Agouti (gene)

Agouti-signaling protein
Identifiers
Symbol	ASIP
Alt. symbols	AGTIL
NCBI gene	434
HGNC	745
OMIM	600201
RefSeq	NM_001672
UniProt	P42127
Other data
Locus	Chr. 20 q11.2-q12
Search for Structures Swiss-model Domains InterPro

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.

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.

In mice

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.

In dogs

In dogs, the agouti gene is associated with various coat colors and patterns.

The alleles at the A locus are related to the production of agouti signalling 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:

• A^y = 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
• a^w = Wild-type agouti (each hair with 3-6 bands alternating black and tan) - also called wolf sable
• a^t = 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)
• a^yt = 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: A^y > a^w > a^t > 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.

• A^y is incompletely dominant to a^t, so that heterozygous individuals have more black sabling, especially as puppies and A^ya^t can resemble the a^wa^w phenotype. Other genes also affect how much black is in the coat.
• a^w is the only allele present in many Nordic spitzes, and is not present in most other breeds.
• a^t 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.

In cats

An Abyssinian kitten displaying the ticked tabby pattern.

The dominant, wild-type A causes the agouti shift phenomenon which causes hairs to be banded with black and red (revealing the underlying tabby pattern), while the recessive non-agouti or "hypermelanistic" allele, a, prevents this shift in the pigmentation pathway. In its homozygous form, aa, this results in 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 O allele is also epistatic over the aa genotype. That is, the A to a mutation does not have a discernible effect on red or cream colored cats, resulting in these cats displaying tabby striping independent of their genotype at this locus. This explains why you can usually see the tabby pattern in the orange patches of non-agouti tortoiseshell cats, but not in the black or brown patches.

The black alleles is a 2 base pair frameshift deletion, and is thought to cause a complete loss of function of ASIP.

• 
  A cat hair showing banded agouti coloration]]
• 
  An agouti dog]]

In horses

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.

A hypothesized third option, A^t, 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/A^t appear bay, while A^t/A^t and A^t/a horses are seal brown in the presence of a dominant Extension allele E. One genetics testing lab began offering a test for A^t, 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.

• 
  Bay horses, which have a functional Agouti protein, have a "red" body and black mane, tail, and lower legs.]]
• 
  Black horses lack a functional Agouti protein, and produce black pigment in the entire coat.
• 
  The pale areas on this bay horse are due to the pangaré trait

Agouti phenotypes

A/A

wildtype, homozygous. Visually, the horse may be bay, buckskin, bay dun, amber champagne, and so on, or gray, or any member of the red family. However, such a horse will never be black, grullo, and so on, nor will a homozygous A horse ever produce uniform-black offspring.

A/a

wildtype, heterozygous agouti. Visually indistinguishable from homozygous A. With the right partner, such horses have the ability to produce black colored foals.

a/a

homozygous recessive. In the presence of a dominant E allele, the horse's coat will be black.

History

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. He described an order of dominance between the alleles and the associated phenotypes:

• a, the least dominant, must be homozygous to be observed and is responsible for unrestricted black coat (non-agouti black),
• A^t, only visible in the homozygous form or when paired with a, is responsible for the black-and-tan seal brown coat,
• A, visible when homozygous or when paired with a or A^t, is responsible for the standard bay coat,
• A+, dominant, is responsible for the wildtype wild bay coat.

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 more than six alleles at the Agouti locus, including A^t which produces black-and-tan.

It is still likely that to some extent, the "shade" of coat color may be regulated by unrelated genes for traits like "sooty", and that the phenotypes of sooty or dark bays/browns may overlap.