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#REDIRECT [[Agouti-signaling protein]] {{R from merge}}
{{protein
|HGNCid=745
|Name=[[Agouti-signaling protein]]
|Symbol=[[ASIP]]
|AltSymbols=AGTIL
|EntrezGene=434
|OMIM=600201
|RefSeq=NM_001672
|UniProt=P42127
|PDB=
|ECnumber=
|Chromosome=20
|Arm=q
|Band=11.2
|LocusSupplementaryData=-q12
}}
[[File:Haar1.JPG|thumb|right|A [[cat]] hair showing light and dark bands caused by alternating production of [[agouti-signaling protein]] and [[alpha-Melanocyte-stimulating hormone|α-MSH]].]]
The '''agouti gene''' encodes the [[agouti-signaling protein]] (ASIP), a [[paracrine]] signaling molecule involved in red-black pigment type-switching.<ref>{{cite journal | vauthors = Millar SE, Miller MW, Stevens ME, Barsh GS | title = Expression and transgenic studies of the mouse agouti gene provide insight into the mechanisms by which mammalian coat color patterns are generated | journal = Development | volume = 121 | issue = 10 | pages = 3223–32 | date = October 1995 | pmid = 7588057 }}</ref> 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 [[horse]]s, 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) [[protein]]s, 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.<ref name=OMIM-ASIP>{{OMIM|600201}}</ref>

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. <!--This is why no matter the color of your sweater, your cat's hair will ALWAYS show perfectly.--> 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.<ref name=drogemuller2006>{{cite journal | vauthors = Drögemüller C, Giese A, Martins-Wess F, Wiedemann S, Andersson L, Brenig B, Fries R, Leeb T | title = The mutation causing the black-and-tan pigmentation phenotype of Mangalitza pigs maps to the porcine ASIP locus but does not affect its coding sequence | journal = Mammalian Genome | volume = 17 | issue = 1 | pages = 58–66 | date = January 2006 | pmid = 16416091 | doi = 10.1007/s00335-005-0104-1 }}</ref><ref name=AtJAX>{{cite web |url=http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=alleleDetail&key=14 |title=a<sup>t</sup> Spontaneous Allele Detail |publisher=The Jackson Laboratory |date=2009-05-23 |access-date=2009-05-26}}</ref>

==In mice==
As of 1979, there were 17 known alleles of agouti in mice.<ref name=Silvers1979>{{cite web |url=http://www.informatics.jax.org/wksilvers/frames/frame2-1.shtml |title=The Agouti and Extension series of Alleles, Umbrous and Sable |access-date=2019-05-11 |last=Silvers |first=Willys K. | name-list-format = vanc |publisher=Springer Verlag |website=The Jackson Laboratory |date=1979}}<!-- What to do with a book published in 1979, posted on the web in 2003, and revised in 2008? --></ref> 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.<ref name=OMIM-ASIP/> 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 [[tissue (biology)|tissues]] including [[liver]], [[muscle]], and [[adipose|fat]].<ref name=Klebig1995>{{cite journal | vauthors = Klebig ML, Wilkinson JE, Geisler JG, Woychik RP | title = Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 11 | pages = 4728–32 | date = May 1995 | pmid = 7761391 | pmc = 41780 | doi = 10.1073/pnas.92.11.4728 | bibcode = 1995PNAS...92.4728K }}</ref>

The mouse agouti gene is found on chromosome 2.<ref name=OMIM-ASIP/>

==In dogs==
[[File:Bucuresti, Romania, acelasi dulau, frumos de Cotroceni.JPG|thumb|right|An agouti dog, also called wolf sable]]
In [[dog]]s, the agouti gene is associated with various coat colors and patterns.<ref>{{Cite web|url=http://www.doggenetics.co.uk/tan.html|title=Dog Coat Colour Genetics|website=www.doggenetics.co.uk|access-date=2017-09-25}}</ref>

