A non-epistatic interaction of agouti and extension in the fox, Vulpes vulpes

Abstract

Agouti and extension are two genes that control the production of yellow-red (phaeomelanin) and brown-black (eumelanin) pigments in the mammalian coat. Extension encodes the melanocyte-stimulating hormone receptor (MC1R) while agouti encodes a peptide antagonist of the receptor. In the mouse, extension is epistatic to agouti, hence dominant mutants of the MC1R encoding constitutively active receptors are not inhibited by the agouti antagonist, and animals with dominant alleles of both loci remain darkly pigmented. In the fox the proposed extension locus is not epistatic to the agouti locus. We have cloned and characterized the MC1R and the agouti gene in coat colour variants of the fox (Vulpes vulpes). A constitutively activating C125R mutation in the MC1R was found specifically in darkly pigmented animals carrying the Alaska Silver allele (EA). A deletion in the first coding exon of the agouti gene was found associated with the proposed recessive allele of agouti in the darkly pigmented Standard Silver fox (aa). Thus, as in the mouse, dark pigmentation can be caused by a constitutively active MC1R, or homozygous recessive status at the agouti locus. Our results, demonstrating the presence of dominant extension alleles in foxes with significant red coat colouration, suggest the ability of the fox agouti protein to counteract the signalling activity of a constitutively active fox MC1R.

The Melanocortin 1 Receptor (MC1R): More Than Just Red Hair

“…By contrast, dominant gain-of-function mutations of the MC1R resulted in black hair due to increased eumelanin biosynthesis. Subsequently, a similar pattern of action has been reported in a variety of other animals with loss-offunction leading to yellow or red hair and dominant mutations leading to black pigment (16,(23)(24)(25)(26)(27)(28)(29)). Cone's paper (22) is worth re-reading, 8 years on, for the insights it provided about the MC1R and human pigmentation; that the MC1R would lead to red hair in man; that mutant alleles of the MC1R would be common; and that the gene would be of interest to those interested in human evolution.…”

Two cysteine substitutions in the MC1R generate the blue variant of the arctic fox (Alopex lagopus) and prevent expression of the white winter coat

“…Sequence comparison for MC1R regions that span amino acid 5 (amino acid 1-9 in the left box) and 280 (region 276-284, or 274-282 in mouse which has a two aa deletion). For the regions illustrated, additional species have been shown to be identical to species included in this figure [5,[10][11][12]16,18,25,26]. rable to the TM2/TM3 -mutations might be foreseen.…”

“…Inter-species crossing between the winter white arctic fox and the standard silver variant (aaE + E + ) of the red fox (Vulpes vulpes) provide firm evidence for a functional agouti protein in the arctic fox. The standard silver fox do not carry a functional agouti protein, and the red color found in the offspring (named Golden island) must therefore be ascribed the functional "arctic" agouti protein [17,25].…”

“…These have been functionally tested in cell assays, and have been found to produce a constitutively active receptor causing eumelaninization mediated through the cAMP pathway [11,14,19,25,26]. Except for the silver fox, these mutations are almost completely epistatic to the agouti gene, even in the heterozygous state.…”

Four novel variants in MC1R in red-haired South African individuals of European descent: S83P, Y152X, A171D, P256S

“…It has been cloned (Mountjoy et al, 1992) and mapped to human chromosome 16q24.3 (Gantz et al, 1994;Magenis et al, 1994). In mammals the orthologue of the MC1R gene, the extension locus (e), was found mutated in those with red and yellow coat colours (Robbins et al, 1993;Vage et al, 1997). Studies on the molecular basis of the red hair and pale skin phenotype in humans have shown that the MC1R gene plays a role in this pigmentation type (Valverde et al, 1995;Box et al, 1997;Koppula et al, 1997;Smith et al, 1998;Rana et al, 1999).…”