Which Of The Following Statements Does Not Apply To The Variation In Human Skin Color?

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What Controls Variation in Human Skin Colour?

• Gregory S Barsh

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• Published: October thirteen, 2003
• https://doi.org/x.1371/periodical.pbio.0000027

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Citation: Barsh GS (2003) What Controls Variation in Human Peel Color? PLoS Biol 1(ane): e27. https://doi.org/10.1371/journal.pbio.0000027

Published: October 13, 2003

Copyright: © 2003 Public Library of Science. This is an open up-access article distributed under the terms of the Public Library of Science Open up-Access License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Diversity of man appearance and form has intrigued biologists for centuries, but nearly 100 years afterwards the term "genetics" was coined by William Bateson in 1906, the genes that underlie this diversity are an unsolved mystery. 1 of the nearly obvious phenotypes that distinguish members of our species, differences in peel pigmentation, is also one of the near enigmatic. At that place is a tremendous range of human skin color in which variation tin can be correlated with climates, continents, and/or cultures, yet we know very little about the underlying genetic architecture. Is the number of common skin colour genes closer to five, 50, or 500? Do proceeds- and loss-of-function alleles for a small set of genes give ascension to phenotypes at opposite ends of the pigmentary spectrum? Has the result of natural selection on similar pigmentation phenotypes proceeded independently via like pathways? And, finally, should nosotros care nigh the genetics of man pigmentation if information technology is only peel-deep?

Why Should We Care?

From a clinical perspective, inadequate protection from sunlight has a major impact on human health (Armstrong et al. 1997; Diepgen and Mahler 2002). In Commonwealth of australia, the lifetime cumulative incidence of skin cancer approaches 50%, yet the oxymoronic "smart tanning" industry continues to grow, and there is controversy over the extent to which different types of melanin can influence susceptibility to ultraviolet (UV) radiation (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, agreement the genetic architecture of human skin color is probable to provide a greater appreciation of underlying biological mechanisms, much in the aforementioned way that mutational hotspots in the cistron TP53 accept helped to educate society about the risks of tobacco (Takahashi et al. 1989; Toyooka et al. 2003).

From a basic science perspective, variation in homo pare color represents an unparalleled opportunity for prison cell biologists, geneticists, and anthropologists to learn more about the biogenesis and movement of subcellular organelles, to ameliorate characterize the relationship between genotypic and phenotypic variety, to further investigate human origins, and to understand how recent human being evolution may have been shaped by natural selection.

The Color Variation Toolbox

Historically, measurement of man skin color is frequently based on subjective categories, e.g., "moderate brown, rarely burns, tans very hands." More recently, quantitative methods based on reflectance spectrophotometry have been applied, which allow reddening caused by inflammation and increased hemoglobin to be distinguished from darkening acquired past increased melanin (Alaluf et al. 2002b; Shriver and Parra 2000; Wagner et al. 2002). Melanin itself is an organic polymer built from oxidative tyrosine derivatives and comes in two types, a cysteine-rich reddish–yellow form known as pheomelanin and a less-soluble blackness--brown form known as eumelanin (Figure 1A). Discriminating among pigment types in biological samples requires chemical extraction, just is worth the effort, since the little we practise know about common variation in human pigmentation involves pigment blazon-switching. The characteristic phenotype of fair peel, freckling, and carrot-ruby hair is associated with large amounts of pheomelanin and minor amounts of eumelanin and is acquired past loss-of-function alleles in a single cistron, the melanocortin 1 receptor (MC1R) (Sturm et al. 1998; Rees 2000) However, MC1R variation has a significant result on pigmentation only in populations where reddish hair and fair skin are common (Rana et al. 1999; Harding et al. 2000), and its primary effects—to promote eumelanin synthesis at the expense of pheomelanin synthesis, or vice versa— contribute trivial to variation of skin reflectance among or between major ethnic groups (Alaluf et al. 2002a).

