Monday, March 14, 2022

Vitamin D scarcity and natural selection


In humans who are dark-skinned or who live above the Arctic Circle, natural selection has favored those who use vitamin D more efficiently or have workarounds of one sort or another for vitamin D scarcity. Yakut family, Wikicommons (Uyban)



Vitamin D is less easily obtained by some people than by others. It is less available to those who are dark-skinned or who live above the Arctic Circle. Because less UV light enters the skin for biosynthesis, natural selection has favored individuals who use this vitamin more efficiently or have workarounds of one sort or another (Frost 2009; Frost 2012; Frost 2018).


Vitamin D levels are thus naturally lower in Arctic and dark-skinned humans. Some variation exists even among Europeans, with levels being lower in darker-skinned southern Europeans than in lighter-skinned northern Europeans (Snellman et al. 2009; van der Wielen et al. 1995).


Unfortunately, vitamin D deficiency is diagnosed on the basis of norms developed for light-skinned people from temperate latitudes. Inuit and African Americans are thus diagnosed as “deficient” and offered vitamin supplementation, which has the effect of bathing their body tissues in concentrations of vitamin D that they and their ancestors have not experienced for tens of thousands of years, if not longer.


If  Arctic and darker-skinned humans naturally have lower levels of vitamin D, their optimal range of levels will likewise be lower, and toxic effects may occur at levels that lie within the optimal range of Europeans. You may have been told that this cannot happen because toxicity occurs only if you ingest huge amounts of this vitamin. Actually, toxicity begins at relatively low levels. In light-skinned humans from the temperate zone, the optimal range seems to extend only from 40 nmol/L to 100 nmol/L:


·         The total mortality rate is about 50% greater in men whose vitamin D levels are either below 46 nmol/L or above 98 nmol/L (Michaelsson et al. 2010).

·         The risk of prostate cancer is significantly greater below 40 nmol/L and above 60 nmol/L (Tuohimaa 2008; Tuohimaa et al. 2009).

·         Mortality for 7 types of cancer (endometrial, esophageal, gastric, kidney, non-Hodgkin's lymphoma, pancreatic, ovarian) is significantly greater below 45 nmol/L and above 124 nmol/L (Helzlsouer et al. 2010).

·         The risk of pancreatic cancer is significantly greater above 100 nmol/L (Stolzenberg-Solomon et al. 2010).

·         The risk of cardiovascular disease is significantly greater below 50 nmol/L and above 62.5 nmol/L, and mortality from all causes is significantly greater above 122.5 nmol/L (Davis 2009).


Perhaps most worrisome, studies on mice indicate a U-shaped response curve for the aging process, with premature aging associated with both too little and too much vitamin D (Tuohimaa 2009; Tuohimaa et al. 2009).


Vitamin D metabolism and gene-culture coevolution among the Inuit


To what extent has the safe range of vitamin D been shifted downward in Arctic and dark-skinned humans? To answer that question, we need to understand gene-culture coevolution. When humans enter a new environment, they adapt by pushing the bounds of phenotypic plasticity—they do the most with what they have already. There is then natural selection for genetic variants that can stabilize this new pattern of adaptation and make it more innate. A new phenotype thus ends up becoming a new genotype.


Traditionally, Inuit coped with vitamin D scarcity through a high-meat/low-cereal diet and through extended breastfeeding of children for two years or longer. This diet not only provided vitamin D but also helped the body use this vitamin more efficiently, specifically by means of β-casein in breast milk, unknown substances in meat, and absence of phytic acid (Frost 2018). 


Those cultural adaptations were followed by physiological adaptations: receptors that bind more tightly to the vitamin D molecule; a lower set-point for calcium-regulated release of parathyroid hormone; and conversion of vitamin D at a higher rate from its common form to its most active form. Inuit breast milk might also be richer in β-casein (Frost 2018).


That gene-culture coevolution has been notably demonstrated by a genome study of the Greenland Inuit, whose marine diet has apparently selected for genetic variants that help their bodies digest and use polyunsaturated fatty acids (Fumagalli et al. 2015).


