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.

Taking the piss out of paleoanthropology

This is pretty cool.  John, Lee et al. are calling it the "Malapa soft tissue project" and (*gasp*) it's about finding the truth, a quest that unites all of us scientists and science-lovers, rather than finding your version of the truth that can be pitted against someone else's who may or may not have been mucking around in your territory.

Makes my proposal for "Blind paleoanthropology" that I outlined here,  seem not so ridiculous... maybe.

Update: After reading through the FAQ (scroll down to see it here), it sounds more like a new-fangled way to find collaborators rather than a new-fangled way of doing science. But as people join in, we'll see how this unfolds.

Should we cut Darwin out of parts of the human skin color story?

A great deal of my students seem to think so!

My freshmen students and I have just spent a semester reading through Nina Jablonski’s book Skin: A Natural History in which she lays out a hypothesis for the evolution of human skin color variation based on natural selection, a.k.a. Darwinian evolution.

[I think it's a fantastic book for introducing anthropology to freshmen (written by a dear friend who I happen to also greatly admire), so I built a class around it.]

The Darwinian explanation* for human skin color goes like this...

Where there is intense UV radiation (the tropics) people adapted to its destructive powers by evolving natural sunscreen, that is, lots of melanin in their skin.

Conversely, in areas where there is relatively little UV (away from the tropics, going towards the poles), people lost pigmentation in order to maximize the sun’s stimulation of Vitamin D synthesis in the skin (something that melanin inhibits).

Your skin color is about the UV environment of your ancestors. Thus, Seal and Heidi Klum are explained.

As all adaptive scenarios need be, these phenotypes are linked to reproductive success. Highly melanized skin is the primitive condition in humans, that our common ancestor in Sub-Saharan Africa evolved post-fur loss to prevent UV radiation from destroying folate—a process that can lead to death and birth defects of offspring. Once humans began dispersing around the globe, the ones to live in low UV environs evolved poorly melanized skin in order to allow enough vitamin D to be synthesized by a mother so that her fetus could form properly and then eventually grow up to reproduce successfully too. We're specifically talking about the development of the skeleton, since vitamin D is necessary for calcium to do its thing.

That women are lighter than men around the globe supports this notion that allowing UV to penetrate the skin during pregnancy is important.

Perhaps the strongest support for this hypothesis is the stunning map of the globe that Jablonski and Chaplin put together. With some exceptions, global distribution of UV intensity is positively correlated with the amount of melanin in indigenous humans so they were able to construct pretty accurate predictions of human skin color around the world based on UV.

Seal's ancestors are from Africa, while Heidi's are from Scandanavia.

[Of course, before that, Heidi's ancestors, like Seal's and yours and mine and everyone else's, lived in Africa.]

It’s an elegant explanation for the evolution of human skin color variation, and one that has gained a lot of support. But the vitamin D aspect of the story is definitely not a hypothesis preferred by all.

And then of course, as reported here on the MT recently, even a mega-study on vitamin D can't tell us for sure what levels are required to stave off health problems, or even what those health risks are!

But it's difficult to go into the details and nuance of these issues about skin color variation and vitamin D while introducing evolution to students. For many of my students, this is the first time that they’ve learned about evolution in a scholarly setting and we perform activities to illustrate the differences between Lamarckian evolution and Darwinian selection. Of course we also discuss all the known evolutionary forces—mutation, gene flow, drift, and selection—not just selection.

Few students are able to digest all of this the first time they learn it. And regardless of the explanations for why that may be (i.e. instruction quality, lack of effort, difficulty with the concepts, too much bias and misunderstanding brought into the classroom, etc…), it takes longer than a semester to understand how natural selection works and how it does not work.

For many students, the moment that they grasp natural selection, they begin to see the world through selection-colored spectacles. Everything has a reason, much like Dr. Pangloss's philosophy in Voltaire’s Candide. And it’s not just physical features... behaviors become adaptive by default as well.

It’s fine if these ideas are understood to be hypotheses, accounting for the complexities of the genes and physiological processes that lie behind the traits, and accounting for the limitations to testing them. But all too often students blindly assume that natural selection explains EVERYTHING.

