The evolution of human skin pigmentation involved the interactions of genetic, environmental, and cultural variables (2024)

2.1. Folate‐dependent processes and their role in the evolution of eumelalin‐rich pigmentation

Research conducted first in the 1970s suggested that eumelanin in the skin may be protective against degradation of folate (Branda & Eaton,¹⁹⁷⁸). Appreciation of the centrality of folate in regulating DNA synthesis and repair grew rapidly in subsequent years, especially after the connection between folate deficiencies and the then common class of birth defects, neural tube defects, became widely recognized on the basis of epidemiological and experimental studies (Bower & Stanley,¹⁹⁸⁹; Elwood,¹⁹⁸³; Fleming & Copp,¹⁹⁹⁸; MRC Vitamin Study Research Group,¹⁹⁹¹). Folate, primarily in the form of 5‐methyltetrahydrofolate (5‐MTHF), is used at the cellular level for DNA production, the cysteine cycle, and regulation of hom*ocysteine. Knowledge of the specific actions, enzymatic and genetic regulation, and environmental sensitivity of folate grew quickly in light of increasing appreciation of the vitamin's extensive clinical significance (Branda & Blickensderfer,¹⁹⁹³; Giovannucci etal.,¹⁹⁹⁵; Luco*ck & Daskalakis,²⁰⁰⁰; Luco*ck etal.,²⁰⁰¹; Mastropaolo & Wilson,¹⁹⁹³). Appreciation of the importance of folate to DNA production and cell proliferation during embryogenesis and spermatogenesis and its likely sensitivity to UVR lead to initial formulations of a hypothesis about the protective effect of eumelanin pigmentation with respect to successful pregnancy outcomes (Jablonski,^{1992, 1999}). This work was further elaborated when it became possible to examine patterns of human skin pigmentation (as provided in reports of standardized skin reflectance measurements taken from indigenous peoples) relative to levels of remotely sensed UVR as measured by the NASA Total Ozone Mapping Spectrometer 7 (TOMS‐7) satellite (McPeters etal.,¹⁹⁹⁶). The TOMS‐7 and subsequent NASA satellites revolutionized the study of the effects of UVR on biological systems because they provided standardized, global, spatially continuous and gridded data that made it possible to assess the potential for biological damage due to solar irradiation, given the column ozone amount and cloud conditions on any day, for most places on earth (Langston etal.,²⁰¹⁷). The demonstration that human skin pigmentation was more highly correlated to UVB than to latitude (Jablonski & Chaplin,²⁰⁰⁰) or environmental parameters such as total solar irradiance, temperature, humidity, or rainfall. Chaplin (²⁰⁰⁴) indicated that UVR was the most important environmental determinant of skin pigmentation.

The nature of the specific protective effect of eumelanin in the epidermis and its effects of evolutionary fitness depends fundamentally on where the pigment is localized in the skin. Different wavelengths of UVR penetrate the skin to different depths of the epidermis and dermis, depending on the skin site, the amount and location of eumelanin, and the degree of keratinization of the skin (Meinhardt etal.,²⁰⁰⁸). Eumelanin is concentrated within keratinocytes in the stratum basale of the epidermis and in this position can afford considerable protection against damage by UVR, especially UVB (Fajuyigbe etal.,²⁰¹⁸; Fajuyigbe & Young,²⁰¹⁶). The stratum corneum itself affords some protection against UVB, but the degree of protection afforded depends on the thickness of individual layers, the number of layers, the degree of hydration of epidermis (Bruls etal.,¹⁹⁸⁴). The protective effect of stratum corneum itself is more significant with respect to UVB shielding in skin with less eumelanin content, but the magnitude of this effect is variable and, overall, minor compared to that of eumelanin itself (Hennessy etal.,²⁰⁰⁵; Kaidbey etal.,¹⁹⁷⁹; Olivarius etal.,¹⁹⁹⁷).

Most of the attention paid to the UVB shielding effects of eumelanin has been concerned with the sparing of damage to DNA and mitigation of carcinogenesis because of the pigment's significant UVR absorptive abilities, which slow the formation of highly mutagenic cyclobutane pyrimidine dimers (CPD) (Fajuyigbe etal.,²⁰¹⁸). The localization of most eumelanin in the stratum basale also serves to protect the capillary bed of the dermis from UVR, especially UVB. Penetration of UVA into the stratum basale is considerably greater and potentially more harmful in lightly pigmented skin (Meinhardt etal.,²⁰⁰⁸). Attention in this connection has been paid primarily to the cosmetic effects of UVA on the breakdown of connective tissues in the dermis (Battie etal.,²⁰¹⁴), but the demonstrated effects of UVA on vasodilation of arteries in the capillary bed of the dermis (Liu etal.,²⁰¹⁴) suggest that control of blood pressure may be of more fundamental importance.

Evidence for the hypothesis that permanent dark pigmentation in hominin skin was an adaptation to protect against UVR‐induced degradation of folate in the skin was originally based on direct effects on fertility such as potential embryo loss or faulty spermatogenesis (Jablonski & Chaplin,²⁰⁰⁰). These effects are hard to demonstrate in living human subjects or through retrospective epidemiological studies. Folate levels and folate metabolism are affected by primary folate deficiency, non‐folate B‐vitamin nutrient deficiencies, and genetic variations that influence cellular folate accumulation and utilization (Perry etal.,²⁰⁰⁴; Stover,²⁰⁰⁹), and these factors were generally not considered in 20th‐century surveys of folate levels within and between populations. The clearest epidemiological demonstration of the possible folate‐sparing effect of dark pigmentation against UVR challenge came from a study demonstrating the lower prevalence of NTDs in darkly pigmented as opposed to lightly pigmented South Africans, despite the greater affluence and presumed better diet of the latter group (Buccimazza et al., ¹⁹⁹⁴). Experimental studies of the effects of UVA and UVB on serum and red cell folate conducted in vitro and in vivo have yielded mixed results and have been difficult to interpret because of inconsistencies in experimental conditions and folate assay standardization (Borradale etal.,²⁰¹⁴; Borradale & Kimlin,²⁰¹²; f*ckuwatari etal.,²⁰⁰⁹; Gambichler etal.,²⁰⁰¹; Juzeniene etal.,²⁰⁰⁹; Wolf & Kenney,²⁰¹⁹), but most studies have found depletion of folate to varying degrees, depending on the wavelength and duration of UVR exposure, the pre‐exposure folate level, and the species of folate being assayed. Experimental demonstration of a decline in epidermal 5‐MTHF following UVA exposure in individuals with lightly pigmented but not darkly pigmented skin (Hasoun etal.,²⁰¹⁵) is potentially more significant because it indicates the importance of UVR‐induced folate depletion in the skin after a short UVR exposure and possible systemic depletion following prolonged exposure.

Appreciation of the central importance of folate on human health through its effects of DNA synthesis and methylation (Stover,²⁰⁰⁹) has been augmented in the last 20years by research demonstrating direct effects of folate on vascular function. These effects are pertinent to the evolution of skin pigmentation because of the role played by folate (as 5‐MTHF and as its further derivative, tetrahydrobiopterin, or BH₄) in improving nitric oxide (NO)‐mediated endothelial function and affecting vasodilation, blood pressure, and thermoregulation (Alexander etal.,²⁰¹³; Ng etal.,²⁰⁰⁹; Stanhewicz etal., ,^{2012, 2015}). UVA triggers cutaneous vasodilation, probably by releasing NO from preexisting stores of nitrite in the dermis (Liu etal.,²⁰¹⁴). The discovery that lower NO levels contributed to attenuated vasodilation in response to local heating of the skin of older individuals and that these responses could be restored by folate administration (Kenney,²⁰¹⁷) led to studies aimed at discovering the likely molecular mechanisms whereby folate improved NO bioavailability and protected endothelial function (Stanhewicz & Kenney,²⁰¹⁷). Recent findings indicating that acute UVB exposure attenuated NO‐mediated vasodilation of the cutaneous microvasculature via degradation of 5‐MTHF led to the pursuit of studies examining the effects of skin pigmentation, age, and folate status on vasodilation and thermoregulation (Wolf & Kenney,²⁰¹⁹). Available evidence indicates that folate degradation in response to UVR exposure is likely dose‐dependent and requires relatively large doses, repeated prolonged exposures, or both to observe reductions in serum or red blood cell folate (Wolf & Kenney,²⁰¹⁹). These environmental conditions would have been met in the early history of the genus hom*o when hominins were active in the sun or at least exposed to strong, equatorial sunlight for most daylight hours without the benefit of body coverings.

The sum of the effects of UVR‐induced folate loss on hominins cannot be accurately estimated, but there is little doubt that lowered fertility due to embryo loss and impaired spermatogenesis combined with impairments of vasodilation and temperature regulation would have represented direct and severe selective pressures favoring conservation of folate through increased eumelanin in the functionally naked skin of early hom*o. This does not mean that early hom*o had “dark skin,” but that selection favoring enhanced eumelanin pigmentation in the skin was evolving early in the evolution of the genus, along with polymorphisms in genes affecting folate metabolism. Because folate metabolism is regulated by several enzymes, including methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR), and because the activity of these enzymes varies according to different functional polymorphisms, these polymorphisms appear to have evolved in response to seasonal availability of folate and levels of UVR (Jones etal.,²⁰¹⁸; Luco*ck etal., ,^{2010, 2017}). It is thus probable that multiple mechanisms, including enhanced eumelanin pigmentation and conservation of folate through modification of enzymatically controlled metabolism, evolved in the face of seasonally dependent variations in folate availability and UVR levels.

2.2. Vitamin D and skin pigmentation

The importance of vitamin D in connection with the evolution of human skin pigmentation was first introduced by Murray (Murray,¹⁹³⁴) and later elaborated by Loomis (Loomis,¹⁹⁶⁷). These were based, at that time, on the recognition of the physiological importance of vitamin D in the growth and maintenance of the skeleton and understanding that production of vitamin D could be catalyzed only by specific wavelengths of UVR, from about 290–320nm, in the UVB range. Loomis originally opined that “white skins” had evolved to maximize cutaneous photoconversion of 7‐dehydrocholesterol (7‐DHC) into vitamin D under low UVB conditions at high latitudes and that “black skins” had evolved to protect against vitamin D toxicity due to potential overproduction of vitamin D at low latitudes under high UVB conditions (Loomis,¹⁹⁶⁷). Research into the mechanisms of cutaneous vitamin D synthesis by Holick and colleagues provided evidence that the process was tightly photochemically controlled and that the eumelanin content of the skin determined the rate of conversion of 7‐DHC to previtamin D₃ (pre‐D). (Clemens etal.,¹⁹⁸²; Holick etal.,^{1980, 1981}). This body of research demonstrated that increased eumelanin content of the skin could not be implicated in preventing vitamin D toxicity, but that depigmented skin facilitated cutaneous vitamin D production because of the fact that eumelanin competes with 7‐DHC for UVB photons (Holick etal.,¹⁹⁸¹). This research laid the groundwork for subsequent studies establishing the nature and genetic basis of the selective forces acting on the evolution of skin pigmentation in populations dispersing into and inhabiting regions of lower and more highly seasonal UVB (Beleza, Santos, etal.,²⁰¹³; Gozdzik etal.,²⁰⁰⁸; Hanel & Carlberg,^2020a; Izagirre etal.,²⁰⁰⁶; Jablonski & Chaplin,^{2000, 2010}; Makova & Norton,²⁰⁰⁵).

The body of research pertaining to the importance of vitamin D in bone metabolism and many cellular and immunological processes is now immense and is reviewed elsewhere (Lips,^{2006, 2007}; Lips etal.,²⁰¹⁴; Sassi etal.,²⁰¹⁸). Issues raised about the strength of natural selection acting to reduce eumelanin pigmentation in order to enhance cutaneous vitamin D synthesis (Elias etal.,²⁰⁰⁹; Elias & Williams,^{2013, 2016}; Robins,²⁰⁰⁹) have been countered by considerable evidence. The claim that loss of eumelanin and enhancement of cutaneous vitamin D production did not significantly improve the reproductive success of hominins dispersing to high latitudes (Robins,²⁰⁰⁹) was called into question by challenging incorrect assertions, including the claim that, even at the highest latitudes, stored vitamin D alone is sufficient to meet physiological needs during months when the UVB in sunlight is insufficient to catalyze cutaneous vitamin D production (Chaplin & Jablonski,^{2009, 2013}). Other claims centering around reduction in epidermal eumelanin having been selected for altered epidermal barrier functions have also been found deficient. These have focused on the significance of reduced levels of the protein filaggrin in the stratum corneum, leading to enhanced cutaneous synthesis of pre‐D and also on the argument that reduction in eumelanin production was favored by natural selection because of the importance of conserving energy (Elias & Williams,²⁰¹³). These explanations failed to demonstrate any significant evolutionary advantage for reduction of filaggrin (Jablonski & Chaplin,²⁰¹³), and further study of variation in loss of function genes affecting filaggrin in the epidermis failed to demonstrate a relationship between genetic variants and latitude (as a surrogate for UVB and cutaneous vitamin D synthesis potential) (Eaaswarkhanth etal.,²⁰¹⁶).

