Variation In Human Pigmentation Research Articles

Uncovering molecular mechanisms for amelanotic/hypopigmented primary cutaneous melanoma.

A portion of approximately 2-20% of cutaneous melanoma (CM) are diagnosed as amelanotic/hypopigmented melanoma (AHM) and represent a challenge for early diagnosis. Since the degree to which somatic mutations and copy number aberrations (CNA) in genes associated with skin-lightening or albinism may contribute to the loss of tumour pigmentation in AHM samples has not yet been addressed, we have investigated loss of function mutations of key pigmentation genes in matched germline and AHM as well as pigmented melanoma (PM) tumour DNA samples. An analysis of clinical and histopathological characteristics together with whole exome sequencing data of 34 fresh frozen primary CM, graded according to the amount of pigmentation present was performed. Together with germline and somatic variant analysis, 30 samples were previously analysed for CNA changes. This study focussed on germline and somatic variants in the coding region of 16 genes known to be associated with albinism/hypopigmentation or variation in human pigmentation in all samples. Chromosomal regions encompassing these 16 genes were examined for DNA copy loss or gain. The finding that red hair related MC1R and TYR R402Q loss of activity gene variant alleles and genotypes are associated with AHM was validated in this study. Germline AHM-related gene variants were enriched in 70% (n=7 of 10) of AHM patients vs 8.3% (n=2 of 24) of PM patients. This surprisingly high frequency of rare germline variants in AHM patients constitutes the "first hit" and confirms that AHM patients are more likely to be albinism allele carriers than patients with PM. Next, in CNA analysis of each tumour sample, 50% (n=4 of 8) AHM samples with a pigmentation gene variant had LOH in the region containing the corresponding gene, and 25% (=2 of 8) had loss-of-heterozygosity (LOH) in chromosomal regions of two AHM-related genes. This study proposes that the likely molecular mechanism for development of amelanogenesis in AHM is carriage of an albinism/hypopigmentation allele followed by LOH of the corresponding gene in the tumour.

MFSD12 mediates the import of cysteine into melanosomes and lysosomes.

Dozens of genes contribute to the vast variation in human pigmentation. Many of these encode proteins that localize to the melanosome, the lysosome-related organelle that synthesizes pigment, but have unclear functions 1,2. Here, we describe the MelanoIP method for rapidly isolating melanosomes and profiling their labile metabolite contents. We use it to study MFSD12, a transmembrane protein of unknown molecular function that when suppressed causes darker pigmentation in mice and humans 3,4. We find that MFSD12 is required to maintain normal levels of cystine, the oxidized dimer of cysteine, in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation 5,6. Tracing and biochemical analyses show that MFSD12 is necessary for the import of cysteine into melanosomes, and, in non-pigmented cells, lysosomes. Indeed, loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal storage disease caused by inactivation of the lysosomal cystine exporter CTNS (Cystinosin)7–9. Thus, MFSD12 is an essential component of the long-sought cysteine importer for melanosomes and lysosomes.

The Evolution of Tanning Needs Its Day in the Sun.

Variation in human pigmentation has long been an area of interest in biological anthropology, with the advent of genetic technologies allowing deeper plumbing of its evolutionary history. Genome-wide scans of selection show that pigmentation genes have undergone some of the strongest selection in many geographically distant populations. A variety of hypotheses for the photoprotective effects of melanin have been developed, but these hypotheses, as well as genetic studies, focus nearly exclusively on constitutive (basal) pigmentation levels. Failing to consider the contribution of the ultraviolet radiation (UVR) environment neglects the true interface between humans and our environment. Data drawn largely from dermatology demonstrate that constitutive pigmentation and tanning response are weakly coupled in populations from East Asia and the Americas. This suggests a possible role for persistent, UVR-induced pigmentation as a convergent adaptation akin to the protective effect of constitutive pigmentation. The adaptive potential of tanned skin, particularly in the Americas, where constitutive pigmentation is lower than expected, may fill in an important gap in our understanding of the evolution of skin color.

