Просмотр кода страницы Agouti coloration genetics

{{Short description|Gene responsible for color variations in many species}}
[[File:Haar1.JPG|thumb|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, the  [[Agouti-signaling protein]] (ASIP) is responsible for variations in color in many species. ''Agouti'' works with ''[[extension gene|extension]]'' to regulate the color of [[melanin]] which is produced in hairs. The agouti protein causes red to yellow pheomelanin to be produced, while the competing molecule [[Alpha-Melanocyte-stimulating hormone|α-MSH]] signals production of brown to black eumelanin. In wildtype mice, alternating cycles of agouti and α-MSH production cause [[agouti (coloration)|agouti coloration]]. Each hair has bands of yellow which grew during agouti production, and black which grew during α-MSH production. Wildtype mice also have light-colored bellies. The hairs there are a creamy color the whole length because the agouti protein was produced the whole time the hairs were growing.<ref name=Furumura1996>{{cite journal | vauthors = Furumura M, Sakai C, Abdel-Malek Z, Barsh GS, Hearing VJ | title = The interaction of agouti signal protein and melanocyte stimulating hormone to regulate melanin formation in mammals | journal = Pigment Cell Research | volume = 9 | issue = 4 | pages = 191–203 | date = August 1996 | pmid = 8948501 | doi = 10.1111/j.1600-0749.1996.tb00109.x }}</ref><ref name=OMIM-ASIP>{{OMIM|600201}}</ref>

In mice and other species, loss of function mutations generally cause a darker color, while gain of function mutations cause a yellower coat.<ref name=Fontanesi2010/>

==Mice==
[[File:Agouti_Mice.jpg|thumb|right|Both of these mice are viable yellow agouti a<sup>vy</sup>; however, the mouse on the right does not express it due to epigenetic methylation.]]
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-style = 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>

*Lethal yellow ''A<sup>y</sup>'' causes yellow coloration and obesity. It is dominant to all other alleles in the series. When homozygous, it is lethal early in development.<ref name=Silvers1979/>
*Viable yellow ''A<sup>vy</sup>'' looks similar to lethal yellow and also causes obesity, but is not lethal when homozygous. Homozygous viable yellow mice can be variable in color from clear yellow through mottled black and yellow to a darker color similar to the agouti color.<ref name=Silvers1979/>
*Intermediate yellow ''a<sup>iy</sup>'' causes a mottled yellow coloration, which like viable yellow can sometimes resemble agouti.<ref name=Silvers1979/>
*Sienna yellow ''A<sup>sy</sup>'' heterozygotes are a dark yellow, while homozygotes are generally a clearer yellow.<ref name=Silvers1979/>
*White-bellied agouti ''A<sup>W</sup>'' mice have agouti coloration, with hairs that are black at the tips, then yellow, then black again, and white to tan bellies.<ref name=Silvers1979/>
*Agouti A looks like ''A<sup>W</sup>'' but the belly is dark like the back.<ref name=Silvers1979/>
*Black and tan ''a<sup>t</sup>'' causes a black back with a tan belly. ''A/a<sup>t</sup>'' heterozygotes look like ''A<sup>W</sup>'' mice.<ref name=Silvers1979/>
*Nonagouti ''a'' mice are almost completely black, with only a few yellow hairs around the ears and the genitals.<ref name=Silvers1979/>
*Extreme nonagouti ''a<sup>e</sup>'' mice are fully black, and is recessive to all other alleles in the series.<ref name=Silvers1979/>

This is not a complete list of mouse agouti alleles.

The nonagouti allele ''a'' is unusually likely to revert to the black-and-tan allele ''a<sup>t</sup>'' or to the white-bellied agouti allele ''A<sup>W</sup>''.<ref>{{cite journal|doi=10.1101/gad.8.4.481 |title=Molecular analysis of reverse mutations from nonagouti (A) to black-and-tan (A(t)) and white-bellied agouti (Aw) reveals alternative forms of agouti transcripts |date=1994 |last1=Bultman |first1=S. J. |last2=Klebig |first2=M. L. |last3=Michaud |first3=E. J. |last4=Sweet |first4=H. O. |last5=Davisson |first5=M. T. |last6=Woychik |first6=R. P. |journal=Genes & Development |volume=8 |issue=4 |pages=481–490 |pmid=8125260 |doi-access=free }}</ref>

