Farid and Abder, J Primatol 2013, 3:1
http://dx.doi.org/10.4172/2167-6801.1000116
Primatology
Research
Article
Review
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Progressive Genetic Architecture of Human Skin Pigmentation
Menaa F1* and Menaa A2
1
2
Fluorotronics USA, Inc. and Global Innovation & Trade, Inc., CA, USA
Department of Clinical Nutrition and Anti-Aging Medicine Medical Center, Saint-Philbert de Grand Lieu, Loire Atlantique, France
Abstract
Skin pigmentation is an important human phenotypic trait whose regulation, in spite of recent advances,
has not been fully understood. Global variation in skin pigmentation is one of the most striking examples of
environmental adaptation in humans. From genome-wide association studies (GWAS), almost four hundreds loci
have been identified as candidate genes in model organisms. Nevertheless, only few of them have been found to
be significantly associated with human skin pigmentation differences in African, Asian, and European populations.
Further, the evolutionary history of different pigmentation genes is rather complex: some loci have been subjected
to strong positive selection, while others evolved under the relaxation of functional constraints in low ultraviolet (UV)
environment.In this manuscript, we report the current genetic architecture implicated in human skin pigmentation.
Eventually, we conclude that this complex trait is strived to a bright future.
Abbreviations: ACH: Adrenocorticotropic hormone; ALDH1A1:
Aldehyde dehydrogenase 1A1; CNV: Copy number variation;
CREB1: cAMP response element-binding protein 1; CYP19A1:
Cytochrome P450, family 19, subfamily A, polypeptide 1; DCT:
Dopachrometautomerase; DRD2: Dopanine receptor D2; EDN3: Endothelin 3 EGF-R: Epidermal growth factor receptor; GWAS:
Genome-wide association studies; KITLG: KIT ligand; MATP:
Membrane associated transporter (aka SLC45A2); MC1-R:
Melanocortin type 1 receptor (alpha MSH receptor); MIF: Melanizationinhibiting factor; MITF: Microphthalmia-associated transcription
factor; MSH: Melanocyte-stimulating hormone; MYO5A: Myosin VA
(heavy chain 12, myoxin); NGS: Next-generation sequencing OCA2:
Oculocutaneous albinism II; OPRM1: Opioid receptor, mu 1; POMC:
Proopiomelanocortin; SLC24A5: Solute carrier family 24 member 5;
SNP: Single nucleotide polymorphism; TYRP1: Tyrosinase-related
protein 1; UVR: Ultraviolet radiation
Keywords: Skin pigmentation; Genetics; GWAS; Evolution;
Environment; Humans
Human Melanogenesis: An Overview
Human skin pigmentation is a fascinating multi-disciplinary
research topic that includes cell biology, genetics and anthropology,
enabling us to patch up a clear picture of the Homo sapiens´ evolution
[1-2]. Melanocytes (i.e. pigment cells) are derived from a stem cell
of neural-crest origin [1,3]. They are specialized in the synthesis of
melanosomes (i.e. melanin-bearing organelles), which are then acquired
by keratinocytes, and transported within them to the epidermal surface
[4]. The subsequent relative melanogenesis (i.e. production of the
melanin, a key pigment) thereby contributes to the appearance of the
skin as well as to its protection from damage by ultraviolet radiation
(UVR) [1,3,4]. The expression of melanocytes is influenced by factors
(e.g. melanization-inhibiting factor (MIF), UVR, drugs) localized in
specific areas of the skin to thus produce specific pigmentation patterns
[1].Skin pigmentation within and between populations (i.e. nonadmixed and admixed ones, respectively) can be quantified by using
accurate and objective technology such as reflectance spectroscopy
(aka reflectometry) at specific wavelengths (i.e. measurement of
reflected light across the visible spectrum – range of 400-800 nm) [5].
Indeed, it has been noticed that variation in both cellular structure
(e.g. biodistribution of melanosomes) and biochemical pathways
(e.g. relative genetic expression and specific combined genetic effects)
J Primatol
ISSN: 2167-6801 JPMT, an open access journal
underlies pigmentation differences among groups. For instance, while
all humans have approximately the same number of melanosomes, the
melanosomes of darkly pigmented individuals contain more melanin,
are larger, and are distributed singly instead of being grouped into a
membrane [6].