A key consideration in understanding the evolution of skin pigmentation in people living under high and less seasonally variable UVR conditions—generally within the tropics—is the degree to which eumelanin pigmentation actually slows the cutaneous biosynthesis of vitamin D. Recent experimental work done by Young and colleagues on human subjects has demonstrated that darkly pigmented individuals (Fitzpatrick type VI according to study protocols) exhibited a melanin vitamin D inhibition factor of 1.3–1.4 relative to lightly pigmented individuals (Fitzpatrick type II) (Young etal.,²⁰²⁰). They reasoned that this significant, but relatively modest, inhibitory effect may have been due to the fact that photoconversion of 7‐DHC into pre‐D occurs mostly in the stratum granulosum and stratum spinosum of the epidermis, above the heavily melanized layers of the basal epidermis (Young etal.,²⁰²⁰).

Vitamin D serves many critical functions in the body, and deficiency in the vitamin increases susceptibility to a range of developmental, chronic, and infectious diseases via its effects on the epigenome and on the expression of many genes on nearly all organs and tissue types in the body (Bora & Cantorna,²⁰¹⁷; Bustamante etal.,²⁰²⁰; Caccamo etal.,²⁰¹⁸; Carlberg,²⁰¹⁹; Sassi etal.,²⁰¹⁸). The recognition that vitamin D improves endothelial function by signaling for the transcription of endothelial nitric oxide synthase (eNOS) and thereby acting to preserve production of NO and healthy peripheral vascular function augments our understanding of the vitamin's consummate importance in human physiology and has potentially great consequences for our understanding of the evolution of skin pigmentation (Wolf etal.,²⁰²⁰; Wolf & Kenney,²⁰¹⁹). Vitamin D is produced in the upper epidermis through UVB‐induced catalysis of 7‐DHC into pre‐D, and it is required in the dermis to preserve NO production required for healthy vasodilation. This important function of vitamin D probably accounts for the intriguing finding of reduced all‐cause mortality in a large cohort of lightly pigmented Scandinavian women reported by Lindqvist and colleagues (Lindqvist etal.,²⁰²⁰). The role of vitamin D’s role in eNOS signaling, control of vasodilation, and regulation of blood pressure warrants further investigation in an evolutionary context with respect to the evolution of skin pigmentation under low UVR conditions (Wolf etal.,²⁰²⁰). It is also of potentially great relevance in clinical contexts with respect to the importance of low and carefully controlled doses of natural UVR sufficient to produce vitamin D and maintain healthy vasodilation and blood pressure (Alfredsson etal.,²⁰²⁰; Wolf etal.,²⁰²⁰). This consideration is of particular concern in habitually indoor‐dwelling people, older people with attenuated cutaneous vitamin D production abilities, and darkly pigmented people living in low UVR environments.

The manifest importance of vitamin D in human physiology implies that complex, genetically based mechanisms for establishing and maintaining vitamin D sufficiency have evolved in the course of human evolution. Modification of the production and packaging of eumelanin in the skin affects the penetration of UVB into the epidermis and the physical potential for photoconversion of 7‐DHC into pre‐D, but levels of vitamin D can and are affected by many other processes and pathways. Advances in genomics and archeogenomics have made possible a significant shift in our understanding of these processes in recent years, to the extent that there is now greater appreciation of how the evolution of genetic variants associated with vitamin D metabolism and signaling has evolved in concert with skin pigmentation. As modern populations have dispersed and undergone bottlenecks and admixture, variant genes encoding for proteins responsible for photoconversion of 7‐DHC into pre‐D (Kuan etal.,²⁰¹³) and governing transport, metabolism, and signaling of vitamin D, including DHCR7, GC, CYP2R1, and CYP24A1 (Hanel & Carlberg,^{2020a, 2020b}), have undergone changes in frequency appeared and become common. Genetic changes affecting vitamin D metabolism rather than skin pigmentation have been particularly important (Hanel & Carlberg,^{2020a, 2020b}), especially at extreme northern high latitudes where levels of UVB are low and highly seasonal, creating conditions for only short and sporadic cutaneous photosynthesis of vitamin D (Chaplin & Jablonski,²⁰¹³; Jablonski & Chaplin,²⁰¹⁰). Lastly, the nature of the genetic changes occurring was being mediated by numerous lifestyle variables (including diet, typical body coverings and kinds of shelter, and patterns of daily activity) which affected vitamin D status and would have contributed to individual survival and reproductive success. Thus, consideration of the contingent nature of biocultural compromises in different places and at different times is essential to the study of the evolution of human skin pigmentation and human health (Chaplin & Jablonski,²⁰¹³). Genetically driven changes in skin pigmentation favoring less integumental eumelanin were only one factor in the “adaptive equation” contributing to healthy vitamin D status.

2.3. Likely skin pigmentation of early hom*o sapiens

The probable loss of most body hair during the early evolution of the genus hom*o left the body highly vulnerable to the effects of UVR, as well as to many other potentially harmful physical, chemical, and biological agents. The evolution of protective eumelanin‐rich constitutive pigmentation in the tropical‐dwelling, African ancestors of all modern people was probably a step‐by‐step process involving many genetic loci. Early in the history of skin pigmentation genomics, considerable attention was focused on the primacy of a selective sweep affecting the MC1R locus to eliminate variation and establish permanent dark pigmentation in the human lineage (Rana etal.,¹⁹⁹⁹; Rogers etal.,²⁰⁰⁴). Since those early studies, the field of skin pigmentation genomics has been revolutionized by the development of high‐throughput sequencing technologies coupled with the application of genome‐wide association studies (GWAS) for identifying multiple genes associated with human skin pigmentation and the execution of genome‐wide scans of natural selection. These developments have made possible the identification of many genes contributing to skin pigmentation, and the degree to which they have been acted upon by natural selection (Feng etal.,²⁰²¹). For many loci of interest, application of coalescent studies on specific derived alleles has made possible estimation of when was the most recent common ancestor of existing derived alleles first occurred.

Based on these studies, it is possible to estimate that multiple derived alleles contributed to the evolution of dark pigmentation in ancestral H. sapiens. These include two derived alleles of the major facilitator superfamily domain‐containing protein 12 (MFSD12), which appeared at or near the time of origin of H. sapiens, about 0.3mya (Crawford etal.,²⁰¹⁷; Feng etal.,²⁰²¹). Other candidate loci, including multiple alleles of the DNA damage‐binding protein 1 (DDB1), may also have been present in early H. sapiens because of their presence at high frequencies in modern African and in some non‐European populations today (Crawford etal.,²⁰¹⁷; Feng etal.,²⁰²¹) (Figure1), thus suggesting that derived alleles were carried in one of the populations that dispersed along the southern and southeast Asian coasts and into Melanesia. Detailed examination of the geographical pattern of variation in one of these alleles, rs7948623 (T), further suggests that it may have been under positive selection, resulting in further skin darkening, in regions of the world including East Africa, parts of South Asia, and Melanesia with extremely high environmental UVR (Feng etal.,²⁰²¹). The key point is that the ancestor of all H. sapiens had darkly pigmented, but not necessarily maximally darkly pigmented, skin (Chaplin,²⁰⁰⁴; Hanel & Carlberg,^2020a). In Africa today, and among many South Asians and Melanesians, there is great variation in the darkness of “darkly pigmented” skin that appears to be due to variations in UVR intensity (Chaplin,²⁰⁰⁴; Jablonski & Chaplin,^2014a). Genomic studies of the last two decades have revealed that the genetic “palette” of skin pigmentation gene variants is great and that many combinations of multiple variant genes have contributed to the complex pattern of skin pigmentation phenotypes and genotypes observed today. Under more highly seasonal UVR regimes, the evolution of enhanced tanning abilities and genes contributing to rapid development of facultative pigmentation has been favored (Quillen etal.,²⁰¹⁹). Despite the manifest importance and relevance of tanning genetics to skin cancer dynamics and skin esthetics, relatively little genomics‐based research on the topic has been done, especially in African and indigenous American populations. Although advances in evolutionary skin pigmentation genetics have been enormous, there is an urgent need to validate candidate skin pigmentation variants using GWAS and scans of natural selection, using functional experiments in vitro and in vivo (Feng etal.,²⁰²¹).

3.1. Africa

The earliest history of H. sapiens occurred in Africa and has been reconstructed through a combination of sparse fossil evidence and inferences from archeogenomics (Galway‐Witham & Stringer,²⁰¹⁸; Henn etal.,²⁰¹⁸; Hublin etal.,²⁰¹⁷; Stringer,²⁰¹⁶; White etal.,²⁰⁰³). The skeletal traits which define H. sapiens emerged in Africa over the course of about 100,000years, from 0.3 to 0.2mya (Galway‐Witham & Stringer,²⁰¹⁸). By 0.2mya, diverse forms of anatomically modern humans lived in Africa, mostly in dispersed regional and environmental enclaves, and pursued technologically and artistically complex but locally distinctive cultures (Scerri etal.,²⁰¹⁸). The genetic history of modern people in Africa thus reflects deep roots, and complex patterns of isolation and reticulation. Some of the reasons for this can be readily appreciated when the vastness, ecological diversity, and remarkable latitudinal extent of Africa are considered. Other reasons are demographic. Until the advent of agriculture and animal husbandry in Africa about 5 kya, most populations of hunter‐gatherers were relatively small, scattered, and probably experienced repeated bottlenecks and periods of expansion due to sometimes dramatic environmental perturbations (Ambrose,¹⁹⁹⁸; Hsieh etal.,²⁰¹⁶; Powell etal.,²⁰⁰⁹).

In the specific context of human skin pigmentation evolution in Africa, the diversity of UVR regimes in the African continent, including the highly seasonal pattern of UVB in the far south, is one of many factors that must be appreciated (Coussens etal.,²⁰¹⁵; Jablonski & Chaplin,^2014a). These patterns are reflected in the complex mosaic of genes that contribute to skin pigmentation across Africa today (Crawford etal.,²⁰¹⁷; Feng etal.,²⁰²¹; Lin etal.,²⁰¹⁸; Martin etal.,²⁰¹⁷; Rocha,²⁰²⁰). The strong and relatively seasonally invariant UVR regimes of East Africa, including the Horn of Africa and the East African coast, have continued to drive selection for increasingly dark skin pigmentation in these regions (Chaplin,²⁰⁰⁴; Feng etal.,²⁰²¹; Jablonski & Chaplin,^{2000, 2014a}). This trend has also been influenced by the wearing of relatively little clothing during daylight hours and while active, up to and including historical times, because of extreme environmental heat. A trend toward increasing pigmentation darkening also appears to have occurred in West Africa, but the combination of genetic variants contributing to this is less clear (Crawford etal.,²⁰¹⁷; McEvoy etal.,²⁰⁰⁶). The nature of the genes and genetic epistasis contributing to the enhancement of dark constitutive pigmentation and tanning abilities in equatorial African people (and elsewhere) is still poorly understood, but it is likely that insights will come from functional genomic studies and those focused on the study of recently admixed populations in order to determine causal effects (Beleza, Johnson, etal.,²⁰¹³; Lona‐Durazo etal.,²⁰¹⁹; Rocha,²⁰²⁰).

The other major phenomena that have influenced the evolution of skin pigmentation in Africa were recent human dispersals, but not those associated with European colonialism. The first of these was the dispersal of people from Eurasia via the Afro‐Arabian Peninsula into eastern and southern Africa. These people carried derived variants of SLC24A5 (solute carrier family 24 [sodium/potassium/calcium exchanger], member 5) associated with depigmented skin (Martin etal.,²⁰¹⁷). These variants spread relatively quickly southward, beginning around 5,000yr (Crawford etal.,²⁰¹⁷), and were favored under positive selection in the far southern latitudes of Africa among Khoe‐san hunter‐gatherers and pastoralists, especially in the last 2,000yr (Lin etal.,²⁰¹⁸; Martin etal.,²⁰¹⁷). The evidence for positive selection for SLC24A5 variants that conferred some skin lightening in the indigenous Khoe‐san peoples inhabiting the lower and more seasonal UVR conditions of southern Africa is significant. It complements evidence that non‐synonymous mutations in the MC1R locus exist in the Khoe‐san (John etal.,²⁰⁰³) and that other variant forms of MC1R may have arisen in southern African under relaxed selection. It also illustrates that a new genetic variant can achieve high frequency in human populations after being introduced if it affects a trait that positively impacts fitness. This result is also important because it puts paid to arguments that the relatively light skin pigmentation of the Khoe‐san was due to genetic admixture with Europeans early in colonial history.

The second major dispersal event within Africa that has affected the distribution of skin pigmentation phenotypes and the continuing evolution of skin pigmentation by population admixture is the expansion of Bantu‐language speakers from western Africa into central, eastern, and southern Africa, beginning about 5.6 kya (Li etal.,²⁰¹⁴; Patin etal.,²⁰¹⁷). The timing and nature of dispersals of Bantu‐speaking peoples have been characterized using genome‐wide microsatellite markers and are now understood to have, in general, proceeded from west to east, and then south (Li etal.,²⁰¹⁴). Linguistic, archeological, and genetic evidence for the movement of Bantu‐speaking agriculturalists attests that this was one of the largest and most genetically impactful dispersals in human history because of its effects on preexisting populations of rainforest‐ and desert‐dwelling hunter‐gatherers in western, central, and southern Africa (Patin etal.,²⁰¹⁷). With respect to skin pigmentation, the ingress of very darkly pigmented people into southern Africa in recent millennia appears to have adversely affected vitamin D status and health, especially in modern, mostly urban populations in southernmost Africa (Coussens etal.,²⁰¹⁵). A hypothetical skin pigmentation timeline for the major regions of Africa is presented in Figure2.

