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A β-Defensin Mutation Causes Black Coat Color in Domestic Dogs

Sophie I. Candille et al.

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The marked spectrum of color and diversity of patterns that we see in mammals arises, unexpectedly, from variation in the quantity, quality, and regional distribution of just two types of pigment—black eumelanin and yellow pheomelanin. The appeal of unusual coat colors and patterns has motivated their selection in domestic animals, providing geneticists with a model for studying gene action and interaction that began a century ago and continues today. Most of the work has been carried out in laboratory mice, where studies of more than 100 different coat-color mutations have provided insight into stem cell biology (hair graying), biogenesis of intracellular organelles (pigmentary dilution), and hormone-receptor interactions (switching between the synthesis of eumelanin and pheomelanin).

The latter process—commonly known as pigment “type-switching”—is controlled primarily by the melanocortin system, in which a family of G protein–coupled receptors (identified by virtue of their response to α-melanocyte–stimulating hormone or adrenocorticotrophic hormone) has been implicated not only in pigmentation but also in cortisol production, body weight regulation, and exocrine gland secretion. In most mammals, pigment type-switching is controlled by two genes, the Melanocortin 1 receptor (Mc1r) and Agouti, which encode a seven transmembrane–domain receptor and its extracellular ligand, respectively. Indeed, our current understanding of melanocortin biology stems from the identification in laboratory mice of Mc1r mutations as the cause of recessive yellow and Agouti mutations as the cause of lethal yellow.

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Production of yellow versus black pigment in dogs is controlled by three genes: Mc1r, Agouti, and CBD103. Dogs carrying wild-type alleles for all three genes have a yellow coat resulting from Agouti antagonism of Mc1r signaling in melanocytes (yellow Great Dane, top). Dogs carrying a loss-of-function mutation at Mc1r have a yellow coat, regardless of their genotype at Agouti or CBD103 (yellow Labrador Retriever, middle). Dogs carrying wild-type alleles for Mc1r and Agouti, together with the dominant black allele of CBD103 (KB) have a black coat resulting from the interaction between a β-defensin and Mc1r (black Curly Coated Retriever, bottom).

Clarence Cook Little, who developed many of the original laboratory mouse strains and founded The Jackson Laboratory, was also one of the first dog geneticists. He recognized that dominant inheritance of a black coat was mediated differently in dogs than in other animals (1). Using classical linkage analysis, we realized that the dominant black gene represented a previously unrecognized component of the melanocortin pathway (2). Unexpectedly, we found the responsible gene to encode a β-defensin, a secreted protein previously studied for its role in immunity.

The identification of dominant black (formally, an allele of the “K locus”) relied on two major advances in dog genetics: the sequencing of the dog genome and recognition that the distinctive genetic structure of dog breeds allows for efficient gene mapping (3). Dogs were domesticated from wolves more than 15,000 years ago and expanded into a diverse population until the recent establishment of dog breeds. This population history is well-suited for high-resolution genetic mapping of old traits, like black coat color, that are found in multiple modern breeds. Using a combination of pedigree analysis and association studies within and among dog breeds, we identified a mutation in a β-defensin gene, CBD103, that correlates with black coat color in 38 different breeds. We confirmed the role of CBD103 in pigment type-switching by demonstrating that the dog gene causes a black coat in transgenic mice. CBD103 is a member of a large family of secreted peptides with structures similar to that of Agouti and is highly expressed in dog skin.

We used biochemical and cell-based assays to show that CBD103, like Agouti, binds competitively to the Mc1r, leading to an updated model of the pigment type-switching pathway (see figure). Moreover, studies with another β-defensin and additional melanocortin receptors reveal the potential for extensive cross-talk between β-defensins and the melanocortin system. In humans and other animals, β-defensins are highly polymorphic in sequence and copy number. Current β-defensin research is focused primarily on the immune system. This stems from the early discovery of defensins in phagocytic cells and their antimicrobial properties in vitro, together with more recent work demonstrating that defensins can act as receptor-specific chemotactic agents. Our work indicates that β-defensins do more than defend and suggests that the marked molecular variation in this family supplies a diverse and rapidly evolving family of ligands for G protein–coupled receptors in many different biologic systems.

Summary References

  1. C. C. Little, The Inheritance of Coat Color in Dogs (Comstock, Ithaca, NY, 1957).
  2. J. A. Kerns et al., Genetics176, 1679 (2007).
  3. K. Lindblad-Toh et al., Nature438, 803 (2005).

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