Obesity-related genetic variants, human pigmentation, and risk of melanoma

Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5, NEGR1, FLJ35779, ETV5, CADM2, and NUDT3 genes were nominally significantly associated with hair color among 5,876 individuals of European ancestry. The genetic score combining 35 independent obesity-risk loci was significantly associated with darker hair color (beta-coefficient per ten alleles = 0.12, P value = 4 × 10(-5)). However, single SNPs or genetic scores showed non-significant association with tanning ability. We further examined the SNPs at the FTO locus for their associations with pigmentation and risk of melanoma. Among the 783 SNPs in the FTO gene with imputation R (2) quality metric >0.8 using the 1,000 genome data set, ten and three independent SNPs were significantly associated with hair color and tanning ability respectively. Moreover, five independent FTO SNPs showed nominally significant association with risk of melanoma in 1,804 cases and 1,026 controls. But none of them was associated with obesity or in linkage disequilibrium with obesity-related variants. FTO locus may confer variation in human pigmentation and risk of melanoma, which may be independent of its effect on obesity.

Polymorphisms upstream of the melanocortin‐1 receptor coding region are associated with human pigmentation variation in a Brazilian population

We describe an association of two SNPs, rs3212345:C>T and rs3212346:G>A, located approximately 2.5 kb upstream of the melanocortin-1 receptor (MC1R) translation initiation codon, with pigmentation phenotype variation in a Southeast Brazilian miscegenated population. One hundred thirty-eight genetically unrelated subjects, with multicolor phenotype, were selected from the southeast region of Brazil. Skin, hair and eye color, and tanning ability were rated. Genotypes for each SNP (rs3212345:C>T and rs3212346:G>A) were determined. A logistic regression analysis was performed with the additive model to determine which of the polymorphisms contributed to a specific phenotype. We found that the rs3212345:C>T is associated with light skin, red hair, and poor tanning ability, while the rs3212346:G>A is associated with dark skin, black hair, and strong tanning ability. The presence of rs3212345-C and rs3212346-A alleles in human, chimpanzee, gorilla, orangutan, and marmoset genomes suggests that they are the ancestral alleles. These data suggest that the rs3212345-T and rs3212346-G alleles may have contributed to lighter pigmentation phenotypes in modern humans. Genotyping for these SNPs may prove useful to the fields of molecular anthropology and forensic genetics.

Gene–gene interactions contribute to eye colour variation in humans

Prediction of phenotypes from genetic data is considered to be the first practical application of data gained from association studies, with potential importance for medicine and the forensic sciences. Multiple genes and polymorphisms have been found to be associated with variation in human pigmentation. Their analysis enables prediction of blue and brown eye colour with a reasonably high accuracy. More accurate prediction, especially in the case of intermediate eye colours, may require better understanding of gene-gene interactions affecting this polygenic trait. Using multifactor dimensionality reduction and logistic regression methods, a study of gene-gene interactions was conducted based on variation in 11 known pigmentation genes examined in a cohort of 718 individuals of European descent. The study revealed significant interactions of a redundant character between the HERC2 and OCA2 genes affecting determination of hazel eye colour and between HERC2 and SLC24A4 affecting determination of blue eye colour. Our research indicates interactive effects of a synergistic character between HERC2 and OCA2, and also provides evidence for a novel strong synergistic interaction between HERC2 and TYRP1, both affecting determination of green eye colour.

What is the connection between red hair and Tourette syndrome?

Tourette syndrome is a chronic, idiopathic, childhood onset neuropsychiatric disorder with both motor and vocal tics. Tourette syndrome occurs worldwide and the clinical features are similar irrespective of the country of origin, with genetic causes suspected, but to date not proven. A link between red hair colour and Tourette syndrome has been hypothesised as a result of an observation that red hair is over represented in this condition. A causal association between red hair and melanocortin-1 receptor has been shown, and is the only gene that is known to explain physiological variation in human pigmentation. Melanocortins are believed to be involved in many disease states including pigmentary disorders, adrenal disorders, obesity, anorexia, prolonged and neuropathic pain, and inflammatory response. The mode of inheritance for Tourette syndrome is thought to be autosomal recessive, same as for red hair with both aggregating in families. To explore the hypothesis, 168 postal questionnaires sent to Tourette syndrome patients on the registry of the 'Tourette Syndrome Association of Australia', were analysed. In this study 22, 13% (95% CI 8.9-19.4) of the Tourette syndrome population had red hair. Data from Australian studies suggests, the normal population with red hair is 2-6%. The proportions of red haired individuals in this study were significantly higher than five of the eight population control groups. Fifty five percent of the Tourette syndrome patients had relatives with red hair. Of these 30% were first degree and 46% were second degree relatives, with a further 24% of more distant relatives. Many Tourette syndrome patients had multiple red haired relatives, since 90 patients yielded a total of 181 relatives with red hair. If this hypothesis is correct the MCIR gene, through a neurological effect, or a gene for Tourette syndrome, located on chromosome 16 in the vicinity of MC1R, could be on the causal pathway. As these figures demonstrate, the hypothesis that there is an association between red hair and Tourette syndrome needs further evaluation.

