The agouti gene encodes the agouti-signaling protein (ASIP), a paracrine signaling molecule involved in red-black pigment type-switching. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte (pigment cell) produces the yellow to red phaeomelanin, or the brown to black eumelanin. This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the agouti. In other species such as horses, it determines what parts of the body are red or black.
|Locus||Chr. 20 q11.2-q12|
There are two signalling molecules which compete to bind with melanocortin 1 receptor (MC1R) proteins, the agouti-signaling protein (ASIP) and the alpha-Melanocyte-stimulating hormone (α-MSH). Activation by α-MSH causes production of the darker eumelanin, while activation by ASIP causes production of the redder phaeomelanin.
In many species, successive pulses of ASIP block contact between α-MSH and MC1R, resulting in alternating production of eumelanin and pheomelanin; hairs are banded light and dark as a result. In other species, ASIP is regulated such that it only occurs in certain parts of the body. The light undersides of most mammals are due to the carefully controlled action of ASIP. Additionally, the Agouti locus is the site of mutations in several species that result in black-and-tan pigmentations.
As of 1979, there were 17 known alleles of agouti in mice. Two dominant mutations on Agouti, lethal yellow and viable yellow, cause yellow coats in mice. Both of these also cause obesity, features of type II diabetes, and a higher likelihood of tumors. In normal mice Agouti is only expressed in the skin during hair growth, but these dominant yellow mutations cause it to be expressed in other tissues including liver, muscle, and fat.
The mouse agouti gene is found on chromosome 2.
The alleles at the A locus are related to the production of agouti-signaling protein (ASIP) and determine whether an animal expresses an agouti appearance and, by controlling the distribution of pigment in individual hairs, what type of agouti. There are four known alleles that occur at the A locus:
- Ay = Fawn or sable (tan with black whiskers and varying amounts of black-tipped and/or all-black hairs dispersed throughout) - fawn typically referring to dogs with clearer tan and sable to those with more black shading
- aw = Wild-type agouti (each hair with 3-6 bands alternating black and tan) - also called wolf sable
- at = Tan point (black with tan patches on the face and underside) - including saddle tan (tan with a black saddle or blanket) 
- a = Recessive black (black, inhibition of phaeomelanin)
- ayt = Recombinant fawn (black with tan patches on the face and underside) has been identified in numerous Tibetan Spaniels and a Tibetan Mastiff. Its hierarchical position is not yet understood.
Most texts suggest that the dominance hierarchy for the A locus alleles appears to be as follows: Ay > aw > at > a; however, research suggests the existence of pairwise dominance/recessiveness relationships in different families and not the existence of a single hierarchy in one family.
- Ay is incompletely dominant to at, so that heterozygous individuals have more black sabling, especially as puppies and Ayat can resemble the awaw phenotype. Other genes also affect how much black is in the coat.
- aw is the only allele present in many Nordic spitzes, and is not present in most other breeds.
- at includes tan point and saddle tan, both of which look tan point at birth. Modifier genes in saddle tan puppies cause a gradual reduction of the black area until the saddle tan pattern is achieved.
- a is only present in a handful of breeds. Most black dogs are black due to a K locus allele.
The dominant, wild-type A allows hairs to be banded with black and red (revealing the underlying tabby pattern), while the recessive non-agouti or "hypermelanistic" allele, a, causes black pigment production throughout the growth cycle of the hair. Thus, the non-agouti genotype (aa) masks or hides the tabby pattern, although sometimes a suggestion of the underlying pattern can be seen (called "ghost striping"), especially in kittens. The sex-linked orange coloration is epistatic over agouti, and prevents the production of black pigment.
In normal horses, ASIP restricts the production of eumelanin to the "points": the legs, mane, tail, ear edges, etc. In 2001, researchers discovered a recessive mutation on ASIP that, when homozygous, left the horse without any functional ASIP. As a result, horses capable of producing true black pigment had uniformly black coats. The dominant, wildtype allele producing bay is symbolized as A, while the recessive allele producing black is symbolized as a. Extension is epistatic over agouti and will cause chestnut coloration regardless of what agouti alleles are present.
A hypothesized third option, At, might restrict black pigment to a black-and-tan pattern called seal brown. This allele would be recessive to A and dominant to a, such that horses with the genotype A/At appear bay, while At/At and At/a horses are seal brown in the presence of a dominant Extension allele E. One genetics testing lab began offering a test for At, but it was later found to be inaccurate and is no longer offered.
The black allele is caused by an 11 base pair deletion in exon 2 of ASIP.
In total, there are two known agouti alleles, and two more hypothesized. In order of most dominant to least, these are:
- A+ (hypothesized) would be responsible for the wild bay coat, where the black does not extend as far up the legs as in bay.
- A is responsible for the standard bay coat.
- At (hypothesized) would be responsible for the black-and-tan seal brown coat.
- a, the least dominant, is responsible for unrestricted black coat (non-agouti black),.
The cause behind the various shades of bay, particularly the genetic factors responsible for wild bay and seal brown, have been contested for over 50 years. In 1951, zoologist Miguel Odriozola published "A los colores del caballo" in which he suggested four possible alleles for the "A" gene, A+, A, At, and a, in order of most dominant to least.
This was accepted until the 1990s, when a new theory became popular. The new theory suggested that shades of bay were caused by many different genes, some which lightened the coat, some which darkened it. This theory also suggested that seal brown horses were black horses with a trait called pangare. Pangaré is an ancestral trait also called "mealy", which outlines the soft or communicative parts of the horse in buff tan.
The combination of black and pangaré was dismissed as the cause of brown in 2001, when a French research team published Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus). This study used a DNA test to identify the recessive a allele on the Agouti locus, and found that none of the horses fitting the phenotype of seal brown were homozygous for the a allele.
Since 2001, the mechanisms of the variations within the "bay" category remain unclear. Ongoing research suggests that Odriozola's theories may have been correct, evidenced by a parallel condition in mice. Mice have several alleles at the Agouti locus, including At which produces black-and-tan.
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