The alleles at the A locus are related to the production of agouti-signaling protein (ASIP) and determine whether an animal expresses an [[agouti gene|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<sup>y</sup>'' = 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<sup>w</sup>'' = Wild-type agouti (each hair with 3-6 bands alternating black and tan) - also called wolf sable
* ''a<sup>t</sup>'' = Tan point (black with tan patches on the face and underside) - including saddle tan (tan with a black saddle or blanket) <ref>{{cite journal | vauthors = Dreger DL, Schmutz SM | title = A SINE insertion causes the black-and-tan and saddle tan phenotypes in domestic dogs | journal = The Journal of Heredity | volume = 102 Suppl 1 | issue = | pages = S11-8 | year = 2011 | pmid = 21846741 | doi = 10.1093/jhered/esr042 }}</ref><ref name="pmid23519866">{{cite journal | vauthors = Dreger DL, Parker HG, Ostrander EA, Schmutz SM | title = Identification of a mutation that is associated with the saddle tan and black-and-tan phenotypes in Basset Hounds and Pembroke Welsh Corgis | journal = The Journal of Heredity | volume = 104 | issue = 3 | pages = 399–406 | date = 2013 | pmid = 23519866 | doi = 10.1093/jhered/est012 }}</ref>
* ''a'' = Recessive black (black, inhibition of phaeomelanin)
* ''a<sup>yt</sup>'' = 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<sup>y</sup> > a<sup>w</sup> > a<sup>t</sup> > 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.<ref>{{cite journal | vauthors = Kerns JA, Newton J, Berryere TG, Rubin EM, Cheng JF, Schmutz SM, Barsh GS | title = Characterization of the dog Agouti gene and a nonagoutimutation in German Shepherd Dogs | journal = Mammalian Genome | volume = 15 | issue = 10 | pages = 798–808 | date = October 2004 | pmid = 15520882 | doi = 10.1007/s00335-004-2377-1 }}</ref>
* ''A<sup>y</sup>'' is incompletely dominant to ''a<sup>t</sup>'', so that heterozygous individuals have more black sabling, especially as puppies and ''A<sup>y</sup>a<sup>t</sup>'' can resemble the ''a<sup>w</sup>a<sup>w</sup>'' phenotype. Other genes also affect how much black is in the coat.
* ''a<sup>w</sup>'' is the only allele present in many Nordic spitzes, and is not present in most other breeds.
* ''a<sup>t</sup>'' 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==
The dominant, wild-type ''A'' allows hairs to be banded with black and red (revealing the underlying [[Tabby cat|tabby]] pattern), while the recessive ''non-agouti'' or "hypermelanistic" allele, ''a'', causes black pigment production throughout the growth cycle of the hair.<ref>{{cite journal | vauthors = Eizirik E, Yuhki N, Johnson WE, Menotti-Raymond M, Hannah SS, O'Brien SJ | title = Molecular genetics and evolution of melanism in the cat family | journal = Current Biology | volume = 13 | issue = 5 | pages = 448–53 | date = March 2003 | pmid = 12620197 | doi = 10.1016/S0960-9822(03)00128-3 }}</ref> 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.

The black alleles is a 2 base pair [[frameshift]] deletion, and is thought to cause a complete loss of function of [[Agouti-signaling protein|ASIP]].<ref>{{cite paper|title=Molecular genetics and evolution of melanism in the cat family |vauthors= Eizirik E, Yuhki N, Johnson WE, Menotti-Raymond M, Hannah SS, O'Brien SJ |journal=Current Biology |volume= 13 |issue= 5 |pages= 448–53 |date=2003 |pmid=12620197 |url=https://www.cell.com/current-biology/fulltext/S0960-9822(03)00128-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0960982203001283%3Fshowall%3Dtrue|doi= 10.1016/S0960-9822(03)00128-3 }}</ref><ref>{{cite journal | vauthors = Kaelin CB, Xu X, Hong LZ, David VA, McGowan KA, Schmidt-Küntzel A, Roelke ME, Pino J, Pontius J, Cooper GM, Manuel H, Swanson WF, Marker L, Harper CK, van Dyk A, Yue B, Mullikin JC, Warren WC, Eizirik E, Kos L, O'Brien SJ, Barsh GS, Menotti-Raymond M | title = Specifying and sustaining pigmentation patterns in domestic and wild cats | journal = Science | volume = 337 | issue = 6101 | pages = 1536–41 | date = September 2012 | pmid = 22997338 | pmc = 3709578 | doi = 10.1126/science.1220893 | bibcode = 2012Sci...337.1536K }}</ref>
{{Gallery
|title=
|width=| height=
|align=center
|footer=
|File:Arthur, the cat.jpg
|A [[tabby cat]], which has a functional agouti gene.
|File:Black cat 1 (1).jpg
|A [[black cat]], which lacks a functional agouti gene and so cannot signal [[MC1R]] to produce red pigment.
}}

==In horses==
In normal horses, [[Agouti-signaling protein|ASIP]] restricts the production of eumelanin to the "points": the legs, mane, tail, ear edges, etc.<ref name=VGLintro-A>{{cite web |url=http://www.vgl.ucdavis.edu/services/coatcolor.php#genea |title=Gene A: Distribution of Black Pigmented Hair |publisher=UC Davis Veterinary Genetics Laboratory |access-date=2009-05-26}}</ref> 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.<ref name="Rieder_2001" /> The dominant, [[wildtype]] [[allele]] producing [[bay (horse)|bay]] is symbolized as ''A'', while the [[recessive]] allele producing [[black (horse)|black]] is symbolized as ''a''. ''Extension'' is [[epistatic]] over ''agouti'' and will cause [[chestnut (coat)|chestnut]] coloration regardless of what ''agouti'' alleles are present.