Association of Polymorphic Sites in the OCA2 Gene with Eye Colour Using the Tree Scanning Method

A number of genes are considered to affect normal variation in human pigmentation. Recent studies have indicated that OCA2 is the crucial gene involved in the high variation of iris colour present among populations of European descent. In this study, eleven polymorphisms of the OCA2 gene were examined in search of their association with different pigment traits. The evolutionary tree scanning method indicated that the strongest phenotypic eye colour variation is associated with the branch defined by nonsynonymous change rs1800407, which refers to amino acid causing change Arg419Gln located in exon 13. Single SNP analysis indicated that allele 419Gln is associated with green/hazel iris colour (p < 0.001). According to tree scanning analysis, the proportion of eye colour variation explained by this nucleotide position is merely 4%. Thus, additional variation present in the OCA2 gene and perhaps some other pigment related genes must be taken into account in order to explain the high phenotypic variation in iris colour.

Hermansky–Pudlak HPS1/pale ear Gene Regulates Epidermal and Dermal Melanocyte Development

The pale ear (ep) mouse strain is a model for the Hermansky-Pudlak syndrome type 1 (HPS-1), an autosomal recessive disorder causing pigmentary dilution, visual disturbances, bleeding diatheses, pulmonary fibrosis, and granulomatous colitis. The ep mice have a coat color very similar to the black-colored parental strain, C57BL/6. However, the ears and tails of ep mice are significantly hypopigmented compared with the control animals, suggesting that the gene mutation in ep mice reveals a differential regulation of melanocyte function in dorsal back skin melanocytes versus tail or ear skin. In this study, we analyzed the mutant phenotype in detail and determined that in the tail, the defective gene causes delayed onset of interfollicular epidermal melanocyte tyrosinase activity, decreased numbers of melanocytes in the interfollicular epidermis and dermis, and severe immaturity of tail epidermal melanosomes, findings not observed in dorsal back follicular melanocytes. These results highlight differences between follicular and interfollicular melanocyte biology and demonstrate that defects in the ep protein not only affect melanosome biogenesis, but also play a developmental role in determining interfollicular epidermal and dermal melanocyte function. The implications of these findings for the mechanisms governing physiologic variation in human pigmentation and for the pathogenesis of vitiligo are discussed.

Human pigmentation variation: Evolution, genetic basis, and implications for public health

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 trait. Numerous genetic studies have indicated that the average proportion of genetic variation due to differences among major continental groups is just 10-15% of the total genetic variation. In contrast, skin pigmentation shows large differences among continental populations. The reasons for this discrepancy can be traced back primarily to the strong influence of natural selection, which has shaped the distribution of pigmentation according to a latitudinal gradient. Research during the last 5 years has substantially increased our understanding of the genes involved in normal pigmentation variation in human populations. At least six genes have been identified using genotype/phenotype association studies and/or direct functional assays, and there is evidence indicating that several additional genes may be playing a role in skin, hair, and iris pigmentation. The information that is emerging from recent studies points to a complex picture where positive selection has been acting at different genomic locations, and for some genes only in certain population groups. There are several reasons why elucidating the genetics and evolutionary history of pigmentation is important. 1) Pigmentation is a trait that should be used as an example of how misleading simplistic interpretations of human variation can be. It is erroneous to extrapolate the patterns of variation observed in superficial traits such as pigmentation to the rest of the genome. It is similarly misleading to suggest, based on the "average" genomic picture, that variation among human populations is irrelevant. The study of the genes underlying human pigmentation diversity brings to the forefront the mosaic nature of human genetic variation: our genome is composed of a myriad of segments with different patterns of variation and evolutionary histories. 2) Pigmentation can be very useful to understand the genetic architecture of complex traits. The pigmentation of unexposed areas of the skin (constitutive pigmentation) is relatively unaffected by environmental influences during an individual's lifetime when compared with other complex traits such as diabetes or blood pressure, and this provides a unique opportunity to study gene-gene interactions without the effect of environmental confounders. 3) Pigmentation is of relevance from a public health perspective, because of its critical role in photoprotection and vitamin D synthesis. 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.

