In response to a recent article by Jones et al. (Nutrients 10: 554⁻568, 2018) [1], we agree that three distinctive features evolved in Homo erectus prior to the emergence of modern humans.[...]

Elias, Peter M

Williams, Mary L

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UCSFUC San Francisco Previously Published WorksTitleComment on: The Vitamin D–Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas, Nutrients 2018, 10, 554Permalinkhttps://escholarship.org/uc/item/8rw0p0bqJournalNutrients, 10(11)ISSN2072-6643AuthorsElias, Peter MWilliams, Mary LPublication Date2018DOI10.3390/nu10111753 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CalifornianutrientsCommentComment on: The Vitamin D–Folate Hypothesis asan Evolutionary Model for Skin Pigmentation: AnUpdate and Integration of Current Ideas, Nutrients2018, 10, 554Peter M. Elias * and Mary L. WilliamsDepartment of Dermatology, University of California San Francisco and Veterans Affairs Medical Center,4150 Clement Street, San Francisco, CA 94121, USA; elias.williams1@gmail.com* Correspondence: peter.elias@ucsf.edu; Tel.: +1-(415)-750-2091; Fax: +1-(415)-750-2106Received: 10 October 2018; Accepted: 9 November 2018; Published: 14 November 2018Keywords: Evolution; folic acid; pigmentation; skin; ultraviolet irradiation; vitamin DDear Editor,In response to a recent article by Jones et al. (Nutrients 10: 554–568, 2018) [1], we agree that threedistinctive features evolved in Homo erectus prior to the emergence of modern humans. These includethe widespread dispersal of eccrine glands; a dramatic reduction in furry pelage, followed by densepigmentation of recently exposed skin. It is now widely accepted that the first two events evolvedeither in close succession or concurrently in order to facilitate heat dispersion as hominins venturedonto torrid, dry open savannahs in response to sustained megadroughts that fragmented and shranktropical forests [2].Yet, the basis for the subsequent development of deep cutaneous pigmentation continues toprovoke intense debate. Though no one doubts that cutaneous pigmentation evolved in responseto exposure to potentially toxic levels of ultraviolet B irradiation (UVB) in equatorial Africa [3],the contentious issue is “why.” Jones et al. take issue with our proposition that pigmentation evolvedto optimize permeability and antimicrobial barrier function in the hostile, infectious soup of equatorialAfrica [4–6]. This hypothesis is based upon our prior descriptions of multiple functional advantagesendowed upon darkly vs. lightly pigmented humans and mice [7,8]. However, Jones et al. disputeour conclusion, based upon earlier studies that showed a less-efficient barrier in African-Americans.But our data were based upon differences in degrees of pigmentation across several different ethnicgroups—not upon racial categories—a distinction that should be abandoned, in any case, because ofthe large genetic variations among humans of different ethnicities, as well as the omnipresent risk ofracial stereotyping.Aside from the skin barrier concept, two other hypotheses continue to be advanced to explain thedevelopment of dense cutaneous pigmentation: first, to prevent the development of skin cancers—theso-called ‘genotoxic hypothesis’ [9]; and second, the possibility that skin darkened to prevent thephotodegradation of folic acid and its biologically active metabolites [3,10]. We do not dispute thenotion that folic acid deficiency occasionally results in severe congenital anomalies (e.g., neuraltube defects, such as spina bifida) that could impair reproductive success. We also are fully awarethat folic acid, its metabolites, and its regulatory genes can be readily degraded in vitro by UVirradiation [11]. Moreover, Jones’ group has identified latitude-dependent and UV-sensitive differencesin the expression of several genes that regulate