OMIA 000211-9615 : Coat colour, merle in Canis lupus familiaris

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Incompletely Dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2006

Species-specific name: This is the classic M (Merle) locus (Little, 1957)

Species-specific symbol: M locus

Mapping: Using a genome scan with the "multiplexed Minimal Screening Set 2" of 327 canine microsatellites genotyped on 9 merle and 32 non-merle Shetland Sheepdogs, Clark et al. (2006) LD-mapped the merle locus to a single marker (FH2537) on chromosome CFA10. A search of homologous regions in the genomes of humans and mice revealed the SILV gene as a comparative positional candidate.

Molecular basis: Sequencing of a very likely comparative positional candidate gene (SILV or PMEL17; now known as PMEL) (see Mapping section above) in Shetland Sheedogs of the three merle genotypes by Clark et al. (2006) revealed "an insertion of a tRNA-derived SINE . . . . The insertion occurs at the boundary of intron 10 and exon 11 and is flanked by a 15-bp target site duplication . . . . The SINE insertion is in reverse orientation, with the 5′ end closer to exon 11."

Having noticed in a mixed-breed non-merle dog some ophthalmologic abnormalities similar to those seen in merle dogs, Imamoto et al. (2011) discovered that this mixed-breed dog was actually carrying the above SINE-insertion PMEL merle mutation, and was therefore a cryptic merle.

By investigating merle-related coat colour and length of SINE insertion in 175 dogs, Ballif et al. (2018) concluded that "there is a continuum of merle insertion lengths associated with a spectrum of coat color and patterns and that genotype-phenotype exceptions and overlap make it difficult to strictly assign certain insertion sizes with an expected coat color, although some generalizations are possible".

Murphy et al. (2018) reported that "In fragment analyses from 259 dogs heterozygous for Merle, we observed a spectrum of oligo(dT) lengths spanning 25 to 105 base pairs (bp), with ranges that correspond to the four varieties of the merle phenotype: cryptic (25-55 bp), dilute (66-74 bp), standard (78-86 bp), and harlequin (81-105 bp). Somatic contractions of the oligo(dT) were observed in 43% of standard and 51% of harlequin merle dogs. A small proportion (4.6%) of the study cohort inherited de novo contractions or expansions of the Merle allele that resulted in dilute or harlequin coat patterns, respectively". These authors concluded that "The phenotypic consequence of the Merle SINE insertion directly depends upon oligo(dT) length. In transcription, we propose that the use of an alternative splice site increases with oligo(dT) length, resulting in insufficient PMEL and a pigment dilution spectrum, from dark grey to complete hypopigmentation. We further propose that during replication, contractions and expansions increase in frequency with oligo(dT) length, causing coat variegation (somatic events in melanocytes) and the spontaneous appearance of varieties of the merle phenotype (germline events)".

After an extensive analysis involving 181 dogs of 14 breeds, each with a detailed Merle phenotype, Langevin et al. (2018) identified the following seven alleles, defined by "binning" on the basis of SINE insertion length, which, in effect, is a continuous variable. Four of these alleles had been previously reported.

Non-Merle: m (wild type; no SILV SINE insertion; 171bp); phenotype = No Merle pattern – solid coat

Cryptic Merle: Mc (200-230bp); phenotype = No Merle pattern – solid coat; = "cryptic" of Murphy et al. (2018)

Cryptic merle: Mc+ (231-246bp); phenotype = No Merle pattern – solid coat; = "cryptic" of Murphy et al. (2018)

Atypical merle: Ma (247-254bp); phenotype = No Merle pattern – diluted–brownish hue; = "cryptic" of Murphy et al. (2018)

Atypical Merle: Ma+ (255-264bp); phenotype = Muted, undefined, diluted–brownish hue = "dilute" of Murphy et al. (2018)

Merle: M (265-268bp); phenotype = Classic Merle = "standard" of Murphy et al. (2018)

Harlequin Merle: Mh (269-280bp); phenotype = Minimal Merle, areas deleted to white, tweed = "harlequin" of Murphy et al. (2018)

Langevin et al. (2018) provide detailed illustrated descriptions of the Merle phenotype of 24 genotypes comprising pairs of the above alleles. They also noted that "M/M genotypes . . . [and] heterozygous Mh genotypes seem to predispose an individual to hearing and/or vision impairments".

