gene suppressed is said to be hypostatic
    atavism - the chance combination of genes that allows a long-suppressed or hidden characteristic to finally come to expression



    References (with links to PubMed)
    [1] Newton, J.M., Wilkie, A.L., He, L., Jordan, S.A., Metallinos, D.L., Holmes, N.G., Jackson, I.J. and Barsh, G.S. Melanocortin 1 receptor variation in the domestic dog. Mammaliam Genome 11:24-30 (2000).
    [2] Dupin, E. and Douarin, N.M. Development of melanocyte precursors from the vertebrate neural crest. Oncogene 22:3016-3023 (2003).
    [3] Wilkie, A.L., Jordan, S.A. and Jackson, I.J. Neural crest progenitors of the melanocyte lineage: coat color patterns revisited. Development 129:3349-3357 (2002).
    [4] Boissy, R.E. and Nordlund, J.J. Molecular basis of congenital hypopigmentary disorders in humans: a review. Pigment Cell Res 10:12-24 (1997).
    [5] Tada, A., Suzuki, I., Im, S., Davis, M.B., Cornelius, J., Babcock, G., Nordlund, J.J. and Abdel-Malek, Z.A. Endothelin-1 is a paracrine growth factor that modulates melanogenesis of the human melanocytes and participates in their responses to ultraviolet radiation. Cell Growth Diff 9:575-584 (1998).
    [6] Silvers, W.K. and Russell, E.S. An experimental approach to action of genes at the agouti locus in mouse. J. Exp. Zool 130:199-220 (1955).
    [7] Seiberg M. Keratinocyte-melanocyte interactions during melanosome transfer. Pigment Cell Res. 14:236-42 (2001).
    [8] Ozeki H., Ito S., Wakamatsu K. and Ishiguro I. Chemical characterization of pheomelanogenesis starting from dihydroxyphenylalanine or tyrosine and cysteine. Effects of tyrosinase and cysteine concentrations and reaction time. Biochim et Biophys Acta 1336:539-548 (1997).
    [9] Wolff, G.L. Regulation of yellow pigment formation in mice: a historical perspective. Pigment Cell Res 16:2-15 (2003).
    [10] Kobayashi, T., Urabe, K., Winder, A.J., Jimenez-Cervantes, C., Imokawa, G., Brewington, T., Solano, F., Garcia-Borron, J.C. and Hearing, V.J. Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase in melanin biosynthesis. EMBO J 13:5818-5825 (1994).
    [11] Tsukamoto, K., Jackson, I.J., Urabe, K., Montague, P.M. and Hearing, V.J. A second tyrosinase-related protein, TRP-2, is a melanogenic enzyme termed DOPAchrome tautomerase. EMBO J 11:519-526 (1992).
    [12] Kobayashi, T., Imokawa, G., Bennett, D.C. and Hearing, V.J. Tyrosinase stabilization by Tyrp1 (the brown locus protein). J Biol Chem 273:31801-31805 (1998).
    [13] Lu, D., Willard, D., Patel, I.R., Kadwell, S., Overton, L., Kost, T., Luther, M., Chen, W., Woychik, R.P., Wilkinson, W.O. and Cone, R.D. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371:799-802 (1994).
    [14] Thody, A.J. and Graham, A. Does alpha-MSH have a role in regulating skin pigmentation in humans ? Pigment Cell Res 11:265-274 (1998).
    [15] Furumura, M., Sakai, C., Potterf, S.B., Vieria, W.D., Barsh, G.S. and Hearing, V.J. Characterization of genes modulated during phaeomelanogensis using differential display. Proc Natl Acad Sci 95:7374-7378 (1998).
    [16] Collinson, D.F. Mastiff coat colour. OEMC newsletter 8:31-36 (1999).
    [17] Kerns, J.A., Oliver, M., Lust, G. and Barsh, G.S. Exclusion of melanocortin-1 receptor (Mc1r) and agouti as candidates for dominant black in dogs. J. Heredity 94:75-79 (2003).
    [18] Schmutz, S.M., Berryere, T.G. and Goldfinch, A.D. TYRP1 and MC1R genotypes and their effects on coat color in dogs. Mammalian Genome 13:380-387 (2002).
    [19] Schmidtz, B.H. and Schmutz, S.M. Linkage mapping of TYR to dog chromosome 21. Animal Genetics 33:476-477 (2002).
    [20] Little, C.C. The inheritance of coat color in dogs. Comstock Pub (1957).
    [21] Robbins, L.S., Nadeau, J.H., Johnson, K.R., Kelly, M.A., Roselli-Rehfuss, L., Baach, E., Mountjoy, K.G. and Cone, R.D. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72:827-834 (1993).
    [22] Schmutz, S.M., Moker, J.S., Berryere, T.G., Christison, K.M. and Dolf, G. An SNP is used to map MC1R to dog chromosome 5. Animal Genetics 32:43-44 (2001).
    [23] Everts, R.E., Rothuizen, J. and van Oost, B.A. Identification of a premature stop codon in the melanocyte-stimulating hormone receptor gene (MC1R) in Labrador and Golden retrievers with yellow coat colour. Animal Genetics 31:194-199 (2000).
    [24] Schmutz, S.M., Berryere, T.G., Ellinwood, N.M., Kerns, J.A. and Barsh, G.S. MC1R Studies in dogs with melanistic mask or brindle patterns. J. Heredity 94:69-73 (2003).
    [25] Ibsen, H.L. Tricolor inheritance. IV The tripleallelomorphic series in guinea pigs. Genetics 4:597-606 (1919).
    [26] Chase, H.B. Studies on the tricolor pattern of the guinea pig. II. The distribution of black and yellow as affected by white spotting and by imperfect dominance in the tortoiseshell series of alleles. Genetics 24:610-643 (1939).
    [27] Punnet, R.C. On the Japanese rabbit. J. Genet 14:230-240 (1924).
    [28] Beermann, F., Rossier, A. and Guyonneau, L. Inactivation of the mouse DCT gene. Pigment Cell Res. 16:577-578 (2003).


    Copyright (c)2005 Bill Hood, all rights reserved