Additional variation stems from mutations and polymorphisms
in the many genes that compose the pigmentation pathway,
including differences in tyrosinase activity (encoded by TYR gene),
which is the rate-limiting enzyme for melanogenesis [7]. In theory,
the pigmentation of unexposed areas of the skin (i.e. constitutive
pigmentation) is relatively unaffected by environmental influences
(e.g. UV) during an individual’s lifetime when compared with other
complex traits such as blood pressure or diabetes, and this provides a
unique opportunity to study gene-gene interactions without the effect
of environmental confounders [4,8]. The genetic regulation of pigment
metabolism within the epidermal melanin units is being clarified. In
some mammals, the function of epidermal melanin units issignificantly
influenced by hormones which may be regulated by radiation received
through the eyes [4].
However, the inheritance of skin color in humans is not well
understood. Most of the loci governing pigmentation are pleiotropic,
color being only one of the traits affected by them [9]. Indeed,
pigmentation, which is primarily determined by the amount, the type,
and the distribution of melanin, shows a remarkable diversity in human
populations, and in this sense, it is an atypical and complex trait [10].
For instance, fair-skinned individuals are at higher risk of several types
of skin cancer, particularly in regions with high UVR incidence, and
dark-skinned individuals living in high latitude regions are at higher
risk for diseases caused by deficient or insufficient vitamin D levels [8].
*Corresponding author: Menaa F, Executive Director, Fluorotronics USA,
Inc. and Global Innovation & Trade, Inc., CA, USA, Tel: +1(858)274-2728;
E-mail: [email protected]
Received November 09, 2013; Accepted November 12, 2013; Published
December 27, 2013
Citation: Menaa F, Menaa A, (2013) Progressive Genetic Architecture of Human
Skin Pigmentation. J Primatol 3: 116. doi:10.4172/2167-6801.1000116
Copyright: © 2013 Menaa F, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Volume 3 • Issue 1 • 1000116
Citation: Menaa F, Menaa A, (2013) Progressive Genetic Architecture of Human Skin Pigmentation. J Primatol 3: 116. doi:10.4172/2167-6801.1000116
Page 2 of 5
Nevertheless, there is strong evidence for inter-specific homology
of pigmentation loci in mammals, and so, the situation in humans
may not be radically different. The racial differences in skin color
may have resulted from the action of natural genetic selection [9,11].
Besides, owing to its undeniable visibility, skin color has always had
a sociologic connotation which has, up to the present time, caused
division between people [2]. Therefore, to understand the diversity of
skin color now observed in people of the five continents, one has to go
back in history [2]. Eventually, the ongoing deeper determination of
the genetic basis of skin pigmentation differences between populations,
especially admixed, is providing clues about our evolutionary history,
and may have clinical implications (e.g. the pigment stimulatory agent
9-cis retinoic acid regulated by ALDH1 gene might be valuable in the
treatment of hypopigmentary disorders, such as vitiligo [12]).
II. Association of Human Genes with Skin PigmentationHuman
skin color may be the most rapidly evolving trait in our species, with
relatively closely related populations showing quite large differences
in average pigmentation levels. The inter-population variation in
pigmentation was estimated at 88%, compared to 10-15% for arbitrarily
selected genetic markers [13]. During the last decade, research has
substantially increased our understanding of the genes involved in
normal pigmentation variation in admixed human populations [8,14].
This was notably possible thanks to the development of state-of-the art
technologies (e.g. arrays, next-generation sequencing (NGS)) and the
International Hap-Map Project, that permit worldwide human GWAS
studies (e.g. rapid, cost-effective and high resolution determination of
a high number of potentially functional nucleotide polymorphisms
(SNPs) and copy-number variations (CNVs)), as well as measurement
of the genetic distance (FST) between two populations (e.g. modern
populations and a hypothetical ancestral population).
