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)
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.[...]
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)[...]
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.[...]
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.
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, s
uch 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.[...]
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)[...]
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)
[...]
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.[...]
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.
A
part 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.
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 [...]
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. M
SHR
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
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.
Black skin, white skin, Asian skin – what’s the difference?
Originally Posted by al-Bosni
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