Download Human pigmentation genetics: the difference is only skin deep

Review articles
Human pigmentation genetics:
the difference is only skin deep
Richard A. Sturm,1* Neil F. Box,1 and Michele Ramsay2
Summary
There is no doubt that visual impressions of body form and color are important
in the interactions within and between human communities. Remarkably, it is
the levels of just one chemically inert and stable visual pigment known as melanin
that is responsible for producing all shades of humankind. Major human genes
involved in its formation have been identified largely using a comparative genomics approach and through the molecular analysis of the pigmentary process
that occurs within the melanocyte. Three classes of genes have been examined
for their contribution to normal human color variation through the production
of hypopigmented phenotypes or by genetic association with skin type and
hair color. The MSH cell surface receptor and the melanosomal P-protein are
the two most obvious candidate genes influencing variation in pigmentation
phenotype, and may do so by regulating the levels and activities of the
melanogenic enzymes tyrosinase, TRP-1 and TRP-2. BioEssays 20:712–721,
1998. r 1998 John Wiley & Sons, Inc.
Introduction
Color in our genes—what role does environment play?
Being on the surface of the body and so readily observable,
eye, hair, and skin pigmentation can offer some of the
simplest means for studying and analyzing the action of
genes.(1) Differences in these human color traits can be
graded between individuals of darkest to those of lightest
pigmentation along a continuum. Rather than recognition of
such subtlety, however, distinct groupings are commonly
spoken of as black, white, red, or yellow with a predominant
black/white dualism in popular categorization. Many genes
contribute toward producing these different color shades by
1Centre
for Molecular and Cellular Biology, University of Queensland,
Brisbane, Queensland, Australia.
2Department of Human Genetics, School of Pathology, South African
Institute for Medical Research and University of the Witwatersrand,
Johannesburg, South Africa.
*Correspondence to: Richard A. Sturm, Centre for Molecular and
Cellular Biology are at the University of Queensland, Brisbane, Qld
4072 Australia; E-mail: [email protected]
Abbreviations used: BOCA, brown oculocutaneous albinism; DHICA,
5,6-dihydroxyindole-2-carboxylic acid; DOPA, 3,4-dihydroxyphenylalanine; EGF, epidermal growth factor; MC1R, melanocortin receptor-1
gene; MSHR, melanocyte-stimulating hormone receptor; OA, ocular
albinism; OCA, oculocutaneous albinism; ROCA, rufous oculocutaneous albinism; TRP, tyrosinase-related protein; TYR, tyrosinase gene;
TYRP, tyrosinase-related protein gene.
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taking part in the synthesis of different amounts or kinds of
substances that give rise to the visible color differences. In
the case of skin and hair color, such differences are produced
by virtually one pigment known as melanin,(2) which has a
variety of functions,(3) including photoprotection, routing of the
optic nerve tracts, and possibly the scavenging of free
radicals. By incorporating different chemical subunits, the
melanin polymer can vary from black/brown to red/yellow,
which can account for some of the color qualities, with
melanin particle size, shape, density, and distribution contributing to the degree of opacity.
The degree of pigmentation of the small group of ancestral
humans originating in Africa,(4) and who radiated through the
rest of the world, was presumably uniform, of unknown pigmentation state, but probably within the range of darker skin tones.
The first depiction of variable pigmentation in man(5) dates
back to about 1300 BC and was found on the walls of the tomb
of Sethos I. It shows a relatively fair-skinned Libyan and a
very dark Nubian, together with an Asian and Egyptian who
had skin tones between these two. Problems arise in defining
an individuals true pigmentation however, because skin color
can be influenced by environmental factors or may change
with age, and hair can be bleached or simply dyed. Even brief
exposure to sunlight may result in persistent changes in the
amount of cutaneous melanin; hence evaluation of these
traits can become quite subjective if not properly analyzed
and will introduce a confounding variable when attempting to
link genotype with phenotype. Attempts to study the genetic
BioEssays 20:712–721, r 1998 John Wiley & Sons, Inc.
Review articles
basis of human pigmentation began with the work of Gertrude
and Charles Davenport early in the twentieth century, when
they examined the inheritance of eye,(6), hair,(7) and skin
colors.(8) Sewall Wright(9) recognized that each of these traits
are physiologically connected, and must be considered together when discussing their inheritance. As an extension of
their work on these traits in Caucasians, the Davenports also
began an analysis of skin color inheritance in the children of
marriages between people of black African and white Caucasian descent, suggesting that as little as two gene pairs would
be sufficient to explain the phenotypes of the offspring of
these unions which was always of intermediate pigmentation.