folic acid metabolism (cited in [12]), which they citeas further evidence in favor of the folic acid hypothesis. Jones et al. rely upon such results to defendthe possibility that dense pigmentation evolved in the ultraviolet-drenched environs of Sub-SaharanAfrica to prevent degradation of this critical nutrient.Nutrients 2018, 10, 1753; doi:10.3390/nu10111753 www.mdpi.com/journal/nutrientsNutrients 2018, 10, 1753 2 of 4However, all of these data are correlative, and inconsistent with an expanding body of evidenceagainst the folic acid hypothesis. Bolstered by the benefit of knowledge of skin structure and function,as well as the field of clinical dermatology, we summarize here the key arguments against the folicacid hypothesis: (1) The lack of direct evidence that incident UV irradiation reduces circulating folicacid levels. (2) In contrast to test tube studies, the fact that very little UV-B can reach the depthsof the skin where folic acid and its metabolites circulate [13]. In an attempt to rescue this concept,it has been noted that UV-A sensitizers in the blood, such as riboflavin, could amplify UV-inducedphotodegradation [14], though the huge excess of circulating albumen and bilirubin would likelydampen any such risk of photosensitization [15]. (3) The very low incidence of congenital anomaliesserious enough to interfere with reproductive fitness, even in populations that exhibit subnormalfolic acid levels [16,17]. (4) The observation that neural tube defects are much more common in somenorthern countries (i.e., the United Kingdom and Ireland—1 in 100–400 births) in comparison to moresouthern latitudes (continental Europe and Latin America—0.75 in 100,000 births). Thus, neural tubedefects can result from causes other than folic acid deficiency. (5) The ready bioavailability of folic acidfrom multiple dietary sources that were widely available in Sub-Saharan Africa when pigmentationevolved. (6) Most importantly, there is direct (as opposed to correlative) evidence that UV-B and UV-A,even when repeatedly administered and at supraphysiologic doses for the therapy of inflammatorydermatoses, such as psoriasis, do not reduce circulatory folic acid levels [18–20]. In light of the above,as well as further evidence against the folic acid hypothesis presented in [21], we respectfully submitthat the folic acid hypothesis is simply untenable.We would also note that the vitamin D corollary of the “yin-yang” hypothesis, as presented byJones et al. (i.e., that pigment dilution occurred in response to a need to bolster cutaneous vitamin Dproduction as modern humans emigrated from Africa into Europe), is equally flawed. A re-examinationof the famed “Loomis diagram” [22] shows that, with the exception of humans who migrated behindretreating glaciers to the far north of Europe, only moderate pigment dilution occurred everywhere elsein Eurasia. For example, Chinese and Japanese family members, residing at widely separated latitudes,exhibit comparable degrees of pigmentation (cited in [6]). Moreover, circulating vitamin D levels arehigher in northern Europeans than in central and southern Europeans [23]. Finally, how can Jones et al.reconcile several recent population genetic studies which have demonstrated the persistence of darkpigmentation in Mesolithic populations of southern, central, and northern Europeans as recently as7 thousand years ago (e.g., [24])? Indeed, even in the far North, light pigmentation evolved only in thelast 5000 years—and not during 30,000+ years that humans had occupied Eurasia [25]. Note also thatrickets appeared only after the rise of the Industrial Age, when pollution darkened European skies,and that osteoporosis is less common in African-American people then in people of northern Europeanextraction (see [4–6,21]). These observations support recent studies showing that, rather than changesin pigmentation