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Unpacking Human Evolution to Find the Genetic Determinants of Human Skin Pigmentation

      How many genes determine variation in human skin color? The apparent simplicity of the question is belied by the complex evolutionary history of our species with regard to this trait. This question was first addressed in a seminal 1964 paper, ''On the inheritance of human skin colour,'' by
      • Harrison G.A.
      • Owen J.J.T.
      Studies on the inheritance of human skin colour.
      . This work is notable in (1) using reflectance spectroscopy to quantify skin pigmentation;(2) focusing on population samples with varying levels of genetic admixture; and (3) using a genetic approach to investigate evolutionary questions.
      Prior to the adoption of reflectome-try-based measurements of skin pig-mentation, researchers relied on subjective assessments of pigmentation using reference tiles like those produced by Felix von Luschen. Although they have been widely used for 50 years, these tiles result in rough categorical estimates with large inter-observer error (unpublished data) unsuitable for quantitative genetic analysis. Harrison and Owen, on the other hand, measured reflected light across the visible spectrum in relatively unadmixed West Africans and Europeans, as well as in four admixed groups (F1 hybrid, European backcross, West African backcross, and F2 hybrid). By using measurements that were truly continuous and considering both population means and variance, these investigators were able to estimate the quantitative genetic underpinnings of this trait and, in doing so, established the importance of admixed human populations in studies of skin color. Without this innovative approach to measuring skin color in appropriately identified admixed populations, many of the recent advances in our under-standing of the genetics of human skin color would not have been possible.
      Human 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. One study has estimated the interpopulation variation in pigmentation at 88%, compared to 10-15% for arbitrarily selected genetic markers (
      • Relethford J.H.
      Apportionment of global human genetic diversity based on craniometrics and skin color.
      ). Variation in both cellular structure and biochemical pathways underlies pigmentary differences among groups. For example, 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 (
      • Sturm R.A.
      • Box N.F.
      • Ramsay M.
      Human pigmentation genetics: the difference is only skin deep.
      ). Additional variation stems from mutations in the many genes that compose the pigmentation pathway, including differences in tyrosinase activity (encoded by the TYR gene), which is the rate-limiting enzyme for melanogenesis (
      • Fuller B.B.
      • Spaulding D.T.
      • Smith D.R.
      Regulation of the catalytic activity of preexisting tyrosinase in black and Caucasian human melanocyte cell cultures.
      ).
      In the past few years we have made dramatic advances in our understanding of the genetic basis of normal pigmentation variation (for reviews, see
      • Parra E.J.
      Human pigmentation variation: evolution, genetic basis, and implications for public health.
      ;
      • Sturm R.A.
      Molecular genetics of human pigmentation diversity.
      ). To date, 11 genes are known to influence skin pigmentation levels within and between various human populations. Studies have focused largely on candidate genes or admixture linkage in recently admixed populations (primarily with West African/European or Indigenous American/European parental populations) and genomewide association studies in non-admixed populations. One exception is a genome-wide association study in South Asians—a population that has substantial old admixture (
      • Stokowski R.P.
      • Pant P.V.
      • Dadd T.
      • et al.
      A genomewide association study of skin pigmenta-tion in a South Asian population.
      ). As Harrison and Owen realized, admixed populations are essential for understanding pigmentation differences among populations, since the alleles at many of the functional loci are fixed or nearly fixed. In the absence of genetic variation, it is impossible to map the effect of a locus.
      Based on their partitioning of variance using data fromF1, backcrossed, andF2 individuals, Harrison and Owen pre-dicted that a minimum of six to eight genes underlie the skin color differences between European and West African populations. More recently, researchers considering contemporary admixed populations, which had undergone ad-mixture for many more generations, estimated that at least 10 genes contribute to population-level differences between European and West African populations (
      • Parra E.J.
      • Kittles R.A.
      • Shriver M.D.
      Implica-tions of correlations between skin color and genetic ancestry for biomedical research.
      ). At present, SLC24A5, SLC45A2 (MATP), KITLG, OCA2, TYR,and ASIPhave been implicated (reviewed in
      • Sturm R.A.
      Molecular genetics of human pigmentation diversity.
      ). Additional genes and separate mutations likely are responsible for the differences between Indigenous Americans and Europeans. Ancestry informative markers in CYP19A1, MYO5A, and SLC24A5 have shown admixture linkage in Hispanic populations (