For instance, large-scale SNP data from human populations of
African, European and Asian origin interestingly showed that ancestral
alleles are more conserved in the African populations, but strong
divergence has been noticed in genes related to skin pigmentation, UV
radiation and dietary adaptations [15]. The reasons for this discrepancy
(i.e. high phenotypic variation in skin pigmentation) between human
populations can be traced back primarily to the strong influence of
natural selection, which has shaped the distribution of pigmentation
according to a latitudinal gradient at the continental level [8,16]. A large
number of hypotheses involving, at least partially, genetic adaptation
via natural selection (e.g. strong positive correlation with UV radiation
intensity), have been proposed to explain human variation in skin
color. Genetic evidence for positive selection has been also presented.
Indeed, several studies have shed light on the complex evolutionary
genetic history of human variation in skin color, reporting a large
number of gene variations (>100) associated or linked in shaping the
skin pigmentation phenotype [16-19]. Studies have focused largely on
candidate genes or admixture linkage in recently admixed populations
(i.e. primarily with West African/European or Indigenous American/
European parental populations) and GWAS in non-admixed
populations [20]. One exception is a GWAS in South Asians - a
population that has substantial old admixture [21]. To date, the number
of genes that contribute to level differences in skin pigmentation within
and between various human populations is estimated to eleven [14,20].
Among them, few genes (e.g. SLC45A2 (MATP), OCA2, TYRP1, DCT,
KITLG, EGFR, DRD2 and PPARD) were specifically associated with
the melanin pathway, and presented significant variability patterns
between Europeans (i.e. OCA2, TYRP1 and KITLG), Africans (i.e.
DCT, EGFR and DRD2) and Asians (i.e. OCA2, DCT, KITLG, EGFR
J Primatol
ISSN: 2167-6801 JPMT, an open access journal
and DRD2), which were compatible with the hypothesis of local positive
in Europeans and in Asians, whereas signals were scarce in Africans
[14,16]. Also, it was suggested from the overall genetic analysis of 51
human populations that light skin color is the derived state and is of
independent origin in Europeans and Asians, whereas dark skin color
seems of unique origin, reflecting the ancestral state in humans [16].
Polymorphisms in two genes, ASIP and OCA2, have been suggested
to play a shared role in shaping light and dark pigmentation across
the globe, whereas SLC24A5, MATP, and TYRP1 had a predominant
role in the evolution of light skin in Europeans but not in East Asians
[17]. Previous research clearly showed TP53BP1 gene involvement in
adaptive selection in Africans, whereas TYRP1 and SLC24A5 genes
showed evidence of adaptive selection in Caucasians [18,21]. Ancestry
informative markers in CYP19A1, MYO5A, and SLC24A5 have
shown admixture linkage in Hispanic populations [22]. Several groups
found marked over-representations of pigmentation genes among the
strongest genomic signatures of selection in Europeans [16,23,24].
Evidence of selection in pigmentation genes is more than twice
higher than randomly selected genes in both Chinese and European
populations [25]. These pigmentation genes are significantly more
likely to have high FST than randomly chosen regions of the genome
[26].
Taken together, these consistent findings obviously support: (i) the
inheritance of the human skin pigmentation trait; (ii) a case for the
recent convergent evolution of a lighter pigmentation phenotype in
Europeans and East Asians; (iii) a putative photo-protection mechanism
against sun-induced skin damage/cancer that has driven the evolution
of human skin pigmentation (e.g. implication of altered genes such as
TP53BP1, EGFR and perhaps RAD50); (iv) the presence of additional
gene alterations responsible for the differences between indigenous
Americans and Europeans. Nevertheless, as first addressed by Harrison
and Owen five decades ago [5], information about the exact number of
genes that determine variation in human skin color is lacking. Indeed,
a substantial number of differences in skin color among populations
cannot be explained. Interestingly, more than 370 pigmentation loci
(171 cloned genes and 207 uncloned genes) putatively involved in skin
color have been identified in mouse models, and catalogued in the
International Federation of Pigment Cell Societies (IFPCS) database
(http://www.espcr.org/micemut/). The size of this database gives
credence to the hypothesis that, in addition to common variants, many
rare variants may also contribute to pigmentation variation in humans.
