And God said, Let the earth bring forth the living creature after his kind,...Genesis 1:24
shades of color distributed throughout their hair coats. Mutations in the MC1R can add interesting color patterns ranging from the all black phenotype of Chinese Meishan pigs to the all red color of the Irish Setter. Given the number of alleles within baramins (created kinds), much of the diversity at this locus must have developed since the genetic bottleneck at the Flood where only a single breeding pair was preserved for most baramins. Similarly, humans carry more alleles than can be accounted for by Noah and his family. Since mutations at this locus are not known to directly cause any disease and they add to the beauty and variety we see today, it appears that this locus was designed to vary. Furthermore, since there are non-random patterns that have been observed which cannot be explained by known selection factors, it appears plausible that many of these mutations may actually be directed.
The MC1R is expressed on the surface of melanocytes. There are two basic types of pigments produced by melanocytes. Pheomelanin is a red to yellow pigment; eumelanin is a darker, more photoprotective brown to black pigment. Activation of the MC1R by its ligand, primarily α-melanocyte stimulating hormone (α-MSH), switches biosynthesis from the default pathway for pheomelanin to production of eumelanin. Mammals commonly have a MC1R antagonist, the agouti protein, which competitively binds the MC1R preventing its ligand from binding and activating it. Thus, by varying levels of α-MSH and agouti protein, the wild type receptor can effectively switch melanin biosythesis between these two forms of melanin (García-Borrón, Sánchez-Laorden, and Jiménez- Cervantes 2005; Klungland and Våge 2000).
Humans normally respond to ultraviolet (UV) light by increasing production of the MC1R ligand. When the ligand binds the MC1R, there is activation of the G protein and stimulation of adenylyl cyclase. Through a series of biochemical reactions that follow, the melanocyte switches from pheomelanin to eumelanin biosynthesis; this protects the skin from many of the damaging effects of UV light. However, this pathway is impaired in individuals with red hair and fair skin with poor tanning ability (García-Borrón, Sánchez- Laorden, and Jiménez-Cervantes 2005).
amino acid receptor. Newton et al. (2000) compared the nucleotide sequence from seven breeds and found six polymorphic sites. Two of these were synonymous changes. Two of the nonsynonymous changes, T105A and P159Q, may have no significant effect on receptor function. This is suspected because the first varied between animals of the same breed and in the case of the second, specific to the Doberman, it is not correlated with variant phenotypes and glutamine, Q, is found in this position in the chicken receptor.
There are two amino acid substitutions in the dog that may be related to phenotypic variation in coat color. The first is an R306ter mutation found in the Yellow Labrador, Golden Retriever, and Irish Setter. This truncated receptor appears non-functional and this loss of function mutation correlates perfectly with the yellow/red phenotype in all breeds tested with the exception of the Red Chow. Interestingly, the allele carried by the Yellow Labrador is distinct from that of the Golden Retriever and Irish Setter. This has led to speculation that the R306ter mutation has arisen twice, or undergone gene conversion (Newton et al. 2000).
The second substitution, S90G, may be associated with a constitutively active receptor and the black phenotype. It occurs in the second TM domain where other activating mutations have been known to occur. However, further biochemical studies will be necessary to establish the functional significance, if any, of this variant (Newton et al. 2000). Additionally, it has been known for years that the dominant black phenotype in dogs can be inherited in an unusual manner. Recent studies showed variation in the MC1R gene could not account for the phenotype in the black Labrador Retriever (Kerns et al. 2007). This led to the discovery that another protein, recently identified as ß-defensin, can act as a MC1R ligand and contribute to coat color in dogs (Candille et al. 2007).
The dog MC1R is 96% identical to that of the Arctic fox (Vulpes lagopus; Newton et al. 2000). A variant allele in the Arctic fox containing two mutations, G5C and F280C, was associated with the blue phenotype, which is darker and does not express the typical white winter coat. One or both of these mutations appear to result in a constitutively active receptor, although further biochemical studies are needed to clarify the underlying basis for this (Våge et al. 2005).
