1 Heredity 2006 Vol: 97(3):222-234. DOI: 10.1038/sj.hdy.6800861

Genetics, development and evolution of adaptive pigmentation in vertebrates

The study of pigmentation has played an important role in the intersection of evolution, genetics, and developmental biology. Pigmentation's utility as a visible phenotypic marker has resulted in over 100 years of intense study of coat color mutations in laboratory mice, thereby creating an impressive list of candidate genes and an understanding of the developmental mechanisms responsible for the phenotypic effects. Variation in color and pigment patterning has also served as the focus of many classic studies of naturally occurring phenotypic variation in a wide variety of vertebrates, providing some of the most compelling cases for parallel and convergent evolution. Thus, the pigmentation model system holds much promise for understanding the nature of adaptation by linking genetic changes to variation in fitness-related traits. Here, I first discuss the historical role of pigmentation in genetics, development and evolutionary biology. I then discuss recent empirically based studies in vertebrates, which rely on these historical foundations to make connections between genotype and phenotype for ecologically important pigmentation traits. These studies provide insight into the evolutionary process by uncovering the genetic basis of adaptive traits and addressing such long-standing questions in evolutionary biology as (1) are adaptive changes predominantly caused by mutations in regulatory regions or coding regions? (2) is adaptation driven by the fixation of dominant mutations? and (3) to what extent are parallel phenotypic changes caused by similar genetic changes? It is clear that coloration has much to teach us about the molecular basis of organismal diversity, adaptation and the evolutionary process.

Mentions
Figures
Figure 1: Variation in dorsoventral pattern in laboratory mice and natural populations of P. polionotus. A large deletion in the transcription-box 15 (Tbx15) gene results in a lateral shift in the dorsal–ventral boundary (and modifications of craniofacial morphology) as shown in this laboratory mouse (a and b; on the Agouti black and tan genetic background) described by Candille et al (2004). A similar color pattern phenotype is observed in natural populations of beach mice relative to their darker mainland conspecific, the oldfield mouse (c and d). Spontaneous laboratory mutants can mimic naturally occurring phenotypic variation and provide candidate genes for adaptive traits. Figure 2: Genetic pathway regulating mammalian melanogenesis and phenotypic effects on individual hair pigment and pattern. (a) Circulating -MSH (a derivative of POMC) activates Mc1r, a G-protein-coupled transmembrane receptor, and signals via cAMP. Intracellularly, tyrosine is oxidized to dopaquinone, a reaction catalyzed by the enzyme tyrosinase (Tyr). Cyclic AMP is thought to affect the enzymatic activity of tyrosinase as well as eumelanic-specific enzymes, tyrosinase-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct). When all three of these enzymes function properly, eumelanin (brown to black pigment) is deposited in melanosomes. Agouti, the inverse agonist of Mc1r, binds to Mc1r with the aid of the extracellular protein Atrn to repress intracellular cAMP levels, resulting in the 'switch' to the production of pheomelanin (yellow to red pigment). The production of pheomelanin is dependent on the incorporation of cystine, whose uptake is at least partially regulated by xCT (the Slc7a11 locus). (b) Overall coat color in mammals is determined by the density of melanin and the distribution of melanin (or melanin types) on individual hairs. Pigment on individual hairs ranges from fully pigmented with dark eumelanin to complete absence of pigment resulting in albino hairs. Typical wild-type hairs in mammals have a subterminal band of light-colored pheomelanin flanked by darker eumelanin, providing an overall brushed appearance. Figure 3: Convergent evolution of adaptive pigmentation in the Tularosa Basin of New Mexico. The Carrizozo lava field is separated from the gypsum sand dunes of White Sands by 25 km of desert grasslands. Western fence lizards, Sceloporus undulatus, rock pocket mice, Chaetodipus intermedius (melanic and wild-type morphs) and apache pocket mice, Perognathus flavescens (blanched morph) are pictured on the substrate where they were captured. Figure 4: Agouti is a strong candidate gene for variation in vertebrate pigmentation and patterning in natural populations. (a) Deer mice (P. maniculatus) have banded dorsal hairs and light-colored ventral hairs. (b) Deer mice, which inhabit the light-colored Sand Hills in Nebraska, have dorsal hairs with a wider subterminal band, generating an overall golden color, better matched to the lighter sandy substrate they inhabit. (c) Mutations in Agouti's dorsal promoter region provide a plausible mechanism for the observed phenotypic change in dorsal but not ventral pigmentation.