Eventually, future larger studies may provide evidence about exact
mechanistic pathways that mediate selection [27].
Key Loci Associated with Human Melanogenesis
MC1-R
Melanocortin type 1 receptor (MC1-R), a seven pass transmembrane G protein coupled receptor, is a key control point in
melanogenesis. MC1-R gene was the first gene identified that explains
substantial phenotypic variance in human pigmentation [28]. It
concurs with UV radiation-driven model of skin color evolution by
which mutations, leading to lower melanin levels and decreased photoprotection, are subject to purifying selection at low latitudes - while
being tolerated or even favored at higher latitudes - because they
facilitate UV-dependent vitamin D production [29]. Non-synonymous
MC1-R variants, which are frequent in Europe and North Africa, are
recent and might have emerged after the separation of East and West
Eurasian populations [29]. MC1-R expression is regulated by peptides
(melanocyte-stimulating hormone (MSH) and adrenocorticotropic
Volume 3 • Issue 1 • 1000116
Citation: Menaa F, Menaa A, (2013) Progressive Genetic Architecture of Human Skin Pigmentation. J Primatol 3: 116. doi:10.4172/2167-6801.1000116
Page 3 of 5
hormone (ACH)) resulting from proopiomelanocortin (POMC)
cleavage [30]. MC1-R variants (i.e. loss-of-function mutations) that
led in a switch from eumelanin to phaeomelanin production were
associated with pale skin color and red hair in humans of primarily
European origin (i.e. Neanderthals) [31], suggesting that inactive
MC1-R variants evolved independently in both modern humans and
Neanderthals.
However, no activating mutations in MC1-R gene have been
described to date [32]. Although study of the MC1-R may provide
insights into the lightening of skin color observed in most European
populations, research of variants still requires to be performed in
other populations, where MC1-R could experience different selective
pressures [33]. Indeed, a previous study concluded that MC1-R is
under strong functional constraint in Africa, where any diversion
from eumelanin production (black pigmentation) appears to be
evolutionarily deleterious. Although many of the MC1-R aminoacid variants observed in non-African populations do affect MC1-R
function, and contribute to high levels of MC1-R diversity in Europeans,
no evidence, in either the magnitude or the patterns of diversity, was
found for its enhancement by selection; rather, analyses showed that
levels of MC1-R polymorphism simply reflect neutral expectations
under relaxation of strong functional constraint outside Africa [28].
SLC24A5
SLC24A5 gene encodes the trans-Golgi network Nckx5 protein
with potassium-dependent sodium-calcium exchange activity that
regulates human epidermal melanogenesis[34-38]. The International
HapMap Project (http://hapmap.ncbi.nlm.nih.gov/) discovered an
amino-acid substitution in this gene(SLC24A5*Thr111) [34]. The
SLC24A5*Thr111 allele, inserted into DNA of melanocytes, showed
significant decrease in cation exchange and down-regulation of
melanin, possibly modifying the acidity-induced tyrosine activity
and the skin lightening [23]. The mutation, predominantly fixed in
European populations, largely contributes to explain human skin
color divergence between Europeans and West Africans or Europeans
and East Asians [17,34], meantime underlying a substantial selective
pressure in Europe, which might be recent [18]. Likewise to other
gene candidates such as SLC45A2, OPRM1 and EGFR, a recent study
has define SLC24A5 as a valuable contributor to skin pigmentation
differences between Indigenous American and Europeans [37].
KITLG
c-Kit ligand (Kitlg) influences melanocyte proliferation, melanin
distribution and activates keratinocytes to produce promelanogenic
factors [42]. Thereby, the Kitlg/c-Kit signaling pathway is important in
the onset of human familial pigmentary diseases [43]. Europeans and
East Asians shared derived alleles at the KITLG locus, and regulatory
genomic regions surrounding the gene had a significant relative effect on
human populations’ skin color (e.g. natural variation of pigmentation)
[44]. Regulatory differences of KITLG homologues regions may be
explained by an evolutionary change (i.e. natural variation) [44,45].
