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Key Words melanin, melanocortin 1 receptor (MC1R), eumelanin, pheomelanin, red hair
Abstract Differences in skin and hair color are principally genetically determined and are due to variation in the amount, type, and packaging of melanin polymers produced by melanocytes secreted into keratinocytes. Pigmentary phenotype is genetically complex and at a physiological level complicated. Genes determining a number of rare Mendelian disorders of pigmentation such as albinism have been identified, but only one gene, the melanocortin 1 receptor (MC1R), has so far been identified to explain variation in the normal population such as that leading to red hair, freckling, and sun-sensitivity. Genotype-phenotype relations of the MC1R are reviewed, as well as methods to improve the phenotypic assessment of human pigmentary status. It is argued that given advances in model systems, increases in technical facility, and the lower cost of genotype assessment, the lack of standardized phenotype assessment is now a major limit on advance.
CONTENTS INTRODUCTION BIOLOGY OF HUMAN PIGMENTATION Melanocytes and Melanogenesis Types of Melanin Body Site and Temporal Variation Functions of Melanin Defining Pigmentary Phenotypes ALBINISM AND RELATED DISORDERS Oculocutaneous Albinism Type 1 (OCA1, MIM 203100) Oculocutaneous Albinism Type 2 (OCA2, MIM 203200) Oculocutaneous Albinism Type 3 (OCA3, MIM 203290) THE MELANOCORTIN 1 RECEPTOR (MC1R), (MIM 155555) Red Versus Yellow [alpha]MSH and Human Pigmentation Genotype-Phenotype Correlation at the MC1R Spectrum of Sequence Diversity at the MC1R Role of Agouti in Man Evolution at the MC1R FUTURE STUDIES AND THE DEFINITION OF PHENOTYPE Phenotype of MC1R Variants Against "Black Skin"
Variation in skin pigmentation-skin and hair color--between people of different genetic ancestries is one of the most striking human characteristics (84). Study, and selection, of animals with particular pigmentary phenotypes has been of economic importance (5, 54, 55); pigmentation in the mouse and birds are classical experimental systems to study gene action (5, 54, 55,104); and at the same time, even among nonexperts, it is widely understood that human skin color and hair color are largely under genetic control, reflecting a person's genetic heritage (97). One would have expected, therefore, the study of the genetics of skin and hair color in man to be a subject of much study: it isn't. For instance, we remain almost completely ignorant of such simple issues as the mode of inheritance of blonde hair. Indeed, although textbooks frequently refer to hair or eye color as an example to illustrate the role of genetics in understanding human diversity of form, until recently little was known of the genetic mechanisms underpinning normal variation in skin and hair color (14, 97).
Over the past ten years this situation has begun to change (5, 54, 56, 93, 106). Advances based on the asset of the mouse fancy (5, 55, 104), coupled with the facility of modern molecular technology, have allowed the identification of a number of genes important in the determination of skin and hair color in man. The genetics of many Mendelian disorders of medical importance such as albinism (63) have become clearer: Existing clinical classifications have been shown to be inadequate, and mechanistic likenesses between what were once thought to be distinct processes outlined (63). This review briefly discusses these conditions, but takes as its focus advances in our understanding of pigmentary variation within what may be arbitrarily, but usefully, defined as the normal population, describing in some detail the role of the melanocortin 1 receptor in human pigmentation (MC1R)--the only gene identified to date that appears to underpin variation in the normal population (93).
The review is structured into four parts. The first outlines the biology of human pigmentation, highlighting methodological issues in the assessment of pigmentary phenotype. The emphasis is on the assessment of phenotype and presentation of an outline of how complicated (rather than necessarily complex) phenotype can be. In the second section, the major Mendelian disorders of pigmentation--chiefly albinism--are briefly summarized. The third section deals in some detail with the melanocortin 1 receptor (MC1R), its genetics and molecular physiology, and what we know of the relation between MC1R genotype and human phenotype. Finally, I discuss areas that need to be developed and explored further, paying particular attention to the need to develop appropriate assay systems to understand the genetics of human pigment diversity.