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    • . . . Further, reptiles, amphibians and teleost fish can regulate body color by aggregation or concentration of melanin granules in melanocytes (also referred to as melanophores) via a mechanism controlled by the melanin-concentrating hormone (Kawauchi et al, 1983; Nery and Castrucci, 1997). . . .
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    • . . . Additional insights will likely come from the zebrafish model system, which shows ample variation in both striping and spotting (Parichy, 2003; Kelsh, 2004), and from emerging model systems, like Peromyscus, where the combination of natural variation in patterning, ability to breed in the lab and new genomic tools make it possible to identify genes, and even the molecular changes, contributing to adaptive mammalian patterning (Hoekstra et al, in press). . . .
    • . . . Recent work, primarily in zebrafish, has focused on understanding the genetic and developmental processes controlling these more colorful pigment cells (Kelsh, 2004) and will help identify the genetic basis of traits which rely on the interaction of multiple chromatophore cell types. . . .
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    • . . . In addition, complementary vertebrate systems, such as zebrafish, are providing additional pigmentation genes (Haffter et al, 1996; Odenthal et al, 1996; Kelsh et al, 2004), one of which (Slc24a5) has recently been linked to variation in human skin coloration (Lamason et al, 2006) . . .
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    • . . . The first pigmentation gene to be cloned, tyrosinase-related-protein-1 (Tyrp1), was initially thought to be the gene responsible for the albino mouse mutant, but albinism was later mapped, cloned, sequenced and correctly attributed to the tyrosinase locus (Jackson, 1988; Kwon et al, 1989) . . .
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    • . . . In addition, complementary vertebrate systems, such as zebrafish, are providing additional pigmentation genes (Haffter et al, 1996; Odenthal et al, 1996; Kelsh et al, 2004), one of which (Slc24a5) has recently been linked to variation in human skin coloration (Lamason et al, 2006) . . .
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    • . . . Historically, biologists have used two parallel approaches to study evolutionary change, one working at the level of genotype and a second working at the level of phenotype (Lewontin, 1974) . . .
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    • . . . Castle initially thought these size differences reflected different alleles of the major gene responsible for hooding; however, Wright showed that so-called modifier genes were responsible for variation in hood size, providing the first experimental demonstration of epistasis (Little, 1917) . . .
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    • . . . Similar patterns of variation have been observed in many vertebrates, including lizards (Figure 3; Norris and Lowe, 1964), and corresponding selection experiments have been conducted (Luke, 1989) . . .
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    • . . . It is also important to note that many melanic organisms are not associated with mutations in Mc1r, suggesting that other genes are responsible for their melanic coloration (MacDougall-Shackleton et al, 2003; Mundy and Kelly, 2003; Rosenblum et al, 2004) . . .
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    • . . . All known mutations in the Mc1r locus, many of which are adaptive, occur in the coding region, either as amino-acid changes or small deletions (Table 3, Majerus and Mundy, 2003) . . .
    • . . . In several cases, melanism has been linked to dominant or semidominant mutations in the Mc1r locus (Majerus and Mundy, 2003; Mundy, 2005), likely causing hyper or constitutive activation of Mc1r . . .
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    • . . . It has been predicted that the same genes will often underlie parallel changes in closely related organisms because there are only a limited number of genetic changes free of antagonistic pleiotropic effects (Haldane, 1932; Gould and Lewontin, 1979; Maynard Smith et al, 1985) . . .
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    • . . . However, genetic crosses in deer mice, Peromyscus maniculatus, have already pointed to regulatory changes in Agouti as being responsible for adaptive coloration (Figure 4, Hoekstra et al, in preparation; Dice, 1941; McIntosh, 1956; Dodson, 1982) . . .
  67. Miller MW, Duhl DMJ, Vrieling H, Vrieling H, Cordes SP, Ollmann MM et al. Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation. Genes Dev 7: 454-467 , (1993) .
    • . . . In mice, allelic variation at the agouti locus is largely responsible for dorsoventral differences in pigment type (Bultman et al, 1992; Miller et al, 1993; Millar et al, 1995) . . .
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    • . . . In mice, allelic variation at the agouti locus is largely responsible for dorsoventral differences in pigment type (Bultman et al, 1992; Miller et al, 1993; Millar et al, 1995) . . .