Agouti production is regulated by multiple different promoter regions, capable of promoting transcription just in the ventral (belly) area, as seen in white-bellied agouti and black-and-tan mice, or all across the body but just during a specific part of the hair growth cycle, as seen in agouti and white-bellied agouti.<ref>{{cite journal|doi=10.1073/pnas.91.12.5667 |title=Differences in dorsal and ventral pigmentation result from regional expression of the mouse agouti gene |date=1994 |last1=Vrieling |first1=H. |last2=Duhl |first2=D. M. |last3=Millar |first3=S. E. |last4=Miller |first4=K. A. |last5=Barsh |first5=G. S. |journal=Proceedings of the National Academy of Sciences |volume=91 |issue=12 |pages=5667–5671 |doi-access=free |pmid=8202545 |pmc=44057 |bibcode=1994PNAS...91.5667V }}</ref>

Lethal yellow and viable yellow 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 | doi-access = free }}</ref> The ''mahogany'' locus interacts with ''Agouti'' and a mutation there can override the pigmentation and body weight effects of lethal yellow.<ref name=Gunn1999>{{cite journal|doi = 10.1038/18217|title = The mouse mahogany locus encodes a transmembrane form of human attractin|year = 1999|last1 = Gunn|first1 = Teresa M.|last2 = Miller|first2 = Kimberly A.|last3 = He|first3 = Lin|last4 = Hyman|first4 = Richard W.|last5 = Davis|first5 = Ronald W.|last6 = Azarani|first6 = Arezou|last7 = Schlossman|first7 = Stuart F.|last8 = Duke-Cohan|first8 = Jonathan S.|last9 = Barsh|first9 = Gregory S.|journal = Nature|volume = 398|issue = 6723|pages = 152–156|pmid = 10086356|bibcode = 1999Natur.398..152G|s2cid = 4371433}}</ref>

Viable yellow agouti mice can inherit epigenetic differences from their dam affecting how yellow or brown they become.<ref>{{cite journal|doi=10.1038/15490 |title=Epigenetic inheritance at the agouti locus in the mouse |date=1999 |last1=Morgan |first1=Hugh D. |last2=Sutherland |first2=Heidi G.E. |last3=Martin |first3=David I.K. |last4=Whitelaw |first4=Emma |journal=Nature Genetics |volume=23 |issue=3 |pages=314–318 |pmid=10545949 |s2cid=21512043 }}</ref>

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

==Dogs==
{{see also|Dog coat genetics#A (agouti) locus}}
[[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 | pages = S11-8 | year = 2011 | issue = Suppl 1 | pmid = 21846741 | doi = 10.1093/jhered/esr042 | doi-access =  }}</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 | doi-access = free }}</ref>
* ''a'' = Recessive black (black, inhibition of phaeomelanin)
* ''a<sup>yt</sup>'' = Recombinant fawn (expresses a varied phenotype depending on the breed) has been identified in numerous Tibetan Spaniels and individuals in other breeds, including the Dingo. Its hierarchical position is not yet understood.<ref name="Dreger1">{{cite journal|author=Dayna L Dreger|display-authors=etal|date=May 29, 2019|title=True Colors: commercially-acquired morphological genotypes reveal hidden allele variation among dog breeds, informing both trait ancestry and breed potential|url=https://www.biorxiv.org/content/10.1101/654343v1.full#disqus_thread|journal=PLOS ONE|volume=14|issue=10|article-number=e0223995|doi=10.1371/journal.pone.0223995|pmc=6816562|pmid=31658272|bibcode=2019PLoSO..1423995D|access-date=September 23, 2019|doi-access=free}}</ref><ref>''[http://www.doggenetics.co.uk/tan.html#saddle Agouti Series]''</ref><ref name="Dreger2">{{cite journal|author=Dayna L Dreger|display-authors=etal|date=Jul 3, 2020|title=Atypical Genotypes for Canine Agouti Signaling Protein Suggest Novel Chromosomal Rearrangement|journal= Genes|volume=11|issue=7|page=739|doi=10.3390/genes11070739|pmid=32635139|pmc=7397341|doi-access=free}}</ref>

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 | s2cid = 27945452 }}</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.