Further work by Stern,(10) in 1953, by Harrison and Owen,(11)
in 1964, and by Kalla,(12) in 1969, raised the number to 3–6
gene pairs. These classical studies, however, were based on
the hypothesis that the genes involved worked in simple and
equally additive ways, which is clearly an inadequate model
for how genes act and interact.(13)
Despite these numerous formal genetic studies, there is
no definitive understanding of the ways in which genes
determine human pigmentation. Insight into the process is
now coming from the new genomic strategies and genotyping
technologies that use comparative genomics to identify mammalian pigmentation genes, the study of hypopigmented
human phenotypes to characterize dysfunctional genes, and
polymorphism studies on variation within these genes in
diverse human populations. The goal of understanding the
differences of human pigmentation, so often reduced to the
single index of color, becomes one of much higher complexity
in identifying and understanding the nature of the genes
expressed in the melanocyte cell and how they interact. Only
upon this understanding will the heritable basis of the physical trait of color be revealed.
This review focuses on three classes of melanocyte genes
that may well underlie and expand our knowledge of this most
obvious of physical traits (Table 1). First, some of the
enzymes involved in the synthesis of melanin are considered;
second, the role of a protein mutated in several hypopigmented conditions is examined; and third, a cell surface
receptor that may regulate the pigmentation process is
discussed. Ultimately, studies to identify functionally significant polymorphisms and to determine their level of variation
in human populations will provide an explanation for how
pigmentation differences have evolved and allow a true
molecular understanding of the dynamics of color genes in
different cultures and societies. The three gene systems
discussed here are the strongest candidates yet identified but
will not be the only genes determining human pigmentation.
Melanin and the melanosome—the basis of the
human paint palette
Melanin is synthesized in a multistep biochemical pathway
that operates within a specialized intracellular organelle
known as the melanosome (Figs. 1, 2). This particle is
secreted through the dendritic processes of the melanocyte
cell to the surrounding keratinocytes and hair follicles in
cutaneous tissue or, alternatively, is retained by the melanocytes of the eye.(14) There are easily recognized differences in
melanosome qualities of ethnic groups, as shown in ultrastructural studies of the skin.(15) Although the number of melanocytes is essentially constant, the number, size, and the
manner in which the melanosomes are distributed within the
keratinocytes vary. In general, more deeply pigmented skin
contains numerous single large melanosomal particles that
are ellipsoidal and intensely melanotic. Lighter pigmentation
is associated with smaller and less dense melanosomes that
are clustered in membrane bound groups. Melanosomes in
black African skin are .0.8 µm, with Asian and Caucasian
melanosomes averaging ,0.8 µm,(16) but there is variation in
melanosome size within these groups. These distinct patterns of melanosome type and distribution are present at birth
and are not determined by sun exposure.(17) It is possible that
the formation of either single or aggregated melanosomes
depends more on melanosome size, which may be influenced by nongenetic factors,(16) as well as genetic factors.
Usually, the relative size and density of the melanosomes in
the keratinocyte correlates with skin tone and dispersed
larger granules give rise to darker complexions. Differences
in the degree of melanization, as well as chemical differences
in the melanin pigments contained within the melanosome
are determining factors in the visual gradation of skin and hair
color.