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    • . . . The vast majority of known mutations in the Agouti gene that cause subtle changes in pigmentation phenotypes in laboratory mice occur at the level of Agouti expression, whereas the complete abrogation of Agouti occurs through lesions in the Agouti coding region (Miltenberger et al, 2002) . . .
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    • . . . Beginning in 18th century China and Japan, so-called mouse fanciers collected, maintained and bred together unusual morphs of wild mice (Morse, 1978); in doing so, these novice geneticists generated mice with a large diversity of color variation, much of which is represented today in laboratory mice . . .
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    • . . . Since then, nearly 100 genes affecting pigmentation have been cloned in mice, but almost an equal number have yet to be identified (Bennett and Lamoreux, 2003), and new loci are accumulating as a result of chemical mutagenesis programs (Mouse Genome Database) . . .
  72. Mundy NI. A window on the genetics of evolution: MC1R and plumage colouration in birds. Proc Roy Soc B-Biol Sci 272: 1633-1640 , (2005) .
    • . . . Birds, like mammals, produce both pigment types (for a review, see Mundy, 2005), but reptiles lack pheomelanin (Ito and Wakamatsu, 2003), suggesting that either reptiles have the lost the ability to produce pheomelanin or that mammals and birds independently have evolved the ability to produce pheomelanin . . .
    • . . . In several cases, melanism has been linked to dominant or semidominant mutations in the Mc1r locus (Majerus and Mundy, 2003; Mundy, 2005), likely causing hyper or constitutive activation of Mc1r . . .
    • . . . So the question remains: why is Mc1r repeatedly co-opted for adaptation? Perhaps the most compelling argument is that Mc1r appears to be largely free from pleiotropic effects (Mundy, 2005); in other words, changes in Mc1r appear to be specific to pigmentation and, thus, free from developmental constraints . . .
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    • . . . Despite these challenges, this approach has been especially successful for simple color polymorphisms segregating in natural populations of non-model organisms (eg, Ritland et al, 2001; Theron et al, 2001; Nachman et al, 2003; Mundy et al, 2004), although functional verification of the role of mutations in these genes is still needed . . .
  74. Mundy NI, Kelly J. Evolution of a pigmentation gene, the melanocortin-1 receptor, in primates. Am J Phys Anthropol 121: 67-80 , (2003) .
    • . . . It is also important to note that many melanic organisms are not associated with mutations in Mc1r, suggesting that other genes are responsible for their melanic coloration (MacDougall-Shackleton et al, 2003; Mundy and Kelly, 2003; Rosenblum et al, 2004) . . .
  75. Nachman MW, Hoekstra HE, D'Agostino SL. The genetic basis of adaptive melanism in pocket mice. Proc Natl Acad Sci 100: 5268-5273 , (2003) .
    • . . . Despite these challenges, this approach has been especially successful for simple color polymorphisms segregating in natural populations of non-model organisms (eg, Ritland et al, 2001; Theron et al, 2001; Nachman et al, 2003; Mundy et al, 2004), although functional verification of the role of mutations in these genes is still needed . . .
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    • . . . In addition, several genes, Rab27a, Myo5a and Mlph, are well studied as models for organelle transport because they coordinate the transport and distribution of melanosomes, both eumelanosomes and pheomelanosomes, in melanocytes (Nascimento et al, 2003) . . .
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    • . . . Further, reptiles, amphibians and teleost fish can regulate body color by aggregation or concentration of melanin granules in melanocytes (also referred to as melanophores) via a mechanism controlled by the melanin-concentrating hormone (Kawauchi et al, 1983; Nery and Castrucci, 1997). . . .
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    • . . . Similar patterns of variation have been observed in many vertebrates, including lizards (Figure 3; Norris and Lowe, 1964), and corresponding selection experiments have been conducted (Luke, 1989) . . .
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    • . . . In addition, complementary vertebrate systems, such as zebrafish, are providing additional pigmentation genes (Haffter et al, 1996; Odenthal et al, 1996; Kelsh et al, 2004), one of which (Slc24a5) has recently been linked to variation in human skin coloration (Lamason et al, 2006) . . .