      • Hoggart C.L.
      • Parra E.J.
      • Shriver M.D.
      • et al.
      Control of confounding of genetic associations in stratified populations.
      ). However, many more genes must be identified to account for the full range of variation within and among all human populations.
      Through analysis in admixed populations, rather than through the more widely used genome-wide association study approach, a picture of the evolutionary genetic architecture of human skin pigmentation is emerging and proving to be quite intricate.
      • Lamason R.L.
      • Mohideen M-L
      • Mest J.
      • et al.
      SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans.
      identified a mutation in SLC24A5 associated with the golden phenotype in zebrafish. An amino-acid substitution in the human homolog (SLC24A5*Thr111), discovered by the HapMap project, was found to have the single largest effect of any known gene on skin color differences between Europeans and West Africans. Interestingly, this mutation, which is fixed across most of Europe, is rare (~2.5%) in East Asia, suggesting that the mutations responsible for lighter skin pigmentation are not shared across these populations. SLC45A2 has also been shown to have a pattern or variation similar to SLC24A5, with the European skin-lightening allele being largely restricted to Europe and not found in East Asian populations (
      • Norton H.L.
      • Kittles R.A.
      • Parra E.J.
      • et al.
      Genetic evidence for the convergent evolution of light skin in Europeans and East Asians.
      ). This finding suggests that the mutation rose to fixation in Europe relatively recently, possibly under substantial selective pressure. To determine if the SLC24A5*Thr111 allele found in European populations has a functional effect on melanogenesis,
      • Ginger R.S.
      • Askew S.E.
      • Ogborne R.M.
      • et al.
      SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis.
      inserted it into the DNA of cultured melanocytes. The resulting modification in the trans-Golgi network-associated protein NCKX5 showed both a substantial decrease in cation exchange and downregulation of melanin production. Based on these observations, Ginger etal. hypothesize that this mutation could change the acidity in the trans-Golgi network, thereby modifying the activity of tyrosine, or, based on the timing of SLC24A5 expression during cell proliferation, it could modulate the trafficking of premelanosomes. These functional and admixturebased studies have been supplemented recently by several studies of genomic selection at pigmentation genes.
      The distributions of SLC24A5 and SLC45A2, in particular, and skin pigmentation more generally, show a steeper cline than is found for most human genes and phenotypes. This raises questions about the types of evolutionary forces that would give rise to such a pattern. Harrison and Owen were among the first to take a genetic approach to this question by examining the differences in skin reflectance levels (and, by inference, the genes of persons of known admixture). The variation among these admixed individuals sheds light on the differences that have evolved between West African and European populations. Recently, dozens of scans for selection across the human genome have confirmed strong, repeated selection on skin pigmentation genes in nearly every population considered (see Figure 1). This evidence is found more frequently in non-African populations than in African populations. This finding may be associated with the relatively recent colonization of new environments by these populations, as older selection is often more difficult to detect. In the Old World, a few genes show selection in both East Asian and European populations (e.g., KITLG), but there is also evidence of independent evolution of light skin pigmentation in European and East Asianpopulations—meaningthe shared phenotype does not result from a shared ancestral mutation. This is illustrated in the example of SLC24A5and SLC45A2, both of which show signatures of selection in Europe, but not elsewhere. These selective events mirror the migration of humans into Europe and Asia within the past 50,000 years. However, not all selective events were recent. For example, patterns of genetic variation at EDN3 support selection on pigmentation in the common ancestors of all humans prior to their divergence (
      • McEvoy B.
      • Beleza S.
      • Shriver M.D.
      The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model.
      ). Some researchers have suggested that this may reflect the initial darkening of skin pigmentation in pre-human ancestors as they lost the fur that protects the light skin of our chimpanzee cousins.
      Figure thumbnail gr1
      Figure 1The evolutionary genetic architecture of skin pigmentation in three populations. Although gene flow has occurred among human populations, differences in the allele frequencies at pigmentation genes are observed among. The genes listed have demonstrated signatures of selection as (1) shared among all humans, (2) shared between East Asian and European populations, (3) unique to East Asian populations, (4) unique to European populations, and (5) unique to West African populations.
