Biophysical evidence to support and extend the vitamin D-folate hypothesis as a paradigm for the evolution of human skin pigmentation.

OBJECTIVE: To test the "vitamin D-folate hypothesis for the evolution of human skin pigmentation." METHODS: Total ozone mapping spectrometer (TOMS) satellite data were used to examine surface UV-irradiance in a large (n = 649) Australian cross-sectional study population. Genetic analysis was used to score vitamin D- and folate-related gene polymorphisms (n = 22), along with two pigmentation gene variants (IRF4-rs12203592/HERC2-rs12913832). Red cell folate and vitamin D3 were measured by immunoassay and HPLC, respectively. RESULTS: Ultraviolet radiation (UVR) and pigmentation genes interact to modify blood vitamin levels; Light skin IRF4-TT genotype has greatest folate loss while light skin HERC2-GG genotype has greatest vitamin D3 synthesis (reflected in both TOMS and seasonal data). UV-wavelength exhibits a dose-response relationship in folate loss within light skin IRF4-TT genotype (305 > 310 > 324 > 380 nm). Significant vitamin D3 photosynthesis only occurs within light skin HERC2-GG genotype, and is maximal at 305 nm. Three dietary antioxidants (vitamins C, E, and ß-carotene) interact with UVR and pigmentation genes preventing oxidative loss of labile reduced folate vitamers, with greatest benefit in light skin IRF4-TT subjects. The putative photosensitiser, riboflavin, did not sensitize red cell folate to UVR and actually afforded protection. Four genes (5xSNPs) influenced blood vitamin levels when stratified by pigmentation genotype; MTHFR-rs1801133/rs1801131, TS-rs34489327, CYP24A-rs17216707, and VDR-ApaI-rs7975232. Lightest IRF4-TT/darkest HERC2-AA genotype combination (greatest folate loss/lowest vitamin D3 synthesis) has 0% occurrence. The opposing, commonest (39%) compound genotype (darkest IRF4-CC/lightest HERC2-GG) permits least folate loss and greatest synthesis of vitamin D3 . CONCLUSION: New biophysical evidence supports the vitamin D-folate hypothesis for evolution of skin pigmentation.

Distribution of variants in multiple vitamin D-related loci (DHCR7/NADSYN1, GC, CYP2R1, CYP11A1, CYP24A1, VDR, RXRα and RXRγ) vary between European, East-Asian and Sub-Saharan African-ancestry populations.

BACKGROUND: The frequency of vitamin D-associated gene variants appear to reflect changes in long-term ultraviolet B radiation (UVB) environment, indicating interactions exist between the primary determinant of vitamin D status, UVB exposure and genetic disposition. Such interactions could have health implications, where UVB could modulate the impact of vitamin D genetic variants identified as disease risk factors. However, the current understanding of how vitamin D variants differ between populations from disparate UVB environments is limited, with previous work examining a small pool of variants and restricted populations only. METHODS: Genotypic data for 46 variants within multiple vitamin D-related loci (DHCR7/NADSYN1, GC, CYP2R1, CYP11A1, CYP27A1, CYP24A1, VDR, RXRα and RXRγ) was collated from 60 sample sets (2633 subjects) with European, East Asian and Sub-Saharan African origin via the NCBI 1000 Genomes Browser and ALFRED (Allele Frequency Database), with the aim to examine for patterns in the distribution of vitamin D-associated variants across these geographic areas. RESULTS: The frequency of all examined genetic variants differed between populations of European, East Asian and Sub-Saharan African ancestry. Changes in the distribution of variants in CYP2R1, CYP11A1, CYP24A1, RXRα and RXRγ genes between these populations are novel findings which have not been previously reported. The distribution of several variants reflected changes in the UVB environment of the population's ancestry. However, multiple variants displayed population-specific patterns in frequency that appears not to relate to UVB changes. CONCLUSIONS: The reported population differences in vitamin D-related variants provides insight into the extent by which activity of the vitamin D system can differ between cohorts due to genetic variance, with potential consequences for future dietary recommendations and disease outcomes.

Early lifecycle UV-exposure calibrates adult vitamin D metabolism: Evidence for a developmentally originated vitamin D homeostat that may alter related adult phenotypes.