Ultimately, all melanins are derived by oxidation of the
amino acid tyrosine, with two distinct types of melanin
compounds of variable molecular weight produced in a
bifurcated biosynthetic pathway. The underlying structure of
the melanin polymer, however, remains uncertain.(2) The
black/brown pigments are produced by the synthesis of
eumelanin, with the red/yellow colors produced through an
alternative sulfur-containing compound commonly known as
pheomelanin but which is of an indeterminate nature. Each
melanocyte has the capacity to synthesize both types of
pigment and when they do the outcome is mixed melanin.(18)
After a century of speculation, theory and difficult degradative
and synthetic chemical investigation (2) major advances in the
understanding of the enzymology of the melanin biosynthetic
pathway have only occurred during the past decade through
a molecular genetic dissection of mouse coat colors.(1,19)
Originally the production of the melanin biopolymer was
thought to involve only one copper-containing enzyme, known
as tyrosinase. Tyrosinase certainly catalyzes the first critical
step of the melanin pathway, the hydroxylation of tyrosine to
dopa; it is also involved in two subsequent steps. The first two
tyrosinase-catalyzed reactions are common to eumelanogenesis and pheomelanogenesis. It is known that they diverge
after the formation of dopaquinone (Fig. 2), but the mecha-
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TABLE 1. Human Pigmentation Genes
Gene
symbol
TYR
TYRP1
TYRP2
P
MC1R
Mouse
homologue
Albino (c)
Brown (b)
Slaty (slt)
Pink-eyed dilute (p)
Extension (e)
Chromosome
Phenotype
Protein
Function/
activity
11q14–21
9p23
13q31–32
15q11.2–12
16q24.3
OCA1
OCA3/ROCA
Unknown
OCA2, BOCA
Red hair
Tyrosinase
TRP-1
TRP-2
P-protein
MSHR
Tyrosine hydroxylation; DOPA oxidase
DHICA oxidase
Dopachrome tautomerase
Melanosomal transmembrane protein
G-protein-coupled receptor
The synthesis and polymerization of the melanin precursors take place in the specialized melanosomal organelle
where tyrosinase has a characteristic pattern of posttranslational glycosylation. The melanosomal structure correlates with the type of melanin within,(14) as illustrated in
Figure 1.
Stage I of the developing eumelanosome is a spherical
vacuole, derived from the endoplasmic reticulum, that elongates into an ellipsoidal organelle. Tyrosinase and other
enzymes are transported from the Golgi complex to the
developing melanosome (stage II) by vesiculoglobular bodies, which then begin to synthesize melanin (stage III).
Melanin eventually fills the eumelanosome (stage IV). The
early spherical vacuole of the developing pheomelanosome
is similar (stages I–IV), but the pheomelanosome remains
round throughout its maturation.
Figure 1. Variation in melanosome structure and distribution in different groups. A single skin melanocyte cell interdigitating with keratinocyte cells is partitioned into three sections.
Shown within the melanocyte are the four stages of melanosome formation from budding from the Golgi apparatus, to
the fully pigmented stage IV melanosomes migrating up the
dendritic processes of the cell and secreted into the keratinocytes. In African populations, the melanosomes remain as
singular heavily pigmented particles while in Asians and
Europeans the melanosomes cluster in membrane bound
organelles giving different skin complexions.
nisms responsible for this divergence are poorly understood.
The eumelanins are derived from the metabolites of dopachrome, whereas the pheomelanins derive from metabolites
of cysteinyldopa. The eumelanin pathway is favored in the
absence of thiol compounds; the switch from pheomelanogenesis to eumelanogenesis might be regulated by the availability of cysteine.(20) In addition to tyrosinase, however, two other
enzymes are now known also to take part in the eumelanic
pathway: the isomerization of dopachrome to DHICA catalyzed by dopachrome tautomerase(21) and the oxidation of
DHICA performed by the enzyme DHICA oxidase.(22,23)
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Identification, function, and variation of
representative human pigmentation genes
The tyrosinase-related protein gene family
The most dramatic example of gene action in pigmentation is
seen in the complete loss of color resulting from the inability
to form melanin. Albinism has been recorded in almost every
species and the way in which the genes responsible for
hypopigmented states have been identified demonstrates the
power that a comparative molecular genetic approach has
given to the study of pigmentation in humans. Hypopigmentation takes many forms and albinism in humans was first
attributed to a single locus because two albinos produced
similarly albino offspring.(8) This is not always the case; a
single exception(24) provides evidence that more than one
locus is involved. Cloning of the first albinism gene (TYR) was
achieved in 1987, using antibodies to the tyrosinase enzyme(25) to screen a cDNA expression library. Cross-species
comparison subsequently showed this cDNA to map to the
mouse albino c-locus and the functionality of the TYR gene in
albinism has been demonstrated beyond doubt through its
ability to rescue the albino phenotype in transgenic animals.(26,27) In humans, loss-of-function mutations in the TYR
gene are known as tyrosinase-negative or OCA1 albinism.