      Among the most striking findings of many of these studies is the magnitude of the selection seen at skin pigmentation genes. A detailed description of the evolutionary pressures influencing skin pigmentation can be found in Jablonski and
      • Chaplin G.
      • Jablonski N.G.
      Human skin pigmentation as an adaptation to UV radiation.
      . Briefly, most research supports the hypothesis that darker skin pigmentation evolved— possibly more than once—because it reduces photolysis of folic acid, which protects against neural tube defects and is essential in DNA replication and repair, among other functions. There is more controversy surrounding the pre-vailing hypotheses for the adaptive benefit of lighter skin pigmentation. In a low UVR environment, less dermal melanin allows for the production of more vitamin D3 (needed for normal skeletal development as well as proper functioning of the immune and cardio-vascular systems). However, there is ongoing debate over the primacy of vitamin D in contributing to differential fitness (
      • Robins A.H.
      The evolution of light skin color: role of vitamin D disputed.
      ;Chaplin and
      • Jablonski N.G.
      • Chaplin G.
      The evolution of human skin coloration.
      ).
      Despite the ongoing investigations into the most likely pressures, what is clear is that selection on skin pigmentation has been as strong as or stronger than the selection on genes involved in immunity, reproduction, and diet— all of which are essential for human fitness. Several groups found marked over-representations of pigmentation genes among the strongest genomic signatures of selection in Europeans (
      • Lao O.
      • de Gruijter J.M.
      • van Duijn K.
      • et al.
      Signatures of positive selection in genes asso-ciated with human skin pigmentation as revealed from analyses of single nucleotide polymorphaisms.
      ;
      • Voight B.F.
      • Kudaravalli S.
      • Wen X.
      • et al.
      A map of recent positive selection in the human genome.
      ;
      • Myles S.
      • Somel M.
      • Tang K.
      • et al.
      Identifying genes underlying skin pigmentation differences among human populations.
      ). Pigmentation genes are more than twice as likely to show evidence of selection than randomly selected genes in both Chinese and European populations (
      • Williamson S.H.
      • Hubisz M.J.
      • Clark A.G.
      • et al.
      Localizing recent adaptive evolution in the human genome.
      ), and are significantly more likely to have high FST, a measure of the genetic distance between two populations, than randomly chosen regions of the genome (
      • Pickrell J.K.
      • Coop G.
      • Novembre J.
      • et al.
      Signals of recent positive selection in a worldwide sample of human populations.
      ). Taken together, the more than 25 pigmentation genes showing evidence of selection suggest a history of selection on skin color that likely stretches back to before the emergence of the first anatomically modern Homo sapiens.
      Despite the many genes already implicated in human skin color variation, a substantial number of the differences among populations cannot be explained. There are more than 350 putative pigmentation loci identified in mouse models and cataloged in the IFPCS color genes database (http://www.espcr.org/micemut/); what, if any, role these genes play in the unexplained variation in human pigmentation remains unknown. The size of this database gives credence to the hypothesis that many rare variants may contribute to pigmentation variation in humans. Identifying these rare variants will only be possible with the increased use of dense marker panels and sequencing to assess non-European and admixed populations. Moreover, it is essential that genome sequences be associated with phenotypes. Identification of variation among populations or individuals at known pigmentation genes fails to demonstrate that this variation manifests in phenotypic differences.
      Unpacking the ramifications of human evolution in shaping the genetic architecture and distribution of human skin pigmentation requires accurate and objective measurement techniques. Although self-report and subjective assessments may be sufficiently informative to identify genes for some traits (e.g., albinism, red hair, and blue eye color), more complete quantitative genetic analyses require measurements of the skin using reflectometry at specific wavelengths. As a larger fraction of the variation in human skin color is distributed across rather than within populations, admixed populations are an efficient means to discover genes and to study their combined effects. These components, employed together in Harrison and Owen more than 45 years ago, have shaped modern research into the evolutionary genetics of human skin pigmentation.

      Conflict Of Interest

      The authors state no conflict of interest.

      To Cite This Article

      Quillen EE, Shriver MD (2011). Unpacking human evolution to find the genetic determinants of human skin pigmentation. J Invest Dermatol 131: E5–E7

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