[And this leads down the slippery slope to Social Darwinism so it's not something to take lightly.]

Now, even though the adaptationist perspective is rampant, that’s not at all the pattern that emerges when students interpret and explain human skin color.

They do the exact opposite! They take natural selection and adaptation out of half of the story!

Here’s (my paraphrasing of) how many of my freshmen students answer when they are asked to explain the Darwinian folate/Vitamin D hypothesis offered by Jablonski in her book:

Natural Selection explains melanized skin in the tropics because it acts as a natural sunscreen to protect against harmful UV. However, for the non-melanized people in regions with little UV exposure… well, they don't have much melanin because “they don’t need it.”

Depending on how you interpret that (aside from the possibilities that I'm not doing my job well enough, that they're not listening in class, or that they're not doing the reading), the students are invoking genetic drift, neutral theory, or Lamarckian principles! And Darwin is totally out.

I doubt many are aware of the theoretical significance of their answers. But by erroneously explaining a Darwinian concept, they're offering us a window into their intuition.

Just so we’re all on the same page, here’s a translation of the various scenarios for the loss of a trait, like pigmentation:

1. If losing it is beneficial, then those who have lost it will out-survive and out-reproduce others and future generations will have more have-nots than haves. If it’s crucial to survival and reproduction, then the loss will become fixed in the population as an adaptation. - Darwinian adaptation through natural (or sexual) selection
2. If you don’t need it then you can lose it without issue. Reproductive success does not depend on whether or not you have the trait or not, so chance alone will determine how prevalent haves or have-nots will be in any given generation. Relaxed selection plus chance can ultimately lead to the elimination of alleles all together! Furthermore, there is a constant and low mutation rate and while selection is weeding out deleterious mutations in some genes, or while it is favoring adaptive mutations in some genes, the mutations in genes for traits that do not affect evolutionary fitness can accumulate. As long as these mutations are not harmful and purged by selection, they can disrupt the gene and either damage the trait or cause complete loss. - Genetic drift and neutral theory (both with relaxed selection)
3. If you don’t use it, you’ll lose it, meaning that the trait can fade within a lifetime if it's neglected. That neglected trait is passed on to future generations which will continue to experience its decline if they also stop using it, and if that’s widespread throughout the population, then that trait disappears. (It’s assumed that if a trait is not used that it’s not "needed," which is why the casual wording of this scenario can be similar to #2.) - Lamarckian evolution

The first two scenarios, #1 and #2, are widely accepted as biological phenomena, so they are valid hypotheses for the loss of pigmentation in people who live far from the tropics. The third scenario is seen by the scientific community as a misconceived foil to “real” evolution, having fascinating historical interest and useful pedagogical appeal, but that is all.

Okay then, how can we interpret what I've called this "intuitive" response by my students?

First of all, tanning is certainly enabling this muddling of Darwin. That skin color changes in response to stimulation by UV (and hormones!) and is not static during life makes it complex and matches it to UV in a non-evolutionary way, a way that they're used to assuming. A way that people around the world assume to be! Some of my Kenyan friends think that my skin would look like theirs if only I stopped wearing sunscreen lotion while I visit Kenya.

And second, if students think of melanin as natural sunscreen, then it's probably easy for them to take that metaphor too far and liken it, conceptually, to sunscreen lotion.

You apply sunscreen lotion when you need it and you don't apply it when you don't need it. You need it on the Equator, yet you don't need it as much far from the Equator. This feeds back into their evolutionary story: Melanized skin evolves to be where it's needed and it evolves away where it's not needed. This is, I think, the intuitive rationale behind my students' answers. Relaxed selection, neutral theory, and genetic drift provide the backing scientific power. Plus, pigmentation loss in other animals is overwhelmingly explained this way.

But, additionally, "need" can be one way to casually express the concept of Lamarckian "striving." Are my students really Lamarckists when they say that white people are that way because their ancestors didn't need much melanin? It's hard to say.