Review articles
Figure 2. Schematic of the pheomelanosome and eumelanosome with the biosynthetic pathway of the two types of melanin
outlined. The globular structure of TYR
(white), TRP-1 (brown), and TRP-2 (slate)
proteins is illustrated showing the presence of an epidermal growth factor (EGF)like repeat and the metal-binding sites for
copper (blue) or zinc (green) that make up
the binuclear active sites. The P-protein is
an integral membrane protein that may
mediate the formation of a melanogenic
complex formed in the eumelanosome.
TYR was not the first gene identified using anti-tyrosinase
antibodies, as a gene that was later found to map to the
mouse brown b-locus on chromosome 4 had already been
cloned in 1986 using a similar strategy.(28) The corresponding
human gene became known as tyrosinase-related protein
(TYRP) because of its apparent similarity to the tyrosinase
enzyme.(29) This TRP-1 protein is thought to encode the
enzymatic activity in melanin biogenesis known as DHICAoxidase.(22,23) In 1988, a second TYRP gene was identified by
sequence homology, and the encoded protein became known
as TRP-2; this gene encodes dopachrome tautomerase.(30,31)
The three tyrosinase related proteins have an overall identity
of approximately 40%, are around 500 amino acids in size,
and are postulated to have a common globular structure (Fig.
2). The bulk of the protein is located inside the melanosome
and a short C-terminal fragment in the cytosol is connected by
a transmembrane domain.(32) An epidermal growth factor
(EGF)-like repeat present toward the C-terminus is thought to
mediate protein–protein interactions possibly in a high molecular weight melanogenic complex,(33,34) which includes the
P-locus protein(35) (Fig. 2); two metal-binding domains serve
as the active sites of each enzyme.
The chromosomal locations of the loci for the three human
TYRP genes have been determined, and searches have
been conducted for functional polymorphisms that could
explain natural variation in pigmentation phenotypes as well
as several hypopigmented states. The TYR gene on chromosome 11q14–21 is encoded in five exons spanning more than
50–65 kb.(36,37) Many alleles responsible for OCA1 albinism
have been identified,(38) but ethnic differences in the tyrosinase protein are rare, with only two apparently nonpatho-
genic amino acid substitutions reported. The Y192S(39) and
R402Q variant substitutions are found in all populations
except in Asian.(40,41) Thus, the expectation that a polymorphism in the tyrosinase protein sequence would be a principal
determinant of normal variation in human pigmentation would
appear to be unlikely. Results obtained from melanocytes
cultured from different skin types, however, apparently correlate melanin content with in situ tyrosinase activity,(42) there
being 10 times more tyrosinase activity in black skin as
compared with white skin. This difference was apparently not
attributable to different levels of tyrosinase protein in skin
(however, see ref. 43), and the molecular basis for this
catalytic difference is unknown. Post-translational control of
tyrosinase protein has been suggested as a possible explanation,(42) with alterations in formation of the melanogenic
complex a valid possibility.
The TYRP1 genomic locus encoding the TRP-1 protein is
located on chromosome 9p23. The 24.6-kb region encompassing this locus has been completely sequenced with the
coding region contained in seven exons.(44,45) Two polymorphic AC dinucleotide microsatellites have been identified that
can be used for linkage studies.(44–47) The mouse Tyrp1 gene
is known to be associated with lightening of coat color as a
result of several b-locus mutations,(1) and for this reason the
gene was studied as a candidate for the cause of two
hypopigmented conditions known as brown and rufous oculocutaneous albinism (BOCA and ROCA) (Fig. 3). Linkage
studies in families with BOCA have excluded TYRP1 from
playing a role in this form of hypopigmentation,(47) but scanning of the TYRP1 exons has shown the molecular basis for
ROCA. A form of albinism(48) in an African-American neonate
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The TRP-2 protein is associated with dopachrome tautomerase activity and is encoded by 8 exons at the TYRP2
locus on chromosome 13q31–32.(44,50) Amino acid substitutions are present in the mouse Tyrp2 gene, which maps
genetically to the slaty coat color mutant.(1) It is to be
expected that some form of human albinism would result from
TYRP2 loss of function but, as yet, none has been reported.