OBJECTIVES: Within the Developmental Origins of Adult Disease (DOHaD) model, early life environmental exposures can confer a long-term legacy on human health. This mechanism may be adaptive or maladaptive depending on lifestyle circumstances. This article examines the role of first trimester UV-exposure on late-life vitamin D levels, and potentially related adaptive and maladaptive phenotypes (height and osteoporosis respectively). METHODS: Six hundred and forty nine subjects were examined for vitamin D2 and D3 (HPLC) and height (stadiometer). Osteoporosis was assessed with an extensive medical history questionnaire. RESULTS: Solar irradiance over the first 90 days postconception correlated positively with late-life vitamin D3 (R2 = .0140; P = .0082; ß = .1075), but not vitamin D2 levels. It also correlated positively with female adult height (R2 = .170; P = .0103; ß = .1291) and negatively with the occurrence of female osteoporosis (P = .0495). All data were adjusted for age and gender as appropriate (unadjusted data also provided). From a contemporary perspective, vitamin D levels varied significantly according to season of blood sampling as might be predicted (P = .0009). CONCLUSIONS: Increased solar irradiance/UV exposure during the first trimester of pregnancy calibrates adult vitamin D metabolism, which is an important hormone in maintaining calcium balance. This may explain how very early lifecycle UV exposure can influence skeletal development (adult height) and modify risk for the skeletal degenerative disorder osteoporosis. The data demonstrate humans are tuned to the world (exposome) in ways we have not yet fully considered, and which are entrained at the earliest phase of the lifecycle.

Vitamin D and folate: A reciprocal environmental association based on seasonality and genetic disposition.

OBJECTIVES: The purpose of this study was (1) to elucidate any reciprocal seasonal relationship that might exist between red cell folate (RCF) and serum vitamin D3 Levels; (2) to explore whether folate-related gene variants that influence/alter DNA-thymidylate and methyl group biosynthesis modify any associations detected in objective 1; and (3) to consider whether these processes might influence reproductive success consistent with the "folate-vitamin D-UV hypothesis of skin pigmentation" evolutionary model. METHODS: A large (n = 649) Australian cross-sectional study population was examined. Polymerase chain reaction (PCR)/Restriction fragment length polymorphism (RFLP) analysis was used to genotype C677T-MTHFR, C1420T-SHMT, T401C-MTHFD and 2R > 3R-TS. RCF was measured by chemiluminescent immunoassay and vitamin D2 and D3 by HPLC. RESULTS: RCF and photosynthesized vitamin D3 , but not RCF and dietary vitamin D2 , exhibit a significant reciprocal association in spring and summer. Three folate genes (C677T-MTHFR, C1420T-SHMT, and 2R > 3R-TS) strengthen this effect in spring, and another (T401C-MTHFD) in summer. Effects are seasonal, and do not occur over the whole year. CONCLUSIONS: Findings are consistent with what might be required for the "folate-vitamin D-UV hypothesis of skin pigmentation" model. It suggests genetic influence in provision of one-carbon units by 5,10-methylene-H4 folate, may be an important factor in what appears to be a clear seasonal relationship between vitamin D3 and folate status.

The influences of genes, the environment, and social factors on the evolution of skin color diversity in India.

OBJECTIVES: Skin color is a highly visible and variable trait across human populations. It is not yet clear how evolutionary forces interact to generate phenotypic diversity. Here, we sought to unravel through an integrative framework the role played by three factors-demography and migration, sexual selection, and natural selection-in driving skin color diversity in India. METHODS: Skin reflectance data were collected from 10 diverse socio-cultural populations along the latitudinal expanse of India, including both sexes. We first looked at how skin color varies within and between these populations. Second, we compared patterns of sexual dimorphism in skin color. Third, we studied the influence of ultraviolet radiation on skin color throughout India. Finally, we attempted to disentangle the interactions between these factors in the context of available genetic data. RESULTS: We found that the relative importance of these forces varied between populations. Social factors and population structure have played a stronger role than natural selection in shaping skin color diversity across India. Phenotypic overprinting resulted from additional genetic mutations overriding the skin lightening effect of variants such as the SLC24A5 rs1426654-A allele in some populations, in the context of the variable influence of sexual selection. Furthermore, specific genotypes are not associated reliably with specific skin color phenotypes. This result has relevance for DNA forensics and ancient DNA research. CONCLUSIONS: India is a crucible of macro- and micro-evolutionary forces, and the complex interactions of physical and social forces are visible in the patterns of skin color seen today in the country.