3.2. Coastal south and southeast Asia, Melanesia, and Australia

The timing and routes of the dispersal of H. sapiens into Eurasia, and the population sizes of dispersing populations, have been studied intensively by geneticists and genomicists in the last 20years and are now reasonably well understood (Henn etal., ,^{2012, 2016}; Nielsen etal.,²⁰¹⁷; Pagani etal.,²⁰¹⁶; Reyes‐Centeno etal.,²⁰¹⁴). The number, timing, and exact routes of these dispersals are still debated, but genetic and paleontological evidence indicates that the first groups of H. sapiens dispersed out of Africa beginning about 70 kya, following a primarily coastal route from the Afro‐Arabian Peninsula into south and southeast Asia, thence into Melanesia and, eventually, into Australia (Groucutt etal.,²⁰¹⁵; James etal.,²⁰¹⁹; Malaspinas etal.,²⁰¹⁶; Pagani etal.,²⁰¹⁶; Posth etal.,²⁰¹⁶; Reyes‐Centeno,²⁰¹⁶; Reyes‐Centeno etal.,²⁰¹⁴). Divergence of populations ancestral to modern Papuans and Aboriginal Australian from Eurasians is estimated from genomic evidence to have occurred 72–51 kya, after which time admixture of ancient Denisovans with an ancestral Papuan‐Australian population occurred (Malaspinas etal.,²⁰¹⁶).

Populations dispersing and living along the coasts of southern and southeastern Asia in the Late Pleistocene experienced strong and seasonally relatively invariant UVR levels, favoring maintenance of dark pigmentation, probably involving selection on ancestral gene variants MFSD12 and DDB1 (Feng etal.,²⁰²¹) and variant forms of SLC24A5 and OCA2 (Jinam etal.,²⁰¹⁷; Stokowski etal.,²⁰⁰⁷). The contribution of Denisovan genes to these populations is recognized (Gittelman etal.,²⁰¹⁶; Jinam etal.,²⁰¹⁷) but the genetic contribution of Denisovans to skin pigmentation is not yet clearly established. In considering the evolution of skin pigmentation in these populations, the effects of population size, diet, and habitual raiment must be considered, even if the strength of these influences cannot be quantified easily. The populations dispersing along these coasts were hunter‐gatherers and probably of small population size. Some of these, notably several so‐called “Negrito” populations, manifest genetic evidence of severe population bottlenecks as well as recent admixture (Jinam etal.,²⁰¹⁷). Based on ethnographic accounts of living Andamanese, these people ate traditional diets of fish, wild boar, shellfish, turtle, and turtle eggs, along with foraged tubers and fruits (Headland,¹⁹⁸⁹; Sahani,²⁰¹⁰). They also wore few, if any, body coverings. This lifestyle conduced to a high level of vitamin D sufficiency, thereby rendering unlikely the development of any level of vitamin D insufficiency as long as a traditional diet was being consumed. This may have released a selective constraint on further pigment darkening.

Knowledge of the skin pigmentation phenotypes and pigmentation genes of Melanesians and Australian Aboriginals is limited, but the available data indicate that skin pigmentation is very dark, with Bougainvilleans exhibiting the darkest levels of pigmentation measured by reflectometry among people living today (Jablonski & Chaplin,²⁰⁰⁰; Norton etal.,²⁰⁰⁶). Similar, extremely dark pigmentation reportedly existed among Aboriginal Tasmanians (Diamond,²⁰⁰⁵). Melanesian populations notably lack evidence for purifying selection at the MC1R locus (Norton etal.,²⁰¹⁵) and, thus, their extremely dark pigmentation must be accounted for by enhanced eumelanin production and tanning abilities controlled by other genes, possibly MFSD12 and DDB1, and others. Under these conditions, dark skin pigmentation evolved to what appears to be a threshold level, past which no further darkening appears to be possible (Chaplin,²⁰⁰⁴). It is noteworthy that the people who exhibit some of the darkest skin pigmentation observed are not only exposed to extremely high environmental UVR, but, traditionally, wear few clothes and eat diets rich in fish. These are also mostly coastal and island populations that have also been relatively isolated throughout most of history because of lack of accessibility over land. Thus, they were not subject to high levels of admixture from mainland groups. These populations are exemplars of one of the extremes of skin pigmentation evolution, occurring as the result of people being isolated in geographic dead‐ends, while simultaneously experiencing little admixture and positive selection. In these cases, diets replete in vitamin D may have worked to further promote the evolution of increasingly dark, protective eumelanin pigmentation up to a threshold level. This hypothesis invites further study of genes affecting skin pigmentation, vitamin D metabolism, and the eumelanin threshold effect. A hypothetical skin pigmentation timeline for coastal South and Southeast Asia, Melanesia, and Australia is presented in Figure3.

3.3. Hinterland Eurasia and the Americas

The evolution of skin pigmentation in Eurasia, especially in Europe, has been the focus of considerable attention (Norton,²⁰¹⁹; Quillen etal.,²⁰¹⁹), especially with the advent of archeogenomics and the functional genomic interpretation of skin pigmentation genes in ancient Eurasian populations. New and comprehensive reviews of Eurasian skin pigmentation genomics in relation to historical genomics should be consulted for details, especially with regard to the movements of peoples and genes in historic times and their likely effects on skin pigmentation (Allentoft etal.,²⁰¹⁵; Hanel & Carlberg,^2020a; Ju & Mathieson,²⁰²⁰; Røyrvik etal.,²⁰¹⁸). Here, I reiterate salient points of those reviews and other works and supplement them sparingly with some additional insights.

Inferences about the likely evolutionary factors affecting human skin pigmentation among people living at high latitudes in Eurasia have been mooted in the literature for nearly a century (Loomis,¹⁹⁶⁷; Murray,¹⁹³⁴). Emphasis on loss of pigmentation in order to promote cutaneous vitamin D photosynthesis at high latitudes has been emphasized, but so too has the importance of consumption of vitamin D‐rich foods in regions where cutaneous biosynthesis is insufficient to fulfill year‐round needs for the vitamin (Chaplin & Jablonski,²⁰¹³; Jablonski & Chaplin,^{2000, 2010}). Elucidation of the genetic basis for depigmentation began with the landmark study in which a zebrafish model was used to demonstrate the action of the SLC24A5 variant common to northwestern European people (Lamason etal.,²⁰⁰⁵). The absence of the same variant in East Asian peoples living at similar latitudes (Lamason etal.,²⁰⁰⁵; Norton etal.,²⁰⁰⁷) inaugurated an intensive search for the genes responsible for depigmentation in East Asians. Subsequent historical genomic studies of modern and ancient populations have shown that depigmentation in Europeans, especially among far northern‐dwelling peoples, occurred in a step‐wise fashion, beginning with a shared variant of the Kit ligand (KITLG) gene in the common ancestor of western European and east Asian people (Hanel & Carlberg,^2020a; Lao etal.,²⁰⁰⁷; Sulem etal.,²⁰⁰⁷). Extreme depigmentation in northwestern Europeans involved multiple skin pigmentation genes and appears to have been further promoted by the introduction of agriculture (Brace etal.,²⁰¹⁹). At the highest European latitudes, including Scotland, genetic variants contributing to mostly depigmented or lightly pigmented skin comprise one component of the biocultural compromise necessary for survival and reproductive success under low and markedly seasonal UVB at extreme high latitudes (Chaplin & Jablonski,²⁰¹³). Modifications of genes affecting the production and metabolism of vitamin D constitute another part of this compromise, in some cases offsetting extreme depigmentation in high‐latitude Eurasian populations (Hanel & Carlberg,^2020a). The last component of the high‐latitude biocultural compromise is a vitamin D‐rich diet, focused on oily fish and, depending on the location, also including marine mammals and wild or domesticated reindeer (Chaplin & Jablonski,²⁰¹³; de Barros Damgaard etal.,²⁰¹⁸; Ross etal.,²⁰⁰⁶). The fragility of the biocultural compromise at high latitudes in Eurasia is illustrated by the high prevalence of chronic lifestyle diseases, including cardiovascular disease and metabolic syndrome, in populations that mostly or completely abandon vitamin D‐rich diets (Chaplin & Jablonski,²⁰¹³; Ross etal.,²⁰⁰⁶).

The evolutionary trend toward depigmented skin in high‐latitude Eurasian populations involved numerous genes affecting skin pigmentation and vitamin D metabolism and did not result in uniform adaptive strategies across the great expanse of northern Eurasia favoring extreme depigmentation (Hanel & Carlberg,^{2020a, 2020b}). Rather, what we observe is that skin pigmentation has evolved as part of a larger genetic and cultural package favoring enhanced availability and economical utilization of dietary and cutaneously synthesized vitamin D. Because habitation of far‐northern latitudes in Eurasia was predicated on the development of material culture, including sewn clothing, which afforded protection against extreme cold and wind, the surface area of skin available for cutaneous vitamin D production was reduced, thereby intensifying the selective pressure for depigmentation. A further consideration is that increased thickening of the stratum corneum in response to repeated outdoor conditions and UVR (Oh etal.,²⁰⁰⁴) would also have served to attenuate any possible cutaneous vitamin D production under these conditions (Young etal.,²⁰²⁰).

In far northwestern Europe, the extreme physical isolation of people in northernmost Britain at the end of the Pleistocene and early Holocene favored maximal skin depigmentation and a near absence of eumelanin in the skin. This was made possible by positive selection for the classic depigmentation variant of SLC24A5, and by relaxation of selection pressure on the MC1R locus, resulting in high levels of polymorphism at the locus (Harding etal.,²⁰⁰⁰; Latreille etal.,²⁰⁰⁹; Rees,²⁰⁰⁰). Under these circ*mstances, cutaneous production of vitamin D could be maximized during the few months when photocatalytic UVB wavelengths were present in the sunlight (Chaplin & Jablonski,²⁰¹³; Jablonski & Chaplin,^{2000, 2010}). During the millennia in prehistoric and early historic times when people did not travel widely or migrate to other climes, this highly depigmented skin phenotype worked well. Because their UVR regimes were markedly different from those of people in the tropics, they experienced only short periods of UVB during the height of the summer and sunburns would have been rare (Chaplin & Jablonski,²⁰¹³; Jablonski & Chaplin,²⁰¹⁰). Outdoor lifestyles meant that people adapted to gradually changing durations and intensities of UVR—mostly UVA—exposure throughout the year, to which their skin adapted primarily by thickening of the stratum corneum; the fact that they could develop only negligible protection from melanin production did not matter because the challenge from UVB was not severe or prolonged (Bech‐Thomsen & Wulf,¹⁹⁹⁵; Hennessy, Oh, Rees, etal.,²⁰⁰⁵; Sheehan etal.,¹⁹⁹⁸). Under these conditions, mostly depigmented skin was not a liability because it did not detract from health and well‐being and did not affect reproductive success. This situation changed markedly when people from northwestern and northern Europe began to travel and migrate to sunnier places in colonial times, and experience high episodic or sustained loads of UVR (Jablonski,²⁰¹²). Historical migrations of people from northern Europe to far southern Europe, Africa, Australia, and tropical latitudes of the Americas in the last 200years, along with the increased popularity of holiday travel, caused dramatic shifts in the nature of UVR exposure, and increased prevalence of all skin cancers (Latreille etal.,²⁰⁰⁹; Rees,²⁰⁰³; Sturm etal.,²⁰⁰³).

The evolution of skin lightening in northeastern Asia occurred under similar, but not identical, conditions of generally low and seasonal UVB as those of northwestern Europe (Chaplin & Jablonski,²⁰¹³; Jablonski & Chaplin,²⁰⁰⁰). Among the most interesting facts to emerge in the study of the evolution of human skin pigmentation evolution is that different suites of genes have influenced depigmentation in northern Europeans and East Asians. Recent research on the function of the upstream region of KITLG shared by the common ancestor of all Eurasians shows that the region was under stronger selective pressure in East Asians, possibly because it conferred depigmentation along with greater resistance to cold (Yang etal.,²⁰¹⁸). This appears to have complemented selection on an OCA2 (oculocutaneous albinism, type 2) variant absent in Europeans (Yang etal.,²⁰¹⁶) and a variant of MFSD12 (Adhikari etal.,²⁰¹⁹) to create a comparable level of depigmentation conducive to cutaneous vitamin D production. Thus, depigmentation in the ancestors of modern western Europeans and East Asians provides an excellent of convergent evolution (Norton etal.,²⁰⁰⁷; Yang etal.,²⁰¹⁶). Natural selection has acted upon on different genes and gene variants in response to comparable environmental forces to produce comparable physiological solutions to a problem affecting health and reproductive success.

East Asians and western Europeans share visibly similar “light” skin, but their responses to UVR are different. The skin of East Asians has a higher density of melanosomes and produces more eumelanin and pheomelanin in response to UVR exposure than does the skin or western Europeans (Hennessy, Oh, Diffey, etal.,²⁰⁰⁵; Hennessy, Oh, Rees, etal.,²⁰⁰⁵). Thus, most East Asian people can tan, whereas many Europeans, especially northern Europeans, can tan only slightly or not at all. The development and persistence of tanning abilities are conferred by many genes operating on melanin production, distribution, and breakdown in the skin (Del Bino etal.,²⁰¹⁸) and tanning abilities, like depigmentation, have evolved multiple times independently in human history under conditions of seasonally strong UVR (Martínez‐Cadenas etal.,²⁰¹³; Quillen,²⁰¹⁵; Quillen etal.,²⁰¹⁹). The moderate tanning abilities among some Scandinavians and northern Europeans appear to have been conferred by recent genetic admixture across northern Eurasia (Hanel & Carlberg,^2020a), but other factors, including altered epistatic interactions among pigmentation genes, may have also contributed.