A 2021 study found distinct genetic causes for fawn and sable, which it refers to as "dominant yellow" and "shaded yellow". Both have a more active hair cycle promoter than the wildtype agouti, but dominant yellow also has a more active ventral promoter. The hair cycle promoter involved in these colors is thought to have arisen about 2 million years ago in an extinct species of canid, which later hybridized with wolves.<ref>{{cite journal|title=Dog colour patterns explained by modular promoters of ancient canid origin|date=2021 |doi=10.1038/s41559-021-01524-x |last1=Bannasch |first1=Danika L. |last2=Kaelin |first2=Christopher B. |last3=Letko |first3=Anna |last4=Loechel |first4=Robert |last5=Hug |first5=Petra |last6=Jagannathan |first6=Vidhya |last7=Henkel |first7=Jan |last8=Roosje |first8=Petra |last9=Hytönen |first9=Marjo K. |last10=Lohi |first10=Hannes |last11=Arumilli |first11=Meharji |last12=Lohi |first12=Hannes |last13=Kere |first13=Juha |last14=Daub |first14=Carsten |last15=Hytönen |first15=Marjo |last16=Araujo |first16=César L. |last17=Quintero |first17=Ileana B. |last18=Kyöstilä |first18=Kaisa |last19=Kaukonen |first19=Maria |last20=Arumilli |first20=Meharji |last21=Salonen |first21=Milla |last22=Sarviaho |first22=Riika |last23=Niskanen |first23=Julia |last24=Hundi |first24=Sruthi |last25=Puurunen |first25=Jenni |last26=Sulkama |first26=Sini |last27=Karjalainen |first27=Sini |last28=Sukura |first28=Antti |last29=Syrjä |first29=Pernilla |last30=Airas |first30=Niina |journal=Nature Ecology & Evolution |volume=5 |issue=10 |pages=1415–1423 |pmid=34385618 |bibcode=2021NatEE...5.1415B |s2cid=229549711 |display-authors=1 |doi-access=free |pmc=8484016 }}</ref>

==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 | s2cid = 19021807 | doi-access = free }}</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.

{| class="wikitable"
|+ Agouti alleles in cats
|-
! scope="col" width=10%| Allele
! scope="col" width=5%| Symbol
! scope="col" width=10%| Image
! scope="col" width=40%| Description
! scope="col" width=35%| Mutation
|-
! scope="row" | Agouti
| ''A''
| [[File:Arthur, the cat.jpg|150px]]
| [[Tabby cat|Tabby]] pattern thanks to a functional agouti gene.
| Wildtype
|-
! scope="row" | Nonagouti
| ''a''
| [[File:Black cat 1 (1).jpg|150px]]
| [[black cat|Black]], which lacks a functional agouti gene and so cannot signal [[MC1R]] to produce red pigment.
| A 2 base pair [[frameshift]] deletion thought to cause a complete loss of function<ref>{{cite journal|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 |doi= 10.1016/S0960-9822(03)00128-3 |s2cid= 19021807 |doi-access= free }}</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 | display-authors = 6 | 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>
|}

==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.

{| class="wikitable"
|+ Agouti alleles in horses
|-
! scope="col" width=10%| Allele
! scope="col" width=5%| Symbol
! scope="col" width=10%| Image
! scope="col" width=50%| Description
! scope="col" width=25%| Mutation
|-
! scope="row" | Bay
| ''A''
| [[File:500px photo (42598376).jpeg|150px]]
| [[Bay horse|Bay]] pattern due to a functional agouti gene. The body is red while the "points", the mane, tail, and lower legs, are black.
| Wildtype
|-
! scope="row" | Black
| ''a''
| [[File:Champion Dales Pony.jpg|150px]]
| [[black horse|Black]] horses produce black pigment in the entire coat because they lack a functional Agouti protein.
| An 11 base pair frameshift deletion in exon 2<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 | s2cid = 2012676 | 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>
|}

===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 | doi = 10.1093/genetics/46.9.1143 | pmid = 13877241 | pmc = 1210264 | url = http://www.genetics.org/cgi/reprint/46/9/1143.pdf | url-status = live | archive-url = https://web.archive.org/web/20080905062605/http://www.genetics.org/cgi/reprint/46/9/1143.pdf | archive-date = 2008-09-05 }}</ref>

