Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog - PubMed (original) (raw)

Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog

Leigh Anne Clark et al. Proc Natl Acad Sci U S A. 2006.

Abstract

Merle is a pattern of coloring observed in the coat of the domestic dog and is characterized by patches of diluted pigment. This trait is inherited in an autosomal, incompletely dominant fashion. Dogs heterozygous or homozygous for the merle locus exhibit a wide range of auditory and ophthalmologic abnormalities, which are similar to those observed for the human auditory-pigmentation disorder Waardenburg syndrome. Mutations in at least five genes have been identified as causative for Waardenburg syndrome; however, the genetic bases for all cases have not been determined. Linkage disequilibrium was identified for a microsatellite marker with the merle phenotype in the Shetland Sheepdog. The marker is located in a region of CFA10 that exhibits conservation of synteny with HSA12q13. This region of the human genome contains SILV, a gene important in mammalian pigmentation. Therefore, this gene was evaluated as a candidate for merle patterning. A short interspersed element insertion at the boundary of intron 10/exon 11 was found, and this insertion segregates with the merle phenotype in multiple breeds. Another finding was deletions within the oligo(dA)-rich tail of the short interspersed element. Such deletions permit normal pigmentation. These data show that SILV is responsible for merle patterning and is associated with impaired function of the auditory and ophthalmologic systems. Although the mutant phenotype of SILV in the human is unknown, these results make it an intriguing candidate gene for human auditory-pigmentation disorders.

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Figures

Fig. 1.

Fig. 1.

SINE insertion in SILV segregates with merle phenotype. (A) Tricolored (black, sable, and white), nonmerle Shetland Sheepdog (mm). (B) Blue merle Shetland Sheepdog (Mm). (C) Double merle Shetland Sheepdog (MM). (Left) Phenotypes. (Center) Exon 11 PCR products. (Right) Length markers.

Fig. 2.

Fig. 2.

Structure of wild-type canine SILV and sequence of the SINE insertion site in merle dogs. The putative lariat branch point sequence is boxed. Splicing acceptors are indicated by bold type. In merle dogs, the splicing acceptor is located in the 15-bp duplicated sequence (underlined) that flanks the SINE insertion. The average insertion size (not including the duplicated sequence) for the merle dogs analyzed herein is 253 bp.

Fig. 3.

Fig. 3.

Mutation analysis of SILV and its segregation in six breeds. PCR on genomic DNA from a sable/white Collie (lane 2), blue merle Collie (lane 3), black/white Border Collie (lane 4), blue merle Border Collie (lane 5), red Australian Shepherd (lane 6), blue merle Australian Shepherd (lane 7), brindle Cardigan Welsh Corgi (lane 8), blue merle Cardigan Welsh Corgi (lane 9), black/tan Dachshund (lane 10), red dapple Dachshund (lane 11), fawn Great Dane (lane 12), blue merle Great Dane (lane 13), and harlequin Great Danes (lanes 14 and 15).

Fig. 4.

Fig. 4.

Sequence alignment of the SINE insertion in eight merle dogs from seven breeds (Shetland Sheepdog “Sheltie,” Collie, Border Collie, Australian Shepherd “Aussie,” Cardigan Welsh Corgi, Dachshund, and Great Dane) and three nonmerle dogs from two breeds (Shetland Sheepdog and Great Dane) with the smaller insertion.

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