Analysis of the TYRP2 coding region from the same Australian Caucasian samples from individuals with different hair
colors also exhibited a similar lack of variation (Box and
Sturm, unpublished data). The collective absence or low level
of polymorphism in the TYRP gene family in the human
populations studied argues that differences in normal patterns of melanization are not produced by differences in the
encoded catalytic activity of these enzymes. This does not
rule out the possibility that different TRP protein levels or
enzymatic activity within the melanosomal complex are responsible for variation in pigmentation. Indeed, such variation
is apparent when melanocytes have been cultured from
individuals of different skin types(43) and assays performed for
each of the three melanogenic enzymes. It is the control of
these proteins in the melanosome that is really the chief
determinant of pigmentation phenotype and it is this regulation that must be understood.
Figure 3. Individuals representing four different types of
oculocutaneous albinism. Top left, defect in the TYR gene in a
Caucasian child classified as OCA1 or tyrosinase-negative
OCA. Hypopigmented phenotypes found in the South African
black population include defects in the P-gene, classified as
OCA2 or tyrosinase-positive OCA(top right), the TYRP1 gene,
classified as OCA3 or ROCA(bottom left), and a BOCA
phenotype heterozygous for a known P-gene ‘‘OCA2’’ causing mutation and possibly another P gene mutation (bottom
right).
was shown to be caused by the loss of TYRP1 gene
expression via a homozygous single A-base deletion within
exon 6. This same protein-truncating mutation and an additional loss-of-function mutation were also identified in adults
with ROCA.(49) As TYRP1 is the third albinism locus to be
identified, phenotypes caused by mutations in this gene are
referred to as OCA3. Although the OCA3 newborn expressed
normal amounts of tyrosinase that was catalytically active in
cell lysates, tyrosinase activity was reduced by 70% when
assayed in melanocytes cultured from the patient.(48) This
may suggest that a loss of TRP-1 protein disrupts the correct
formation of the melanosomal complex and thereby inhibits
melanin synthesis, resulting in the hypopigmented phenotype. No other coding region mutations were detected in the
analysis of South African(49) and Australian Caucasian samples
from individuals with different hair colors,(45) indicating that
TRP-1 protein sequence variation is unlikely to play a major
role in normal color variation.
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The P-locus and hypopigmentation
Not all genes that cause clinically significant forms of hypopigmentation are members of the TYRP family. The most
common form of albinism worldwide, tyrosinase-positive oculocutaneous albinism, is most often caused by mutations in a
gene encoding a structural protein whose function remains
poorly understood. As this was the second albinism gene to
be identified, the locus was designated OCA2. The OCA2
locus maps to chromosome 15q11.2–12,(51) and the gene is
the human homologue, P, of the mouse pink-eyed dilution
locus, p.(52,53) Mutations at the p locus on mouse chromosome 7 are associated with a reduction in eumelanin synthesis, with apparently little effect on pheomelanin production.
The P gene spans 250–600 kb, has 25 exons of which the first
is noncoding, and codes for an 838-amino acid protein with
12 transmembrane domains.(53) Most functional studies on
the P gene have been done in the mouse and, since the
human P gene cDNA was shown to restore pigment production in mouse p null melanocyte cell lines, whereas mutant P
gene cDNA did not,(54) the conclusions are probably applicable to both. The protein encoded by the P gene has been
shown to be an integral component of the melanosomal
membrane(55) and was originally thought to be a transporter of
small molecules, possibly tyrosine, the precursor for melanin
biosynthesis. A study by Gahl et al.,(56) however, suggested
that it is unlikely to be a significant tyrosine transporter. The P
protein has been shown to be part of a high-molecular-weight
melanogenic complex, including TYR, TRP-1, and TRP-2,
Review articles
that is associated with the melanosomal membrane. The
high-molecular-weight forms of TYR, TRP-1, and TRP-2 are
absent in mice that do not express p, suggesting that the P
protein may play a role in stabilizing the complex and in the
regulation of the levels of expression of the TYRP gene
family.(35,57)
Mutations in the P gene are responsible for at least three
different types of albinism—tyrosinase-positive oculocutaneous albinism (OCA2),(51–53) ocular albinism (OA),(58) and
BOCA(59)—suggesting that different mutations alter the level
of functioning of the P gene and the stability of the melanogenic complex (Fig. 3). A study on a large OCA2 pedigree of
triracial origin demonstrated a common 2.7-kb deletion in the
P gene,(60) and this mutation was found to be widespread
throughout sub-Saharan Africa(61) and in African-Americans(62). Numerous other P gene mutations have been
identified in individuals with OCA2, although none was
present at high frequency.(58,62,63) During the search for mutations in the P gene, several apparently nonpathogenic variants were identified, and some of these had markedly
different frequencies in different population groups. For example, R305W occurred at a frequency of 0.83 in caucasoids
but at a frequency of only 0.10 in blacks.(63). If this is a
functionally significant mutation, it may indicate that the P
gene plays a role in normal pigment variation.