{| class="wikitable"
|+ Additional hypothesized agouti alleles in horses
|-
! scope="col" width=10%| Name
! scope="col" width=5%| Symbol
! scope="col" width=10%| Image
! scope="col" width=50%| Description
|-
! scope="row" | Wild or Wildtype bay
| ''A<sup>+</sup>''
| [[File:Halterstandingshotarabianone.jpg|150px]]
| [[Wildtype]] bay pattern, wherein the black points do not extend so far up the legs.
|-
! scope="row" | Seal brown
| ''A<sup>t</sup>''
| [[File:Kevin Tornado Zlosyn 2005.jpg|150px]]
| [[seal brown (horse)|Seal brown]] color, extremely dark brown coat color, distinguished from black by the presence of red on the flanks, muzzle, and around the eyes.
|}

[[Image:Ardennerpäerd.jpg|thumb|right|The pale areas on this bay horse are due to the pangaré trait]]
This was accepted until the 1990s, when a different hypothesis 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> It proposed 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]].<ref name=sponenberg7>Sponenberg 2003, pg 123. Fig. 9.10. "The mealy effect generally is lighter and more yellow than residual nonblack areas (which tend to be redder) on very sooty horses."</ref> 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 seal 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"/><ref name=DunCentralStation>{{cite web |url=http://www.duncentralstation.com/BrownBayDun.html |title=Brown/Bay Dun |work=Dun Central Station |author=Nancy Castle |date=2008-03-01 |access-date=2008-03-04| archive-url= https://web.archive.org/web/20080310202549/http://www.duncentralstation.com/BrownBayDun.html| archive-date= 10 March 2008}}</ref>

In 2007 one genetics lab began offering a test for what they believed was a marker for seal brown, and later for an agouti allele which they believed caused the brown color.<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 |archive-url=https://web.archive.org/web/20090522151520/http://www.petdnaservicesaz.com/Equine.html |archive-date=2009-05-22 }}</ref><ref>{{cite web | archive-url=https://web.archive.org/web/20140303185536/http://www.diomics.com/DIOMICS/PetDNA-Equine-Info_files/BrownPaintHorseJournal0410.pdf | archive-date=March 3, 2014 | title=Believe in Brown |url=http://www.diomics.com/DIOMICS/PetDNA-Equine-Info_files/BrownPaintHorseJournal0410.pdf}}</ref> However, the underlying research was never published and the test was suspended by 2015 due to unreliable results.<ref>{{cite web | url=http://www.petdnaservicesaz.com/equine-testing/understanding-equine-dna-and-agouti/ |title=Understanding Equine DNA and Agouti|archive-url=https://web.archive.org/web/20150924071732/http://www.petdnaservicesaz.com/equine-testing/understanding-equine-dna-and-agouti/|archive-date=2015-09-24}}</ref><ref name=colorgenetics>{{Cite web|url=http://colorgenetics.info/equine/enigmatic-brown-horse|title=The Enigmatic Brown Horse &#124; Color Genetics}}</ref>

The genetic alleles that create seal brown and wildtype bay remain unknown. It is still hypothesized that to some extent, the darkening of coat color in some bays may be regulated by unrelated genes for traits like "[[sooty (coat)|sooty]]".<ref name=Dun>{{cite web |url=http://www.duncentralstation.com/BrownBayDun.html |title=Brown/Bay Dun |work=Dun Central Station |author=Nancy Castle |date=2008-03-01 |access-date=2008-03-04| archive-url= https://web.archive.org/web/20080310202549/http://www.duncentralstation.com/BrownBayDun.html| archive-date= 10 March 2008 <!--DASHBot-->}}</ref>

==Donkeys==
Most donkeys have creamy to gray-white areas on the belly and around the muzzle and eyes, called light [[point coloration|points]] or [[pangare]]. However, a recessive variant of agouti causes those areas to be the same color as the body in a pattern called no light points or NLP, which is similar to recessive black in other mammals. This allele can be found in [[Norman donkey]]s and American [[miniature donkey]]s.<ref name=Abitbol2015/>
{| class="wikitable"
|+ Agouti alleles in donkeys
|-
! scope="col" width=10%| Allele
! scope="col" width=5%| Symbol
! scope="col" width=10%| Image
! scope="col" width=40%| Description
! scope="col" width=35%| Mutation
|-
! scope="row" | Light points
| ''A''
| [[File:Poland. Warsaw. Praga Północ 005.JPG|150px]]
| A gray dun donkey with a white belly and white around the muzzle
| Wildtype
|-
! scope="row" | No light points
| ''a<sup>nlp</sup>''
| [[File:Donkey 002.jpg|150px]]
| A gray dun donkey with no white areas
| A single nucleotide polymorphism pc.349 T > C<ref name=Abitbol2015>{{cite journal | vauthors = Abitbol M, Legrand R, Tiret L | title = A missense mutation in the agouti signaling protein gene (ASIP) is associated with the no light points coat phenotype in donkeys | journal = Genetics, Selection, Evolution | volume = 47 | page = 28 | date = April 2015 | issue = 1 | pmid = 25887951 | pmc = 4389795 | doi = 10.1186/s12711-015-0112-x | doi-access = free }}</ref>
|}