Following the amelioration of climatic conditions at the end of the Pleistocene, the development of extensive steppe grasslands across much of hinterland Eurasia created a theater for rapid human population growth associated with animal husbandry, and relatively rapid, bidirectional east–west movements of people (Allentoft etal.,²⁰¹⁵; Damgaard etal.,²⁰¹⁸). The results of genomic, linguistic, and archeological studies show a gradual transition from Bronze Age pastoralists of West Eurasian ancestry toward horse‐mounted warrior peoples of increased East Asian ancestry (Damgaard etal.,²⁰¹⁸). The rise and expansion of agriculture from Anatolia and Iran saw incursions of agriculturalists into southern and central Europe, increasingly displacing earlier hunter‐gatherer populations (Skoglund & Mathieson,²⁰¹⁸). The evolution of skin pigmentation genes and phenotypes of the region reflects these dramatic movements, and the influence of relatively few genes of major effect transmitted over long distances by admixture (Ju & Mathieson,²⁰²⁰). Of these, the effect of the classic depigmentation variant of SLC24A5 is greatest, with recent evidence showing that this variant reached western Europe by admixture from Anatolian agriculturalists followed by continued positive selection (Ju & Mathieson,²⁰²⁰). Recent genomic evidence indicates that some of the hunter‐gatherer populations of Mesolithic western Europe and Britain had moved along the coast from the Iberian Peninsula into northern France, and thence up the Atlantic coast, making use of marine food resources as they went (Brace etal.,²⁰¹⁹). In this context, the much‐discussed dark or “dark to black” skin reconstructed for “Cheddar Man,” a Mesolithic inhabitant of Cheddar Gorge in Somerset, England (Brace etal.,²⁰¹⁹), becomes more clearly understandable and less sensational. Traditional hunter‐gatherer diets centered around coastal marine sources, hunted terrestrial game, and foraged plant foods are rich in vitamin D and make it possible for people to continue to live healthy reproductive lives while maintaining “dark” and highly tannable skin. Skin depigmentation in northwestern Europe occurred gradually, over many millennia, with the introduction of the classic SLC24A5 variant being the last and most dramatic step in the process after the introduction of agriculture.