The role of the P gene in normal pigment variation remains
uncertain. A locus for brown eye color and brown hair color
was linked to markers on 15q11–12, with the P gene the most
likely candidate gene.(64) Skin reflectance tests on obligate
OCA2 carriers, presumably with a mutation in one copy of the
P gene, showed that they had significantly lighter skin
pigmentation than individuals without a family history of
albinism, with a more marked difference in males than in
females.(65) Furthermore, individuals with Prader-Willi syndrome (PWS) and Angelman syndrome (AS) with deletions of
15q11–13, particularly deletions including part of the P gene,
are often hypopigmented relative to other family members.(66,67) Since hemizygosity for the P gene in PWS patients
is significantly correlated with hypopigmentation, the presence of functionally significant variants in the intact gene may
account for the hypopigmented phenotype. A recent P gene
haplotype study by Spritz et al.(68) in PWS patients showed
many diverse haplotypes associated with hypopigmentation
and suggested that the intact P allele may have reduced
expression because of complex gene regulation in this
chromosomal region or that it was due to the deletion of a
second pigment locus close to the P gene. In BOCA, where
one chromosome appears to have an ‘‘OCA2’’ mutation and
the other chromosome an apparently ‘‘mild’’ mutation, only
about 70% of patients have eye involvement.(47) Perhaps
individuals with two mild mutations would fall within the
normal range of pigmentation, but veer toward the lighter end
of the spectrum. Only through the identification of functionally
significant variants and analysis of their distribution in different populations would the role of the P gene in normal skin
color determination become clearer.
The melanocyte-stimulating hormone receptor
Because of its striking character, red hair has featured as a
primary focus of investigation among geneticists interested in
human pigmentation traits. The Davenports(7) began a description of the inheritance of red hair color, and subsequent
studies have investigated large numbers of family groups in
an attempt to discover its mode of transmission. The description of red hair is recognized to include the hair colors that
grade from very light strawberry blonde through carrot red to
dark auburn(69,70); and it has also been noted that red hair may
be present as beard and axillary hair in combination with
scalp hair of another color. Furthermore, many red-haired
children become brunettes as they grow older, or at the very
least, the color darkens.(69,71) The red hair trait in most cases
presents with fair skin and freckles or ephilides (72); freckles
are not restricted to the red phenotype, as they may also be
present in combination with other hair and skin types. Two
investigators(69,73) have observed that a relatively high number of distinctly non-red-haired individuals have a small
proportion of red scalp hairs when examined microscopically,
although these investigators did not mention whether these
cases were associated with freckled skin or with any red body
hair.
The inheritance pattern of red hair in a six-generation
family was consistent with an autosomal recessive mode of
inheritance,(74) although initial studies had suggested a more
complex pattern.(9) More than a half-century ago, Neel(75)
attempted to assess whether the mode of transmission of
obviously visible red pigment within the scalp hair was
recessive or dominant to other hair colors. Of 114 offspring
from 26 couples in which both partners had red hair, 101 were
redheads and 13 had hair of some other color. It is important
to note that if red hair were transmitted as a simple recessive
trait, all the offspring would exhibit the trait. The ratio of
non-red-haired to red-haired offspring was still low, however,
prompting the conclusion that red hair is dependent on a
single incompletely recessive factor that is hypostatic to the
factors determining black or dark brown hair color. Data
obtained by Rife(71) supported this conclusion and provided
evidence that red hair is inherited dominant to blonde.