==Rabbits==
In rabbits, the wildtype is agouti with a light belly, and a recessive non-agouti allele causes a black coat. A third allele, possibly a mutation to a regulator or promoter region, is thought to cause black and tan color. The nonagouti allele is estimated to have first appeared before 1700.<ref name=Fontanesi2010>{{cite journal | vauthors = Fontanesi L, Forestier L, Allain D, Scotti E, Beretti F, Deretz-Picoulet S, Pecchioli E, Vernesi C, Robinson TJ, Malaney JL, Russo V, Oulmouden A | display-authors = 6 | title = Characterization of the rabbit agouti signaling protein (ASIP) gene: transcripts and phylogenetic analyses and identification of the causative mutation of the nonagouti black coat colour | journal = Genomics | volume = 95 | issue = 3 | pages = 166–75 | date = March 2010 | pmid = 20004240 | doi = 10.1016/j.ygeno.2009.11.003 | doi-access =  }}</ref>

''Agouti'' is linked to the ''wideband'' gene, with about a 30% crossover rate.<ref name=Sawin1934>{{cite journal | vauthors = Sawin PB | title = Linkage of "WIDE-BAND" and "AGOUTI" genes: The Agouti Gene and a Modifier Shown to Be Situated on the Same Chromosome in the Domesticated Rabbit | journal = Journal of Heredity | volume = 25 | issue = 12 | year = 1934 | pages = 477–481 | doi = 10.1093/oxfordjournals.jhered.a103864 }}</ref>

Like white bellied agouti mice, rabbits with wildtype agouti produce transcripts with different untranslated 5' ends that have different dorsal and ventral expression. The 1A exon is only expressed in the belly region and may be responsible for the lighter color there.<ref name=Fontanesi2010/>

{| class="wikitable"
|+ Agouti alleles in rabbits
|-
! scope="col" width=10%| Allele
! scope="col" width=5%| Symbol
! scope="col" width=10%| Image
! scope="col" width=40%| Description
! scope="col" width=35%| Mutation
|-
! scope="row" | Agouti
| ''A''
| [[File:Rabbit_(agouti)_04.jpg|150px]]
| Chestnut, sometimes called agouti. Hairs are banded black and yellow, and the belly is light. This resembles the mouse's light bellied agouti.
| Wildtype
|-
! scope="row" | Black and tan
| ''a<sup>t</sup>''
| [[File:LapinTitus.jpg|150px]]
| Black otter, black with a white belly. [[Tan rabbit]]s are all this color, but also have the wideband pattern and rufous color causing their bellies to be fiery orange.
| 11 kb deletion in hair-cycle-specific promoter region <ref>{{cite journal | url=https://onlinelibrary.wiley.com/doi/abs/10.1111/age.12881 | title=A deletion spanning the promoter and first exon of the hair cycle-specific ASIP transcript isoform in black and tan rabbits | year=2020 | doi=10.1111/age.12881 | last1=Letko | first1=A. | last2=Ammann | first2=B. | last3=Jagannathan | first3=V. | last4=Henkel | first4=J. | last5=Leuthard | first5=F. | last6=Schelling | first6=C. | last7=Carneiro | first7=M. | last8=Drögemüller | first8=C. | last9=Leeb | first9=T. | journal=Animal Genetics | volume=51 | issue=1 | pages=137–140 | pmid=31729778 | s2cid=208034608 | url-access=subscription }}</ref>
|-
! scope="row" | Nonagouti
| ''a''
| [[File:Black rabbit.JPG|150px]]
| Black self. All hairs are fully black.
| Single base pair frameshift insertion in exon 2 causing loss of function<ref name=Fontanesi2010/>
|}

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{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 | doi = 10.1242/dev.121.10.3223 | pmid = 7588057 }}
{{refend}}

[[Category:Genetics]]