Environmental selection during the last ice age on the mother-to-infant transmission of vitamin D and fatty acids through breast milk.

Because of the ubiquitous adaptability of our material culture, some human populations have occupied extreme environments that intensified selection on existing genomic variation. By 32,000 years ago, people were living in Arctic Beringia, and during the Last Glacial Maximum (LGM; 28,000-18,000 y ago), they likely persisted in the Beringian refugium. Such high latitudes provide only very low levels of UV radiation, and can thereby lead to dangerously low levels of biosynthesized vitamin D. The physiological effects of vitamin D deficiency range from reduced dietary absorption of calcium to a compromised immune system and modified adipose tissue function. The ectodysplasin A receptor (EDAR) gene has a range of pleiotropic effects, including sweat gland density, incisor shoveling, and mammary gland ductal branching. The frequency of the human-specific EDAR V370A allele appears to be uniquely elevated in North and East Asian and New World populations due to a bout of positive selection likely to have occurred circa 20,000 y ago. The dental pleiotropic effects of this allele suggest an even higher occurrence among indigenous people in the Western Hemisphere before European colonization. We hypothesize that selection on EDAR V370A occurred in the Beringian refugium because it increases mammary ductal branching, and thereby may amplify the transfer of critical nutrients in vitamin D-deficient conditions to infants via mothers' milk. This hypothesized selective context for EDAR V370A was likely intertwined with selection on the fatty acid desaturase (FADS) gene cluster because it is known to modulate lipid profiles transmitted to milk from a vitamin D-rich diet high in omega-3 fatty acids.

The roles of vitamin D and cutaneous vitamin D production in human evolution and health.

Most of the vitamin D necessary for the maintenance of human health and successful reproduction is made in the skin under the influence of a narrow portion of the electromagnetic spectrum emitted from the sun, namely ultraviolet B radiation (UVB). During the course of human evolution, skin pigmentation has evolved to afford protection against high levels of UVR while still permitting cutaneous production of vitamin D. Similar pigmentation phenotypes evolved repeatedly as the result of independent genetic events when isolated human populations dispersed into habitats of extremely low or high UVB. The gradient of skin color seen in modern human populations is evidence of the operation of two clines, one favoring photoprotection near the equator, the other favoring vitamin D production nearer the poles. Through time, human adaptations to different solar regimes have become more cultural than biological. Rapid human migrations, increasing urbanization, and changes in lifestyle have created mismatches between skin pigmentation and environmental conditions leading to vitamin D deficiency. The prevalence and significance for health of vitamin D deficiencies, and the definition of optimal levels of vitamin D in the bloodstream are subjects of intense research and debate, but two of the causes of vitamin D deficiency - lack of sun exposure and abandonment of vitamin D rich foods in the diet - are traceable to changes in human lifestyles accompanying urbanization in prehistory.

Frequency of folate-related polymorphisms varies by skin pigmentation.

OBJECTIVES: Folate-mediated 1-carbon transfer processes are vital in human health but are susceptible to independent and interactive influences of genetic variance and environmental exposures. Evidence suggests folate levels may be impacted by genetic variance and environmental UVR, with the effect of UVR levels influenced in part by degree of skin pigmentation. Folate-related genes are also influenced by UVR levels; however, the potential relationship between key folate-related genes and skin pigmentation has not yet been explored. The purpose of this study was to examine potential associations between frequencies of key folate variants and degree of skin pigmentation. METHODS: Association between population prevalence of 17 variants in 9 folate-related genes (MTRR, MTR, MTHFR, CBS, SHMT1, MTHFD1, RFC1, BHMT, TYMS) and the Fitzpatrick skin phototype of populations was assessed via collation of genotypic data from ALFRED (Allele Frequency Database) and 1000 Genomes databases. RESULTS: A significant association between variant frequency and Fitzpatrick phototype was observed for 16 of 17 examined variants (P < .0029 Bonferroni corrected significance threshold in all cases). CONCLUSIONS: These findings demonstrate novel relationships between skin color and folate-related genes, with trends suggesting folate genotypes are selected to maintain homeostasis in the folate system under differing UVR conditions.

