OMIA:000201-9940 : Coat colour, agouti in Ovis aries
In other species: horse , cattle , meadow voles , red fox , pig , domestic cat , rabbit , dog , gray wolf , coyote , goat , Eurasian water mole , Northern mole vole , North American deer mouse , alpaca , leopard , Asiatic golden cat , leopard cat , ass , impala , Colocolo , Kodkod , Arabian camel , Mongolian gerbil , domestic guinea pig , Western roe deer , llama , oldfield mouse
Categories: Pigmentation phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 611742 (trait) , 600201 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: no
Key variant known: yes
Year key variant first reported: 2008
Cross-species summary: This locus, ASIP, encodes the agouti signalling protein, a peptide antagonist of the melanocyte-stimulating hormone receptor (MC1R), which is the product of the extension locus. As explained by Schneider et al. (PLoS Genet 10(2): e1004892; 2015), "The most common causes of melanism (black coat) mutations are gain-of-function alterations in MC1R, or loss-of function alterations in ASIP, which encodes Agouti signaling protein, a paracrine signaling molecule that inhibits MC1R signaling".
Species-specific name: black sheep
Inheritance: Davenport (1905) reported autosomal recessive inheritance of black sheep.
Mapping: Utilising comparative deduction from Adalsteinsson (1983) and Adalsteinsson et al. (1987) that recessive black in sheep is likely to be due to an allele at the agouti (ASIP) locus, and comparative-mapping evidence that the ovine agouti locus should be on chromosome OAR13, Parsons et al. (1999) reported linkage between microsatellite markers on OAR13 and recessive self-colour in Australian Merinos.
By genotyping each of 588 Soay sheep with 251 microsatellites and 4 allozyme markers, Beraldi et al. (2006) linkage-mapped a "coat pattern" (wild-type: lighter belly and rump; self: uniform, more intense colour) locus to the region of chromosome OAR13 that includes the ASIP gene.
Molecular basis: Using the comparative candidate-gene strategy (reinforced by mapping results described above), Norris and Whan (2008) showed that the economically important white coat colour in sheep is due to a 190kb tandem duplication encompassing the ASIP gene, the neighbouring AHCY gene and the promoter for a third gene ITCH. This duplicated promoter is so placed as to cause ubiquitous expression of the ASIP gene immediately downstream from it, resulting in the white phenotype. Black sheep are homozygous for a single copy of ASIP with a non-functional promoter.
Building on the mapping results of Beraldi et al. (2006) in Soay sheep, Gratten et al. (2010) sequenced the ASIP gene in Soay sheep segregating for wild-type and self-colour coat pattern (see mapping results above). They identified two mutations "likely to influence the function of the Agouti protein", namely "A 5-bp deletion, g.100-104delAGGAA (hereafter referred to as D5), was present in exon 2. This is a frameshift mutation that introduces a premature stop codon at amino acid position 64, resulting in a mature peptide that lacks the functionally important cysteine-signalling domain"; and "(g.5172T → A) is a non-synonymous mutation that is predicted to cause a cysteine to serine substitution at codon 126 within the signalling domain of the protein." They also reported a synonymous SNP (g.5051G → C). All three mutations had been reported previously in other breeds, by Smit et al. (2002) and Norris and Whan (2008). Gratten et al. reported that "All six self-type sheep were homozygous for a putatively non-functional haplotype comprising D5, g.5051C and g.5172A, whereas wild-type sheep were either homozygous for a functional haplotype containing the non-deleted allele at g.100–104 (referred to as N5), g.5051G and g.5172T (N=4), or were heterozygous at all three positions (N=2)."
By conducting a GWAS on 99 Finnsheep phenotyped for coat colour and pattern, and each genotyped with the Illumina ovine SNP50K BeadChip (yielding 47,303 informative SNPs), Li et al. (2013) identified SNP s66432.1 in the ASIP gene as showing the strongest association with white vs non-white, with the A allele of this SNP being strongly associated with (dominant) white and the G allele with (recessive) non-white in a segregation analysis.
Zhang et al. (2017) "disrupted sheep agouti signaling protein gene by CRISPR/Cas9. A total of seven indels were identified in 5 of 6 born lambs. Each targeted lamb happened at least two kinds of modifications, and targeted lambs with multiple modifications displayed variety of coat color patterns. Three lambs with 4 bp deletion showed badgerface with black body coat color in two lambs, and brown coat color with light ventral pigmentation in another one. The black-white spotted color was observed in two lambs with 2 bp deletion." (This study involves genetically modified organisms (GMO)).