• Abdel‐Malek, Z. (2009). Constitutive pigmentation, melanogenesis, and the UV response. Pigment Cell & Melanoma Research, 22(3), 344. 10.1111/j.1755-148X.2009.00569_2.x [PubMed] [CrossRef] [Google Scholar]
• Adhikari, K., Mendoza‐Revilla, J., Sohail, A., Fuentes‐Guajardo, M., Lampert, J., Chacón‐Duque, J. C., Hurtado, M., Villegas, V., Granja, V., Acuña‐Alonzo, V., Jaramillo, C., Arias, W., Lozano, R. B., Everardo, P., Gómez‐Valdés, J., Villamil‐Ramírez, H., Silva de Cerqueira, C. C., Hunemeier, T., Ramallo, V., … Ruiz‐Linares, A. (2019). A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia. Nature Communications, 10(1), 358. 10.1038/s41467-018-08147-0 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Alaluf, S., Atkins, D., Barrett, K., Blount, M., Carter, N., & Heath, A. (2002). Ethnic variation in melanin content and composition in photoexposed and photoprotected human skin. Pigment Cell Research, 15(2), 112–118. 10.1034/j.1600-0749.2002.1o071.x [PubMed] [CrossRef] [Google Scholar]
• Alaluf, S., Heath, A., Carter, N., Atkins, D., Mahalingam, H., Barrett, K., Kolb, R., & Smit, N. (2001). Variation in melanin content and composition in Type V and VI photoexposed and photoprotected human skin: The dominant role of DHI. Pigment Cell Research, 14(5), 337–347. 10.1034/j.1600-0749.2001.140505.x [PubMed] [CrossRef] [Google Scholar]
• Alexander, L. M., Kutz, J. L., & Kenney, W. L. (2013). Tetrahydrobiopterin increases NO‐dependent vasodilation in hypercholesterolemic human skin through eNOS‐coupling mechanisms. American Journal of Physiology ‐ Regulatory, Integrative and Comparative Physiology, 304(2), R164–R169. 10.1152/ajpregu.00448.2012 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Alfredsson, L., Armstrong, B. K., Butterfield, D. A., Chowdhury, R., de Gruijl, F. R., Feelisch, M., Garland, C. F., Hart, P. H., Hoel, D. G., Jacobsen, R., Lindqvist, P. G., Llewellyn, D. J., Tiemeier, H., Weller, R. B., & Young, A. R. (2020). Insufficient sun exposure has become a real public health problem. International Journal of Environmental Research and Public Health, 17(14), 5014. 10.3390/ijerph17145014 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Allentoft, M. E., Sikora, M., Sjögren, K.‐G., Rasmussen, S., Rasmussen, M., Stenderup, J., Damgaard, P. B., Schroeder, H., Ahlström, T., Vinner, L., Malaspinas, A.‐S., Margaryan, A., Higham, T., Chivall, D., Lynnerup, N., Harvig, L., Baron, J., Casa, P. D., Dąbrowski, P., … Willerslev, E. (2015). Population genomics of Bronze Age Eurasia. Nature, 522(7555), 167–172. 10.1038/nature14507 [PubMed] [CrossRef] [Google Scholar]
• Ambrose, S. H. (1998). Late Pleistocene human population bottlenecks, volcanic winter, and differentiation of modern humans. Journal of Human Evolution, 34(6), 623–651. 10.1006/jhev.1998.0219 [PubMed] [CrossRef] [Google Scholar]
• Andersen, S., Jakobsen, A., & Laurberg, P. (2012). Vitamin D status in North Greenland is influenced by diet and season: Indicators of dermal 25‐hydroxy vitamin D production north of the Arctic Circle. British Journal of Nutrition, FirstView, 110(1), 50–57. 10.1017/S0007114512004709 [PubMed] [CrossRef] [Google Scholar]
• Andersen, S., Laurberg, P., Hvingel, B., Kleinschmidt, K., Heickendorff, L., & Mosekilde, L. (2013). Vitamin D status in Greenland is influenced by diet and ethnicity: A population‐based survey in an Arctic society in transition. The British Journal of Nutrition, 109(5), 928–935. 10.1017/s0007114512002097 [PubMed] [CrossRef] [Google Scholar]
• Aoki, K. (2002). Sexual selection as a cause of human skin colour variation: Darwin's hypothesis revisited. Annals of Human Biology, 29(6), 589–608. 10.1080/0301446021000019144 [PubMed] [CrossRef] [Google Scholar]
• Basu Mallick, C., Iliescu, F. M., Möls, M., Hill, S., Tamang, R., Chaubey, G., Goto, R., Ho, S. Y. W., Gallego Romero, I., Crivellaro, F., Hudjashov, G., Rai, N., Metspalu, M., Mascie‐Taylor, C. G. N., Pitchappan, R., Singh, L., Mirazon‐Lahr, M., Thangaraj, K., Villems, R., & Kivisild, T. (2013). The light skin allele of SLC24A5 in South Asians and Europeans shares identity by descent. PLoS Genetics, 9(11), e1003912. 10.1371/journal.pgen.1003912 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Battie, C., Jitsukawa, S., Bernerd, F., Del Bino, S., Marionnet, C., & Verschoore, M. (2014). New insights in photoaging, UVA induced damage and skin types. Experimental Dermatology, 23(S1), 7–12. 10.1111/exd.12388 [PubMed] [CrossRef] [Google Scholar]
• Bech‐Thomsen, N., & Wulf, H. C. (1995). Photoprotection due to pigmentation and epidermal thickness after repeated exposure to ultraviolet light and psoralen plus ultraviolet A therapy. Photodermatology, Photoimmunology & Photomedicine, 11(5–6), 213–218. 10.1111/j.1600-0781.1995.tb00172.x [PubMed] [CrossRef] [Google Scholar]
• Beleza, S., Johnson, N. A., Candille, S. I., Absher, D. M., Coram, M. A., Lopes, J., Campos, J., Araújo, I. I., Anderson, T. M., Vilhjálmsson, B. J., Nordborg, M., Silva, A. C., Shriver, M. D., Rocha, J., Barsh, G. S., & Tang, H. (2013). Genetic architecture of skin and eye color in and African‐European admixed population. PLoS Genetics, 9(3), e1003372. 10.1371/journal.pgen.1003372 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Beleza, S., Santos, A. M., McEvoy, B., Alves, I., Martinho, C., Cameron, E., Shriver, M. D., Parra, E. J., & Rocha, J. (2013). The timing of pigmentation lightening in Europeans. Molecular Biology and Evolution, 30(1), 24–35. 10.1093/molbev/mss207 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Blum, H. F. (1961). Does the melanin pigment of human skin have adaptive value?Quarterly Review of Biology, 36(1), 50–63. [PubMed] [Google Scholar]
• Bonilla, C., Gutierrez, G., Parra, E. J., Kline, C., & Shriver, M. D. (2005). Admixture analysis of a rural population of the state of Guerrero, Mexico. American Journal of Physical Anthropology, 128(4), 861–869. 10.1002/ajpa.20227 [PubMed] [CrossRef] [Google Scholar]
• Bora, S., & Cantorna, M. T. (2017). The role of UVR and vitamin D on T cells and inflammatory bowel disease. Photochemical & Photobiological Sciences, 16(3), 347–353. 10.1039/C6PP00266H [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Borradale, D. C., Isenring, E., Hacker, E., & Kimlin, M. G. (2014). Exposure to solar ultraviolet radiation is associated with a decreased folate status in women of childbearing age. Journal of Photochemistry and Photobiology B: Biology, 131(5), 90–95. 10.1016/j.jphotobiol.2014.01.002 [PubMed] [CrossRef] [Google Scholar]
• Borradale, D. C., & Kimlin, M. G. (2012). Folate degradation due to ultraviolet radiation: Possible implications for human health and nutrition. Nutrition Reviews, 70(7), 414–422. 10.1111/j.1753-4887.2012.00485.x [PubMed] [CrossRef] [Google Scholar]
• Bower, C., & Stanley, F. J. (1989). Dietary folate as a risk factor for neural‐tube defects: Evidence from a case‐control study in Western Australia. The Medical Journal of Australia, 150(11), 613–619. 10.5694/j.1326-5377.1989.tb136723.x [PubMed] [CrossRef] [Google Scholar]
• Brace, S., Diekmann, Y., Booth, T. J., van Dorp, L., Faltyskova, Z., Rohland, N., Mallick, S., Olalde, I., Ferry, M., Michel, M., Oppenheimer, J., Broomandkhoshbacht, N., Stewardson, K., Martiniano, R., Walsh, S., Kayser, M., Charlton, S., Hellenthal, G., Armit, I., … Barnes, I. (2019). Ancient genomes indicate population replacement in Early Neolithic Britain. Nature Ecology & Evolution, 3(5), 765–771. 10.1038/s41559-019-0871-9 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Branda, R. F., & Blickensderfer, D. B. (1993). Folate deficiency increases genetic damage caused by alkylating agents and y‐irradiation in Chinese hamster ovary cells. Cancer Research, 53(22), 5401–5408. [PubMed] [Google Scholar]
• Branda, R. F., & Eaton, J. W. (1978). Skin color and nutrient photolysis: An evolutionary hypothesis. Science, 201(4356), 625–626. 10.1126/science.675247 [PubMed] [CrossRef] [Google Scholar]
• Bruls, W. A. G., Slaper, H., Van Der Leun, J. C., & Berrens, L. (1984). Transmission of human epidermis and stratum corneum as a function of thickness in the ultraviolet and visible wavelengths. Photochemistry and Photobiology, 40(4), 485–494. 10.1111/j.1751-1097.1984.tb04622.x [PubMed] [CrossRef] [Google Scholar]
• Buccimazza, S. S., Molteno, C. D., Dunne, T. T., & Viljoen, D. L. (1994). Prevalence of neural tube defects in Cape Town. South Africa. Teratology, 50(3), 194–199. 10.1002/tera.1420500304 [PubMed] [CrossRef] [Google Scholar]
• Bustamante, M., Hernandez‐Ferrer, C., Tewari, A., Sarria, Y., Harrison, G. I., Puigdecanet, E., Nonell, L., Kang, W., Friedländer, M. R., Estivill, X., González, J. R., Nieuwenhuijsen, M., & Young, A. R. (2020). Dose and time effects of solar simulated ultraviolet radiation on the in vivo human skin transcriptome. British Journal of Dermatology, 182(6), 1458–1468. 10.1111/bjd.18527 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Byard, P. J. (1981). Quantitative genetics of human skin color. Yearbook of Physical Anthropology, 24(S2), 123–137. 10.1002/ajpa.1330240506 [CrossRef] [Google Scholar]
• Caccamo, D., Ricca, S., Currò, M., & Ientile, R. (2018). Health risks of hypovitaminosis D: A review of new molecular insights. International Journal of Molecular Sciences, 19(3), 892. 10.3390/ijms19030892 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Carlberg, C. (2019). Vitamin D: A micronutrient regulating genes. Current Pharmaceutical Design, 25(15), 1740–1746. 10.2174/1381612825666190705193227 [PubMed] [CrossRef] [Google Scholar]
• Chaplin, G. (2004). Geographic distribution of environmental factors influencing human skin coloration. American Journal of Physical Anthropology, 125(3), 292–302. 10.1002/ajpa.10263 [PubMed] [CrossRef] [Google Scholar]
• Chaplin, G., & Jablonski, N. G. (2002). Environmental correlates of human skin color, revisited. American Journal of Physical Anthropology, 117(S34), 53. 10.1002/ajpa.20010 [CrossRef] [Google Scholar]
• Chaplin, G., & Jablonski, N. G. (2009). Vitamin D and the evolution of human depigmentation. American Journal of Physical Anthropology, 139(4), 451–461. 10.1002/ajpa.21079 [PubMed] [CrossRef] [Google Scholar]
• Chaplin, G., & Jablonski, N. G. (2013). The human environment and the vitamin D compromise: Scotland as a case study in human biocultural adaptation and disease susceptibility. Human Biology, 85(4), 529–552. 10.3378/027.085.0402 [PubMed] [CrossRef] [Google Scholar]
• Clemens, T. L., Henderson, S. L., Adams, J. S., & Holick, M. F. (1982). Increased skin pigment reduces the capacity of skin to synthesise vitamin D₃. The Lancet, 319(8263), 74–76. 10.1016/S0140-6736(82)90214-8 [PubMed] [CrossRef] [Google Scholar]
• Coussens, A. K., Naude, C. E., Goliath, R., Chaplin, G., Wilkinson, R. J., & Jablonski, N. G. (2015). High‐dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV‐1 replication in urban Southern Africans. Proceedings of the National Academy of Sciences, 112(26), 8052–8057. 10.1073/pnas.1500909112 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Crawford, N. G., Kelly, D. E., Hansen, M. E. B., Beltrame, M. H., Fan, S., Bowman, S. L., Jewett, E., Ranciaro, A., Thompson, S., Lo, Y., Pfeifer, S. P., Jensen, J. D., Campbell, M. C., Beggs, W., Hormozdiari, F., Mpoloka, S. W., Mokone, G. G., Nyambo, T., Meskel, D. W., … Tishkoff, S. A. (2017). Loci associated with skin pigmentation identified in African populations. Science, 358(6365), eaan8433. 10.1126/science.aan8433 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Damgaard, P. D. B., Marchi, N., Rasmussen, S., Peyrot, M., Renaud, G., Korneliussen, T., Moreno‐Mayar, J. V., Pedersen, M. W., Goldberg, A., Usmanova, E., Baimukhanov, N., Loman, V., Hedeager, L., Pedersen, A. G., Nielsen, K., Afanasiev, G., Akmatov, K., Aldashev, A., Alpaslan, A., … Willerslev, E. (2018). 137 ancient human genomes from across the Eurasian steppes. Nature, 557(7705), 369–374. 10.1038/s41586-018-0094-2 [PubMed] [CrossRef] [Google Scholar]
• Darwin, C. (1871). The descent of man, and selection in relation to sex. London: John Murray. [Google Scholar]
• de Barros Damgaard, P., Martiniano, R., Kamm, J., Moreno‐Mayar, J. V., Kroonen, G., Peyrot, M., Barjamovic, G., Rasmussen, S., Zacho, C., Baimukhanov, N., Zaibert, V., Merz, V., Biddanda, A., Merz, I., Loman, V., Evdokimov, V., Usmanova, E., Hemphill, B., Seguin‐Orlando, A., … Willerslev, E. (2018). The first horse herders and the impact of early Bronze Age steppe expansions into Asia. Science, 360(6396), eaar7711. 10.1126/science.aar7711 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Del Bino, S., Duval, C., & Bernerd, F. (2018). Clinical and biological characterization of skin pigmentation diversity and its consequences on UV impact. International Journal of Molecular Sciences, 19(9), 2668. 10.3390/ijms19092668 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Dennell, R., & Petraglia, M. D. (2012). The dispersal of hom*o sapiens across southern Asia: How early, how often, how complex?Quaternary Science Reviews, 47, 15–22. 10.1016/j.quascirev.2012.05.002 [CrossRef] [Google Scholar]
• Diamond, J. M. (1991). The rise and fall of the third chimpanzee. London: Radius. [Google Scholar]
• Diamond, J. M. (2005). Geography and skin color. Nature, 435, 283–284. 10.1038/435283a [PubMed] [CrossRef] [Google Scholar]
• Diffey, B. L. (1991). Solar ultraviolet radiation effects on biological systems. Physics in Medicine and Biology, 36(3), 299–328. 10.1088/0031-9155/36/3/001 [PubMed] [CrossRef] [Google Scholar]
• Diffey, B. L. (1999). Human exposure to ultraviolet radiation. In Hawk J. L. M. (Ed.), Photodermatology (pp. 5–24). Arnold. [Google Scholar]
• Eaaswarkhanth, M., Xu, D., Flanagan, C., Rzhetskaya, M., Hayes, M. G., Blekhman, R., Blekhman, R., & Gokcumen, O. (2016). Atopic dermatitis susceptibility variants in filaggrin hitchhike hornerin selective sweep. Genome Biology and Evolution, 8(10), 3240–3255. 10.1093/gbe/evw242 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• El Hayek, J., Egeland, G., & Weiler, H. (2010). Vitamin D status of Inuit preschoolers reflects season and vitamin D intake. The Journal of Nutrition, 140(10), 1839–1845. 10.3945/jn.110.124644 [PubMed] [CrossRef] [Google Scholar]
