What Makes Different Skin Colors

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• v.1(1); 2003 October
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PLoS Biol. 2003 Oct; one(one): e27.

What Controls Variation in Human Skin Colour?

Diversity of human advent and grade has intrigued biologists for centuries, but nearly 100 years after the term "genetics" was coined by William Bateson in 1906, the genes that underlie this diversity are an unsolved mystery. One of the nearly obvious phenotypes that distinguish members of our species, differences in skin pigmentation, is also one of the virtually enigmatic. In that location is a tremendous range of man skin color in which variation tin can be correlated with climates, continents, and/or cultures, even so we know very picayune about the underlying genetic architecture. Is the number of common peel colour genes closer to 5, fifty, or 500? Do gain- and loss-of-function alleles for a small set of genes give rise to phenotypes at opposite ends of the pigmentary spectrum? Has the effect of natural selection on similar pigmentation phenotypes proceeded independently via similar pathways? And, finally, should we care about the genetics of human pigmentation if it is but skin-deep?

Why Should We Intendance?

From a clinical perspective, inadequate protection from sunlight has a major bear upon on human health (Armstrong et al. 1997; Diepgen and Mahler 2002). In Australia, the lifetime cumulative incidence of skin cancer approaches 50%, yet the oxymoronic "smart tanning" industry continues to abound, and there is controversy over the extent to which unlike types of melanin tin can influence susceptibility to ultraviolet (UV) radiations (Schmitz et al. 1995; Wenczl et al. 1998). At the other end of the spectrum, inadequate exposure to sunlight, leading to vitamin D deficiency and rickets, has been generally cured by nutritional advances made in the early 1900s. In both cases, understanding the genetic architecture of human pare color is likely to provide a greater appreciation of underlying biological mechanisms, much in the same way that mutational hotspots in the gene TP53 accept helped to educate social club about the risks of tobacco (Takahashi et al. 1989; Toyooka et al. 2003).

From a basic science perspective, variation in human skin color represents an unparalleled opportunity for cell biologists, geneticists, and anthropologists to learn more than nigh the biogenesis and movement of subcellular organelles, to improve characterize the relationship between genotypic and phenotypic diversity, to farther investigate human origins, and to empathise how recent human evolution may take been shaped past natural selection.

The Color Variation Toolbox

Historically, measurement of man skin colour is ofttimes based on subjective categories, due east.1000., "moderate chocolate-brown, rarely burns, tans very easily." More recently, quantitative methods based on reflectance spectrophotometry have been applied, which allow reddening caused past inflammation and increased hemoglobin to be distinguished from darkening caused by increased melanin (Alaluf et al. 2002b; Shriver and Parra 2000; Wagner et al. 2002). Melanin itself is an organic polymer congenital from oxidative tyrosine derivatives and comes in 2 types, a cysteine-rich ruddy–yellow class known as pheomelanin and a less-soluble blackness--brown course known as eumelanin (Figure 1A). Discriminating amidst pigment types in biological samples requires chemic extraction, merely is worth the endeavor, since the piddling nosotros do know about common variation in human pigmentation involves pigment type-switching. The characteristic phenotype of fair pare, freckling, and carrot-red pilus is associated with big amounts of pheomelanin and small-scale amounts of eumelanin and is caused by loss-of-office alleles in a single gene, the melanocortin 1 receptor (MC1R) (Sturm et al. 1998; Rees 2000) However, MC1R variation has a meaning effect on pigmentation merely in populations where red hair and off-white pare are common (Rana et al. 1999; Harding et al. 2000), and its chief effects—to promote eumelanin synthesis at the expense of pheomelanin synthesis, or vice versa— contribute footling to variation of peel reflectance among or between major ethnic groups (Alaluf et al. 2002a).

Biochemistry and Histology of Different Peel Types

(A) Activation of the melanocortin 1 receptor (MC1R) promotes the synthesis of eumelanin at the expense of pheomelanin, although oxidation of tyrosine past tyrosinase (TYR) is required for synthesis of both pigment types. The membrane-associated send protein (MATP) and the pink-eyed dilution poly peptide (P) are melanosomal membrane components that contribute to the extent of pigment synthesis inside melanosomes. (B) There is a slope of melanosome size and number in dark, intermediate, and light skin; in add-on, melanosomes of dark pare are more than widely dispersed. This diagram is based on one published by Sturm et al. (1998) and summarizes data from Szabo et al. (1969), Toda et al. (1972), and Konrad and Wolff (1973) based on individuals whose recent ancestors were from Africa, Asia, or Europe.