Breed: Merino (Sheep) (VBO_0001508).
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|ASIP||agouti signaling protein||Ovis aries||13||NC_056066.1 (63591538..63668259)||ASIP||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|714||Merino (Sheep)||White fleece||ASIP||Wt||insertion, gross (>20)||Naturally occurring variant||Oar_rambouillet_v1.0||13||a 190kb tandem duplication encompassing the ASIP gene, the neighbouring AHCY gene and the promoter for a third gene ITCH||2008||18493018|
|1112||Recessive black||ASIP||a||missense||Naturally occurring variant||Oar_rambouillet_v1.0||13||g.66474980T>A||c.376T>A||p.(C126S)||Published as g.5172T>A (Norris et al. 2008). cDNA and protein positions based on NM_001134303.1 and NP_001127775.1||2008||18493018||The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.|
|1111||Recessive black||ASIP||a||deletion, small (<=20)||Naturally occurring variant||Oar_rambouillet_v1.0||13||g.66475132_66475136del||published as g.100_105del / D5 and predicted to result in a frame shift followed by a premature stop codon 63 amino acids downstream of the start site||2002||12354151||The genomic location on Oar_rambouillet_v1.0 was determined by Katie Eager, EMAI, NSW Department of Primary Industries.|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2019||Rochus, C.M., Westberg Sunesson, K., Jonas, E., Mikko, S., Johansson, A.M., Rochus, C.M., Westberg Sunesson, K., Jonas, E., Mikko, S., Johansson, A.M. :|
|Mutations in ASIP and MC1R: dominant black and recessive black alleles segregate in native Swedish sheep populations. Anim Genet 50:712-717, 2019. Pubmed reference: 31475378 . DOI: 10.1111/age.12837.|
|2017||Zhang, X., Li, W., Liu, C., Peng, X., Lin, J., He, S., Li, X., Han, B., Zhang, N., Wu, Y., Chen, L., Wang, L. :|
|Alteration of sheep coat color pattern by disruption of ASIP gene via CRISPR Cas9. Sci Rep 7:8149, 2017. Pubmed reference: 28811591 . DOI: 10.1038/s41598-017-08636-0.|
|2016||Hepp, D., Gonçalves, G.L., Moreira, G.R., de Freitas, T.R. :|
|Epistatic interaction of the melanocortin 1 receptor and agouti signaling protein genes modulates wool color in the Brazilian Creole sheep. J Hered 107:544-52, 2016. Pubmed reference: 27288530 . DOI: 10.1093/jhered/esw037.|
|2013||Feulner, P.G., Gratten, J., Kijas, J.W., Visscher, P.M., Pemberton, J.M., Slate, J. :|
|Introgression and the fate of domesticated genes in a wild mammal population. Mol Ecol :, 2013. Pubmed reference: 23786437 . DOI: 10.1111/mec.12378.|
|Li, M.H., Tiirikka, T., Kantanen, J. :|
|A genome-wide scan study identifies a single nucleotide substitution in ASIP associated with white versus non-white coat-colour variation in sheep (Ovis aries). Heredity (Edinb) :, 2013. Pubmed reference: 24022497 . DOI: 10.1038/hdy.2013.83.|
|2012||Barrett, R.D. :|
|Bad coat, ripped genes: cryptic selection on coat colour varies with ontogeny in Soay sheep. Mol Ecol 21:2833-5, 2012. Pubmed reference: 22676073 . DOI: 10.1111/j.1365-294X.2012.05560.x.|
|Gratten, J., Pilkington, J.G., Brown, E.A., Clutton-Brock, T.H., Pemberton, J.M., Slate, J. :|
|Selection and microevolution of coat pattern are cryptic in a wild population of sheep. Mol Ecol 21:2977-90, 2012. Pubmed reference: 22432567 . DOI: 10.1111/j.1365-294X.2012.05536.x.|
|2011||Fontanesi, L., Dall'Olio, S., Beretti, F., Portolano, B., Russo, V. :|
|Coat colours in the Massese sheep breed are associated with mutations in the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes. Animal 5:8-17, 2011. Pubmed reference: 22440696 . DOI: 10.1017/S1751731110001382.|
