OMIA 000214-9615 : Coat colour, white spotting in Canis lupus familiaris

In other species: domestic cat , cattle , horse , water buffalo , domestic guinea pig

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 193510 , 103500

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2007

Cross-species summary: Variable degree of white spotting ranging from tiny white spots up to completely white animals. The absence of pigment is caused by the absence of skin melanocytes ("leucism"), not by failure in the biochemical reactions required for pigment synthesis.

Species-specific symbol: S

Inheritance: This locus was described by Little (1957). As summarised by Körberg et al. (2014), Little "described four different alleles at this locus with phenotypic effects ranging from solid (S, . . .), to a completely white coat, caused by homozygosity for the Extreme white allele (sw, . . .). The two intermediate phenotypes were named Irish spotting (si, . . .) and piebald (sp, . . .). Irish spotting is characterized by modest white spotting, often present as a white collar and a white belly, as demonstrated by breeds such as the Bernese Mountain dog and Basenji. Piebald-coloured dogs display limited to extensive white spotting and the phenotype is observed in several breeds, including the Beagle and Fox Terrier."

Mapping: van Hagen et al. (2004) were able to exclude KIT and EDNRB from the list of candidate genes for white spotting.

Using a linkage analysis of "5 families with heterozygous parents and offspring that included 11 white, 6 brown, and 19 spotted dogs", each genotyped for 1500 SNPs having a genome-wide coverage (with an average spacing of 1.6Mb), Leegwater et al. (2007) mapped this locus to a region of chromosome CFA20 which contains a very likely comparative candidate gene, namely MITF.

In a landmark study, Karlsson et al. (2007) mapped the white-spotting locus to less than 1 Mb on CFA20 via one of the first Genome-Wide Association Studies (GWAS) using 27,000 SNPs on just a few (approx 20) dogs. Subsequent fine mapping implicated the positional candidate gene MITF.

By conducting a proof-of-principle across-breed GWAS on "31 cases for white spotting from 11 breeds and 31 controls from 14 breeds", each genotyped with the Affymetrix Version 2 Custom Canine SNP (comprising 49,663 SNPs), Bannasch et al. (2010) confirmed the white-spotting locus to be MITF on CFA20.

Molecular basis: In the words of Karlsson et al. (2007), "Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF". As summarised by Körberg et al. (2014), Karlsson et al. (2007) identified "a short list of three candidate mutations within or in the vicinity of the MITF-M promoter, and one in the MITF-1B exon located upstream of MITF-M. The first of these is a canine-specific short interspersed nucleotide element (SINEC-Cf element), located about 3 kb upstream of the MITF-M transcription start site (TSS). The SINE insertion was only found in dogs presenting the extreme white (sw/sw) or piebald (sp/sp) phenotypes, and was absent in Irish-spotted (si/si) and solid (S/S) dogs. . . . The second candidate (SNP#21), a SNP located approximately 1.2 kb upstream of MITF-M TSS, occurs in a highly conserved region and the A allele at this locus is associated with white spotting alleles . . . . The third polymorphism is a variable length polymorphism (Lp) approximately 100 bp upstream of the MITF-M TSS. Long variants of the Lp (LpWhite) are associated with all three white-spotting alleles (sw, sp and si), whereas all solid dogs examined carried short Lp variants .. . , [from here on named LpSolid]. The fourth candidate mutation, a 12 bp deletion in exon 1B (Exon1B_del) also showed a very strong association with white spotting. It was found on all Extreme white and Piebald chromosomes tested, but it was also found in the heterozygous state in 4 out of 76 solid dogs."

Extensive sequence comparisons of MITF in wolves and dogs enabled Körberg et al. (2014) to conclude that "the simple repeat polymorphism [Lp above] has been a target for selection during dog domestication and breed formation", that it "affects promoter activity" by affecting "cooperativity between transcription factors binding on either flanking sides of the repeat"; and hence "the simple repeat polymorphism is a key regulator of white spotting in dogs".