• Elias, P. M. (2005). Stratum corneum defensive functions: An integrated view. Journal of Investigative Dermatology, 125(2), 183–200. 10.1111/j.0022-202X.2005.23668.x [PubMed] [CrossRef] [Google Scholar]
• Elias, P. M., & Friend, D. S. (1975). The permeability barrier in mammalian epidermis. The Journal of Cell Biology, 65(1), 180–191. 10.1083/jcb.65.1.180 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Elias, P. M., Menon, G., Wetzel, B. K., & Williams, J. W. (2009). Evidence that stress to the epidermal barrier influenced the development of pigmentation in humans. Pigment Cell & Melanoma Research, 22(4), 420–434. 10.1111/j.1755-148X.2009.00588.x [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Elias, P. M., Menon, G., Wetzel, B. K., & Williams, J. W. (2010). Barrier requirements as the evolutionary “driver” of epidermal pigmentation in humans. American Journal of Human Biology, 22(4), 526–537. 10.1002/ajhb.21043 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Elias, P. M., & Williams, M. L. (2013). Re‐appraisal of current theories for the development and loss of epidermal pigmentation in hominins and modern humans. Journal of Human Evolution, 64(6), 687–692. 10.1016/j.jhevol.2013.02.003 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Elias, P. M., & Williams, M. L. (2016). Basis for the gain and subsequent dilution of epidermal pigmentation during human evolution: The barrier and metabolic conservation hypotheses revisited. American Journal of Physical Anthropology, 161(2), 189–207. 10.1002/ajpa.23030 [PubMed] [CrossRef] [Google Scholar]
• Elwood, J. M. (1983). Can vitamins prevent neural tube defects?Canadian Medical Association Journal, 129(10), 1088–1092. [PMC free article] [PubMed] [Google Scholar]
• Fajuyigbe, D., Lwin, S. M., Diffey, B. L., Baker, R., Tobin, D. J., Sarkany, R. P. E., & Young, A. R. (2018). Melanin distribution in human epidermis affords localized protection against DNA photodamage and concurs with skin cancer incidence difference in extreme phototypes. The FASEB Journal, 32(7), 3700–3706. 10.1096/fj.201701472R [PubMed] [CrossRef] [Google Scholar]
• Fajuyigbe, D., & Young, A. R. (2016). The impact of skin colour on human photobiological responses. Pigment Cell & Melanoma Research, 29(6), 607–618. 10.1111/pcmr.12511 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Feng, Y., McQuillan, M. A., & Tishkoff, S. A. (2021). Evolutionary genetics of skin pigmentation in African populations. Human Molecular Genetics, dab007. 10.1093/hmg/ddab007 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Fleming, A., & Copp, A. J. (1998). Embryonic folate metabolism and mouse neural tube defects. Science, 280, 2107–2109. 10.1126/science.280.5372.2107 [PubMed] [CrossRef] [Google Scholar]
• f*ckuwatari, T., Fujita, M., & Shibata, K. (2009). Effects of UVA irradiation on the concentration of folate in human blood. Bioscience, Biotechnology, and Biochemistry, 73(2), 322–327. 10.1271/bbb.80530 [PubMed] [CrossRef] [Google Scholar]
• Galway‐Witham, J., & Stringer, C. (2018). How did hom*o sapiens evolve?Science, 360(6395), 1296–1298. 10.1126/science.aat6659 [PubMed] [CrossRef] [Google Scholar]
• Gambichler, T., Sauermann, K., Bader, A., Altmeyer, P., & Hoffmann, K. (2001). Serum folate levels after UVA exposure: A two‐group parallel randomised controlled trial. BMC Dermatology, 1(1), 8. 10.1186/1471-5945-1-8 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Giovannucci, E., Rimm, E. B., Ascherio, A., Stampfer, M. J., Colditz, G. A., & Willett, W. C. (1995). Alcohol, low‐methionine, low folate diets, and risk of colon cancer in men. Journal of the National Cancer Institute, 87(4), 265–273. 10.1093/jnci/87.4.265 [PubMed] [CrossRef] [Google Scholar]
• Gittelman, R. M., Schraiber, J. G., Vernot, B., Mikacenic, C., Wurfel, M. M., & Akey, J. M. (2016). Archaic hominin admixture facilitated adaptation to Out‐of‐Africa environments. Current Biology, 26(24), 3375–3382. 10.1016/j.cub.2016.10.041 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Goebel, T., Waters, M. R., & O'Rourke, D. H. (2008). The Late Pleistocene dispersal of modern humans in the Americas. Science, 319(5869), 1497–1502. 10.1126/science.1153569 [PubMed] [CrossRef] [Google Scholar]
• Goodwin, Z. A., & de Guzman Strong, C. (2017). Recent positive selection in genes of the mammalian epidermal differentiation complex locus. Frontiers in Genetics, 7, 227. 10.3389/fgene.2016.00227 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Gozdzik, A., Barta, J. L., Wu, H., Wagner, D., Cole, D. E., Vieth, R., Whiting, S., & Parra, E. J. (2008). Low wintertime vitamin D levels in a sample of healthy young adults of diverse ancestry living in the Toronto area: Associations with vitamin D intake and skin pigmentation. BMC Public Health, 8(1), 336–344. 10.1186/1471-2458-8-336 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Greaves, M. (2014). Was skin cancer a selective force for black pigmentation in early hominin evolution?Proceedings of the Royal Society B: Biological Sciences, 281(1781), 1–10. 10.1098/rspb.2013.2955 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Groucutt, H. S., Petraglia, M. D., Bailey, G., Scerri, E. M. L., Parton, A., Clark‐Balzan, L., Jennings, R. P., Lewis, L., Blinkhorn, J., Drake, N. A., Breeze, P. S., Inglis, R. H., Devès, M. H., Meredith‐Williams, M., Boivin, N., … Scally, A. (2015). Rethinking the dispersal of hom*o sapiens out of Africa. Evolutionary Anthropology, 24(4), 149–164. 10.1002/evan.21455 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Hanel, A., & Carlberg, C. (2020a). Skin colour and vitamin D: An update. Experimental Dermatology, 29(9), 864–875. 10.1111/exd.14142 [PubMed] [CrossRef] [Google Scholar]
• Hanel, A., & Carlberg, C. (2020b). Vitamin D and evolution: Pharmacologic implications. Biochemical Pharmacology, 173, 113595. 10.1016/j.bcp.2019.07.024 [PubMed] [CrossRef] [Google Scholar]
• Harding, R. M., Healy, E., Ray, A. J., Ellis, N. S., Flanagan, N., Todd, C., Dixon, C., Sajantila, A., Jackson, I. J., Birch‐Machin, M. A., & Rees, J. L. (2000). Evidence for variable selective pressures at MC1R. American Journal of Human Genetics, 66, 1351–1361. 10.1086/302863 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Hasoun, L. Z., Bailey, S. W., Outlaw, K. K., & Ayling, J. E. (2015). Rearrangement and depletion of folate in human skin by ultraviolet radiation. British Journal of Dermatology, 173(4), 1087–1090. 10.1111/bjd.13885 [PubMed] [CrossRef] [Google Scholar]
• Headland, T. N. (1989). Population decline in a Philippine Negrito hunter‐gatherer society. American Journal of Human Biology, 1(1), 59–72. 10.1002/ajhb.1310010111 [PubMed] [CrossRef] [Google Scholar]
• Henn, B. M., Botigué, L. R., Peischl, S., Dupanloup, I., Lipatov, M., Maples, B. K., Martin, A. R., Musharoff, S., Cann, H., Snyder, M. P., Excoffier, L., Kidd, J. M., & Bustamante, C. D. (2016). Distance from sub‐Saharan Africa predicts mutational load in diverse human genomes. Proceedings of the National Academy of Sciences, 113(4), E440–E449. 10.1073/pnas.1510805112 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Henn, B. M., Cavalli‐Sforza, L. L., & Feldman, M. W. (2012). The great human expansion. Proceedings of the National Academy of Sciences, 109(44), 17758–17764. 10.1073/pnas.1212380109 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Henn, B. M., Steele, T. E., & Weaver, T. D. (2018). Clarifying distinct models of modern human origins in Africa. Current Opinion in Genetics & Development, 53, 148–156. 10.1016/j.gde.2018.10.003 [PubMed] [CrossRef] [Google Scholar]
• Hennessy, A., Oh, C., Diffey, B. L., Wakamatsu, K., Ito, S., & Rees, J. L. (2005). Eumelanin and pheomelanin concentrations in human epidermis before and after UVB irradiation. Pigment Cell Research, 18(3), 220–223. 10.1111/j.1600-0749.2005.00233.x [PubMed] [CrossRef] [Google Scholar]
• Hennessy, A., Oh, C., Rees, J., & Diffey, B. L. (2005). The photoadaptive response to ultraviolet exposure in human skin using ultraviolet spectrophotometry. Photodermatology, Photoimmunology & Photomedicine, 21(5), 229–233. 10.1111/j.1600-0781.2005.00170.x [PubMed] [CrossRef] [Google Scholar]
• Hippocrates(1849). The Genuine Works of Hippocrates: The Genuine Works of Hippocrates: Translated from the Greek with a preliminary discourse and annotations. (F. Adams, Trans.). William Wood & Co. [Google Scholar]
• Hlusko, L. J., Carlson, J. P., Chaplin, G., Elias, S. A., Hoff*cker, J. F., Huffman, M., Jablonski, N. G., Monson, T. A., O’Rourke, D. H., Pilloud, M. A., & Scott, G. R. (2018). Environmental selection during the last ice age on the mother‐to‐infant transmission of vitamin D and fatty acids through breast milk. Proceedings of the National Academy of Sciences, 115(19), E4426–E4432. 10.1073/pnas.1711788115 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Holick, M., MacLaughlin, J., Clark, M., Holick, S., Potts, J., Anderson, R., Blank, I., Parrish, J., & Elias, P. (1980). Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science, 210(4466), 203–205. 10.1126/science.6251551 [PubMed] [CrossRef] [Google Scholar]
• Holick, M. F., MacLaughlin, J. A., & Doppelt, S. H. (1981). Regulation of cutaneous previtamin D₃ photosynthesis in man: Skin pigment is not an essential regulator. Science, 211(4482), 590–593. 10.1126/science.6256855 [PubMed] [CrossRef] [Google Scholar]
• Hsieh, P., Veeramah, K. R., Lachance, J., Tishkoff, S. A., Wall, J. D., Hammer, M. F., & Gutenkunst, R. N. (2016). Whole‐genome sequence analyses of Western Central African Pygmy hunter‐gatherers reveal a complex demographic history and identify candidate genes under positive natural selection. Genome Research, 26(3), 279–290. 10.1101/gr.192971.115 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Hublin, J.‐J., Ben‐Ncer, A., Bailey, S. E., Freidline, S. E., Neubauer, S., Skinner, M. M., Bergmann, I., Le Cabec, A., Benazzi, S., Harvati, K., & Gunz, P. (2017). New fossils from Jebel Irhoud, Morocco and the pan‐African origin of hom*o sapiens. Nature, 546(7657), 289–292. 10.1038/nature22336 [PubMed] [CrossRef] [Google Scholar]
• Iliescu, F. M., Chaplin, G., Rai, N., Jacobs, G. S., Chaplin, G., Basu Mallick, C., Mishra, A., Thangaraj, K., & Jablonski, N. G. (2018). The influence of genes, the environment, and social factors on the evolution of skin color diversity in India. American Journal of Human Biology, 30(5), e23170. 10.1002/ajhb.23170 [PubMed] [CrossRef] [Google Scholar]
• Izagirre, N., Garcia, I., Junquera, C., de la Rua, C., & Alonso, S. (2006). A scan for signatures of positive selection in candidate loci for skin pigmentation in humans. Molecular Biology and Evolution, 23(9), 1697–1706. 10.1093/molbev/msl030 [PubMed] [CrossRef] [Google Scholar]
• Jablonski, N. G. (1992). Sun, skin colour and spina bifida: An exploration of the relationship between solar ultraviolet radiation, skin colour and neural tube defects. In Bruce N. W. (Ed.), Proceedings of the fifth annual conference of the Australasian society for human biology (pp. 455‐462). Centre for Human Biology. [Google Scholar]
• Jablonski, N. G. (1999). A possible link between neural tube defect and ultraviolet light exposure. Medical Hypotheses, 52(6), 581–582. 10.1054/mehy.1997.0697 [PubMed] [CrossRef] [Google Scholar]
• Jablonski, N. G. (2004). The evolution of human skin and skin color. Annual Review of Anthropology, 33, 585–623. 10.1146/annurev.anthro.33.070203.143955 [CrossRef] [Google Scholar]
• Jablonski, N. G. (2012). Living color: The biological and social meaning of skin color. Berkeley: University of California Press. [Google Scholar]
• Jablonski, N. G., & Chaplin, G. (2000). The evolution of human skin coloration. Journal of Human Evolution, 39(1), 57–106. 10.1006/jhev.2000.0403 [PubMed] [CrossRef] [Google Scholar]
• Jablonski, N. G., & Chaplin, G. (2010). Human skin pigmentation as an adaptation to UV radiation. Proceedings of the National Academy of Sciences, 107(Suppl. 2), 8962–8968. 10.1073/pnas.0914628107 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Jablonski, N. G., & Chaplin, G. (2013). Epidermal pigmentation in the human lineage is an adaptation to ultraviolet radiation. Journal of Human Evolution, 65(5), 671–675. 10.1016/j.jhevol.2013.06.004 [PubMed] [CrossRef] [Google Scholar]
• Jablonski, N. G., & Chaplin, G. (2014a). The evolution of skin pigmentation and hair texture in people of African ancestry. Dermatologic Clinics, 32(2), 113–121. 10.1016/j.det.2013.11.003 [PubMed] [CrossRef] [Google Scholar]
• Jablonski, N. G., & Chaplin, G. (2014b). Skin cancer was not a potent selective force in the evolution of protective pigmentation in early hominins. Proceedings of the Royal Society B: Biological Sciences, 281(1789), 10.1098/rspb.2014.0517 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• James, W. P. T., Johnson, R. J., Speakman, J. R., Wallace, D. C., Frühbeck, G., Iversen, P. O., & Stover, P. J. (2019). Nutrition and its role in human evolution. Journal of Internal Medicine, 285(5), 533–549. 10.1111/joim.12878 [PubMed] [CrossRef] [Google Scholar]
• Jinam, T. A., Phipps, M. E., Aghakhanian, F., Majumder, P. P., Datar, F., Stoneking, M., Sawai, H., Nishida, N., Tokunaga, K., Kawamura, S., Omoto, K., & Saitou, N. (2017). Discerning the origins of the Negritos, first Sundaland people: Deep divergence and archaic admixture. Genome Biology and Evolution, 9(8), 2013–2022. 10.1093/gbe/evx118 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• John, P. R., Makova, K., Li, W.‐H., Jenkins, T., & Ramsay, M. (2003). DNA polymorphism and selection at the melanocortin‐1 receptor gene in normally pigmented southern African individuals. Annals of the New York Academy of Sciences, 994, 299–306. 10.1111/j.1749-6632.2003.tb03193.x [PubMed] [CrossRef] [Google Scholar]
• Jones, P., Luco*ck, M. D., Veysey, M., Jablonski, N. G., Chaplin, G., & Beckett, E. (2018). Frequency of folate‐related polymorphisms varies by skin pigmentation. American Journal of Human Biology, 30(2), e23079. 10.1002/ajhb.23079 [PubMed] [CrossRef] [Google Scholar]