As with Ballif et al. (2018) and Murphy et al. (2018), Langevin et al. (2018) also highlighted "the presence of more than two M Locus alleles in tested samples" of 30 of the 181 dogs tested. This mosaicism , which was observed to "differ between biological materials tested, . . . [namely] buccal swab (terminally differentiated epidermal derivative) . . . [and] sperm cells (germinal cell line)" likely "results from the shortening of the major longer Merle alleles". Thus it appears that the SINE insertion is highly mutable between and within generations.

Clinical features: As reported by Clark et al. (2006) (citing Sorsby and Davey, 1954), "Dogs having Mm and MM genotypes typically have blue eyes and often exhibit a wide range of auditory and ophthalmologic abnormalities"

Strain et al. (2009) assessed a sample of 153 merle dogs from 10 breeds plus one mixed-breed dog and reported "Deafness prevalence in merles overall was 4.6% unilaterally deaf and 4.6% bilaterally deaf. There was a significant association between hearing status and heterozygous versus homozygous merle genotype. For single merles (Mm), 2.7% were unilaterally deaf and 0.9% were bilaterally deaf. For double merles (MM), 10% were unilaterally deaf and 15% were bilaterally deaf. There was no significant association with eye color or sex."

Prevalence: Mizukami et al. (2016) reported the frequency of the SINE-insertion allele as 0.016 in 500 Border collies in Japan.

Langevin et al. (2018): "It seems that some Merle breeds might be enriched for some Merle alleles, but our split cohort (14 breeds) is too small to draw any statistically significant conclusion. More subjects have to be tested to clarify this issue."

In a sample of 123 dogs of the Mudi breed from 11 countries, Pelles et al. (2019) reported that the "most frequent merle genotype . . . was the 'classic' merle (m/M: 61.8%), whereas other variants, such as atypical (m/Ma and m/Ma+: 5.7%), harlequin (m/Mh: 13.8%), double merle (M/M: 0.8%) and mosaic profiles (17.9%) were also observed."

Genetic testing: Langevin et al. (2018): "In light of negative health consequences that may be attributed to certain Merle breeding strategies, we strongly advocate implementation of the refined Merle allele testing for all dogs of Merle breeds to help the breeders in selection of suitable mating partners and production of healthy offspring."

This important message was reinforced by Pelles et al. (2019): "The practical significance of testing this mutation [i.e. genotyping for Merle alleles] is that, phenotypically, not only merle dogs are carriers of this insertion, but also the so-called hidden merle individuals (where the merle phenotype is fully covered by the pheomelanin-dominated colouration) are potentially capable of producing unintentionally homozygous 'double merle' [M/M] progeny with ophthalmologic, viability and auditory impairments."

Breed: Shetland Sheepdog.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
PMEL premelanosome protein Canis lupus familiaris 10 NC_006592.3 (327618..292595) PMEL 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
Numerous breeds Classic Merle PMEL M insertion, gross (>20) "an insertion of a tRNA-derived SINE . . . . The insertion occurs at the boundary of intron 10 and exon 11 and is flanked by a 15-bp target site duplication . . . . The SINE insertion is in reverse orientation, with the 5' end closer to exon 11." Allele M (265-269bp); phenotype = Classic Merle = "standard" of Murphy et al. (2018) 2006 16407134
Numerous breeds No Merle pattern – solid coat PMEL Mc insertion, gross (>20) 10 Mc (208-230bp); phenotype = No Merle pattern – solid coat; = "cryptic" of Murphy et al. (2018) 2018 30235206
Numerous breeds No Merle pattern – solid coat PMEL Mc+ insertion, gross (>20) Mc+ (231-245bp); phenotype = No Merle pattern – solid coat; = "cryptic" of Murphy et al. (2018) 2018 30235206
Numerous breeds No Merle pattern – diluted–brownish hue PMEL Ma insertion, gross (>20) Ma (247-254bp); phenotype = No Merle pattern – diluted–brownish hue; = "cryptic" of Murphy et al. (2018) 2018 30235206
Numerous breeds Muted, undefined, diluted–brownish hue PMEL Ma+ insertion, gross (>20) Ma+ (255-264bp); phenotype = Muted, undefined, diluted–brownish hue = "dilute" of Murphy et al. (2018) 2018 30235206
Numerous breeds Minimal Merle, areas deleted to white, tweed PMEL Mh insertion, gross (>20) Mh (269-277bp); phenotype = Minimal Merle, areas deleted to white, tweed = "harlequin" of Murphy et al. (2018) 2018 30235206