Mice with recessive mutations at the extension locus (e)
show a yellow (pheomelanic) coat color, suggesting that loss
of function at this locus was important in the switching
between eumelanin and pheomelanin synthesis in the melanocyte. An understanding of how this gene was involved in
directing melanin synthesis was established with the cloning
of the extension gene and the finding that it encoded the
mouse melanocyte-stimulating hormone receptor (Mc1r).(76,77)
This finding led to the realization that human melanocyte-
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G-protein activation
EGF
cAMP
Pheomelanin
TYR
TRP1
EGF
P, TRP1, TRP2
EGF
EGF
P-protein
TYR
TRP2
Eumelanin
Figure 4. Diagrammatic structure of the consensus human MSHR protein is shown (blue) with the position of the variants(81) reported to be
associated with red hair (red: R151C, R160W, D294H) or found in individuals but yet to be statistically associated with red hair (green), blonde or
brown hair (yellow: V60L), with the two alleles common in Chinese individuals (black: R67Q, R163Q) and the base insertion reported in Fig. 5
(white: 537insC) indicated. Switching from the pheomelanogenic to the eumelanogenic pathway by receptor stimulated G-protein activation or
the cAMP pathway is illustrated by the induction of the P, TRP-1, and TRP-2 proteins to form eumelanin.
stimulating hormone receptor (MSHR) was a potential candidate for producing the red hair phenotype. The human MC1R
gene encoding the MSHR protein has been localized to
chromosome 16q24.3(78) and codes for a seven-transmembrane domain G-protein-coupled receptor belonging to the
melanocortin receptor subfamily (Fig. 4). MSHR is highly
expressed in melanocytes and interacts with a-MSH to
stimulate pigment production.
The first screen for MSHR variation in humans was
performed in English and Irish individuals, identifying nine
different amino acid substitutions that showed some correlation with red hair and fair skin.(79) Eleven of 38 redheads had
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BioEssays 20.9
two variant MSHR alleles, 20 had only a single variant allele,
and the remaining 7 failed to present any MSHR coding
region variation, suggesting a relatively weak involvement of
MSHR. This result indicates that secondary loci may produce
red hair in the absence of MSHR changes in a significant
proportion of cases,(80) a conclusion unforeseen by the
historic model of inheritance that favored a single incompletely recessive genetic locus as the primary determinant of
the distinctly red trait.
A recent investigation of hair color in Caucasian twins(81)
builds on the initial study of MSHR variation.(79) Twelve amino
acid substitutions were identified (Fig. 4), with significant
Review articles
associations observed between the three variants R151C,
R160W, D294H, and red hair, while a fourth variant, V60L,
had a strong association with fair/blonde hair, perhaps indicating that the MSHR plays a role in both blonde and red hair.
Twenty of the 25 red heads analyzed had two variant MSHR
alleles, and the remaining 5 had only a single variant allele, a
result appearing, in the absence of functional data for each
variant, to be more consistent with the historic hypothesis.
Apart from the V92M allele, the MSHR variant haplotypes
were also significantly associated with lighter skin color in
Caucasians; and two variants, R67Q and R163Q, were
predominant in the Chinese population. As yet, no systematic
population based study has been performed to assess MSHR
variation between ethnic groups and its potential contribution
to skin pigmentation differences. The observation that the
MSHR gene is associated with different skin tones in Caucasians is reason to believe that it may have a major role in
influencing pigmentation within other populations. However, it
has been shown that gene variation within a population can in
some circumstances be greater than that between populations,(82) and MSHR variation may be one such example.
Another result that sheds light on the extent of the genetic
interactions that underlie red hair is the observation that 5 of
13 sets of dizygotic red-haired/non-red-haired twins share
identical MSHR genotypes. All five are most likely to be
identical by descent for this gene, suggesting that MSHR
variation is necessary but not sufficient to generate red hair.
As stated above, the red hair trait is not a simple biological
phenomenon, appearing in the fully developed form with red
scalp hair or an incomplete form exhibiting freckles and red
axillary hair or perhaps freckles alone.(72) The interplay
between different strength alleles of the MSHR locus and
those of a masking genetic background is a possible mechanism controlling the expressivity of the red hair phenotype.
The genetic background is potentially responsible for determining the shade of red hair that is inherited, although
possible association between MSHR alleles and subtype of
red hair is yet to be addressed. Differential expression of any
MSHR promoter variants may also explain the occurrence of
nonred scalp hair in combination with red body hair and
freckles.
