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.

Health effects of vitamin D - another epidemiological conundrum

Forget an apple a day keeping the doctor away, current wisdom suggests that a dose of vitamin D a day will keep every imaginable specialist away.  Vitamin D deficiency has been associated with cancer, cardiovascular disease, immune problems like asthma, flu, tuberculosis, autoimmune diseases like multiple sclerosis, low bone density and osteoporosis, and many other diseases.  As with so many epidemiological studies, however, the evidence for most of these is not unequivocal.  Indeed, it's not even clear what "normal" vitamin D levels should be.  Even so, vitamin D supplementation is big, with almost half of adults over 50 in the US currently taking them.

However, as reported in the NYTimes and elsewhere, a new paper in The Lancet ("Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis", Reid et al., Oct 11) concludes that there's essentially no evidence that vitamin D supplementation improves bone density or prevents osteoporosis.

The paper is a report of a meta-analysis of twenty-three studies, with an average duration of about 2 years.  A total of 4082 participants, 92% women, with an average age of 59, were included in the studies in the meta-analysis.  Nineteen of the studies were of predominantly white women.  Baseline vitamin D was generally within normal levels, women were healthy by and large, and were given vitamin D doses between 500 and 800 units per day.  Some were also given calcium.  Bone mineral density was measured at one to five sites (lumbar spine, femoral neck, total hip, trochanter, total body, or forearm).  The analysis showed a small benefit only at one site (femoral neck), though not in all the studies, and no effect was found at any other site.  The authors conclude,

Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate.

Vitamin D is available in small amounts in some foods, but most mammals, including humans, make their own, induced by exposure to the sun.  Without a doubt, severe vitamin D deficiency can cause osteomalacia (softening of the bones) or rickets (softening of the bones in children), but other health effects aren't so clear.  And, optimal vitamin D levels haven't been agreed upon, and they may well vary by age, sex and ethnicity.

2-yr old rickets patient; Wikipedia

Indeed, people with darker skin don't synthesize as much vitamin D from sun exposure as lighter- skinned people do, but African American women are less susceptible to osteoporosis and fractures than are European women (much has been written about this paradox, including this).  So, even after decades of intense study, there's a lot that's not yet understood about vitamin D and its contributions to health.

Whether or how vitamin D boasts the immune system, or protects against the many diseases it is said to are still open questions.  Multiple studies have shown that TB patients do have lower serum vitamin D levels than healthy controls, but it's not clear that low vitamin D preceded disease, and vitamin D supplementation doesn't seem to speed recovery.  Thus there is the question of cause vs correlation, statistical association vs confounding by unmeasured correlated causal factors.  The same kinds of equivocal findings are true of other diseases.  Further, clinicians don't agree on optimal levels, and excess vitamin D, too, may be associated with risk of some cancers or atrial fibrillation. Each person is likely to react differently to high or low doses, based on genetic variation or other lifestyle factors.

There's much still to be sorted out about the association between vitamin D and health.  Because results have not been definitive, it's likely that the effects of vitamin D are modest, at best, except for long known effects of severe deficiency.  Because vitamin D doesn't act alone, and the complex diseases it has been associated with are themselves associated with multiple risk factors, teasing out the role of vitamin D won't be straightforward.  Another epidemiological conundrum.

Progress on MS, and a somewhat typical genetics story

Multiple sclerosis (MS) is yet another chronic often devastating disease for which cause is not known.  Some epidemiological studies suggest an infectious cause, since cases often clusters geographically, but the fact that prevalence tends to increase with distance from the equator in childhood or adolescence has suggested to other researchers a link with sunlight exposure, and thus perhaps to vitamin D deficiency, because sunlight is important to vitamin D synthesis.  Because causation isn't clear, many also suggest a gene-by-environment interaction, in which some genetic variants react differently to a given environmental factor than other variants do.  And now a new study, reported all over the web, including here, and published in the Annals of Neurology (here, with subscription), reports a genetic link to vitamin D and risk of MS.

