The vitamin D hypothesis: Dead or alive?: Response to Dr. William Grant's "The UVB-vitamin D3-pigment hypothesis is alive and well-AJPA-2016-00237".

Received: 8 August 2016 Accepted: 11 August 2016 DOI 10.1002/ajpa.23078 LETTER TO THE EDITOR The vitamin D hypothesis: Dead or alive? Response to Dr. William Grant’s “The UVB-vitamin D3-pigment hypothesis is alive and well—AJPA-2016-00237” As exempliﬁed by Dr. Grant’s rebuttal, few hypotheses are so thor- still unknown. Even in mammalian skin, pigmentation modulates oughly entrenched in the ﬁeld of evolutionary biology as the pro- numerous other functions, ranging from insolation to camouﬂage, posal that the skin of modern humans lightened in response to a and as we have repeatedly hypothesized, its likely importance for requirement for additional cutaneous vitamin D3 production. We permeability barrier homeostasis (Elias and Williams, 2013; Elias certainly do not dispute the importance of vitamin D for many criti- et al., 2009, 2010). Nonetheless, in our recent review (Elias and cal physiological processes, extending well beyond its ﬁrmly estab- Williams, 2016), we do acknowledge that some pigment dilution not lished role in regulating mineral metabolism (Rosen et al., 2012). only in north-central Europeans, but perhaps also in northern Given its importance, we would respond that natural selection surely Japanese, could have been “driven” in part by a requirement for would have evolved more eﬃcient regulatory mechanisms than additional cutaneous VD3 production, particularly in those popula- latitude-determined gradations in skin pigmentation. Indeed, a rigor- tions whose diets were enriched in tundra fauna, rather than VD3- ous reexamination of the famous Loomis diagram of latitude- enriched marine seafood. dependent changes in pigmentation reveals numerous inaccuracies— In light (no pun intended) of the importance of cutaneous VD3 there is no latitude-dependent “gradient” in pigment dilution (Elias production, we then asked which mechanisms did evolve through natu- and Williams, 2013) [see Fig. 4 in (Elias and Williams, 2016)]. In fact, ral selection to sustain vitamin D homeostasis in northerners? Instead pigmentation did not lighten in a predictable fashion as humans emi- of (or in addition to diminished pigmentation), natural selection grated out of Africa. Very fair pigmentation evolved solely in popula- spawned a number of much more sophisticated, non-pigment-based tions residing far to the north in Europe, as demonstrated by the mechanisms which have sustained cutaneous VD3 homeostasis in recent discovery of darkly pigmented modern humans in southern northern and central Europe as recently as 7.5 kya (Olalde et al., 2014), long dehydrocholesterol reductase increase endogenous levels of the pre- after they had migrated out of Africa. Likewise, virtually all other VD3 precursor, 7-dehydrocholesterol (Kuan et al., 2013). Likewise, we Eurasian populations display intermediate shades of pigmentation, have pointed out that loss-of-function mutations in ﬁlaggrin in Euro- independent of latitude. peans of the far North reduce downstream generation of t-UCA (Thys- Europeans. Loss-of-function mutations in Consider also that melanin is a relatively ineﬃcient UV-B ﬁlter sen et al., 2014). Finally, other mutations that enhanced the absorption, in comparison to another endogenous mechanism that is much more transport, and metabolism of 1,25-dihydrovitamin D3 appear to sustain eﬃcient; that is, transurocanic acid (t-UCA), which intercepts well VD3 levels in darkly pigmented individuals (cited in Elias and Williams, over 50% of incident UV-B, even in darkly pigmented skin (Kripke, 2016). Together, these non-pigment-based polymorphisms explain 1984). Moreover, Michael Holick et al. showed that even dark- why even dark-skinned populations sustain suﬃcient circulating skinned individuals, living at latitudes comparable to New England, blood levels of 25-dihydroxyvitaminD3, unless cultural and life-style can generate suﬃcient vitamin D during normal summer seasons to patterns supervene. Frequently cited reports of subnormal circulat- satisfy year-round VD3 requirements (Holick et al., 1981). Ashley ing 25-hydroxyvitamin D3 levels in darkly pigmented immigrants to Robins (Robins, 2009) eloquently pointed out several further ﬂaws the United Kingdom are counterbalanced by a report of normal of the vitamin D hypothesis, including the relatively rare occurrence levels of 25-hydroxyvitaminD3 in West Indians living in Scotland of rachitic fossils prior to the Industrial Revolution (Castilla et al., (Neer, 1975). 2014). Then, there is the paucity of osteoporosis in darkly pig- In summary, it is to be expected that old hypotheses inevitably will mented individuals living at high latitudes (Aloia, 2008). Finally, and be replaced or modiﬁed as new information becomes available. The perhaps most importantly, melanin exists in many non-sun-exposed vitamin D-pigment hypothesis isn’t dead—just modiﬁed according to organs of mammals, as well as in many pro- and eukaryotic organ- recent compelling information about epidermal biology and evolution- isms (Blois, 1968), where it must mediate other functions, known or ary genetics. Am. J. Phys. Anthropol. 2016; 00-00 wileyonlinelibrary.com/journal/ajpa C 2016 Wiley Periodicals, Inc. V