Of further interest is the report by Neel(75) that two
red-haired parents may occasionally produce non-red-haired
offspring, a situation now explainable by inheritance of a
newly identified MSHR null allele. Figure 5 shows the MSHR
genotypes of a family where two red haired parents have
produced a red and a blonde daughter. The father is heterozygous for a unique 537insC variant that results in a frameshift
and premature stop 58 amino acids later. It is significant that
this insertion is very close to the original recessive extension
deletion, which produces a truncated and inactive MSHR and
therefore the classic mouse extension phenotype.(83) It is
probable that 537insC also produces a null allele and that red
1000710
V60L
R151C
R151C
537insC
V60L
V60L
R151C
537insC
Figure 5. Inheritance of MSHR haplotyes in red- and blondehaired children of two red-haired parents.
hair in the father is directed by the common R151C variant.
The mother also has an R151C as well as a V60L allele. It has
been suggested that red may be dominant to blonde; indeed,
in the mother, R151C directs the appearance of red hair in a
dominant fashion over the V60L allele, which has previously
been associated with blonde hair. This situation is duplicated
in the first girl, who has red hair, but her younger sibling, who
has received V60L from her mother and the null allele from
her father exhibits blonde hair, reinforcing the association of
V60L to blonde hair and providing a possible molecular
explanation for this curious situation. However, as already
described in the analysis of the dizygotic red-haired/non-redhaired twins, other genetic factors besides MSHR could
determine hair color in this family; further inheritance studies
of the 537insC allele are needed to confirm this interpretation.
All MSHR variants that have been identified to date produce
amino acid substitutions, this being the first report of a null
allele. It will be interesting to observe the phenotype of an
individual carrying two null MSHR alleles.
BioEssays 20.9
719
Review articles
Conclusions: what makes people different?
The wide variety of pigment phenotypes seen in human
populations prompts the question of whether there is likely to
have been selection for skin color. Most of the Earth is
populated with more darkly pigmented peoples, with a striking
northern European localization of more lightly pigmented
peoples.(84) One might argue in favor of selection for darkerskinned individuals who are better protected from the harmful
effects of ultraviolet (UV) irradiation, but perhaps this was the
ancestral state. A more likely scenario is that mutations that
arose for lighter skin color have been selected for in individuals with poor dietary vitamin D intake and little exposure to the
sun. Natural selection, although a possible driving force
through latitudinal variation in sunlight, may not readily apply
to humankind, which can so easily alter its environment and
behavior, and where other factors are more important in
choosing partners.
Advances in the study of human pigmentation have only
now come of age as a consequence of using a comparative
genomic approach to understand this complex biological
system. Three well-conserved gene systems—TYRP, P, and
MSHR— have been used to illustrate how this has applied to
the study of pigmentation. However, when considering mammalian pigmentation in general, humans are without an outer
coat of body hair and are somewhat unique, in that the
melanocyte sits at the dermal–epidermal junction secreting
melanin particles into fully exposed cutaneous keratinocytes.
This arrangement does not generally occur in other animals;
in the mouse, for instance, the melanocytes are located
predominantly in the dermal compartment. Although major
advances have been made in identifying pigmentation genes
it may be expected that not all the genes influencing pigmentation in humans will be found through the use of a comparative genomics approach because of this fundamental biological difference. Genetic studies of human populations and
family groups are still required to identify and confirm the role
of pigmentation genes.
Variation in human skin color is clearly a multifactorial trait
with a number of major gene determinants, several modifier
genes, and environmental influences such as exposure to UV
irradiation and gender effects. Our current understanding
suggests that protein sequence variation in the catalytic
enzymes tyrosinase, TRP-1, and TRP-2 that are active in the
melanin biosynthetic pathway is not a major determinant of
pigmentary differences, with very few polymorphisms showing marked differences between population groups. MSHR
appears to play a role in the level of expression of these
enzymes and the P gene seems to be essential in stabilising
the melanogenic complex within the melanosome. Since the
major histological difference between heavily and lightly
pigmented individuals seems to be the packaging and size of
the melanosomes in the keratinocytes, one would perhaps
expect genes that are involved with organelle membrane
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BioEssays 20.9
structure and integrity to be important determinants in skin
color variation. Thus, the variation in MSHR and the P-gene
coding regions are the two most obvious determinants of skin
type and hair color. A consequence of this variation is the
regulation of the levels and activities of the tyrosinase, TRP-1,
and TRP-2 proteins. In essence, the difference is only skin
deep.
Acknowledgment
The authors thank Professor Jennifer Kromberg for providing
photographs of albino patients. We apologize to those authors whose papers we could not cite due to space restrictions.
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