The biology of color.

Coloration mediates the relationship between an organism and its environment in important ways, including social signaling, antipredator defenses, parasitic exploitation, thermoregulation, and protection from ultraviolet light, microbes, and abrasion. Methodological breakthroughs are accelerating knowledge of the processes underlying both the production of animal coloration and its perception, experiments are advancing understanding of mechanism and function, and measurements of color collected noninvasively and at a global scale are opening windows to evolutionary dynamics more generally. Here we provide a roadmap of these advances and identify hitherto unrecognized challenges for this multi- and interdisciplinary field.

The colours of humanity: the evolution of pigmentation in the human lineage.

Humans are a colourful species of primate, with human skin, hair and eye coloration having been influenced by a great variety of evolutionary forces throughout prehistory. Functionally naked skin has been the physical interface between the physical environment and the human body for most of the history of the genus Homo, and hence skin coloration has been under intense natural selection. From an original condition of protective, dark, eumelanin-enriched coloration in early tropical-dwelling Homo and Homo sapiens, loss of melanin pigmentation occurred under natural selection as Homo sapiens dispersed into non-tropical latitudes of Africa and Eurasia. Genes responsible for skin, hair and eye coloration appear to have been affected significantly by population bottlenecks in the course of Homo sapiens dispersals. Because specific skin colour phenotypes can be created by different combinations of skin colour-associated genetic markers, loss of genetic variability due to genetic drift appears to have had negligible effects on the highly redundant genetic 'palette' for the skin colour. This does not appear to have been the case for hair and eye coloration, however, and these traits appear to have been more strongly influenced by genetic drift and, possibly, sexual selection.This article is part of the themed issue 'Animal coloration: production, perception, function and application'.

VDR gene methylation as a molecular adaption to light exposure: Historic, recent and genetic influences.

OBJECTIVES: The vitamin D receptor (VDR) is a member of the nuclear receptor family of transcription factors. We examined whether degree of VDR gene methylation acts as a molecular adaptation to light exposure. We explored this in the context of photoperiod at conception, recent UV irradiance at 305 nm, and gene-latitude effects. METHODS: Eighty subjects were examined for VDR gene-CpG island methylation density. VDR gene variants were also examined by PCR-RFLP. RESULTS: Photoperiod at conception was significantly positively related to VDR methylation density, explaining 17% of the variance in methylation (r2 = 0.17; P = .001). Within this model, photoperiod at conception and plasma 25(OH)D independently predicted methylation density at the VDR-CpG island. Recent UV exposure at 305 nm led to a fivefold increase in mean methylation density (P = .02). Again, UV exposure and plasma 25(OH)D independently predicted methylation density at the VDR-CpG island. In the presence of the BsmI mutant allele, methylation density was increased (P = .01), and in the presence of the TaqI or FokI mutant allele, methylation density was decreased (P = .007 and .04 respectively). Multivariate modelling suggests plasma 25(OH)D, photoperiod at conception, recent solar irradiance, and VDR genotype combine as independent predictors of methylation at the VDR-CpG island, explaining 34% of the variance in methylation (R2 = 0.34, P < .0001). CONCLUSIONS: Duration of early-life light exposure and strength of recent irradiance, along with latitudinal genetic factors, influence degree of VDR gene methylation consistent with this epigenetic phenomenon being a molecular adaptation to variation in ambient light exposure. Findings contribute to our understanding of human biology.

UV-associated decline in systemic folate: implications for human nutrigenetics, health, and evolutionary processes.

