Skin color and vitamin D -- a beautiful theory destroyed by inconvenient facts?

I love a well-done challenge to an iconic evolutionary tale.  Such tales are often easy to devise but hard to test, so I was intrigued to see that there was a new paper challenging what has come to be a well-accepted theory in Anthropology, the story of why skin color lightened as humans left Africa and migrated north.  The new theory is all over the web (here and here, e.g.).  And, there are certainly good reasons to challenge this iconic tale... but they aren't in this paper.

We make most of the vitamin D3 (VD3) circulating in our blood when we're exposed to sunlight.  The synthesize is a multi-step process, and we can store the VD3 we produce for months at a time.  Light skinned people tend to have higher levels of circulating vitamin D3 than dark skinned people, because the dark pigment, melanin, blocks UV, and thus, VD3 synthesis.  Severe vitamin D deficiency leads to rickets, with its deformities and accompanying weakness and so forth, and less severe but chronic low vitamin D3 levels in people with light skin are a risk factor for osteoporosis, bone fractures, and perhaps chronic diseases like type 2 diabetes, and so forth.  Paradoxically, while on average darker skinned women have lower VD3 levels, they are also at lower risk of osteoporosis and fractures than their lighter skinned counterparts.

The wintery Lapporten mountain pass in Lappland, Sweden; Wikipedia

The iconic story about skin color has been that when darkly pigmented humans left Africa 30,000 or so years ago. they were leaving regions in which dark skin was maintained by natural selection, presumably because it really does protect against sunburn and skin cancer.  The descendants who eventually settled in northern Eurasian climes were then in places where lighter skin was beneficial because sunlight was weaker  and the melanin in dark skin would have prevented the synthesis of enough vitamin D to maintain strong bones.  So, during the many generations that it took humans to make their way from Africa to northern Europe, their skin lightened due to natural selection for a beneficial trait.

This hypothesis has been challenged before, for numerous reasons -- notably in a paper by Ashley Robins in the American Journal of Physical Anthropology in 2009.  Among other problems with the hypothesis are that there was no evidence of excessive rickets in the late Pleistocene and early Holocene, when humans were expanding northward, that light and dark skin both can synthesize vitamin D when exposed to sufficient ultraviolet B (UVB) radiation and that early humans in northern Europe would have spent much of the summer and spring outside, partially covered with animal skin, able to manufacture enough VD3 to last through the winter when the rays of the sun were weak.

One might also note that the earliest depictions of human variation in art, not to mention evidence such as mummies, go pretty far back and show that Egyptians and others in their intensely sunny part of the world were not dark-skinned and they knew they were different from sub-Saharan Africans. So were they a back-flow from Europeans who had already become lighter? Or was lightening already a fact of human life before the expansion?  Why are some African indigenes light skinned though living in the open desert?  On the other hand, if sunlight exposure is not the reason that dark skin evolved, why are Americans darker in the tropics, especially those who live in jungle shade?

Now a paper in a recent issue of Evolutionary Biology ("Evidence That Loss-of-Function Filaggrin Gene Mutations Evolved in Northern Europeans to Favor Intracutaneous Vitamin D3 Production", Thyssen et al. -- paywall) challenges the accepted wisdom for another reason.  Thyssen et al. suggest that in northern latitudes, the skin wouldn't have been able to synthesize the required levels of vitamin D by loss of pigmentation alone, but a change in a protein that helps to maintain the skin as a barrier to outside elements could have facilitated increased VD3 synthesis.

We hypothesized that loss-of-function mutations in the epidermal structural protein, filaggrin (FLG), could have evolved to sustain adequate VD3 status. Loss of FLG results in reduced generation of trans-urocanic acid, the principal endogenous ultraviolet-B (UV-B) filter in lightly-pigmented individuals. Accordingly, we identified a higher prevalence of FLG mutations in northern European populations when compared to more southern European, Asian and African populations that correlates significantly with differ- ences in circulating 25-OH-VD3 levels in these same populations.

That is, it was changes in the filaggrin protein that enabled people in northern climates to make enough vitamin D, rather than decreased melanin.  And, indeed, Thyssen et al. write, the difference in skin color from the tropics northward is not nearly as finely graded as filaggrin variants; this, they believe, is a convincing reason that the latter is more likely to explain why northern peoples produce enough VD3.

Vitamin D by frequency of FLG variation; source Thyssen et al.

The authors also write that because people with dark skin can produce vitamin D as efficiently as people with lighter skin, this would have meant no adaptive pressure on skin color as people moved northward.  While skin did lighten in the far north, it didn't lighten everywhere -- Inuit and northern Asians, for whom seafood, the best food source of vitamin D, has long been a large part of the diet, still have substantially pigmented skin.  Some Africans don't, though living in open, sun-blazed unforgiving desert.  And, even the lightest skinned inhabitants of the far north can't synthesize enough VD3 to maintain healthy bones, so something other than pigmentation must have changed.

And indeed the VD3 pathways did change, at least in some people; polymorphisms in genes involved in VD3 synthesis and transport have been identified in Europeans (Wang et al., 2010), and are associated with increased vitamin D3 levels.  Thyssen et al. also report European variants in the FLG gene, which is involved in skin architecture.  The variants seem to enhance UVB sensitivity, but they also seem to increase susceptibility to various conditions such as dry skin, ichthyosis vulgaris, and allergies.

This is sounding like a good story.

But...
There are problems.  The correlation between these variants and VD3 synthesis are, as Thyssen et al. themselves say, currently only correlations, not demonstrated causal relationships.  The authors suggest that looking for FLG variants in Inuit populations could make or break their hypothesis; if they had lower frequencies of these variants, it would be supportive because they have always eaten vitamin D-rich seafoods, and have darker skin than most peoples in the far north.  Nice idea.

Unfortunately for this whole hypothesis, however, the frequencies of the FLG variants that Thyssen et al. are reporting are, well, very low; 7.02% in Sweden, 7.86 in Denmark, 11.0 in Canada.  Yes, there is a gradient (0.91% in Tunisia), but these kinds of frequencies really can't explain why whole populations in northern latitudes don't have rickets. So at present these are strong claims and shouldn't be treated as if they show a major new theory, based on the rather thin evidence available to date.

It's often difficult to reconstruct evolutionary scenarios, which is why strongly held stories such as the vitamin D/skin color story should not be so strongly held.  While there are, we think, compelling reasons to question the conventional wisdom about vitamin D and skin color, this new report isn't yet a convincing replacement.

However, it does raise the question of whether there are other vitamin D synthesis or absorption pathways that aren't yet known, and that might explain, for example, why lower serum vitamin D levels aren't as deleterious in dark-skinned women as in light-skinned women.  Melanin is in some immune pathways, so there could be other correlates of 'climate' that don't involve vitamin D. Indeed, this story may not yet be completely told.