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

The folate pathway mapping supports the need for DNA repair in light skin and melanin synthesis in dark skin.

“This supports the need for DNA repair in light skin and melanin synthesis in dark skin.”

Recent research has extended the vitamin D-folate evolutionary model by adding the need for folate (and hence BH4) in the synthesis of eumelanin and pheomelanin and by considering UVR-folate-gene and UVR-folate-antioxidant interactions.

“recent research has extended this evolutionary model; this addendum adds the need for folate (and hence tetrahydrobiopterin [BH4]) in the synthesis of eumelanin (black/brown pigment) and pheomelanin (yellow/red pigment), it also considers relevant UVR‐folate‐gene and UVR‐folate‐antioxidant interactions.”

Mapping publicly available gene frequency data to folate metabolism suggests that the effect of variant alleles on folate-dependent one-carbon transfer tends to support the evolutionary model, with the thymidylate cycle favored in a light phototype and the purine cycle favored in a dark phototype.

“mapping of rsid to metabolism in Figure 4 suggests the effect of variant alleles on folate dependent one‐carbon transfer tends to support the evolutionary model; that is, based on the disposition of polymorphisms, the thymidylate cycle seems to be favored in a light phototype and the purine cycle favored in a dark phototype.”

Four genes (5 SNPs) were found to modify blood vitamin levels when stratified by pigmentation genotype: MTHFR-rs1801133/rs1801131, TS-rs34489327, CYP24A1-rs17216707, and VDR-ApaI-rs7975232.

“four genes (5xSNPs) were found to modify blood vitamin levels when stratified by pigmentation genotype (Lucock et al., 2021). These genes were MTHFR‐rs1801133/rs1801131, TS‐rs34489327, CYP24A1‐rs17216707, and VDR‐ApaI‐rs7975232.”

UVB and low UVA (near UVB) wavelengths cause the greatest loss of erythrocyte folate, and this is enhanced in a lighter skin phototype with the IRF4 TT genotype rs12203592.

“It has recently been shown that UVB and low UVA (near UVB) wavelengths cause the greatest loss of erythrocyte folate, and that this is enhanced in a lighter skin phototype (IRF4 TT genotype—rs12203592)”

Individuals with the lightest IRF4-TT/darkest HERC2-AA genotype combination, with greatest folate loss and lowest vitamin D3 synthesis, had a 0% occurrence; the opposing commonest compound genotype, darkest IRF4-CC/lightest HERC2-GG, had a 39% occurrence.

“Individuals with the lightest IRF4‐TT/darkest HERC2‐AA genotype combination (greatest folate loss/lowest vitamin D3 synthesis) had a 0% occurrence. By contrast, the opposing, commonest compound genotype (darkest IRF4‐CC/lightest HERC2‐GG) had a 39% occurrence.”

UVR and pigmentation genes interacted to alter blood vitamin levels; the light skin IRF4-TT genotype showed the highest folate loss while the light skin HERC2-GG genotype had the highest vitamin D3 synthesis.

“UVR and pigmentation genes interacted to alter blood vitamin levels; the light skin IRF4‐TT genotype showed the highest folate loss while light skin HERC2‐GG genotype had the highest vitamin D3 synthesis.”

Riboflavin does not sensitize erythrocyte folate to UVR and actually affords anti-oxidative protection toward folate.

“recent research shows that riboflavin, does not sensitize erythrocyte folate to UVR, and actually affords anti‐oxidative protection toward folate”

Collectively, the above findings provide new biophysical evidence to support and extend the vitamin D-folate hypothesis for the evolution of skin pigmentation.

“Collectively, the above findings (Lucock et al., 2021) provide new biophysical evidence to support and extend the vitamin D‐folate hypothesis for the evolution of skin pigmentation.”

Statistically significant vitamin D3 photosynthesis only occurred in individuals with the light skin HERC2-GG genotype and was maximal at 305 nm.

“Statistically significant vitamin D3 photosynthesis only occurred in individuals with the light skin HERC2‐GG genotype and was maximal at 305 nm.”

UV wavelength exhibited a dose-response relationship with respect to folate loss in individuals with the light skin IRF4-TT genotype, with 305 > 310 > 324 > 380 nm.

“UV‐wavelength exhibited a dose–response relationship with respect to folate loss in individuals with the light skin IRF4‐TT genotype (305 > 310 > 324 > 380 nm).”

Folate metabolism is challenged most in light skin phototypes in high UV regimes; IRF4 genotype, MTHFR genotype, and folate act together in a contemporary population, and historically may have acted to drive the evolution of skin pigmentation phenotype as an adaptive mechanism to the prevailing UV exposome.

“Folate metabolism is challenged most in light skin phototypes in high UV regimes. IRF4 genotype, MTHFR genotype, and folate act together in a contemporary population, and hence, historically, may have acted to drive the evolution of skin pigmentation phenotype as an adaptive mechanism to the prevailing UV exposome.”

Three dietary antioxidant vitamins (vitamins C, E, and β-carotene) interacted with UVR and pigmentation genes to prevent oxidative loss of highly labile reduced erythrocyte folate vitamers, with the greatest benefit to individuals with the light skin IRF4-TT genotype.

“three dietary antioxidant vitamins (vitamins C, E, and β‐carotene) interacted with UVR and pigmentation genes to prevent oxidative loss of highly labile reduced erythrocyte folate vitamers. The greatest benefit was to individuals with the light skin IRF4‐TT genotype.”

Recent evidence strongly supports the vitamin D-folate evolutionary model.

“Although hard evidence is now beginning to emerge that strongly supports the vitamin D‐folate evolutionary model (Lucock et al., 2021)”

The study by Lucock and colleagues examines a population that for the most part exhibits an environmentally maladapted pigmentation phenotype because it gathers data from individuals of mostly European ancestry living in a very high UVR regime in Australia.

“Furthermore, the latter study by Lucock and colleagues examines a population that for the most part, exhibits an environmentally “maladapted” pigmentation phenotype since it gathers data from individuals of mostly European ancestry living in a very high UVR regime in Australia.”