A hypothesized third option, ''A<sup>t</sup>'', might restrict black pigment to a black-and-tan pattern called [[Seal brown (horse)|seal brown]].<ref name=PETDNAAZ>{{cite web |url=http://www.petdnaservicesaz.com/Equine.html |title=Equine Testing Services |publisher=Pet DNA Services of AZ |access-date=2009-05-26 |deadurl=yes |archive-url=https://web.archive.org/web/20090522151520/http://www.petdnaservicesaz.com/Equine.html |archive-date=2009-05-22 |df= }}</ref> This allele would be recessive to ''A'' and dominant to ''a'', such that horses with the genotype ''A/A<sup>t</sup>'' appear bay, while ''A<sup>t</sup>/A<sup>t</sup>'' and ''A<sup>t</sup>/a'' horses are seal brown in the presence of a dominant ''Extension'' allele ''E''. One genetics testing lab began offering a test for ''A<sup>t</sup>'',<ref name=PETDNAAZ /> 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''.<ref name="Rieder_2001">{{cite journal | vauthors = Rieder S, Taourit S, Mariat D, Langlois B, Guérin G | title = Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus) | journal = Mammalian Genome | volume = 12 | issue = 6 | pages = 450–5 | date = June 2001 | pmid = 11353392 | doi = 10.1007/s003350020017 | url = https://www.researchgate.net/publication/11985079 | quote = The 11-bp deletion in ASIP exon 2 (ADEx2) alters the amino acid sequence and is believed to extend the regular termination signal by 210 bp to 612 bp. The frameshift initiated by the deletion results in a novel modified agouti-signaling-protein. ADEx2 was completely associated with horse recessive black coat color (A<sup>a</sup>/A<sup>a</sup>) in all horses typed so far }}</ref>

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.
* ''A<sup>t</sup>'' (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),.

{{Gallery
|title=
|width=| height=
|align=center
|footer=
|File:Perschen-Neusath-WJP-4.jpg
|alt3=
|Bay horses, which have a functional Agouti protein, have a "red" body and black mane, tail, and lower legs.]]
|File:Champion Dales Pony.jpg
|alt4=
|Black horses lack a functional Agouti protein, and produce black pigment in the entire coat.
}}

===History===
The cause behind the various shades of bay, particularly the genetic factors responsible for wild bay and [[seal brown (horse)|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'', ''A<sup>t</sup>'', and ''a'', in order of most dominant to least.<ref name=Castle>{{cite journal | vauthors = Castle WE, Singleton WR | title = The palomino horse | journal = Genetics | volume = 46 | issue = 9 | pages = 1143–50 | date = September 1961 | pmid = 13877241 | pmc = 1210264 | url = http://www.genetics.org/cgi/reprint/46/9/1143.pdf | archive-url = https://web.archive.org/web/20080905062605/http://www.genetics.org/cgi/reprint/46/9/1143.pdf | df = | deadurl = no | archive-date = 2008-09-05 }}</ref>

This was accepted until the 1990s, when a new theory became popular.<ref name=Kostelnik>{{cite web |url=http://www.horsecolor.com/basics/starting_point.htm |title=Starting Point |work=The Horse Colors Site | vauthors = Kostelnik B |year=2007 |access-date=2008-03-04| archive-url= https://web.archive.org/web/20080303102629/http://www.horsecolor.com/basics/starting_point.htm| archive-date= 3 March 2008 <!--DASHBot-->}}</ref> 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.<ref name="Rieder_2001"/>

Since 2001, the mechanisms of the variations within the "bay" category remain unclear. Ongoing research suggests that Odriozola's theories may have been correct,<ref name=Morgan>{{cite web |url=http://colormorgans.tripod.com/basecolors.htm |title=The Base Colors |work=Morgan Colors | first = Laura | last = Behning | name-list-format = vanc |date=2008-02-05 |access-date=2008-03-04 |deadurl=no |archive-url=https://web.archive.org/web/20080517142810/http://colormorgans.tripod.com/basecolors.htm |archive-date=2008-05-17 |df= }}</ref> evidenced by a parallel condition in mice. Mice have several alleles at the Agouti locus, including A<sup>t</sup> which produces black-and-tan.<ref name=Mouse>{{cite journal | vauthors = Hustad CM, Perry WL, Siracusa LD, Rasberry C, Cobb L, Cattanach BM, Kovatch R, Copeland NG, Jenkins NA | title = Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus | journal = Genetics | volume = 140 | issue = 1 | pages = 255–65 | date = May 1995 | pmid = 7635290 | pmc = 1206552 | url = http://www.genetics.org/cgi/content/abstract/140/1/255 | archive-url = https://web.archive.org/web/20080908085619/http://www.genetics.org/cgi/content/abstract/140/1/255 | df = | deadurl = no | archive-date = 8 September 2008 }}</ref>

<!-- ==In rabbits==
[[File:Rabbit_(agouti)_04.jpg|thumb|A [[domestic rabbit]] with agouti coloration]] -->

== References ==
{{reflist}}

[[Category:Peptides]]
[[Category:Peptide hormones]]
[[Category:Mammal genes]]

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