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
MITF microphthalmia-associated transcription factor Canis lupus familiaris 20 NC_006602.3 (21772147..21873545) MITF Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Coat colour, white spotting MITF regulatory CanFam3.1 20 g.21836232_21836427ins>del 2007 17906626 This SINE-insertion variant is the first of three possible regulatory variants described by Karlsson et al. (2007). Its genomic location and description were kindly provided by Professor Claire Wade in August 2018.

References


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.
2014 Baranowska Körberg, I., Sundström, E., Meadows, J.R., Rosengren Pielberg, G., Gustafson, U., Hedhammar, Å., Karlsson, E.K., Seddon, J., Söderberg, A., Vilà, C., Zhang, X., Åkesson, M., Lindblad-Toh, K., Andersson, G., Andersson, L. :
A simple repeat polymorphism in the MITF-M promoter is a key regulator of white spotting in dogs. PLoS One 9:e104363, 2014. Pubmed reference: 25116146. DOI: 10.1371/journal.pone.0104363.
2010 Bannasch, D., Young, A., Myers, J., Truvé, K., Dickinson, P., Gregg, J., Davis, R., Bongcam-Rudloff, E., Webster, M.T., Lindblad-Toh, K., Pedersen, N. :
Localization of canine brachycephaly using an across breed mapping approach. PLoS One 5:e9632, 2010. Pubmed reference: 20224736. DOI: 10.1371/journal.pone.0009632.
2009 Andersson, L. :
Genome-wide association analysis in domestic animals: a powerful approach for genetic dissection of trait loci. Genetica 136:341-9, 2009. Pubmed reference: 18704695. DOI: 10.1007/s10709-008-9312-4.
2007 Karlsson, E.K., Baranowska, I., Wade, C.M., Salmon Hillbertz, N.H., Zody, M.C., Anderson, N., Biagi, T.M., Patterson, N., Pielberg, G.R., Kulbokas, E.J., Comstock, K.E., Keller, E.T., Mesirov, J.P., von Euler, H., Kämpe, O., Hedhammar, A., Lander, E.S., Andersson, G., Andersson, L., Lindblad-Toh, K. :
Efficient mapping of mendelian traits in dogs through genome-wide association. Nat Genet 39:1321-8, 2007. Pubmed reference: 17906626. DOI: 10.1038/ng.2007.10.
Leegwater, PA., van Hagen, MA., van Oost, BA. :
Localization of white spotting locus in Boxer dogs on CFA20 by genome-wide linkage analysis with 1500 SNPs. J Hered 98:549-52, 2007. Pubmed reference: 17548862. DOI: 10.1093/jhered/esm022.
2006 Rothschild, MF., Van Cleave, PS., Glenn, KL., Carlstrom, LP., Ellinwood, NM. :
Association of MITF with white spotting in Beagle crosses and Newfoundland dogs. Anim Genet 37:606-7, 2006. Pubmed reference: 17121617. DOI: 10.1111/j.1365-2052.2006.01534.x.
2004 van Hagen, MA., van der Kolk, J., Barendse, MA., Imholz, S., Leegwater, PA., Knol, BW., van Oost, BA. :
Analysis of the inheritance of white spotting and the evaluation of KIT and EDNRB as spotting loci in Dutch boxer dogs. J Hered 95:526-31, 2004. Pubmed reference: 15475400. DOI: 10.1093/jhered/esh083.
2000 Metallinos, D., Rine, J. :
Exclusion of EDNRB and KIT as the basis for white spotting in Border Collies. Genome Biol 1:research0004.1-4, 2000. Pubmed reference: 11178229.
1990 Pape, H. :
The Inheritance of the Piebald Spotting Pattern and Its Variation in Holstein-Friesian Cattle and in Landseer- Newfoundland Dogs Genetica 80:115-128, 1990. Pubmed reference: 2323567.
1957 Little, C.C. :
The inheritance of coat colour in dogs. Comstock Publishing Associates, Cornell University Press, Ithaca, NY :, 1957.

Edit History


  • Created by Frank Nicholas on 04 Jan 2008
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 23 Nov 2012
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  • Changed by Frank Nicholas on 03 Oct 2014