|2010||Gratten, J., Pilkington, JG., Brown, EA., Beraldi, D., Pemberton, JM., Slate, J. :|
|The genetic basis of recessive self-colour pattern in a wild sheep population. Heredity 104:206-14, 2010. Pubmed reference: 19672282 . DOI: 10.1038/hdy.2009.105.|
|Henshall, JM., Whan, VA., Norris, BJ. :|
|Reconstructing CNV genotypes using segregation analysis: combining pedigree information with CNV assay. Genet Sel Evol 42:34, 2010. Pubmed reference: 20701809 . DOI: 10.1186/1297-9686-42-34.|
|2008||Norris, BJ., Whan, VA. :|
|A gene duplication affecting expression of the ovine ASIP gene is responsible for white and black sheep. Genome Res 10.1101/gr.072090.10:, 2008. Pubmed reference: 18493018 . DOI: 10.1101/gr.072090.107.|
|Renieri, C., Valbonesi, A., La Manna, V., Antonini, M., Lauvergne, J.J. :|
|Inheritance of coat colour in Merino sheep. Small Ruminant Research 74:23-29, 2008.|
|Royo, L.J., Alvarez, I., Arranz, J.J., Fernández, I., Rodríguez, A., Pérez-Pardal, L., Goyache, F. :|
|Differences in the expression of the ASIP gene are involved in the recessive black coat colour pattern in sheep: evidence from the rare Xalda sheep breed. Anim Genet 39:290-3, 2008. Pubmed reference: 18384465 . DOI: 10.1111/j.1365-2052.2008.01712.x.|
|2006||Beraldi, D., McRae, AF., Gratten, J., Slate, J., Visscher, PM., Pemberton, JM. :|
|Development of a linkage map and mapping of phenotypic polymorphisms in a free-living population of Soay sheep (Ovis aries). Genetics 173:1521-37, 2006. Pubmed reference: 16868121 . DOI: 10.1534/genetics.106.057141.|
|2003||Klungland, H., Vage, D.I. :|
|Pigmentary switches in domestic animal species Annals of the New York Academy of Sciences 994:331-8, 2003. Pubmed reference: 12851333 .|
|2002||Smit, M.A., Shay, T.L., Beever, J.E., Notter, D.R., Cockett, N.E. :|
|Identification of an agouti-like locus in sheep Animal Genetics 33:383-385, 2002. Pubmed reference: 12354151 .|
|1999||Parsons, Y.M., Fleet, M.R., Cooper, D.W. :|
|The Agouti gene: a positional candidate for recessive self-colour pigmentation in Australian Merino sheep Australian Journal of Agricultural Research 50:1099-1103, 1999.|
|Parsons, Y.M., Fleet, M.R., Cooper, D.W. :|
|Isolation of the ovine Agouti coding sequence Pigment Cell Research 12:394-397, 1999. Pubmed reference: 10614580 .|
|1987||Adalsteinsson, S., Hersteinsson, P., Gunnarsson, E. :|
|Fox colors in relation to colors in mice and sheep Journal of Heredity 78:235-237, 1987. Pubmed reference: 3624844 .|
|1983||Adalsteinsson, S. :|
|Inheritance of colours, fur characteristics and skin quality traits in North European sheep breeds: a review. Livetsock Production Science 10:555-567, 1983.|
|1970||Adalsteinsson, S. :|
|Colour inheritance in Icelandic sheep and relationship between colour, fertility and fertilisation Journal of Agricultural Research in Iceland 2:3-135, 1970.|
|1969||Brooker, M.G., Dolling, C.H.S. :|
|Pigmentation of sheep. II. The inheritance of colour patterns in black Merinos Australian Journal of Agricultural Research 20:387-394, 1969.|
|1965||Hayman, R.H., Cooper, D.W. :|
|The frequency of pigmented sheep in the Australian Merino Wool Technology and Sheep Breeding 12:81-85, 1965.|
|1957||Warwick, B.L., Berry, R,O., Davis, S.P. :|
|Inheritance of recessive black in sheep. Journal of Heredity 48:254–258, 1957.|
|1905||Davenport, C.B. :|
|The origin of black sheep in the flock Science 22:674-5, 1905. Pubmed reference: 17797580 . DOI: 10.1126/science.22.569.674.|
|1880||Darwin, C.R. :|
|Black sheep Nature 23:193, 1880.|
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