BIOLOGY OF HUMAN PIGMENTATION
Skin color is, except in rare pathological instances, the result of three pigments or chromophores: melanin, a brown/black or red/yellow polymer produced by melanocytes; hemoglobin in red blood cells in the superficial vasculature; and third, and to a much lesser degree, dietary carotenoids, sometimes most evident as a yellow color on the palms (90). Systematic differences in skin and hair color worldwide are principally the result of differences in the melanin content of skin.(1)
Melanocytes and Melanogenesis
Melanin is a complex quinone/indole-quinone-derived mixture of biopolymers produced in melanocytes from tyrosine (51, 52, 88). Melanocytes are dendritic neural crest-derived cells that migrate into epidermis in the first trimester. Melanin production is associated with the production of a number of toxic intermediaries and largely takes place within a lysosomal-like granule, the melanosome. Melanosomes are secreted via a poorly characterized process into adjacent keratinocytes. Unlike iris melanocytes, epidermal melanocytes are therefore said to be incontinent, i.e., they secrete their melanin. Melanin chemistry is complex and remains poorly understood for a number of reasons that make chemical characterization difficult: It is a mixture of polymers; many intermediates are unstable and rapidly autooxidize; methods to solubilize melanin alter its primary structure (51, 88).
Hair and epidermal pigmentation are, in so far as melanocytes are concerned, similar processes: in interfollicular skin, pigment is passed from the melanocytes to the adjacent keratinocytes; in hair, a similar process exists, with pigment being added to the growing keratinocytes that will make up the shaft of the hair (hair is just one form of epidermis). In interfollicular skin, the melanocytes are found within the epidermal compartment immediately adjacent or close to the basement membrane. Melanosomes passed to adjacent keratinocytes tend to produce caps over the nuclei, shielding the nuclear material from ultraviolet radiation (UVR). This melanin is most evident in the basal compartment, the site of the keratinocyte proliferative compartment, but melanin remains with keratinocytes as they differentiate and move upwards--this melanin will still exert photoprotective activity on the cells beneath it (by casting a UHV shadow). In hair, the majority of what is visible to the eye is a dead structure, the color is the result of melanocytes in the hair bulb passing their melanin to the adjacent keratinocytes as they undergo high rates of proliferation, stream pass the melanocytes, and then cornify (84, 90).
Types of Melanin
Although the nature of melanin has frustrated precise chemical description, genetic approaches coupled with a number of available chemical assays have allowed some useful insights (5,93). Melanin, with particular relevance to the current context, is commonly described as being of two principal classes: eumelanin, winch is brown or black, and pheomelanin, which results from the incorporation of cysteine, is yellow or red [for reviews see (51, 80, 88, 89, 124, 125)]. One simple classification or description of pigment status is to consider two axes of melanin production: the amount of melanin(s) produced, and the relative amounts of either eumelanin or pheomelanin. The absence or relative absence of both melanin types is associated with white hair; a preponderance of eumelanin, with brown or black hair; and a preponderance of pheomelanin with red or yellow hair. A more precise chemical characterisation of the brown melanin polymers is possible (89).
Finally, color is not merely the result of the chemical composition of the various melanin polymers. Melanin is packaged into melanosomes, and melanosomes vary in shape and size (90). Such differences, by way of light scattering, will influence color, a fact colorfully illustrated by the way amphibians and fish disperse their melanosomes to influence their skin's color characteristics (3).
Body Site and Temporal Variation
Differences in pigmentation between people are largely the result of differences in the amount and types of melanin produced, and the macromolecular structure and packaging of melanin, and not the number of melanocytes. There are, however, differences in pigmentation between different regions of the body as well as differences between people in the respective color of their hair and (interfollicular) skin (90). For instance, people from Northern Europe, such as many Scandinavians, have tight or blonde hair and pale skin but their skin pigment increases in response to UVR to a moderate degree (94). Conversely, many people from Western Europe, such as the Irish, have pale skin, red hair, and a skin that tans little in response to repeated UVR irradiation. In the (relatively) unexposed body sites, such as the buttock, their skin may be similarly colored to that of Scandinavians, but in response to UVR it tans less, and the hair color may well be different--red as compared with blonde (94). Similarly, the color of some Caucasian skin may be similar to that of some Asians and yet the latter appears to have a greater propensity to tan in response to UVR or develop pigmentation after other inflammatory insults (such as from skin disease).
Furthermore, any idea of a unitary pigmentary phenotype has to take into account not only that skin color may vary between different body regions, but also that hair color may vary both in time and site. Scalp hair may be blonde in childhood and become brown or black in adolescence, before becoming white again in middle or old age. Beard or pubic hair may be red, and the scalp hair black or dark brown. Skin color on sun-protected sites such as the buttock will be paler than on exposed sites but, …