OBJECTIVES: The purpose of this study was to examine whether UV exposure alters folate status according to C677T-MTHFR genotype, and to consider the relevance of this to human health and the evolutionary model of skin pigmentation. METHODS: Total Ozone Mapping Spectrometer (TOMS) satellite data were used to examine surface UV-irradiance, as a marker of UV exposure, in a large (n = 649) Australian cross-sectional study population. PCR/RFLP analysis was used to genotype C677T-MTHFR. RESULTS: Overall, cumulative UV-irradiance (42 and 120 days pre-clinic) was significantly negatively related to red cell folate (RCF) levels. When the cohort was stratified by MTHFR-C677T genotype, the relationship between UV-irradiance (42 days pre-clinic) and RCF remained significant only in the cohorts containing carriers of the T allele. Statistically significant z-score statistics and interaction terms from genotype and UV-irradiance (p-interaction) demonstrated that genotype did modify the effect of UV-irradiance on RCF, with the largest effect of UV being demonstrated in the 677TT-MTHFR subjects. CONCLUSIONS: Data provide strong evidence that surface UV-irradiance reduces long-term systemic folate levels, and that this is influenced by the C677T-MTHFR gene variant. We speculate this effect may be due to 677TT-MTHFR individuals containing more 5,10CH2 -H4 PteGlu, and that this folate form may be particularly UV labile. Since UV-irradiance lowers RCF in an MTHFR genotype-specific way, there are likely implications for human health and the evolution of skin pigmentation.

Behavioral thermoregulation in Lemur catta: The significance of sunning and huddling behaviors.

Regulation of body temperature poses significant problems for organisms that inhabit environments with extreme and seasonally fluctuating ambient temperatures. To help alleviate the energetic costs of autonomic responses, these organisms often thermoregulate through behavioral mechanisms. Among primates, lemurs in Madagascar experience uncharacteristically seasonal and unpredictable climates relative to other primate-rich regions. Malagasy primates are physiologically flexible, but different species use different mechanisms to influence their body temperatures. Lemur catta, the ring-tailed lemur, experiences particularly acute diurnal temperature fluctuations in its mostly open-canopy habitat in south and southwest Madagascar. Ring-tailed lemurs are also atypical among lemurs in that they appear to use both sun basking postures and huddling to maintain body temperature when ambient temperatures are cold. To our knowledge, however, no one has systematically tested whether these behaviors function in thermoregulation. We present evidence that ring-tailed lemurs use these postures as behavioral thermoregulation strategies, and that different environmental variables are associated with the use of each posture. Major predictors of sunning included ambient temperature, time of day, and season. Specifically, L. catta consistently assumed sunning postures early after daybreak when ambient temperatures were <13°C, and ceased sunning around 10:00a.m., after ambient temperatures approached 26°C. Sunning occurred more often during austral winter months. Huddling was associated with time of day, but not with ambient temperature or season. We conclude that L. catta tend to sun, rather than huddle, under cold weather conditions when sunning is possible. However, both sunning and huddling are important behavioral adaptations of L. catta that augment chemical thermoregulation and the absence of a dynamic, insulating pelage. Sunning and huddling help to account for the great ecological flexibility of the species, but these adaptations may be insufficient in the face of future changes in protective vegetation and temperature. Am. J. Primatol. 78:745-754, 2016. © 2016 Wiley Periodicals, Inc.

High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans.

Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. We conducted a longitudinal study in two ethnically distinct groups of healthy young adults in Cape Town, supplemented with vitamin D3 in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity.

The evolution of skin pigmentation and hair texture in people of African ancestry.

Our species, Homo sapiens, evolved in Africa, and humanity's highest levels of genetic diversity are maintained there today. Underlying genetic diversity combined with the great range of solar regimes and climatic conditions found in Africa has contributed to a wide range of human integumentary phenotypes within the continent. Millions of Africans have moved, voluntarily and involuntarily, to other continents in the past 2000 years, and the range of integumentary phenotypes among admixed African diaspora populations is enormous. In this contribution, we do not catalog this variation, but provide basic evolutionary background as to how it developed in the first place.

Vitamin D, folate, and potential early lifecycle environmental origin of significant adult phenotypes.