Figure 1. Biochemistry and Histology of Different Skin 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 transport poly peptide (MATP) and the pink-eyed dilution poly peptide (P) are melanosomal membrane components that contribute to the extent of paint synthesis inside melanosomes. (B) In that location is a gradient of melanosome size and number in dark, intermediate, and calorie-free skin; in improver, melanosomes of dark peel are more than widely dispersed. This diagram is based on ane 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.

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More important than the ratio of melanin types is the total amount of melanin produced. In addition, histological characteristics of dissimilar-colored peel provide some clues as to cellular mechanisms that are likely to drive pigmentary variation (Figure 1B). For the aforementioned body region, low-cal- and dark-skinned individuals have similar numbers of melanocytes (there is considerable variation between dissimilar torso regions), only pigment-containing organelles, called melanosomes, are larger, more than numerous, and more pigmented in dark compared to intermediate compared to low-cal pare, 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 germination of dopaquinone from tyrosine, or melanosomal membrane components like the pink-eyed dilution protein (P) or the membrane-associated transporter protein (MATP), which bear upon substrate availability and activity of TYR (Orlow and Vivid 1999; Vivid and Gardner 2001; Newton et al. 2001; Costin et al. 2003), are logical candidates upon which genetic variation could contribute to the variety of human skin colour.

Of equal importance to what happens within melanocytes is what happens outside. Each paint cell actively transfers its melanosomes to most 40 basal keratinocytes; ultimately, skin reflectance is determined by the amount and distribution of pigment granules within keratinocytes rather than melanocytes. In full general, melanosomes of African skin are larger and dispersed more than widely than in Asian or European skin (Figure 1). Remarkably, keratinocytes from dark skin cocultured with melanocytes from calorie-free peel give rising to a melanosome distribution pattern feature of dark peel, and vice versa (Minwalla et al. 2001). Thus, at least ane component of pare color variation represents a gene or genes whose expression and action touch the pigment jail cell environment rather than the paint jail cell itself.

Genetics of Peel Colour

For any quantitative trait with multiple contributing factors, the near important 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 i is able to control for the about important nongenetic cistron, exposure to sunlight.

Statements regarding the number of human pare color genes are attributed to several studies; one of the most consummate is past Harrison and Owen (1964). In that study, skin reflectance measurements were obtained from 70 residents of Liverpool whose parents, grandparents, or both were of European ("with a large Irish component") or Westward African ("generally from coastal regions of Ghana and Nigeria") descent and who were roughly classified into "hybrid" and "backcross" groups on this basis. An try to partition and analyze the variance of the backcross groups led to minimal estimates of 3 to four "effective factors," in this instance, independently segregating genes. Aside from the central give-and-take minimal (Harrison and Owen'south data could also be explained by 30–twoscore genes), i of the more interesting findings was that skin reflectance appeared to exist mainly condiment. In other words, hateful peel reflectance of "F1 hybrid" or "backcross hybrid" groups is intermediate between their respective parental groups.

An alternative approach for considering the number of potential human being pigmentation genes is based on mouse coat color genetics, one of the original models to ascertain and study cistron 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 furnishings outside the pigmentary system, no more than 15 or twenty mutations remain, many of which have been identified and characterized, and most of which take homo homologs in which null mutations cause albinism.

This brings us to the question of candidate genes for skin color, since, like any quantitative trait, a reasonable place to start is with rare mutations known to cause an farthermost phenotype, in this case Mendelian forms of albinism. The underlying assumption is that if a rare null allele causes a complete loss of paint, then a set of polymorphic, i.east., more than frequent, alleles with subtle effects on gene expression will contribute to a spectrum of skin colors. The TYR, P, and MATP genes discussed earlier are well-known causes of albinism whose chief effects are express to paint cells (Oetting and Male monarch 1999); amid these, the P gene is highly polymorphic but the phenotypic consequences of P gene polymorphisms are not yet known.