MS is an autoimmune disease characterized by degradation of the myelin sheath that surrounds and protects nerve cells.  The sheath is like insulation in electric wires, and protects the nerve signal from dissipating as it travels from the brain to where its action is triggered.  Nerve damage occurs due to the inflammation that happens when the body's immune cells attack the nervous system, interrupting the signals sent along the affected nerves.  Sex and age are related to risk, and among sufferers the symptoms vary widely, depending on which nerves are damaged.  Prognosis also varies widely, and is difficult to predict.  Many studies, including but long before GWAS, have found HLA class II genes, and others with modest effect, but the effect varies by whether cases are sporadic or familial.  This all suggests that the disease is heterogeneous, with varied causation -- not at all unusual for complex chronic diseases (nor even for 'simple' genetic disease).   

The aim of the study just reported, carried out by Oxford researchers in collaboration with colleagues at the University of Ottawa in Canada, was to look for rare genetic variants that might explain the excess of cases in some of the 30,000 families participating in a Canadian study of MS, although they do point out that shared family environment could be important.  They began by sequencing the exomes -- all the gene coding regions -- of a randomly selected affected individual from 43 of the 82 families with four or more members with MS (a fairly rare occurrence given that there seems to be a genetic component to risk).  Using families with multiple affected members is well-known to increase the likelihood of finding relative simple and tractable genetic causation.  They didn't in fact find any shared rare variants in this way, so they then focused on MS genes identified in previous GWA studies they had done, that is, comparing cases with unrelated controls.

This eventually led them to zero in on a single change in the CYP27B1 gene that was shared by at least one unaffected parent in the multiply affected families, and by all the affected members.  This is a candidate gene previously tentatively suggested by a GWA study.  They used data from 3046 additional parent-affected child trios, 422 parent-affected sibling pairs and 1873 healthy individuals (in total 12,579 people) from their study to replicate their results.  

As reported in the story in MedicalExpress, the lead author, George Ebers at Oxford, concluded:

"The odds are very much less probable than being hit by lightning", he said. "Is this gene variant causative in multiple sclerosis? Pretty much! The cornerstone for causation has always been the strength of association."

Further, this mutation is known to be associated with low levels of vitamin D, which implies that MS is somehow linked with vitamin D levels.  In the rare instances when people have 2 copies of this variant, they also have rickets, which is also associated with vitamin D levels.   From the conclusion to the paper:

Most biological effects of vitamin D are mediated by calcitriol acting via the vitamin D receptor (VDR). We have previously shown that vitamin D regulates more than 80% of MS associated genes 25, and thus it is likely that lower levels of calcitriol as a result of CYP27B1 mutations leads to a disruption to critical gene-environment interactions important for the developing immune or nervous system which then predisposes to MS.

Indeed, because there are unaffected family members with the mutation -- it was present in 33% of genotyped unaffected family members -- clearly any genetic cause here is more complex than one-to-one.  Or, in rather imprecise genetic jargon, it's "incompletely penetrant".  And indeed, it's a rare variant, present in only a subset of people with MS.  And, clearly, if there is a vitamin D component to causation, it's also not one-to-one, because while prevalence of MS is higher in higher than lower latitudes, it's still a fairly rare disease, even in people with low levels of vitamin D.  The idea of the latitude effect has long been thought to involve sunlight exposure amounts, but other things are correlated with latitude, including immune exposures.  So, as with most complex chronic diseases, causation doesn't come down to simply one mutation or one environmental factor.

The study does appear to implicate vitamin D biology, though in a curious way since the penetrance even of the clearest alleles is far from complete. There are either many pathways to MS, or there is a specific as yet unspecified subset of the diseases with this causation.  It's not really clear what fraction of risk this new gene explains, but the point is not that the gene 'for' MS has been found, but that this particular mutation is associated with low vitamin D levels, as well as some risk of MS.  The roughly 4-1 female-male sex ratio for MS in general, and its usually adult onset, and highly variable pathology all point to very stochastic (probabilistic) effects and/or cofactors that mean there is still much to learn.   But this may be a case where GWAS have made a somewhat greater than usual contribution to risk, not by identifying genes with strong effects but rather by suggesting a train of thought that may perhaps lead to more systematic understanding of a devastating disease.

Sorting out the vitamin D story needs better data, not religious fervor

If even a tenth of what's being said about vitamin D these days is true, those of us astute enough to supplement what we get from the sun are destined for a ripe old age.  Or, if we're already old, and female, taking vitamin D might extend our lives even further.