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    • . . . Independent evolution of pigmentation and pattern has been observed in many vertebrate species, including poison frogs (Vences et al, 2003), orioles (Omland and Lanyon, 2000), cavefish (Strecker et al, 2003) and cichlid fish (Allender et al, 2003), and provides exciting opportunities to ask whether the same or different genes are responsible for convergent phenotypes. . . .
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    • . . . JBS Haldane (1924) suggested that adaptation is driven by the fixation of dominant mutations because of the bias against the establishment of recessives, termed 'Haldane's sieve' (although this prediction may not hold for deleterious mutations previously maintained at mutation-selection balance (Orr and Betancourt 2001)) . . .
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    • . . . Additional insights will likely come from the zebrafish model system, which shows ample variation in both striping and spotting (Parichy, 2003; Kelsh, 2004), and from emerging model systems, like Peromyscus, where the combination of natural variation in patterning, ability to breed in the lab and new genomic tools make it possible to identify genes, and even the molecular changes, contributing to adaptive mammalian patterning (Hoekstra et al, in press). . . .
  83. Peichel CL. Fishing for the secrets of vertebrate evolution in threespine sticklebacks. Dev Dynam 234: 815-823 , (2005) .
    • . . . Through both candidate gene and QTL approaches, a growing number of empirical studies have linked genetic variation to adaptive (nonpigmentation) traits (reviewed in Peichel, 2005) . . .
  84. Protas ME, Hersey C, Kochanek D, Zhou Y, Wilkens H, Jeffery WR et al. Genetic analysis of cavefish reveals molecular convergence in the evolution of albinism. Nat Genet 38: 107-111 , (2006) .
    • . . . Nonetheless, it is certainly possible to change protein structure without measurable antagonistic effects on other traits as demonstrated by amino-acid change in Mc1r and deletions in Oca2 in albino cavefish (Protas et al, 2006) . . .
    • . . . First, in cavefish, multiple populations have lost pigmentation through recessive null alleles at the Oca2 locus (Protas et al, 2006) . . .
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    • . . . Despite these challenges, this approach has been especially successful for simple color polymorphisms segregating in natural populations of non-model organisms (eg, Ritland et al, 2001; Theron et al, 2001; Nachman et al, 2003; Mundy et al, 2004), although functional verification of the role of mutations in these genes is still needed . . .
    • . . . Second, recessive alleles of Mc1r are likely responsible for pale coloration in black bears (Ritland et al, 2001) and Japanese wild mice (Wada et al, 1999) . . .
  86. Rompler H, Rohland N, Lalueza-Fox C, Willerslev E, Kuznetsova T, Rabeder G et al. Nuclear gene indicates coat-color polymorphism in mammoths. Science 313: 62- , (2006) .
    • . . . Perhaps the most intriguing example involves mice and mammoths: a single amino-acid change (Arg65Cys) contributes to adaptive light coloration in beach mice (Hoekstra et al, in press) and the identical amino-acid change at the homologous position is segregating in woolly mammoths (identified through ancient DNA studies), suggesting that mammoths may also have been polymorphic in color (Rompler et al, in press) . . .
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    • . . . For example, three taxonomically diverse squamates have evolved blanched coloration in White Sands, New Mexico (Rosenblum, 2006) . . .
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    • . . . Third, blanched forms of two lizard species are associated with mutations in Mc1r (although breeding studies have not been conducted, based on Mc1r's function, we predict that these are null or reduced function alleles) (Rosenblum et al, 2004) . . .
    • . . . It is also important to note that many melanic organisms are not associated with mutations in Mc1r, suggesting that other genes are responsible for their melanic coloration (MacDougall-Shackleton et al, 2003; Mundy and Kelly, 2003; Rosenblum et al, 2004) . . .
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    • . . . However, it is important to note that little is known about the regulatory mechanisms that govern the expression of Mc1r at the intracellular level (Rouzaud and Hearing, 2005), and that bias toward discovering these coding sequence changes may be due to the ease of assaying Mc1r across vertebrates (based on its conserved structure and single 1 kb exon) . . .
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    • . . . First, a student of Wright, William Russell created a T-stock mouse packed with seven recessive, viable, radiation-induced mutations, six of which were coat color mutations (Russell, 1951) . . .
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    • . . . Mc1r is also part of a larger melanocortin gene family (Mc1r–Mc5r), whose members are specialized in their tissue expression and are involved in diverse pathways from pigmentation to energy homeostasis (Schioth, 2001) . . .