• Ju, D., & Mathieson, I. (2020). The evolution of skin pigmentation associated variation in West Eurasia. Proceedings of the National Academy of Sciences. 118(1), e2009227118. 10.1073/pnas.2009227118 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Juzeniene, A., Tam, T. T. T., Iani, V., & Moan, J. (2009). 5‐Methyltetrahydrofolate can be photodegraded by endogenous photosensitizers. Free Radical Biology and Medicine, 47(8), 1199–1204. 10.1016/j.freeradbiomed.2009.07.030 [PubMed] [CrossRef] [Google Scholar]
• Kaidbey, K. H., Agin, P. P., Sayre, R. M., & Kligman, A. M. (1979). Photoprotection by melanin ‐ a comparison of black and Caucasian skin. Journal of the American Academy of Dermatology, 1(3), 249–260. 10.1016/S0190-9622(79)70018-1 [PubMed] [CrossRef] [Google Scholar]
• Kenney, W. L. (2017). Edward F. Adolph Distinguished Lecture: Skin‐deep insights into vascular aging. Journal of Applied Physiology, 123(5), 1024–1038. 10.1152/japplphysiol.00589.2017 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Klaus, S. N. (1973). Some early scientific studies of skin color. Yale Journal of Biology and Medicine, 46(5), 334–336. [PMC free article] [PubMed] [Google Scholar]
• Kuan, V., Martineau, A., Griffiths, C., Hypponen, E., & Walton, R. (2013). DHCR7 mutations linked to higher vitamin D status allowed early human migration to Northern latitudes. BMC Evolutionary Biology, 13(1), 144. 10.1186/1471-2148-13-144 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Lamason, R. L., Mohideen, M.‐A.‐ P.‐ K., Mest, J. R., Wong, A. C., Norton, H. L., Aros, M. C., Jurynec, M. J., Mao, X., Humphreville, V. R., Humbert, J. E., Sinha, S., Moore, J. L., Jagadeeswaran, P., Zhao, W., Ning, G., Makalowska, I., McKeigue, P. M., O'donnell, D., Kittles, R., … Cheng, K. C. (2005). SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science, 310(5755), 1782–1786. 10.1126/science.1116238 [PubMed] [CrossRef] [Google Scholar]
• Langston, M., Dennis, L., Lynch, C., Roe, D., & Brown, H. (2017). Temporal trends in satellite‐derived Erythemal UVB and implications for ambient sun exposure assessment. International Journal of Environmental Research and Public Health, 14(2), 176. 10.3390/ijerph14020176 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Lao, O., de Gruijter, J. M., van Duijn, K., Navarro, A., & Kayser, M. (2007). Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms. Annals of Human Genetics, 71(3), 354–369. 10.1111/j.1469-1809.2006.00341.x [PubMed] [CrossRef] [Google Scholar]
• Latreille, J., Ezzedine, K., Elfakir, A., Ambroisine, L., Gardinier, S., Galan, P., Hercberg, S., Gruber, F., Rees, J., Tschachler, E., & Guinot, C. (2009). MC1R gene polymorphism affects skin color and phenotypic features related to sun sensitivity in a population of French adult women. Photochemistry and Photobiology, 85(6), 1451–1458. 10.1111/j.1751-1097.2009.00594.x [PubMed] [CrossRef] [Google Scholar]
• Li, S., Schlebusch, C., & Jakobsson, M. (2014). Genetic variation reveals large‐scale population expansion and migration during the expansion of Bantu‐speaking peoples. Proceedings of the Royal Society B: Biological Sciences, 281(1793), 20141448. 10.1098/rspb.2014.1448 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Lieberman, D. E. (2011). Human locomotion and heat loss: An evolutionary perspective. Comprehensive Physiology, 5(1), 99–117. 10.1002/cphy.c140011 [PubMed] [CrossRef] [Google Scholar]
• Lin, M., Siford, R. L., Martin, A. R., Nakagome, S., Möller, M., Hoal, E. G., Bustamante, C. D., Gignoux, C. R., & Henn, B. M. (2018). Rapid evolution of a skin‐lightening allele in southern African KhoeSan. Proceedings of the National Academy of Sciences, 115(52), 13324–13329. 10.1073/pnas.1801948115 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Lindqvist, P. G., Epstein, E., Landin‐Olsson, M., Åkerlund, M., & Olsson, H. (2020). Women with fair phenotypes seem to confer a survival advantage in a low UV milieu. A nested matched case control study. PLoS One, 15(1), e0228582. 10.1371/journal.pone.0228582 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Lips, P. (2006). Vitamin D physiology. Progress in Biophysics and Molecular Biology, 92(1), 4–8. 10.1016/j.pbiomolbio.2006.02.016 [PubMed] [CrossRef] [Google Scholar]
• Lips, P. (2007). Vitamin D status and nutrition in Europe and Asia. Journal of Steroid Biochemistry and Molecular Biology, 103(3–5), 620–625. 10.1016/j.jsbmb.2006.12.076 [PubMed] [CrossRef] [Google Scholar]
• Lips, P., van Schoor, N. M., & de Jongh, R. T. (2014). Diet, sun, and lifestyle as determinants of vitamin D status. Annals of the New York Academy of Sciences, 1317(1), 92–98. 10.1111/nyas.12443 [PubMed] [CrossRef] [Google Scholar]
• Liu, D., Fernandez, B. O., Hamilton, A., Lang, N. N., Gallagher, J. M. C., Newby, D. E., Feelisch, M., & Weller, R. B. (2014). UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase. Journal of Investigative Dermatology Advance Online, 10.1038/jid.2014.27 [PubMed] [CrossRef] [Google Scholar]
• Lona‐Durazo, F., Hernandez‐Pacheco, N., Fan, S., Zhang, T., Choi, J., Kovacs, M. A., Loftus, S. K., Le, P., Edwards, M., Fortes‐Lima, C. A., Eng, C., Huntsman, S., Hu, D., Gómez‐Cabezas, E. J., Marín‐Padrón, L. C., Grauholm, J., Mors, O., Burchard, E. G., Norton, H. L., … Parra, E. J. (2019). Meta‐analysis of GWA studies provides new insights on the genetic architecture of skin pigmentation in recently admixed populations. BMC Genetics, 20(1), 59. 10.1186/s12863-019-0765-5 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Loomis, W. F. (1967). Skin‐pigment regulation of vitamin‐D biosynthesis in man. Science, 157(3788), 501–506. 10.1126/science.157.3788.501 [PubMed] [CrossRef] [Google Scholar]
• Luco*ck, M. D., Beckett, E., Martin, C., Jones, P., Furst, J., Yates, Z., Jablonski, N. G., Chaplin, G., & Veysey, M. (2017). UV‐associated decline in systemic folate: Implications for human nutrigenetics, health, and evolutionary processes. American Journal of Human Biology, 29(2), e22929. 10.1002/ajhb.22929 [PubMed] [CrossRef] [Google Scholar]
• Luco*ck, M. D., & Daskalakis, I. (2000). New perspectives on folate status: A differential role for the vitamin in cardiovascular disease, birth defects and other conditions. British Journal of Biomedical Science, 57(3), 254–260. [PubMed] [Google Scholar]
• Luco*ck, M. D., Daskalakis, I., Hinkins, M., & Yates, Z. (2001). An examination of polymorphic genes and folate metabolsim in mothers affected by spina bifida pregnancy. Molecular Genetics and Metabolism, 73(4), 322–332. 10.1006/mgme.2001.3205 [PubMed] [CrossRef] [Google Scholar]
• Luco*ck, M. D., Glanville, T., Ovadia, L., Yates, Z., Walker, J., & Simpson, N. (2010). Photoperiod at conception predicts C677T‐MTHFR genotype: A novel gene‐environment interaction. American Journal of Human Biology, 22(4), 484–489. 10.1002/ajhb.21022 [PubMed] [CrossRef] [Google Scholar]
• Mackintosh, J. A. (2001). The antimicrobial properties of melanocytes, melanosomes and melanin and the evolution of black skin. Journal of Theoretical Biology, 211(2), 101–113. 10.1006/jtbi.2001.2331 [PubMed] [CrossRef] [Google Scholar]
• Madrigal, L., & Kelly, W. (2007). Human skin‐color sexual dimorphism: A test of the sexual selection hypothesis. American Journal of Physical Anthropology, 132(3), 470–482. 10.1002/ajpa.20453 [PubMed] [CrossRef] [Google Scholar]
• Majumder, P. P., & Basu, A. (2014). A genomic view of the peopling and population structure of India. Cold Spring Harbor Perspectives in Biology, 7(4), a008540. 10.1101/cshperspect.a008540 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Makova, K., & Norton, H. L. (2005). Worldwide polymorphism at the MC1R locus and normal pigmentation variation in humans. Peptides, 26(10), 1901–1908. 10.1016/j.peptides.2004.12.032 [PubMed] [CrossRef] [Google Scholar]
• Malaspinas, A.‐S., Westaway, M. C., Muller, C., Sousa, V. C., Lao, O., Alves, I., Bergström, A., Athanasiadis, G., Cheng, J. Y., Crawford, J. E., Heupink, T. H., Macholdt, E., Peischl, S., Rasmussen, S., Schiffels, S., Subramanian, S., Wright, J. L., Albrechtsen, A., Barbieri, C., … Willerslev, E. (2016). A genomic history of Aboriginal Australia. Nature, 538(7624), 207–214. 10.1038/nature18299 [PubMed] [CrossRef] [Google Scholar]
• Martin, A. R., Lin, M., Granka, J. M., Myrick, J. W., Liu, X., Sockell, A., Atkinson, E. G., Werely, C. J., Möller, M., Sandhu, M. S., Kingsley, D. M., Hoal, E. G., Liu, X., Daly, M. J., Feldman, M. W., Gignoux, C. R., Bustamante, C. D., & Henn, B. M. (2017). An unexpectedly complex architecture for skin pigmentation in Africans. Cell, 171(6), 1340–1353.e1314. 10.1016/j.cell.2017.11.015 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Martínez‐Cadenas, C., López, S., Ribas, G., Flores, C., García, O., Sevilla, A., Smith‐Zubiaga, I., Ibarrola‐Villaba, M., Pino‐Yanes, M. D. M., Gardeazabal, J., Boyano, D., García de Galdeano, A., Izagirre, N., de la Rúa, C., & Alonso, S. (2013). Simultaneous purifying selection on the ancestral MC1R allele and positive selection on the melanoma‐risk allele V60L in South Europeans. Molecular Biology and Evolution, 30(12), 2654–2665. 10.1093/molbev/mst158 [PubMed] [CrossRef] [Google Scholar]
• Mastropaolo, W., & Wilson, M. A. (1993). Effect of light on serum B₁₂ and folate stability. Clinical Chemistry, 39(5), 913. 10.1093/clinchem/39.5.913 [PubMed] [CrossRef] [Google Scholar]
• Mathieson, I., Lazaridis, I., Rohland, N., Mallick, S., Patterson, N., Roodenberg, S. A., Harney, E., Stewardson, K., Fernandes, D., Novak, M., Sirak, K., Gamba, C., Jones, E. R., Llamas, B., Dryomov, S., Pickrell, J., Arsuaga, J. L., de Castro, J. M. B., Carbonell, E., … Reich, D. (2015). Genome‐wide patterns of selection in 230 ancient Eurasians. Nature, 528(7583), 499–503. 10.1038/nature16152 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• McEvoy, B., Beleza, S., & Shriver, M. D. (2006). The genetic architecture of normal variation in human pigmentation: An evolutionary perspective and model. Human Molecular Genetics, 15(suppl_2), R176–181. 10.1093/hmg/ddl217 [PubMed] [CrossRef] [Google Scholar]
• McPeters, R. D., Bhartia, P. K., Krueger, A. J., Herman, J. R., Schlesinger, B. M., Wellemeyer, C. G., Seftor, C. J., Jaross, G., Taylor, S. L., Swissler, T., Torres, O., Labow, G., Byerly, W., & Cebula, R. P. (1996). Nimbus‐7 Total Ozone Mapping Spectrometer (TOMS) Data Products User's Guide. NASA ‐ Scientific and Technical Information Branch. [Google Scholar]
• Meinhardt, M., Krebs, R., Anders, A., Heinrich, U., & Tronnier, H. (2008). Wavelength‐dependent penetration depths of ultraviolet radiation in human skin. Journal of Biomedical Optics, 13(4), 044030. 10.1117/1.2957970 [PubMed] [CrossRef] [Google Scholar]
• Moorjani, P., Thangaraj, K., Patterson, N., Lipson, M., Loh, P.‐R., Govindaraj, P., Berger, B., Reich, D., & Singh, L. (2013). Genetic evidence for recent population mixture in India. The American Journal of Human Genetics, 93(3), 422–438. 10.1016/j.ajhg.2013.07.006 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Moreno‐Mayar, J. V., Potter, B. A., Vinner, L., Steinrücken, M., Rasmussen, S., Terhorst, J., Kamm, J. A., Albrechtsen, A., Malaspinas, A.‐S., Sikora, M., Reuther, J. D., Irish, J. D., Malhi, R. S., Orlando, L., Song, Y. S., Nielsen, R., Meltzer, D. J., & Willerslev, E. (2018). Terminal Pleistocene Alaskan genome reveals first founding population of Native Americans. Nature, 553, 203–207. 10.1038/nature25173 [PubMed] [CrossRef] [Google Scholar]
• MRC Vitamin Study Research Group. (1991). Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. The Lancet, 338(8760), 131–134. 10.1016/0140-6736(91)90133-A [PubMed] [CrossRef] [Google Scholar]
• Murray, F. G. (1934). Pigmentation, sunlight, and nutritional disease. American Anthropologist, 36(3), 438–445. 10.1525/aa.1934.36.3.02a00100 [CrossRef] [Google Scholar]
• Ng, X., Boyd, L., Dufficy, L., Naumovski, N., Blades, B., Travers, C., Lewis, P., Sturm, J., Yates, Z., Townley‐Jones, M., Roach, P., Veysey, M., & Luco*ck, M. (2009). Folate nutritional genetics and risk for hypertension in an elderly population sample. Journal of Nutrigenetics and Nutrigenomics, 2(1), 1–8. 10.1159/000160079 [PubMed] [CrossRef] [Google Scholar]
• Nielsen, R., Akey, J. M., Jakobsson, M., Pritchard, J. K., Tishkoff, S., & Willerslev, E. (2017). Tracing the peopling of the world through genomics. Nature, 541(7637), 302–310. 10.1038/nature21347 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Norton, H. L.The evolution of the human pigmentation phenotype. In O'Rourke D. H. (Ed.), A companion to anthropological genetics (pp. 251‐265). Hoboken, New Jersey: Wiley‐Blackwell. [Google Scholar]
• Norton, H. L., Friedlaender, J. S., Merriwether, D. A., Koki, G., Mgone, C. S., & Shriver, M. D. (2006). Skin and hair pigmentation variation in Island Melanesia. American Journal of Physical Anthropology, 130(2), 254–268. 10.1002/ajpa.20343 [PubMed] [CrossRef] [Google Scholar]
• Norton, H. L., Kittles, R. A., Parra, E., McKeigue, P., Mao, X., Cheng, K., Canfield, V. A., Bradley, D. G., McEvoy, B., & Shriver, M. D. (2007). Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Molecular Biology and Evolution, 24(3), 710–722. 10.1093/molbev/msl203 [PubMed] [CrossRef] [Google Scholar]
• Norton, H. L., Werren, E., & Friedlaender, J. (2015). MC1R diversity in Northern Island Melanesia has not been constrained by strong purifying selection and cannot explain pigmentation phenotype variation in the region. BMC Genetics, 16(1), 1–15. 10.1186/s12863-015-0277-x [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Oh, C., Hennessy, A., Ha, T., Bisset, Y., Diffey, B. L., & Rees, J. L. (2004). The time course of photoadaptation and pigmentation studied using a novel method to distinguish pigmentation from erythema. Journal of Investigative Dermatology, 123(5), 965–972. 10.1111/j.0022-202X.2004.23464.x [PubMed] [CrossRef] [Google Scholar]