genes, nonpigment-related mutations have evolved recently to enhance vitaminD production in northern Europeans. These include: loss-of-function mutations in the epidermalstructural protein; filaggrin [23], which is hydrolyzed into the most potent UV-B absorber in the skin,trans-urocanic acid; and the gene encoding 7-dehydrocholesterol reductase, which would inevitablyresult in elevated levels of 7-dehydrocholesterol, the immediate sterol precursor of previtamin D3 [26].Yet, a moderate degree of skin lightening did occur across Eurasia and southcentral Europe.We proposed that, rather than to enhance vitamin D3 production, evolution favored mutations, such aspolymorphisms in the melanocortin receptor type 1 (MC1R), because dense pigmentation was nolonger necessary in light of less stringent barrier requirements. This well-known concept in clinicalmedicine is called ‘metabolic conservation,’ allowing the diversion of precious calories towards moreurgent priorities [6].Finally, one would anticipate that a molecule as important as vitamin D would be subject towell-designed biological checks and balances, and melanin would be a relatively crude way to controlsuch a critical process. Changes in melanin production by melanocytes and delivery to its destinationin epidermal keratinocytes occur slowly—not in a timely enough fashion to titrate UV absorption on aNutrients 2018, 10, 1753 3 of 4minute-by-minute basis. We therefore conclude that there is little or no credible evidence that pigmentdilution evolved in order to bolster cutaneous vitamin D production.Funding: This research received no external funding.Conflicts of Interest: The authors declare no conflict of interest.References1. Jones, P.; Lucock, M.; Veysey, M.; Beckett, E. The vitamin D-folate hypothesis as an evolutionary model forskin pigmentation: An update and integration of current ideas. Nutrients 2018, 10. [CrossRef] [PubMed]2. Blome, M.W.; Cohen, A.S.; Tryon, C.A.; Brooks, A.S.; Russell, J. The environmental context for the origins ofmodern human diversity: a synthesis of regional variability in African climate 150,000–30,000 years ago.J. Hum. Evol. 2012, 62, 563–592. [CrossRef] [PubMed]3. Jablonski, N.G.; Chaplin, G. The evolution of human skin coloration. J. Hum. Evol. 2000, 39, 57–106.[CrossRef] [PubMed]4. Elias, P.M.; Williams, M.L. Basis for the gain and subsequent dilution of epidermal pigmentation duringhuman evolution: The barrier and metabolic conservation hypotheses revisited. Am. J. Phys. Anthropol. 2016,161, 189–207. [CrossRef] [PubMed]5. Elias, P.M.; Menon, G.; Wetzel, B.K.; Williams, J.J. Evidence that stress to the epidermal barrier influencedthe development of pigmentation in humans. Pigment Cell Melanoma Res. 2009, 22, 420–434. [CrossRef][PubMed]6. Elias, P.M.; Williams, M.L. Re-appraisal of current theories for the development and loss of epidermalpigmentation in hominins and modern humans. J. Hum. Evol. 2013, 64, 687–692. [CrossRef] [PubMed]7. Gunathilake, R.; Schurer, N.Y.; Shoo, B.A.; Celli, A.; Hachem, J.P.; Crumrine, D.; Sirimanna, G.; Feingold, K.R.;Mauro, T.M.; Elias, P.M. pH-regulated mechanisms account for pigment-type differences in epidermal barrierfunction. J. Invest. Dermatol. 2009, 129, 1719–1729. [CrossRef] [PubMed]8. Man, M.Q.; Lin, T.K.; Santiago, J.L.; Celli, A.; Zhong, L.; Huang, Z.M.; Roelandt, T.; Hupe, M.; Sundberg, J.P.;Silva, K.A.; et al. Basis for enhanced barrier function of pigmented skin. J. Invest. Dermatol. 2014, 134,2399–2407. [CrossRef] [PubMed]9. Brenner, M.; Hearing, V.J. The protective role of melanin against UV damage in human skin.Photochem. Photobiol. 