More of import than the ratio of melanin types is the total corporeality of melanin produced. In improver, histological characteristics of unlike-colored skin provide some clues as to cellular mechanisms that are likely to drive pigmentary variation (Figure 1B). For the aforementioned body region, light- and night-skinned individuals accept similar numbers of melanocytes (there is considerable variation between unlike trunk regions), but paint-containing organelles, chosen melanosomes, are larger, more numerous, and more pigmented in night compared to intermediate compared to light skin, corresponding to individuals whose contempo ancestors were from Africa, Asia, or Europe, respectively (Szabo et al. 1969; Toda et al. 1972; Konrad and Wolff 1973). From these perspectives, oxidative enzymes like tyrosinase (TYR), which catalyzes the formation of dopaquinone from tyrosine, or melanosomal membrane components similar the pink-eyed dilution poly peptide (P) or the membrane-associated transporter poly peptide (MATP), which impact substrate availability and activeness of TYR (Orlow and Brilliant 1999; Brilliant and Gardner 2001; Newton et al. 2001; Costin et al. 2003), are logical candidates upon which genetic variation could contribute to the diversity of human pare color.

Of equal importance to what happens inside melanocytes is what happens outside. Each paint cell actively transfers its melanosomes to virtually 40 basal keratinocytes; ultimately, pare reflectance is determined past the corporeality and distribution of pigment granules within keratinocytes rather than melanocytes. In general, melanosomes of African peel are larger and dispersed more widely than in Asian or European pare (Effigy one). Remarkably, keratinocytes from night skin cocultured with melanocytes from low-cal pare give rise to a melanosome distribution pattern feature of dark skin, and vice versa (Minwalla et al. 2001). Thus, at least one component of pare color variation represents a gene or genes whose expression and action affect the paint cell environment rather than the pigment cell itself.

Genetics of Skin Colour

For any quantitative trait with multiple contributing factors, the most of import questions are the overall heritability, the number of genes likely to be involved, and the best strategies for identifying those genes. For skin colour, the broad sense heritability (defined as the overall effect of genetic vs. nongenetic factors) is very high (Clark et al. 1981), provided one is able to control for the well-nigh important nongenetic cistron, exposure to sunlight.

Statements regarding the number of man skin colour genes are attributed to several studies; one of the most complete is past Harrison and Owen (1964). In that written report, skin reflectance measurements were obtained from 70 residents of Liverpool whose parents, grandparents, or both were of European ("with a large Irish component") or West African ("mostly from coastal regions of Ghana and Nigeria") descent and who were roughly classified into "hybrid" and "backcross" groups on this basis. An endeavor to sectionalisation and analyze the variance of the backcross groups led to minimal estimates of three to four "effective factors," in this case, independently segregating genes. Aside from the key discussion minimal (Harrison and Owen's data could likewise be explained by 30–xl genes), one of the more than interesting findings was that skin reflectance appeared to be mainly additive. In other words, hateful skin reflectance of "F1 hybrid" or "backcross hybrid" groups is intermediate between their respective parental groups.

An alternative approach for considering the number of potential homo pigmentation genes is based on mouse coat color genetics, one of the original models to ascertain and study gene action and interaction, for which nearly 100 different genes have been recognized (Bennett and Lamoreux 2003; Jackson 1994). Setting aside mouse mutations that cause white spotting or predominant effects outside the pigmentary system, no more xv or twenty mutations remain, many of which take been identified and characterized, and nearly of which have homo homologs in which null mutations cause albinism.

This brings us to the question of candidate genes for skin color, since, similar any quantitative trait, a reasonable identify to commencement is with rare mutations known to cause an extreme phenotype, in this case Mendelian forms of albinism. The underlying assumption is that if a rare null allele causes a complete loss of pigment, then a set of polymorphic, i.due east., more frequent, alleles with subtle furnishings on factor expression will contribute to a spectrum of skin colors. The TYR, P, and MATP genes discussed earlier are well-known causes of albinism whose principal furnishings are limited to pigment cells (Oetting and Male monarch 1999); amidst these, the P gene is highly polymorphic just the phenotypic consequences of P cistron polymorphisms are not yet known.

Independent of phenotype, a cistron responsible for selection of different pare colors should exhibit a population signature with a large number of alleles and rates of sequence substitution that are greater for nonsynonymous (which change an amino acid in the protein) than synonymous (which do not modify any amino acrid) alterations. Information have been collected just for MC1R, in which the nigh notable finding is a famine of allelic diversity in African samples, which is remarkable given that polymorphism for about genes is greater in Africa than in other geographic regions (Rana et al. 1999; Harding et al. 2000). Thus, while MC1R sequence variation does not contribute significantly to variation in human pare color around the world, a functional MC1R is probably important for dark skin.

Selection for Skin Colour?