ALDH1A1
Aldehyde dehydrogenase 1A1 (Aldh1a1), an enzyme that catalyses
the conversion of lipid aldehydes to lipid carboxylic acids, plays
pleiotropic roles in UVR resistance, melanogenesis and stem cell
maintenance [46]. Initial experiments in the intact epidermis revealed
that the expression of ALDH1A1 gene regulates melanogenesis by
catalysing the conversion of 9-cis retinal to 9-cis retinoic acid, and
potently inducing the accumulation of MITF mRNA, Tyrosinase
mRNA and melanin [46].
Conclusions & Perspectives
Genetic evolution or adaptation of human skin pigmentation? This
question remains of actuality, and a body of evidence suggest both
mechanisms [46-48]. Indeed, over millennia, the ancient ancestors
of modern day humans had to adapt to new environments as they
migrated between continents, hemispheres and countries. The level of
sunlight, and associated UVR in each region, varies enormously, and
is responsible for the plethora of different skin colors seen today. It
is thought that the evolution of darkly pigmented skin came about as
a protective mechanism (i.e. adaptation) in populations moving from
environments with low UVR to high UVR (e.g. arid or tropical regions
near the equator such as Africa, India and South America, or regions of
high altitude such as Tibetan plateau and the Altiplano). Conversely, the
prevalence of lightly pigmented or de-pigmented skin in populations
TYR
The human tyrosinase (TYR) gene represents a key enzyme in
melanin production making him a strong candidate implicated in skin
color variation [29,36,39,40]. A recent global study [29], assessing the
role of its variation in the evolution of skin pigmentation differences
among human populations, observed a higher rate of recent nonsynonymous polymorphisms in the European sample consistent with
the relaxation of selective constraints. Strong evidence for positive
selection is suggested for TYRP1 (TYR-related Protein 1) alleles in
Africans and in Asians [29]. TYR gene product (i.e. tyrosinase) is
up-regulated by miR-203 [39]. This micro-RNA is down-regulated
in melanocytes, and considered as a critical anti-melanoma through
reducing melanosomes transport and promoting melanogenesis by
targeting kinesin superfamily protein 5b (kif5b) as well as through
negative regulation of the cAMP response element-binding protein
1 (CREB1)/microphthalmia-associated transcription factor (MITF)/
Rab27a pathway [40]. Interestingly, tyrosinase and MITF expressions
are also up-regulated in melanocytes by the constitutively highly
expressed Wnt inhibitory factor-1 (WIF-1) [41].
J Primatol
ISSN: 2167-6801 JPMT, an open access journal
Figure 1: The evolutionary genetic architecture of human skin pigmentation.
Genes significantly* associated to the skin color in a given population (i.e.
All humans, East Asians, North Europeans, West Africans). SCL24A5 and
MATP genes mutations are predominantly fixed in the European population
and MITF is involved in a major signaling pathway leading to human skin
pigmentation. Those genes are yellowed.
*according to reported differences in the allele frequencies.
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Citation: Menaa F, Menaa A, (2013) Progressive Genetic Architecture of Human Skin Pigmentation. J Primatol 3: 116. doi:10.4172/2167-6801.1000116
Page 4 of 5
at high latitudes (e.g. regions closer to the poles such as Northern
Europe and East Asia) is related to the low amount of sunlight (i.e.
UVR). The ongoing GWAS and the identification of a larger number of
gene variants (e.g. mutants, SNPs, CNVs) from admixed populations
are drawing a clearer picture of the human genetic architecture of
skin pigmentation and shall contribute to a deeper understanding of
the skin color adaptation mechanisms as well as human evolution and
migration.
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Citation: Menaa F, Menaa A, (2013) Progressive Genetic Architecture of
Human Skin Pigmentation. J Primatol 3: 116. doi:10.4172/2167-6801.1000116
J Primatol
ISSN: 2167-6801 JPMT, an open access journal
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300 Open Access Journals
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Submit your manuscript at: http://omicsgroup.info/editorialtracking/primatology
Volume 3 • Issue 1 • 1000116