The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model

Skin pigmentation varies substantially across human populations in a manner largely coincident with ultraviolet radiation intensity. This observation suggests that natural selection in response to sunlight is a major force in accounting for pigmentation variability. We review recent progress in identifying the genes controlling this variation with a particular focus on the trait's evolutionary past and the potential role of testing for signatures of selection in aiding the discovery of functionally important genes. We have analyzed SNP data from the International HapMap project in 77 pigmentation candidate genes for such signatures. On the basis of these results and other similar work, we provide a tentative three-population model (West Africa, East Asia and North Europe) of the evolutionary-genetic architecture of human pigmentation. These results suggest a complex evolutionary history, with selection acting on different gene targets at different times and places in the human past. Some candidate genes may have been selected in the ancestral human population, others in the 'out of Africa' proto European-Asian population, whereas most appear to have selectively evolved solely in either Europeans or East Asians separately despite the pigmentation similarities between these two populations. Selection signatures can provide important clues to aid gene discovery. However, these should be viewed as complements, rather than replacements of, functional studies including linkage and association analyses, which can directly refine our understanding of the trait.

Evidence for Recent Positive Selection at the Human AIM1 Locus in a European Population

Two missense polymorphisms (E272K and L374F) of the AIM1 locus, encoding a melanocyte differentiation antigen, were shown to have a clear association with human ethnicities. These two nonpathogenic single nucleotide polymorphisms (SNPs) may be associated with human pigmentation variation. In this study, we investigated sequence variation in the coding region and exon-flanking sequence and found low genetic variation only in subjects of European descent. All four statistical tests applied to the 7.55-kb region surrounding the L374F polymorphism detected statistically significant deviations from selective neutrality in Europeans. In addition, haplotype analysis revealed that one haplotype carrying 374F was overrepresented in this population, and the low rate of variation, with some features of selective sweeps, was shown to be statistically significant. These results suggest that positive selection recently has been acting or has acted on at least this region of the melanogenic gene and that an advantageous haplotype spread rapidly in Europe.

Nature, Origin, and Variation of Human Pigmentation

From ancient times to the present, people have speculated on why and by what mechanisms humans could be as Black as some Africans and Australian aborigines to as White as the Celtic speakers of northern Europe. The shades of color in between these extremes illustrate a huge variation in human pigmentation. Because it is one of the most conspicuous traits, pigment variation has led some societies to attach labels and fabricate myths about people of different skin and/or hair colors. In many societies, up until the turn of the century, people of different skin coloration or lack of pigmentation (e.g., albinos) were treated as divine spirits who had special healing powers. Other societies ostracized these same people because they believed they were inferior and strange (Kromberg, Zwane, & Jenkins, 1987; D. Livingstone, 1857). Misunderstandings on pigmentation within the last 30 years have caused debate on the function of melanin and the evolution of skin pigmentation. In an attempt to place the discussion of pigmentation in a Eurocentric context, many authors added further confusion to the debate (Brues, 1975; Daniels, Post, & Johnson, 1972; Harrison, 1973; Montellano, 1993; Morison, 1985; Wasserman, 1965). Work has also been presented by Africans (on the continent and in the diaspora), which has been instrumental in the movements that redefine Blackness and the Africans' cultural and biological relationship with the universe (Barnes, 1988; Diop, 1973, 1974, 1978, 1981; Finch, 1991; King, 1990; Welsing, 1991). The works of Cheikh Anta Diop, Dr. Charles Finch, Carol Barnes, Richard King, Dr. Frances Cress Welsing, and others raised pertinent issues and continued dialogue in the struggle against Eurocentric analyses