Våge et al. (1997) sequenced the MC1R from 17 red foxes (Vulpes vulpes) and found six polymorphic sites. Only one of these, C125R, correlated perfectly with the dominant dark Alaskan phenotype. Unlike examples of a constitutively active receptor in other animals, individuals carrying this mutation could express some pheomelanin based coloration depending on the allele carried at the agouti locus.
different (agouti) locus (Eizirik et al. 2003).
The dominant black phenotype in the jaguar (Panthera onca) is associated with an in frame15 bp deletion that eliminates amino acids 101 to 105. This allele also has two substitutions in one codon resulting in L106T immediately following the deletion. Nucleotide position 825 is T/C polymorphic in the wild type, but only T was found at this position in the allele carrying the deletion (Eizirik et al. 2003).
The semidominant melanistic phenotype in the jaguarundi (Herpailurus yaguarondi) is associated with a 24 bp in frame deletion that eliminates amino acids 95 through 102. This gene also carries nonsynonymous substitutions, P22L, I63V, and Q310R. The first two are conservative in nature. Additionally, cattle carry leucine at position 22 in the wild type receptor; humans and mice have a similar amino acid at 310, lysine. Therefore the authors suggest that the amino acid substitutions likely have less impact on the phenotype than the deletion (Eizirik et al. 2003).
The deletion mutations in the domestic cat, jaguar, and jaguarundi appear to be species specific and have not been detected in melanistic individuals from five other felid species tested: leopard (Panthera pardus), Geoffroy’s cat (Oncifelis geoffroyi), oncilla (Leopardus tigrinus), pampas cat (Lynchailurus colocolo), and Asian golden cat (Catopuma temmincki; Eizirik et al. 2003).
alleles include the common R151C, R160W and D294H, and the less common D84E and R142H. Weaker RHC alleles include V60L, V92M, and R163Q. A number of the other allelic variants may be associated with some degree of loss of function too. Several mechanisms related to loss of function have been identified: decreased ability to stimulate cAMP production from impaired G-protein coupling, retention of MC1R intracellularly resulting in decreased cell surface expression, and decreased affinity of the receptor for its MC ligand (García- Borrón, Sánchez-Laorden, and Jiménez-Cervantes 2005). Additionally, the strong RHC alleles have been shown in vitro to exert a dominant negative effect on wild type receptors (Beaumont et al. 2007).
Variant alleles have been associated with an increased risk of various skin cancers including melanoma. Cancer risk varies depending on which variant alleles are carried. Some of the risk appears to be independent of skin type or hair color, suggesting that the MC1R affects risk through one or more non-pigmentary pathways as well (Bastiaens et al. 2001; Box et. al. 2001; Fargnoli et. al. 2006; Kennedy et al. 2001; Raimondi et al. 2008). There are a number of other factors which affect the risk of melanoma including sun exposure and variants in other genes (Bennett 2008; Fargnoli et al. 2008; Walsh 1999).
Harding et al. (2000) examined MC1R polymorphisms in European, Asian, and African human populations. Five haplotypes were identified in Africans (who were from The Gambia and Ivory Coast), but all substitutions were in silent, third base pair positions. They concluded:
It is true that in humans variant MC1R proteins are often associated with some degree of loss of function. Some of these variants have been shown to be associated with an increased risk of various skin cancers, including malignant melanoma. Certainly the equatorial regions of earth have greater sun exposure which would further increase cancer risk. However, the strong selection suggested by Harding et al. (2000) appears much stronger than these factors can account for.
Flood when a maximum of four alleles would be expected to have been preserved in the unclean animals represented by a single pair on the Ark. The variability in this locus accounts for much of the variability and beauty in coat colors normally seen in animals today. Humans, who have been surveyed in more detail, also show an incredible amount of diversity at this locus that must have arisen since the Flood. No disease is known to be caused by variation in this gene, although some variants may confer an increased risk of certain diseases. Still, the development of these diseases is dependent on other factors. From a creationist viewpoint, the MC1R locus appears to be designed to vary."