BACKGROUND AND OBJECTIVES: Vitamin D and folate are highly UV sensitive, and critical for maintaining health throughout the lifecycle. This study examines whether solar irradiance during the first trimester of pregnancy influences vitamin D receptor (VDR) and nuclear folate gene variant occurrence, and whether affected genes influence late-life biochemical/clinical phenotypes. METHODOLOGY: 228 subjects were examined for periconceptional exposure to solar irradiance, variation in vitamin D/folate genes (polymerase chain reaction (PCR)), dietary intake (food frequency questionnaire (FFQ)) and important adult biochemical/clinical phenotypes. RESULTS: Periconceptional solar irradiance was associated with VDR-BsmI (P = 0.0008(wk7)), TaqI (P = 0.0014(wk7)) and EcoRV (P = 0.0030(wk6)) variant occurrence between post-conceptional weeks 6-8, a period when ossification begins. Similar effects were detected for other VDR gene polymorphisms. Periconceptional solar irradiance was also associated with 19 bp del-DHFR (P = 0.0025(wk6)), and to a lesser extent C1420T-SHMT (P = 0.0249(wk6)), a folate-critical time during embryogenesis. These same genes were associated with several late-life phenotypes: VDR-BsmI, TaqI and ApaI determined the relationship between dietary vitamin D and both insulin (P < 0.0001/BB, 0.0007/tt and 0.0173/AA, respectively) and systolic blood pressure (P = 0.0290/Bb, 0.0299/Tt and 0.0412/AA, respectively), making them important early and late in the lifecycle. While these and other phenotype associations were found for the VDR variants, folate polymorphism associations in later-life were limited to C1420T-SHMT (P = 0.0037 and 0.0297 for fasting blood glucose and HbA1c levels, respectively). We additionally report nutrient-gene relationships with body mass index, thiol/folate metabolome, cognition, depression and hypertension. Furthermore, photoperiod at conception influenced occurrence of VDR-Tru9I and 2R3R-TS genotypes (P = 0.0120 and 0.0360, respectively). CONCLUSIONS AND IMPLICATIONS: Findings identify environmental and nutritional agents that may interact to modify gene-phenotype relationships across the lifecycle, offering new insight into human ecology. This includes factors related to both disease aetiology and the evolution of skin pigmentation.

The role of piloerection in primate thermoregulation.

The insulating properties of the primate integument are influenced by many factors, including piloerection, which raises the hair and insulates the body by creating motionless air near the skin's surface. The involuntary muscles that control piloerection, the musculi arrectores pilorum (MAP), are mostly absent except on the tail in most strepsirhines, and are entirely absent in tarsiers and some lorisids. The absence of piloerection and the reduced effectiveness of pilary insulation in preventing heat loss affected the evolution of behavior and metabolic thermoregulation in these animals. In lemurs, this situation contributed to the use of positional and social behaviors such as sunning and huddling that help maintain thermal homeostasis during day-night and seasonal temperature cycles. It also contributed in many lemurs and lorises to the evolution of a wide variety of activity patterns and energy-conserving metabolic patterns such as cathemerality, daily torpor, and hibernation. The absence of functional MAP in strepsirhines and tarsiers implies the absence of effective piloerection in early primates, and the reacquisition of whole-body MAP in ancestral anthropoids prior to the separation of platyrrhine and catarrhine lineages. © 2013 S. Karger AG, Basel.

Conflict and societal change in late prehistoric eastern North America.

As recently as the 1980s, archeologists focusing on prehistoric eastern North America paid little attention to intergroup conflict. Today the situation is quite different, as indicated by this Special Issue. Archeologists now face three principal challenges: to document the temporal and spatial distribution of evidence of conflict; to identify the cultural and environmental conditions associated with variation in the nature and frequency of warfare over long periods of time and large geographical areas; and to determine the extent to which intergroup tensions contributed to or resulted from changes in sociopolitical complexity, economic systems, and population size and distribution. We present data from habitation and mortuary sites in the Eastern Woodlands, notably the midcontinent, that touch on all three issues. Palisaded sites and victims of attacks indicate the intensity of conflicts varied over time and space. Centuries-long intervals of either high or low intergroup tensions can be attributed to an intensification or relaxation of pressure on resources that arose in several ways, such as changes in local population density; technological innovations, including subsistence practices; and the natural environment.