Independent of phenotype, a cistron responsible for selection of unlike skin 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 practice non change whatever amino acrid) alterations. Data take been collected only for MC1R, in which the most notable finding is a famine of allelic diversity in African samples, which is remarkable given that polymorphism for most 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 peel color around the world, a functional MC1R is probably important for night skin.

Selection for Pare Colour?

Credit for describing the relationship between latitude and skin color in modern humans is unremarkably ascribed to an Italian geographer, Renato Basutti, whose widely reproduced "skin color maps" illustrate the correlation of darker pare with equatorial proximity (Effigy 2). More recent studies by physical anthropologists have substantiated and extended these observations; a recent review and assay of data from more than 100 populations (Relethford 1997) institute that skin reflectance is lowest at the equator, so gradually increases, near 8% per 10° of breadth in the Northern Hemisphere and nearly 4% per 10° of latitude in the Southern Hemisphere. This pattern is inversely correlated with levels of UV irradiation, which are greater in the Southern than in the Northern Hemisphere. An of import caveat is that we do not know how patterns of UV irradiation have changed over time; more than importantly, nosotros do not know when skin color is likely to have evolved, with multiple migrations out of Africa and all-encompassing genetic interchange over the final 500,000 years (Templeton 2002).

Effigy ii. 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. Erratum annotation: The source of this image was incorrectly acknowledged. Corrected 12/xix/03. (B) Summary of 102 skin reflectance samples for males as a function of latitude, redrawn from Relethford (1997).

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Regardless, well-nigh anthropologists accept the notion that differences in UV irradiation have driven choice for dark human skin at the equator and for light homo skin at greater latitudes. What remains controversial are the verbal mechanisms of pick. The about 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 7-dehydrocholesterol into an essential forerunner of cholecaliferol (vitamin D₃); when non otherwise provided by dietary supplements, deficiency for vitamin D causes rickets, a characteristic pattern of growth abnormalities and bony deformities. An frequently-cited anecdote in back up of the vitamin D hypothesis is that Arctic populations whose skin is relatively dark given their latitude, 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 night-skinned humans migrating to polar latitudes tens or hundreds of thousands of years ago experienced similar problems is open up to question. In whatsoever case, a run a risk for vitamin D deficiency can just explain option for light skin. Among several mechanisms suggested to provide a selective advantage for dark skin in weather condition of high UV irradiation (Loomis 1967; Robins 1991; Jablonski and Chaplin 2000), the about tenable are protection from sunburn and skin cancer due to the concrete barrier imposed by epidermal melanin.

Solving the Mystery

Recent developments in several areas provide a tremendous opportunity to better understand the diversity 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 supersede misunderstanding and myths about skin color with education and scientific insight. The aforementioned approaches used to investigate traits such as hypertension and obesity—genetic linkage and association studies—can be applied in a more powerful manner to study human pigmentation, since the sources of ecology variation tin can be controlled and we have a deeper knowledge of the underlying biochemistry and cell biology.

This arroyo 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 colour may prove helpful in designing studies to investigate other quantitative traits. Current debates in the man genetics customs involve strategies for selecting populations and candidate genes to written report, the characteristics of sequence polymorphisms worth pursuing as potential affliction mutations, and the extent to which common diseases are acquired by common (and presumably ancient) alleles. While specific answers will exist dissimilar for every phenotype, there may be common themes, and some answers are better than none.

Harrison and Owen ended their 1964 study of man skin color past stating, "The deficiencies in the data in this written report are keenly appreciated past the writers, but since at that place announced at present to be no opportunities for improving the data, information technology seems justifiable to take the analysis as far every bit possible." Nearly 40 years later, opportunities abound, and the mystery of human pare color is set 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 hither emerged during a give-and-take series on Unsolved Mysteries in Biomedical Enquiry that was initiated by Mark Krasnow and the Medical Scientist Preparation Program at Stanford University.

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