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.
2019 Pelles, Z., Gáspárdy, A., Zöldág, L., Lénárt, X., Ninausz, N., Varga, L., Zenke, P. :
Merle allele variations in the Mudi dog breed and their effects on phenotypes. Acta Vet Hung 67:159-173, 2019. Pubmed reference: 31238727. DOI: 10.1556/004.2019.018.
2018 Ballif, B.C., Ramirez, C.J., Carl, C.R., Sundin, K., Krug, M., Zahand, A., Shaffer, L.G., Flores-Smith, H. :
The PMEL Gene and Merle in the Domestic Dog: A Continuum of Insertion Lengths Leads to a Spectrum of Coat Color Variations in Australian Shepherds and Related Breeds. Cytogenet Genome Res :, 2018. Pubmed reference: 30071510. DOI: 10.1159/000491408.
Langevin, M. :
Merle - SINE Insertion from Mc Mh; The Incredible Story of Merle Privately published https://www.merle-sine-insertion-from-mc-mh.com/order/ :, 2018.
Langevin, M., Synkova, H., Jancuskova, T., Pekova, S. :
Merle phenotypes in dogs - SILV SINE insertions from Mc to Mh. PLoS One 13:e0198536, 2018. Pubmed reference: 30235206. DOI: 10.1371/journal.pone.0198536.
Murphy, S.C., Evans, J.M., Tsai, K.L., Clark, L.A. :
PMEL: correlating genotype with phenotype. Mob DNA 9:26, 2018. Pubmed reference: 30123327. DOI: 10.1186/s13100-018-0131-6.
2016 Mizukami, K., Yabuki, A., Kohyama, M., Kushida, K., Rahman, M.M., Uddin, M.M., Sawa, M., Yamato, O. :
Molecular prevalence of multiple genetic disorders in Border collies in Japan and recommendations for genetic counselling. Vet J 214:21-3, 2016. Pubmed reference: 27387721. DOI: 10.1016/j.tvjl.2016.05.004.
2011 Imamoto, S., Watanabe, M., Iba, M., Imamoto, M., Umeyama, K. :
A mixed-breed dog showing the same gene modification as in a Miniature Dachshund Journal of Animal Clinical Medicine 20:1-5, 2011. DOI: 10.11252/dobutsurinshoigaku.20.1.
2010 Imamoto, S., Imamoto, M., Watanabe, M., Umeyama, K. :
Study on the effect SINE insertion to an SILV (Pmel17) gene on the fundi of longhaired miniature dachshunds Journal of Veterinary Medicine (Japan) 63:385-390, 2010.
2009 Strain, GM., Clark, LA., Wahl, JM., Turner, AE., Murphy, KE. :
Prevalence of deafness in dogs heterozygous or homozygous for the merle allele. J Vet Intern Med 23:282-6, 2009. Pubmed reference: 19192156. DOI: 10.1111/j.1939-1676.2008.0257.x.
2006 Clark, LA., Wahl, JM., Rees, CA., Murphy, KE. :
From The Cover: Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proc Natl Acad Sci U S A 103:1376-81, 2006. Pubmed reference: 16407134. DOI: 10.1073/pnas.0506940103.
Hedan, B., Corre, S., Hitte, C., Dreano, S., Vilboux, T., Derrien, T., Denis, B., Galibert, F., Galibert, MD., Andre, C. :
Coat colour in dogs: identification of the merle locus in the Australian shepherd breed. BMC Vet Res 2:9, 2006. Pubmed reference: 16504149. DOI: 10.1186/1746-6148-2-9.
Platt, S., Freeman, J., di Stefani, A., Wieczorek, L., Henley, W. :