But I also can't help but wonder, What if their confusion is not just due to their theoretical naivete? What if a totally Darwinian explanation for human skin color variation is hard to understand because it just isn't the best explanation?

Maybe my next class should be dedicated to testing and fleshing out how we could test the adaptive hypothesis for human pigmentation loss versus the alternatives.

But even if we did know the real scenario, there would still be lingering questions...

Maybe it's a horrible under appreciation of deep time and convergent evolution...Maybe it's a gross underestimation of mutation and genetic drift...

But why do so many animals in UV-limited habitats (caves and sea floor) lose pigment? Is it just one of the few visible traits that a constant accumulation of mutations can safely derail under the watchful eye of selection?

And what about epigenetics and pigmentation? Hmm?

Oh, I don't know, maybe Stephen Colbert had it right: Pale skin is best for hiding in a snowbank.

* The Darwinian explanation for skin color variation that I describe here (called "Darwinian" because it's about natural selection acting on melanin differently in different environments), is NOT the same as Darwin's which he discusses in Descent of Man.

Vitamin in Deeed!

According to many investigators and perhaps people seeking tidy hypotheses to explain evolutionary change, humans were black in the tropics where our species originated, to protect from the dangers of too much sun.  Even with dark skin, they got so many rays that they were able to make enough vitamin D. Vitamin D is obtained primarily by the effects of UV (solar) radiation enabling a vitamin-D producing reaction in the skin and only minimally by diet.

So we moved north, where there was less sunlight, and (as the story goes) were selected for lighter skin so we would not suffer disease due to vitamin D deficiency.  Such diseases supposedly include osteoporosis or other bone disease -- though if you believe the current hype, vitamin D deficiency (and how that's determined is another story; current thresholds would suggest that almost everyone is deficient) causes almost anything, from diabetes to cancer.  Whites get more UV light because, though there's less exposure in the high latitudes, they have less UV-filtering melanin in their skin.

So far so good.  But the lore on the relevant bone disease is 'fat, fair, female, and forty'.  Blacks as a group (in Europe and the US) do not have as much vit D deficiency-related problems, including  osteoporosis, as whites.  They do not get lots of rays in the north (or deep southern hemisphere) but they  don't need vit D supplements to reduce risk of fractures.

Now, a new study shows that whites who have vit D deficiency suffer strokes at a higher rate. Blacks are known to have higher rates of strokes in generally, but it's whites who apparently have higher stroke risk if they're vit D deficient.  This seems backward from the long-standing evolutionary story (or is it a Just-So story?), and it's not clear why. But what it does suggest is that lighter skin may not have evolved by natural selection in relation to vitamin D per se.

Strokes are serious, often crippling or fatal.  Usually, and probably much more so in pre-industrial times, strokes are rare or post-reproductive, so they have little impact on evolutionary fitness (natural selection).  Blacks in western environments have a higher risk of stroke, but this is generally thought to be due to the effects of lifestyle.  Many have argued that this (and the associated high blood pressure) is genetic--and all sorts of largely fanciful explanations have been offered for it (for example, that slaves whose bodies did not conserve salt died on the Middle Passage from Africa to the Americas).  But careful work by investigators including Charles Rotimi of NIH and Richard Cooper at Loyola Medical school in Chicago, both prominent and capable, have cast doubts on genetic explanations for this health difference.

Lighter skin has evolved at least twice (Europe and Asia) as people expanded north away from the tropics, and darker skin has evolved as Native Americans expanded from the arctic into the American tropics.  A recent and very good PhD student of our Department, Ellen Quillen, has shown in her dissertation some evidence for selection in at least a few genes related to pigment production.   There are always questions to be asked about this kind of research, and some important points have not yet been pinned down completely.  But at least it shows that evolutionary hypotheses related to skin color make considerable plausible sense.  But, then, what was the selective factor, if not health related to vitamin D?

We don't have the answer.  Except that ready acceptance of selective scenarios, rather than more careful and cautious approaches, is too often a part of evolutionary biology, and perhaps especially when it comes to humans.  We hunger to understand, but perhaps we also hunger too much to proffer hypotheses that are not fully baked.