Dr. Jean Lightner
MC1R - a key to the BLOOMING ROSE OF CREATION
"The melanocortin 1 receptor (MC1R) is located on the surface of melanocytes (pigment cells) and is involved with switching melanin synthesis from the lighter red to yellow pheomelanin to the darker brown to black eumelanin. Most animals are capable of producing both pigments and have various The MC1R locus
The MC1R locus codes for a seven transmembrane (TM) G-protein coupled receptor (GPCR). This superfamily has over 1000 members which together account for more than 1% of mammalian genomes. The MC1R belongs to the class A, rhodopsin family, of GPCRs and is one of a five-member subfamily, the melanocortin (MC) receptors. Since receptors in this family and subfamily share many basic features, findings in one receptor may have implications for other receptors in the group (García-Borrón, Sánchez- Laorden, and Jiménez-Cervantes 2005).The MC1R is expressed on the surface of melanocytes. There are two basic types of pigments produced by melanocytes. Pheomelanin is a red to yellow pigment; eumelanin is a darker, more photoprotective brown to black pigment. Activation of the MC1R by its ligand, primarily α-melanocyte stimulating hormone (α-MSH), switches biosynthesis from the default pathway for pheomelanin to production of eumelanin. Mammals commonly have a MC1R antagonist, the agouti protein, which competitively binds the MC1R preventing its ligand from binding and activating it. Thus, by varying levels of α-MSH and agouti protein, the wild type receptor can effectively switch melanin biosythesis between these two forms of melanin (García-Borrón, Sánchez-Laorden, and Jiménez- Cervantes 2005; Klungland and Våge 2000).
Humans normally respond to ultraviolet (UV) light by increasing production of the MC1R ligand. When the ligand binds the MC1R, there is activation of the G protein and stimulation of adenylyl cyclase. Through a series of biochemical reactions that follow, the melanocyte switches from pheomelanin to eumelanin biosynthesis; this protects the skin from many of the damaging effects of UV light. However, this pathway is impaired in individuals with red hair and fair skin with poor tanning ability (García-Borrón, Sánchez- Laorden, and Jiménez-Cervantes 2005).
Dogs (Canis familiaris) and foxes (Vulpes spp.)
All members of the family Canidae are considered monobaraminic (Wood 2006). Within this family the MC1R of dogs and several species of foxes have been sequenced. The gene codes for a 317
There are two amino acid substitutions in the dog that may be related to phenotypic variation in coat color. The first is an R306ter mutation found in the Yellow Labrador, Golden Retriever, and Irish Setter. This truncated receptor appears non-functional and this loss of function mutation correlates perfectly with the yellow/red phenotype in all breeds tested with the exception of the Red Chow. Interestingly, the allele carried by the Yellow Labrador is distinct from that of the Golden Retriever and Irish Setter. This has led to speculation that the R306ter mutation has arisen twice, or undergone gene conversion (Newton et al. 2000).
The second substitution, S90G, may be associated with a constitutively active receptor and the black phenotype. It occurs in the second TM domain where other activating mutations have been known to occur. However, further biochemical studies will be necessary to establish the functional significance, if any, of this variant (Newton et al. 2000). Additionally, it has been known for years that the dominant black phenotype in dogs can be inherited in an unusual manner. Recent studies showed variation in the MC1R gene could not account for the phenotype in the black Labrador Retriever (Kerns et al. 2007). This led to the discovery that another protein, recently identified as ß-defensin, can act as a MC1R ligand and contribute to coat color in dogs (Candille et al. 2007).
The dog MC1R is 96% identical to that of the Arctic fox (Vulpes lagopus; Newton et al. 2000). A variant allele in the Arctic fox containing two mutations, G5C and F280C, was associated with the blue phenotype, which is darker and does not express the typical white winter coat. One or both of these mutations appear to result in a constitutively active receptor, although further biochemical studies are needed to clarify the underlying basis for this (Våge et al. 2005).