2008, 84, 539–549. [CrossRef] [PubMed]10. Jablonski, N.G.; Chaplin, G. The colours of humanity: The evolution of pigmentation in the human lineage.Philos. Trans. R. Soc. Lond B Biol. Sci. 2017, 372, 1–8. [CrossRef] [PubMed]11. Off, M.K.; Steindal, A.E.; Porojnicu, A.C.; Juzeniene, A.; Vorobey, A.; Johnsson, A.; Moan, J. Ultravioletphotodegradation of folic acid. J. Photochem. Photobiol. B. 2005, 80, 47–55. [CrossRef] [PubMed]12. Jones, P.; Lucock, M.; Veysey, M.; Jablonski, N.; Chaplin, G.; Beckett, E. Frequency of folate-relatedpolymorphisms varies by skin pigmentation. Am. J. Hum. Biol. 2018, 30. [CrossRef] [PubMed]13. Parrish, J.A.; Jaenicke, K.F.; Anderson, R.R. Erythema and melanogenesis action spectra of normal humanskin. Photochem. Photobiol. 1982, 36, 187–191. [CrossRef] [PubMed]14. Juzeniene, A.; Thu Tam, T.T.; Iani, V.; Moan, J. 5-Methyltetrahydrofolate can be photodegraded byendogenous photosensitizers. Free Radic. Biol. Med. 2009, 47, 1199–1204. [CrossRef] [PubMed]15. Vorobey, P.; Steindal, A.E.; Off, M.K.; Vorobey, A.; Moan, J. Influence of human serum albumin onphotodegradation of folic acid in solution. Photochem. Photobiol. 2006, 82, 817–822. [CrossRef] [PubMed]16. Northrup, H.; Volcik, K.A. Spina bifida and other neural tube defects. Curr. Probl. Pediatr. 2000, 30, 313–332.[CrossRef] [PubMed]17. Dias, M.; Partington, M.; Section, S. On neurologic, congenital brain and spinal cord malformations and theirassociated cutaneous markers. Pediatrics 2015, 136, e1105–e1119. [CrossRef] [PubMed]18. Juzeniene, A.; Stokke, K.T.; Thune, P.; Moan, J. Pilot study of folate status in healthy volunteers and inpatients with psoriasis before and after UV exposure. J. Photochem. Photobiol. B. 2010, 101, 111–116. [CrossRef][PubMed]19. Cicarma, E.; Juzeniene, A.; Porojnicu, A.C.; Bruland, O.S.; Moan, J. Latitude gradient for melanoma incidenceby anatomic site and gender in Norway 1966–2007. J. Photochem. Photobiol. B. 2010, 101, 174–178. [CrossRef][PubMed]Nutrients 2018, 10, 1753 4 of 420. Gambichler, T.; Bader, A.; Sauermann, K.; Altmeyer, P.; Hoffmann, K. Serum folate levels after UVA exposure:a two-group parallel randomised controlled trial. BMC Dermatol. 2001, 1. [CrossRef]21. Elias, P.M.; Williams, M.L. Evolution: Skin color. In Basics in Human Evolution, 1st ed.; Michael, P., Ed.;Academic Press: London, UK, 2015; pp. 273–283.22. Loomis, W.F. Skin-pigment regulation of vitamin-D biosynthesis in man. Science 1967, 157, 501–506.[CrossRef] [PubMed]23. Thyssen, J.P.; Bikle, D.D.; Elias, P.M. Evidence that loss-of-function filaggrin gene mutations evolved innorthern Europeans to favor intracutaneous vitamin D3 production. Evol. Biol. 2014, 41, 388–396. [CrossRef][PubMed]24. Olalde, I.; Allentoft, M.E.; Sanchez-Quinto, F.; Santpere, G.; Chiang, C.W.; DeGiorgio, M.; Prado-Martinez, J.;Rodriguez, J.A.; Rasmussen, S.; Quilez, J.; et al. Derived immune and ancestral pigmentation alleles in a7,000-year-old Mesolithic European. Nature 2014, 507, 225–228. [CrossRef] [PubMed]25. Wilde, S.; Timpson, A.; Kirsanow, K.; Kaiser, E.; Kayser, M.; Unterlander, M.; Hollfelder, N.; Potekhina, I.D.;Schier, W.; Thomas, M.G.; et al. Direct evidence for positive selection of skin, hair, and eye pigmentation inEuropeans during the last 5,000 y. Proc. Natl. Acad. Sci. USA 2014, 111, 4832–4837. [CrossRef] [PubMed]26. Witsch-Baumgartner, M.; Schwentner, I.; Gruber, M.; Benlian, P.; Bertranpetit, J.; Bieth, E.; Chevy, F.;Clusellas, N.; Estivill, X.; Gasparini, G.; et al. Age and origin of major Smith-Lemli-Opitz syndrome(SLOS) mutations in European populations. J. Med. Genet. 2008, 45, 200–209. [CrossRef] [PubMed]© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Comment on: The Vitamin D–Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas, Nutrients 2018, 10, 554

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Comment on: The Vitamin D⁻Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas, Nutrients 2018, 10, 554.

Comment on: The Vitamin D⁻Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas, Nutrients 2018, 10, 554.

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