Prevalence of unilateral and bilateral deafness in border collies and association with phenotype. J Vet Intern Med 20:1355-62, 2006. Pubmed reference: 17186850.
2003 Schmutz, SM., Berryere, TG., Sharp, CA. :
KITLG maps to canine chromosome 15 and is excluded as a candidate gene for merle in dogs. Anim Genet 34:75-6, 2003. Pubmed reference: 12580795.
1988 Herrman, A., Wegner, W. :
[Eye lesions in aging merle Dachshunds with particular reference to iris atrophy] Praktische Tierarzt 69:33-36, 1988.
1986 Klinckmann, G., Koniszewski, G., Wegner, W. :
Light-microscope investigations on the retinae of dogs carrying the Merle factor Journal of Veterinary Medicine. Series A 33:674-788, 1986. Pubmed reference: 3099512.
1985 Sponenberg, D.P. :
Inheritance of the harlequin color in Great Dane dogs Journal of Heredity 76:224-225, 1985. Pubmed reference: 3998446.
Sponenberg, D.P., Lamoreaux, M.L. :
Inheritance of tweed, a modification of merle, in Australian shepherd dogs Journal of Heredity 76:303-304, 1985. Pubmed reference: 4031467.
1984 Sponenberg, D.P. :
Germline reversion of the merle allele in Australian shepherd dogs Journal of Heredity 75:78 only, 1984. Pubmed reference: 6323572.
1983 Akcan, A., Wegner, W. :
[Changes in the visual pathways and visual centers in Merle syndrome in the dog]. Z Versuchstierkd 25:91-9, 1983. Pubmed reference: 6410614.
1982 Whitney III, J.B., Lamoreux, M.L. :
Transposable elements controlling genetic instabilities in mammals. Journal of Heredity 73:12-18, 1982.
1980 Flach, M., Dausch, D., Wegner, W. :
[Fluorescence angiography in the dachshund. Further findings in Merle syndrome of the dog]. Tierarztl Prax 8:375-83, 1980. Pubmed reference: 6817463.
Wegner, W., Akcan, A. :
[Effects of Merle factor on the optic area in the dog]. Dtsch Tierarztl Wochenschr 87:342, 1980. Pubmed reference: 7006993.
1978 Dausch, D., Wegner, W., Michaelis, W., Reetz, I. :
[Eye changes in the merle syndrome in the dog (author's transl)]. Albrecht Von Graefes Arch Klin Exp Ophthalmol 206:135-50, 1978. Pubmed reference: 418699.
1977 Dausch, D., Wegner, W., Michaelis, M., Reetz, I. :
[Ophthalmological findings in Merle dachshunds]. Dtsch Tierarztl Wochenschr 84:468-75, 1977. Pubmed reference: 340189.
Reetz, I., Stecker, M., Wegner, W. :
Audiometric findings in Dachshunds (merle gene carriers) Deutsche Tierarztliche Wochenschrift 84:273-277, 1977. Pubmed reference: 330141.
1957 Little, C.C. :
The Inheritance of Coat Color in Dogs Comstock Pub. Associates, Ithaca, New York :, 1957.
1954 Sorsby, A., Davey, J.B. :
Ocular associations of dappling (or merling) in the coat colour of dogs. I. Clinical and genetical data Journal of Genetics 52:425-440, 1954.
1953 Ford, L. :
Defective Collie dogs with heterozygous merling Journal of Canine Genetics :24-28, 1953.
1935 Mitchell, A.L. :
Dominant dilution and other colour factors in Collie dogs Journal of Heredity 26:424-430, 1935.

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