Våge et al. (1997) sequenced the MC1R from 17 red foxes (Vulpes vulpes) and found six polymorphic sites. Only one of these, C125R, correlated perfectly with the dominant dark Alaskan phenotype. Unlike examples of a constitutively active receptor in other animals, individuals carrying this mutation could express some pheomelanin based coloration depending on the allele carried at the agouti locus.
Cats (Felidae)
Previous baraminologic research suggested that the family Felidae is a holobaramin (cited in Wood 2006). The cat MC1R is also 317 amino acid residues in length. The black phenotype in the domestic cat (Felis catus) is a recessive trait and has been shown to be associated with a deletion mutation at a
The dominant black phenotype in the jaguar (Panthera onca) is associated with an in frame15 bp deletion that eliminates amino acids 101 to 105. This allele also has two substitutions in one codon resulting in L106T immediately following the deletion. Nucleotide position 825 is T/C polymorphic in the wild type, but only T was found at this position in the allele carrying the deletion (Eizirik et al. 2003).
The semidominant melanistic phenotype in the jaguarundi (Herpailurus yaguarondi) is associated with a 24 bp in frame deletion that eliminates amino acids 95 through 102. This gene also carries nonsynonymous substitutions, P22L, I63V, and Q310R. The first two are conservative in nature. Additionally, cattle carry leucine at position 22 in the wild type receptor; humans and mice have a similar amino acid at 310, lysine. Therefore the authors suggest that the amino acid substitutions likely have less impact on the phenotype than the deletion (Eizirik et al. 2003).
The deletion mutations in the domestic cat, jaguar, and jaguarundi appear to be species specific and have not been detected in melanistic individuals from five other felid species tested: leopard (Panthera pardus), Geoffroy’s cat (Oncifelis geoffroyi), oncilla (Leopardus tigrinus), pampas cat (Lynchailurus colocolo), and Asian golden cat (Catopuma temmincki; Eizirik et al. 2003).
Humans
The human MC1R is found on chromosome 16q (Harding et al. 2000). More than 60 non-conservative variants have been identified (García-Borrón, Sánchez- Laorden, and Jiménez-Cervantes 2005). Some of these variants are associated with fair skin and red hair color (RHC). Strong RHC
Variant alleles have been associated with an increased risk of various skin cancers including melanoma. Cancer risk varies depending on which variant alleles are carried. Some of the risk appears to be independent of skin type or hair color, suggesting that the MC1R affects risk through one or more non-pigmentary pathways as well (Bastiaens et al. 2001; Box et. al. 2001; Fargnoli et. al. 2006; Kennedy et al. 2001; Raimondi et al. 2008). There are a number of other factors which affect the risk of melanoma including sun exposure and variants in other genes (Bennett 2008; Fargnoli et al. 2008; Walsh 1999).
Harding et al. (2000) examined MC1R polymorphisms in European, Asian, and African human populations. Five haplotypes were identified in Africans (who were from The Gambia and Ivory Coast), but all substitutions were in silent, third base pair positions. They concluded:
The absence of amino acid variants in Africa—as well as their low frequency in African Americans and in Asians from Papua New Guinea and India …, where skin pigmentation is typically very dark— implies strong functional constraint on MC1R, probably as a means to minimize sensitivity to UV radiation. (Harding et al. 2000, p. 1354)Harding et al. (2000) begin with the assumption that mutations are relatively random, chance copying errors. Using various statistical tests they infer strong selection within the African population and attribute the incredible diversity of MC1R in Europeans to relaxed functional constraints. Yet, if the populations sampled give a fairly accurate representation of MC1R diversity, there is another viable alternative that should be considered.
It is true that in humans variant MC1R proteins are often associated with some degree of loss of function. Some of these variants have been shown to be associated with an increased risk of various skin cancers, including malignant melanoma. Certainly the equatorial regions of earth have greater sun exposure which would further increase cancer risk. However, the strong selection suggested by Harding et al. (2000) appears much stronger than these factors can account for.
Conclusions
Intrabaraminic diversity clearly indicates that allelic diversity has increased since the time of the
Dr. Jean Lightner