Credit for describing the human relationship between latitude and skin color in modern humans is commonly ascribed to an Italian geographer, Renato Basutti, whose widely reproduced "skin color maps" illustrate the correlation of darker pare with equatorial proximity (Effigy two). More recent studies by physical anthropologists have substantiated and extended these observations; a recent review and analysis of information from more than than 100 populations (Relethford 1997) establish that skin reflectance is everyman at the equator, then gradually increases, well-nigh viii% per 10° of latitude in the Northern Hemisphere and about 4% per 10° of latitude in the Southern Hemisphere. This blueprint is inversely correlated with levels of UV irradiation, which are greater in the Southern than in the Northern Hemisphere. An important caveat is that we do not know how patterns of UV irradiation have changed over time; more importantly, we do not know when skin color is likely to have evolved, with multiple migrations out of Africa and extensive genetic interchange over the last 500,000 years (Templeton 2002).

Relationship of Skin Color to Latitude

(A) A traditional skin color map based on the data of Biasutti. Reproduced from http://anthro.palomar.edu/vary/ with permission from Dennis O'Neil. (B) Summary of 102 pare reflectance samples for males equally a office of latitude, redrawn from Relethford (1997).

Regardless, most anthropologists accept the notion that differences in UV irradiation have driven choice for dark human peel at the equator and for calorie-free human skin at greater latitudes. What remains controversial are the verbal mechanisms of choice. The almost popular theory posits that protection offered by dark skin from UV irradiation becomes a liability in more polar latitudes due to vitamin D deficiency (Murray 1934). UVB (short-wavelength UV) converts vii-dehydrocholesterol into an essential forerunner of cholecaliferol (vitamin D₃); when not otherwise provided by dietary supplements, deficiency for vitamin D causes rickets, a characteristic design of growth abnormalities and bony deformities. An oft-cited anecdote in support of the vitamin D hypothesis is that Arctic populations whose skin is relatively dark given their breadth, such as the Inuit and the Lapp, have had a diet that is historically rich in vitamin D. Sensitivity of modern humans to vitamin D deficiency is evident from the widespread occurrence of rickets in 19th-century industrial Europe, but whether dark-skinned humans migrating to polar latitudes tens or hundreds of thousands of years ago experienced like problems is open up to question. In any example, a risk for vitamin D deficiency tin merely explain selection for calorie-free skin. Among several mechanisms suggested to provide a selective advantage for nighttime skin in atmospheric condition of high UV irradiation (Loomis 1967; Robins 1991; Jablonski and Chaplin 2000), the most tenable are protection from sunburn and skin cancer due to the physical barrier imposed by epidermal melanin.

Solving the Mystery

Recent developments in several areas provide a tremendous opportunity to improve understand the variety of man pigmentation. Improved spectrophotometric tools, advances in epidemiology and statistics, a wealth of genome sequences, and efficient techniques for assaying sequence variation offer the chance to supervene upon misunderstanding and myths virtually skin color with didactics and scientific insight. The same approaches used to investigate traits such every bit hypertension and obesity—genetic linkage and association studies—tin can be applied in a more powerful way to study human pigmentation, since the sources of environmental variation can exist controlled and we take a deeper knowledge of the underlying biochemistry and cell biology.

This approach is especially appealing given the dismal success rate in molecular identification of complex genetic diseases. In fact, understanding more about the genetic architecture of skin color may prove helpful in designing studies to investigate other quantitative traits. Electric current debates in the human genetics community involve strategies for selecting populations and candidate genes to study, the characteristics of sequence polymorphisms worth pursuing equally potential affliction mutations, and the extent to which common diseases are caused by common (and presumably ancient) alleles. While specific answers volition be dissimilar for every phenotype, there may be mutual themes, and some answers are improve than none.

Harrison and Owen concluded their 1964 report of human skin colour by stating, "The deficiencies in the information in this report are keenly appreciated by the writers, but since there announced at present to be no opportunities for improving the data, information technology seems justifiable to take the analysis every bit far as possible." Nearly xl years later, opportunities grow, and the mystery of human peel color is ready to exist solved.

Acknowledgments

I am grateful to members of my laboratory and colleagues who study pigment cells in a variety of different experimental organisms for useful discussions and to Sophie Candille for helpful comments on the manuscript. Many of the ideas presented here emerged during a discussion serial on Unsolved Mysteries in Biomedical Research that was initiated by Mark Krasnow and the Medical Scientist Training Plan at Stanford University.

Footnotes

Gregory S. Barsh is an acquaintance professor of Departments of Genetics and Pediatrics and an associate investigator at the Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States. Email: ude.drofnats.mgmc@hsrabg.

Footnotes

Erratum notation: The source of this image was incorrectly acknowledged. Corrected 12/nineteen/03.

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