Historically, coat color variations in Mus musculus have appealed to both geneticists and mouse fanciers. More recently, these House Mouse strains have served as animal models for studies of pigment cell development, and for disorders that affect melanocytes. In my collection of old genetics books, is a favorite authored by Hans Grüneberg, The Genetics of the Mouse; there are many intriguing coat color strains described, and for the next two posts, I decided to focus on the silver mutation (Dunn and Thigpen, 1930). Silvering was studied on both black and brown coat color backgrounds in mice, and the general effect is to reduce the number of eumelanin (black pigment) granules in some hairs, and to eliminate this pigment from certain areas of the body, and in some entire hairs. In a recent paper, Theos and colleagues (2006) described the morphology of melanosomes (pigment-containing organelles) in silver mice, which harbor a mutation in the PMEL17 gene. These investigators found that the mutant protein (Pmel17si), which normally forms the melanosome scaffold onto which melanins are deposited, is neither exported properly from the endoplasmic reticulum nor endocytosed efficiently, leading to a delay in proteolytic maturation of this structural component. Thus, the number of properly-assembled melanosomes is reduced in the pigment cells of silver mice.
Figure 1. Reduced body pigmentation in the zebrafish mutant fdv, with both shape of pigment cells and distribution of melanin within them affected.
(Schonthaler et al., 2005)
Schonthaler and colleagues (2005) reported on a zebrafish (Danio rerio) silver mutation, identified in a forward genetic screen due to defects in vision and reduced body pigmentation, called fading vision, fdv. Mutant larvae exhibited defects in the retinal pigmented epithelium, a derivative of the neural tube (not neural crest), as well as in the closely-associated outer segments of photoreceptor cells in the neural retina. The affected gene in the fdv zebrafish is PMEL17, referred to by the investigators as silva; characterization of the fdv mutation revealed that it consists of a premature stop codon and results in a truncated protein. The novel information contributed by this zebrafish study is that a mutation that affects development of melanosomes in pigment cells can also affect vision, presumably because of the critical interactions between retinal pigmented epithelium and photoreceptors.
The chicken is the real meat of the PMEL17 story, however, with three different alleles at the Dominant white (I) locus that affect plumage color:
Figure 2. Wild-type, Dominant white, and Smoky phenotypes in Gallus gallus.
(Kerje et al., 2004)
Kerje and colleagues (2004) crossed a red jungle fowl (Gallus gallus) male with several White Leghorn (Dominant white) females, to generate a reference pedigree for plumage color and PMEL17 genotypes. Based on linkage group analyses and the phenotype of silver mice, PMEL17 was selected as a positional candidate gene for the Dominant white plumage phenotype in chickens. In the reference pedigree, segregation at the Dominant white (I), Extended black (E), Barred (B), and Silver (S-different from silver in mice) loci was assessed, and the I locus was epistatic to the other color loci; linkage analysis indicated no recombination between Dominant white and PMEL17. The investigators sequenced PMEL17, using genomic DNA from chickens carrying the wild-type, Dominant white, Smoky, or Dun allele, and determined exon and intron borders.
The Dun variant arose independently of Dominant white, and Dun was found to have a unique deletion, very near to the WAP insertion discovered in Dominant white. Both the Dominant white insertion and the Dun deletion are predicted to disrupt the transmembrane helix region and/or the function of the PMEL17 protein. This result is consistent with the mouse silver data, and with the primary inhibition of eumelanogenesis (black pigment), but not pheomelanogenesis (red pigment) in these animals. Smoky is a revertant allele that arose in the White Leghorn line, and its PMEL17 gene sequence harbors a unique 12-bp deletion in exon 6. This deletion partially rescues the eumelanin defect caused by the WAP insertion in Dominant white. In the discussion, Kerje and colleagues provide the intriguing speculation that variations at the PMEL17 locus may be responsible for red hair in humans.
Next up: Pigment Cells and the Silver Locus: Dog and Pony Show
Dunn, L.C., and Thigpen, L.W. (1930). The silver mouse, a recessive color variation. J. Hered. 21, 495-498.
Schonthaler, H.B., Lampert, J.M., von Lintig, J., Schwarz, H., Geisler, R., and Neuhauss, S.C.F. (2005). A mutation in the silver gene leads to defects in melanosome biogenesis and alterations in the visual system in the zebrafish mutant fading vision. Dev. Biol. 284, 421-436.
Theos, A.C., Berson, J.F., Theos, S.C., et al. (2006). Dual loss of ER export and endocytic signals with altered melanosome morphology in the silver mutation of Pmel17. Mol. Biol. Cell 17, 3598-3612.
Kerje, S. (2004). The Dominant white, Dun and Smoky Color Variants in Chicken Are Associated With Insertion/Deletion Polymorphisms in the PMEL17 Gene. Genetics, 168(3), 1507-1518. DOI: 10.1534/genetics.104.027995