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    • . . . This work was followed by a series of studies of spontaneous mutation rates in the 1960s, when large production colonies were carefully examined for spontaneous coat color variants; more than 100 new genes were identified (Schlager and Dickie, 1966, 1967) . . .
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    • . . . This work was followed by a series of studies of spontaneous mutation rates in the 1960s, when large production colonies were carefully examined for spontaneous coat color variants; more than 100 new genes were identified (Schlager and Dickie, 1966, 1967) . . .
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    • . . . However, modifications of this developmental pathway can generate dramatic variation in pigmenation among vertebrate taxa (Searle, 1968; Bagnara and Hadley, 1973) . . .
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    • . . . Such classic studies linking color variation to environmental heterogeneity span a broad taxonomic scale, from banding in Cepea snails (Sheppard, 1951) to melanism in peppered moths (Kettlewell, 1955) to patterning in water snakes (Camin and Ehrlich, 1958) . . .
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    • . . . Coat color mutations in laboratory mice have served as a premier model for studying gene action in a variety of biological processes (Silvers, 1979), leading to a wealth of information about genes involved in pigmentation and their developmental interactions . . .
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    • . . . More recently, mutations in regulatory regions have been proposed as a mechanism to fine-tune phenotypes because mutations in specific cis-regulatory elements may alter the expression of a protein in particular tissues, while preserving expression in others (Stern, 2000; Carroll et al, 2001; Carroll, 2005b) . . .
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    • . . . Independent evolution of pigmentation and pattern has been observed in many vertebrate species, including poison frogs (Vences et al, 2003), orioles (Omland and Lanyon, 2000), cavefish (Strecker et al, 2003) and cichlid fish (Allender et al, 2003), and provides exciting opportunities to ask whether the same or different genes are responsible for convergent phenotypes. . . .
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    • . . . Around the same time, Sumner conducted a parallel study on the sandy dunes of Florida's Gulf and Atlantic coasts, documenting the extremely pale phenotypes of mice relative to their darker inland counterparts (Figure 1c and d, Sumner, 1929a, 1929b) . . .
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    • . . . Around the same time, Sumner conducted a parallel study on the sandy dunes of Florida's Gulf and Atlantic coasts, documenting the extremely pale phenotypes of mice relative to their darker inland counterparts (Figure 1c and d, Sumner, 1929a, 1929b) . . .
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    • . . . In particular, selective forces such as crypsis, aposematism, thermoregulation, and sexual signaling drive variation in both pigmentation and color pattern (Thayer, 1909; Cott, 1940) . . .
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    • . . . Despite these challenges, this approach has been especially successful for simple color polymorphisms segregating in natural populations of non-model organisms (eg, Ritland et al, 2001; Theron et al, 2001; Nachman et al, 2003; Mundy et al, 2004), although functional verification of the role of mutations in these genes is still needed . . .
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    • . . . Colors produced by xanthophore and iridiphore cells are particularly important for a number of classical traits involved in inter- and intra-specific communication, such as Anolis lizard dewlaps (Tokarz, 1995) and guppy spots (Endler, 1983) . . .
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    • . . . While pigmentation represents a particularly amenable phenotype in which to link phenotypic variation to genes in vertebrates (as is true for the invertebrate pigmentation system (True, 2003) and the anthocyanin pathway in plants (Holton and Cornish, 1995)), analysis of additional traits, including morphological, physiological and behavioral characters, is essential . . .
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    • . . . Independent evolution of pigmentation and pattern has been observed in many vertebrate species, including poison frogs (Vences et al, 2003), orioles (Omland and Lanyon, 2000), cavefish (Strecker et al, 2003) and cichlid fish (Allender et al, 2003), and provides exciting opportunities to ask whether the same or different genes are responsible for convergent phenotypes. . . .
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    • . . . Careful dissection of the agouti regulatory region has revealed two major transcript initiation sites, one for a ventral-specific transcript, which is likely responsive to positional cues established in the embryo, and a second 'hair cycle-specific' transcript involved in switching between alternative types of melanins (described below, Bultman et al, 1994; Vrieling et al, 1994) . . .
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    • . . . Second, recessive alleles of Mc1r are likely responsible for pale coloration in black bears (Ritland et al, 2001) and Japanese wild mice (Wada et al, 1999) . . .
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