The idea that vitamin D promotes bone density is based on solid evidence, but beyond that it's effectiveness is not entirely clear.  Advocates say that vitamin D prevents prostate, breast and other cancers, multiple sclerosis, diabetes, heart disease, osteoporosis, allergies, inflammation, fights the common cold and the flu, and boosts fertility, just to name a few of the benefits being touted.  And, limited sun exposure for mothers during pregnancy could be condemning children to a lifetime of illnesses.  According to a new study,

We have known for some time that mums-to-be with low vitamin D levels during pregnancy run the risk of having ­a child that may develop diabetes.

This latest study concluded that other conditions like asthma, autism, multiple sclerosis (MS) and Alzheimer’s could be related to low levels of maternal vitamin D.

Yes, Vitamin D is "Summer's Superhero"!

“Vitamin D deficiencies are rampant amidst our nation and could possibly lead to an increase in the most troubling diseases of our time,” said Steven Hotze, M.D., founder and CEO of PPVS [Physicians Preference, vitamins and supplements].

Indeed, Mozart may have died of vitamin D deficiency!  Think what music the world is missing because he slept during the day when he should have been sitting in the sun, and composed and caroused all night.

Well, how much of this hype is actually true?   And how would we know?  A Nature News Feature published online on July 6 details an ongoing debate on this question.  Recent recommendations have been that we are all vitamin D deficient, and should be boosting our vitamin D with sometimes megadoses of D3 supplements.  Naturally, many scientists who've been researching this subject now have vested interests in plugging supplements, and, as always, this makes it harder to separate the wheat from the chaff.

In response to all the hype, an 'expert panel' was convened by the Institute of Medicine (a non-profit affiliated with the US National Academy of Sciences) to soberly assess the evidence and make recommendations about healthy vitamin D levels, and who should be taking supplements.  They issued their report last November saying that vitamin D levels recommended by current conventional wisdom were too high, and in fact could even be harmful.  But the report has not gone down easily; panel members have been sent abusive and threatening emails, and so on.  As Nature says,

Much is at stake. By 2009, the amount spent on vitamin-D supplements in the United States had risen tenfold in ten years (see 'Raising the stakes'). Medical practitioners and public-health officials worldwide look to the IOM for guidance on how to interpret the conflicting claims about vitamin D. Yet several vitamin-D proponents say that the IOM's methods, which involved a systematic review of the literature, were flawed. They have accused the panel of misinterpreting data and over-emphasizing the danger of heavy supplementation. Just last month, the Endocrine Society, a professional association of 14,000 researchers and clinicians based in Chevy Chase, Maryland, released guidelines that recommend higher doses than the IOM did.

Why, instead of clearing confusion as was the IOM's goal, has the report sown division and unrest? "The IOM was too definitive in its recommendations," says Michael Holick, an endocrinologist at Boston University School of Medicine in Massachusetts, and an outspoken critic of the IOM panel's conclusions. "Basically, the vitamin-D recommendations are based on low-quality evidence," says Gordon Guyatt, a clinician researcher at McMaster University in Hamilton, Ontario, who has been a consultant on various guidelines. "I think admitting that would have made some of the angst disappear."

(For the record, Holick is not only an outspoken critic of the IOM recommendations, but he has been one of the leading drivers of the vitamin-D-cures-all train for some time, and has a lot to lose if it turns out he has been wrong.)

Indeed, many observers, interested and disinterested alike, recognize that there's a lot of questionable science in the vitamin D field.  It's hard to figure out how recommended levels have been set, there have been few if any prospective studies starting with a cohort of healthy people and following them forward, and many that look at vitamin D in people who are already ill.  Such studies are confounded by the fact that people who are ill tend to stay indoors, out of the sun and thus not synthesizing vitamin D, so it's not possible to know whether the vitamin D deficiency (deficiency according to current standards, however they were determined) preceded and thus led to the illness, or was a result.  Many studies have too few subjects for results to be robust, and so on.

Members of the now disbanded IOM panel are calling for large, multi-year prospective studies, in recognition of the fact that much of the data are from studies that are less credible than they should be.  But this too has generated heated dissent.  As the Nature piece says,

Perhaps IOM panel members underestimated the passion present in the vitamin-D field. Physicians who recommend high doses of vitamin D might not want to believe that the evidence they have trusted isn't quite up to par. "One thing I wasn't aware of before, is the tremendous pressure from industry and investigators who are tied to their religious belief in vitamin D," says Rosen.