• Olivarius, F. F., Wulf, H. C., Therkildsen, P., Poulsen, T., Crosby, J., & Norval, M. (1997). Urocanic acid isomers: Relation to body site, pigmentation, stratum corneum thickness and photosensitivity. Archives of Dermatological Research, 289(9), 501–505. 10.1007/s004030050230 [PubMed] [CrossRef] [Google Scholar]
• Osborne, D. L., & Hames, R. (2014). A life history perspective on skin cancer and the evolution of skin pigmentation. American Journal of Physical Anthropology, 153(1), 1–8. 10.1002/ajpa.22408 [PubMed] [CrossRef] [Google Scholar]
• Pagani, L., Lawson, D. J., Jagoda, E., Mörseburg, A., Eriksson, A., Mitt, M., Clemente, F., Hudjashov, G., DeGiorgio, M., Saag, L., Wall, J. D., Cardona, A., Mägi, R., Sayres, M. A. W., Kaewert, S., Inchley, C., Scheib, C. L., Järve, M., Karmin, M., … Metspalu, M. (2016). Genomic analyses inform on migration events during the peopling of Eurasia. Nature, 538(7624), 238–242. 10.1038/nature19792 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Patin, E., Lopez, M., Grollemund, R., Verdu, P., Harmant, C., Quach, H., Laval, G., Perry, G. H., Barreiro, L. B., Froment, A., Heyer, E., Massougbodji, A., Fortes‐Lima, C., Migot‐Nabias, F., Bellis, G., Dugoujon, J.‐M., Pereira, J. B., Fernandes, V., Pereira, L., … Quintana‐Murci, L. (2017). Dispersals and genetic adaptation of Bantu‐speaking populations in Africa and North America. Science, 356(6337), 543–546. 10.1126/science.aal1988 [PubMed] [CrossRef] [Google Scholar]
• Pavan, W. J., & Sturm, R. A. (2019). The genetics of human skin and hair pigmentation. Annual Review of Genomics and Human Genetics, 20(1), 41–72. 10.1146/annurev-genom-083118-015230 [PubMed] [CrossRef] [Google Scholar]
• Perry, C. A., Renna, S. A., Khitun, E., Ortiz, M., Moriarty, D. J., & Caudill, M. A. (2004). Ethnicity and race influence the folate status response to controlled folate intakes in young women. Journal of Nutrition, 134(7), 1786–1792. 10.1093/jn/134.7.1786 [PubMed] [CrossRef] [Google Scholar]
• Posth, C., Renaud, G., Mittnik, A., Drucker, D. G., Rougier, H., Cupillard, C., Valentin, F., Thevenet, C., Furtwängler, A., Wißing, C., Francken, M., Malina, M., Bolus, M., Lari, M., Gigli, E., Capecchi, G., Crevecoeur, I., Beauval, C., Flas, D., … Krause, J. (2016). Pleistocene mitochondrial genomes suggest a single major dispersal of non‐Africans and a Late Glacial population turnover in Europe. Current Biology, 26(6), 827–833. 10.1016/j.cub.2016.01.037 [PubMed] [CrossRef] [Google Scholar]
• Powell, A., Shennan, S., & Thomas, M. G. (2009). Late Pleistocene demography and the appearance of modern human behavior. Science, 324(5932), 1298–1301. 10.1126/science.1170165 [PubMed] [CrossRef] [Google Scholar]
• Quillen, E. E. (2015). The evolution of tanning needs its day in the sun. Human Biology, 87(4), 352–360. 10.13110/humanbiology.87.4.0352 [PubMed] [CrossRef] [Google Scholar]
• Quillen, E. E., Bauchet, M., Bigham, A. W., Delgado‐Burbano, M. E., Faust, F. X., Klimentidis, Y. C., Mao, X., Stoneking, M., & Shriver, M. D. (2012). OPRM1 and EGFR contribute to skin pigmentation differences between Indigenous Americans and Europeans. Human Genetics, 131(7), 1073–1080. 10.1007/s00439-011-1135-1 [PubMed] [CrossRef] [Google Scholar]
• Quillen, E. E., Norton, H. L., Parra, E. J., Lona‐Durazo, F., Ang, K. C., Illiescu, F. M., Pearson, L. N., Shriver, M. D., Lasisi, T., Gokcumen, O., Starr, I., Lin, Y.‐L., Martin, A. R., & Jablonski, N. G. (2019). Shades of complexity: New perspectives on the evolution and genetic architecture of human skin. American Journal of Physical Anthropology, 168(S67), 4–26. 10.1002/ajpa.23737 [PubMed] [CrossRef] [Google Scholar]
• Rana, B. K., Hewett‐Emmett, D., Jin, L., Chang, B.‐ H.‐J., Sambuughin, N., Lin, M., Watkins, S., Bamshad, M., Jorde, L. B., Ramsay, M., Jenkins, T., & Li, W. H. (1999). High polymorphism at the human melanocortin 1 receptor locus. Genetics, 151(4), 1547–1557. [PMC free article] [PubMed] [Google Scholar]
• Rees, J. L. (2000). The melanocortin 1 receptor (MC1R): More than just red hair. Pigment Cell Research, 13(3), 135–140. 10.1034/j.1600-0749.2000.130303.x [PubMed] [CrossRef] [Google Scholar]
• Rees, J. L. (2003). Genetics of hair and skin color. Annual Review of Genetics, 37, 67–90. 10.1146/annurev.genet.37.110801.143233 [PubMed] [CrossRef] [Google Scholar]
• Reyes‐Centeno, H. (2016). Out of Africa and into Asia: Fossil and genetic evidence on modern human origins and dispersals. Quaternary International, 416, 249–262. 10.1016/j.quaint.2015.11.063 [CrossRef] [Google Scholar]
• Reyes‐Centeno, H., Ghirotto, S., Détroit, F., Grimaud‐Hervé, D., Barbujani, G., & Harvati, K. (2014). Genomic and cranial phenotype data support multiple modern human dispersals from Africa and a southern route into Asia. Proceedings of the National Academy of Sciences, 111(20), 7248–7253. 10.1073/pnas.1323666111 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Roberts, D. F., & Kahlon, D. P. S. (1972). Skin pigmentation and assortative mating in Sikhs. Journal of Biosocial Science, 4(1), 91–100. 10.1017/S002193200000835X [PubMed] [CrossRef] [Google Scholar]
• Roberts, D. F., & Kahlon, D. P. S. (1976). Environmental correlations of skin colour. Annals of Human Biology, 3(1), 11–22. 10.1080/03014467600001101 [PubMed] [CrossRef] [Google Scholar]
• Robins, A. H. (1991). Biological perspectives on human pigmentation. Cambridge Series in Biological and Evolutionary Anthropology. (Vol. 7). Cambridge: Cambridge University Press. [Google Scholar]
• Robins, A. H. (2009). The evolution of light skin color: Role of vitamin D disputed. American Journal of Physical Anthropology, 139(4), 447–450. 10.1002/ajpa.21077 [PubMed] [CrossRef] [Google Scholar]
• Rocha, J. (2020). The evolutionary history of human skin pigmentation. Journal of Molecular Evolution, 88, 77–87. 10.1007/s00239-019-09902-7 [PubMed] [CrossRef] [Google Scholar]
• Rogers, A. R., Iltis, D., & Wooding, S. (2004). Genetic variation at the MC1R locus and the time since loss of human body hair. Current Anthropology, 45(1), 105–124. 10.1086/381006 [CrossRef] [Google Scholar]
• Ross, A. B., Johansson, A., Ingman, M., & Gyllensten, U. (2006). Lifestyle, genetics, and disease in Sami. Croatian Medical Journal, 47(4), 553–565. [PMC free article] [PubMed] [Google Scholar]
• Røyrvik, E. C., Yuldasheva, N., Tonks, S., Winney, B., Ruzibakiev, R., Wells, R. S., & Bodmer, W. F. (2018). Genetic patterning in Central Eurasia: Population history and pigmentation. bioRxiv. 255117. 10.1101/255117 [CrossRef] [Google Scholar]
• Sahani, R. (2010). Nutritional and Health Status of Foragers of Andaman Islands Gauhati University, Guwahati, India. Retrieved from http://hdl.handle.net/10603/67536 [Google Scholar]
• Sassi, F., Tamone, C., & D’Amelio, P. (2018). Vitamin D: Nutrient, hormone, and immunomodulator. Nutrients, 10(11), 1656. 10.3390/nu10111656 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Scerri, E. M. L., Thomas, M. G., Manica, A., Gunz, P., Stock, J. T., Stringer, C., Grove, M., Groucutt, H. S., Timmermann, A., Rightmire, G. P., d’Errico, F., Tryon, C. A., Drake, N. A., Brooks, A. S., Dennell, R. W., Durbin, R., Henn, B. M., Lee‐Thorp, J., deMenocal, P., … Chikhi, L. (2018). Did our species evolve in subdivided populations across Africa, and why does it matter?Trends in Ecology & Evolution, 33(8), 582–594. 10.1016/j.tree.2018.05.005 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Sheehan, J. M., Potten, C. S., & Young, A. R. (1998). Tanning in human skin types II and III offers modest photoprotection against erythema. Photochemistry and Photobiology, 68(4), 588–592. 10.1111/j.1751-1097.1998.tb02518.x [PubMed] [CrossRef] [Google Scholar]
• Skoglund, P., & Mathieson, I. (2018). Ancient genomics of modern humans: The first decade. Annual Review of Genomics and Human Genetics, 19(1), 381–404. 10.1146/annurev-genom-083117-021749 [PubMed] [CrossRef] [Google Scholar]
• Stanhewicz, A. E., Alexander, L. M., & Kenney, W. L. (2015). Folic acid supplementation improves microvascular function in older adults through nitric oxide‐dependent mechanisms. Clinical Science, 129(2), 159–167. 10.1042/cs20140821 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Stanhewicz, A. E., Bruning, R. S., Smith, C. J., Kenney, W. L., & Holowatz, L. A. (2012). Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide‐dependent mechanisms in aged human skin. Journal of Applied Physiology, 112(5), 791–797. 10.1152/japplphysiol.01257.2011 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Stanhewicz, A. E., & Kenney, W. L. (2017). Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutrition Reviews, 75(1), 61–70. 10.1093/nutrit/nuw053 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Stokowski, R. P., Pant, P. V. K., Dadd, T., Fereday, A., Hinds, D. A., Jarman, C., Filsell, W., Ginger, R. S., Green, M. R., van der Ouderaa, F. J., & Cox, D. R. (2007). A genomewide association study of skin pigmentation in a South Asian population. American Journal of Human Genetics, 81(6), 1119–1132. 10.1086/522235 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Stover, P. J. (2009). One‐carbon metabolism‐genome interactions in folate‐associated pathologies. Journal of Nutrition, 139(12), 2402–2405. 10.3945/jn.109.113670 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Stringer, C. (2016). The origin and evolution of hom*o sapiens. Philosophical Transactions of the Royal Society B: Biological Sciences, 371, 1698. 10.1098/rstb.2015.0237 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Sturm, R. A., Duffy, D. L., Box, N. F., Chen, W., Smit, D. J., Brown, D. L., Stow, J. L., Leonard, J. H., & Martin, N. G. (2003). The role of melanocortin‐1 receptor polymorphism in skin cancer risk phenotypes. Pigment Cell Research, 16(3), 266–272. 10.1034/j.1600-0749.2003.00041.x [PubMed] [CrossRef] [Google Scholar]
• Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., Pálsson, S., Jonasson, F., Sigurgeirsson, B., Thorisdottir, K., Ragnarsson, R., Benediktsdottir, K. R., Aben, K. K., … Stefansson, K. (2007). Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genetics, 39(12), 1443–1452. 10.1038/ng.2007.13 [PubMed] [CrossRef] [Google Scholar]
• Swope, V. B., & Abdel‐Malek, Z. A. (2018). MC1R: Front and center in the bright side of dark eumelanin and DNA repair. International Journal of Molecular Sciences, 19(9), 2667. 10.3390/ijms19092667 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Tadokoro, T., Kobayashi, N., Zmudzka, B. Z., Ito, S., Wakamatsu, K., Yamaguchi, Y., Korossy, K. S., Miller, S. A., Beer, J. Z., & Hearing, V. J. (2003). UV‐induced DNA damage and melanin content in human skin differing in racial/ethnic origin. The FASEB Journal, 17, 1177–1179. 10.1096/fj.02-0865fje [PubMed] [CrossRef] [Google Scholar]
• Van den Berghe, P. L., & Frost, P. (1986). Skin color preference, sexual dimorphism and sexual selection: A case of gene culture evolution?Ethnic and Racial Studies, 9, 87–113. [Google Scholar]
• Villmoare, B., Kimbel, W. H., Seyoum, C., Campisano, C. J., DiMaggio, E. N., Rowan, J., Braun, D. R., Arrowsmith, J. R., & Reed, K. E. (2015). Early hom*o at 2.8 Ma from Ledi‐Geraru, Afar, Ethiopia. Science, 347(6228), 1352–1355. 10.1126/science.aaa1343 [PubMed] [CrossRef] [Google Scholar]
• Walter, H. V. (1958). Der zusammenhang von hautfarbenverteilung und intensitat der ultravioletten strahlung. hom*o, 9(1), 1–13. [Google Scholar]
• Wassermann, H. P. (1965). Human pigmentation and environmental adaptation. Archives of Environmental Health, 11(5), 691–694. 10.1080/00039896.1965.10664280 [PubMed] [CrossRef] [Google Scholar]
• White, T. D., Asfaw, B., DeGusta, D., Gilbert, H., Richards, G. D., Suwa, G., & Howell, F. C. (2003). Pleistocene hom*o sapiens from Middle Awash, Ethiopia. Nature, 423, 742–747. 10.1038/nature01669 [PubMed] [CrossRef] [Google Scholar]
• Wolf, S. T., Jablonski, N. G., Ferguson, S. B., Alexander, L. M., & Kenney, W. L. (2020). Four weeks of vitamin D supplementation improves nitric oxide‐mediated microvascular function in college‐aged African Americans. American Journal of Physiology‐Heart and Circulatory Physiology, 319(4), H906–H914. 10.1152/ajpheart.00631.2020 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Wolf, S. T., & Kenney, W. L. (2019). The vitamin D‐folate hypothesis in human vascular health. American Journal of Physiology‐Regulatory, Integrative and Comparative Physiology, 317(3), R491–R501. 10.1152/ajpregu.00136.2019 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Yang, Z., Shi, H., Ma, P., Zhao, S., Kong, Q., Bian, T., Gong, C., Zhao, Q. I., Liu, Y., Qi, X., Zhang, X., Han, Y., Liu, J., Li, Q., Chen, H., & Su, B. (2018). Darwinian positive selection on the pleiotropic effects of KITLG explain skin pigmentation and winter temperature adaptation in Eurasians. Molecular Biology and Evolution, 35(9), 2272–2283. 10.1093/molbev/msy136 [PubMed] [CrossRef] [Google Scholar]
• Yang, Z., Zhong, H., Chen, J., Zhang, X., Zhang, H., Luo, X., Xu, S., Chen, H., Lu, D., Han, Y., Li, J., Fu, L., Qi, X., Peng, Y. I., Xiang, K., Lin, Q., Guo, Y., Li, M., Cao, X., … Su, B. (2016). A genetic mechanism for convergent skin lightening during recent human evolution. Molecular Biology and Evolution, 33(5), 1177–1187. 10.1093/molbev/msw003 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Young, A. R., Claveau, J., & Rossi, A. B. (2017). Ultraviolet radiation and the skin: Photobiology and sunscreen photoprotection. Journal of the American Academy of Dermatology, 76(3, Supplement 1), S100‐S109. 10.1016/j.jaad.2016.09.038 [PubMed] [CrossRef] [Google Scholar]
• Young, A. R., Morgan, K. A., Ho, T.‐W., Ojimba, N., Harrison, G. I., Lawrence, K. P., Jakharia‐Shah, N., Wulf, H. C., Cruickshank, J. K., & Philipsen, P. A. (2020). Melanin has a small inhibitory effect on cutaneous vitamin D synthesis: A comparison of extreme phenotypes. Journal of Investigative Dermatology, 140(7), 1418–1426e.1411. 10.1016/j.jid.2019.11.019 [PubMed] [CrossRef] [Google Scholar]
• Zihlman, A. L., & Cohn, B. A. (1988). The adaptive response of human skin to the savanna. Human Evolution, 3(5), 397–409. 10.1007/BF02447222 [CrossRef] [Google Scholar]