So given all of this, why would one ever think of pouring more research funding down this sink-hole, to identify the obviously minor if not trivial effects over which these debates are centered?  Clear vitamin D deficiencies are not at issue.

Several years ago, we did an extensive review of the vitamin D literature and we, too, were unassailably convinced that most conclusions, from recommended blood levels to the diseases caused by deficiencies, were based on questionable to poor data.  As far as we could tell, basic questions are still unanswered, including almost everything about mechanisms of action.  This is another instance of correlations being assumed to be causation without biological justification.

To put it bluntly, the idea that we are all vitamin D deficient is manifest, blatant biological, and evolutionary clap-trap.  It is at the very least extremely naive and superficial thinking.  We live hugely longer and in better health than our ancestors did, when natural selection--to the extent that it cared--established the required levels for successful survival and reproduction.  So the assertion of pandemic deficiency really can mean no more than that we might be somewhat better off, or live even longer, if we doped up on the advocates' dietary supplements.  Such panacea talk is not new to human society, but in an age of science should be roundly stamped out, because it is misleading.

Supplemental data on vitamin D supplementation

Could the promotional enthusiasm over vitamin D supplementation be screeching to a halt?  Ok, that's too much to hope, but at least the Institute of Medicine has introduced a note of sanity into the discussion.

The IOM was charged with assessing the existing data to determine whether in fact half of us (or more) are deficient in vitamin D, whether deficiency actually does cause all the diseases it's been linked with in recent years -- cancer, diabetes, heart disease, the flu and other infectious diseases, autism, disorders of the immune system such as multiple sclerosis; indeed, most of the diseases of modernity -- whether excess vitamin D intake could be a problem, to establish adequate vitamin D levels, and to suggest gaps in our knowledge about vitamin D and how to fill them.  They also looked at whether calcium supplementation was necessary.

Their report, released on Tuesday, is summarized thus:

The IOM finds that the evidence supports a role for vitamin D and calcium in bone health but not in other health conditions. Further, emerging evidence indicates that too much of these nutrients may be harmful, challenging the concept that “more is better.

Dr Michael Hollick of Boston University is the most prominent proponent of the more-is-better view, and he ain't backin' down now.  Few people do back down from public postures, though of course if they're right they shouldn't.

Adequate vitamin D levels have been difficult to establish, in part because the causes of chronic disease are so difficult to identify.  As the NYT says,

It is not clear how or why the claims for high vitamin D levels started, medical experts say. First there were two studies, which turned out to be incorrect, that said people needed 30 nanograms of vitamin D per milliliter of blood, the upper end of what the committee says is a normal range. They were followed by articles and claims and books saying much higher levels — 40 to 50 nanograms or even higher — were needed.

In a population with high prevalence of chronic disease, it's very easy to establish a link with inadequate vit D (defined, essentially, as the level found in most of the unhealthy population), for someone who wants to believe it.  But, it's often impossible to say which came first, the purportedly low vitamin D levels or disease.  Someone who's chronically ill is less likely to be out in the sun, making vitamin D, than someone who's fit and healthy.  This is a classic case of the correlation doesn't equal causation caveat not being heeded.

The Institute of Medicine says, vitamin D is required to maintain strong bones, but even this is not unequivocal, since African American women have significantly lower vitamin D than European Americans, but significantly lower fracture risk as well.

And, in fact, says the NYT:

Evidence also suggests that high levels of vitamin D can increase the risks for fractures and the overall death rate and can raise the risk for other diseases.  While those studies are not conclusive, any risk looms large when there is no demonstrable benefit.  Those hints of risk are "challenging the concept that 'more is better,' " the committee wrote.

So, once again, what seemed like a simple story, a simple correlation and a simple cure for the ills of modern civilization turns out to have been simplistic.

That's a lesson that really needs to be learned: if something is so elusive it's unlikely to be that important in general or on its own.  And this means that simple hypotheses about function, and especially about evolutionary fitness, can easily become simplistic -- knowingly overlooking complexity in order to tell (or sell) a good story.  Instead of such simplistic Just-So causal or evolutionary stories, a major challenge for modern biology is -- or at least should be -- to face complexity on its own terms.  That's hard as we so often stress on MT, because the career, bureaucracy, and reward systems favor simple, quick-fix kinds of assertions.

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.