Research on indigenous northern Eurasian peoples


Before 2020, the Inuit were the only non-European population for whom we had research on cultural and physiological adaptations to vitamin D scarcity (Frost 2012; Frost 2018). Two studies have since been published on this subject with regard to indigenous peoples in northern Eurasia.


Research by Khrunin et al. (2020)


This research team looked for signals of natural selection in the genomes of eight northern populations: Russians from the Archangelsk and Vologda regions; Izhemski Komi; Priluzski Komi; Veps; Khanty; Mansi; and Nenets. The strongest signal came from two genes: SLC37A2 and PKNOX2. The first gene is expressed when vitamin D3 is present in peripheral blood cells. The authors go on to note:


Deficit of vitamin D is often observed in northern populations, where exposure to sunlight is limited for many months. Hypothetically, mutations in the VDR-controlled SLC37A2 gene may help northern populations adjust to vitamin D levels. At the same time, the same mutations could have effects on alcohol tolerance in these populations through the PKNOX2 gene, located on the opposite strand of DNA in the same locus. 


The second gene, PKNOX2, is associated with alcohol addiction in mice and humans. The authors add that this finding “is of special interest in the context of the well-known alcohol addiction that occurs widely in indigenous populations of Northern Eurasia.”


Could vulnerability to alcoholism be a side-effect of adaptation to vitamin D scarcity? The hypothesis is interesting, although I lean more toward another explanation. Some populations, like those around the Mediterranean, have had a long history of drinking fermented beverages instead of water, which might be contaminated with bacteria that cause dysentery and other diseases. Consequently, natural selection has favored individuals who have higher levels of alcohol dehydrogenase and other physiological adaptations that make alcohol less toxic. Conversely, other populations, like northern Eurasians, have consumed fermented beverages for a shorter time, and their bodies are less adapted to alcohol (Nabhan 2004, pp. 27-30; Ridley 2000).


Research by Malyarchuk (2020)


This is a study of a single polymorphic gene, GC, in several indigenous peoples of northeastern Siberia (Eskimos, Chukchi, Koryaks), central Siberia (Evens, Evenks, Yakuts), southern Siberia (Tuvinians, Shorts, Altaians, Buryats), and western Siberia (Kets, Khanty, Mansi, Selkups, Nenets, Nganasans). The GC gene produces a protein that is the main carrier of vitamin D in the body.


One GC variant, specifically the T variant at rs4588, is much less frequent in northeast and central Siberians (5.4%, 3.1%) than in southern and western Siberians (28.6%, 27.5%). Conversely, the G variant is much more frequent in the northeast and center (32.1%, 46.9%) than in the south and west (16.1%, 12.5%). I initially thought the reason was a higher level of European admixture in southern and western Siberia. But there is little European admixture in East Asians, and they resemble southern and western Siberians in having the same high frequency of the T variant (26.1%).


The G variant may have become more frequent in northeast and central Siberians as an adaptation to vitamin D scarcity. As one goes farther north, the skin produces less vitamin D because less UV light enters the skin. More research is needed, however, on two other factors: (1) amount of vitamin D from dietary sources; and (2) skin pigmentation. It may be that southern Siberians are somewhat darker-skinned than northern Siberians, although that isn’t my impression. These points are made by Malyarchuk (2020) in the Results and Discussion section. Researchers should study:


… the gene-environment interactions by taking into account the vitamin D status of the indigenous population, ethnicity, influence of environmental conditions (the level of natural ambient light and seasonal patterns), and specifics of nutrition. The influence of such factors on the distribution of GC polymorphism variants is evidenced by the data obtained in this work on the high prevalence of haplotypes encoding the Gc1F isoform in northeast Asia under condition of low intensity of solar radiation. In addition, an important factor contributing to vitamin D deficiency may be a relatively high level of melanin in the skin of representatives of the Arctic peoples, which prevents the penetration of ultraviolet rays into the skin and thereby hinders the synthesis of vitamin D3




Davis, C.D. (2009). Vitamin D and health: can too much be harmful? American Journal of Lifestyle Medicine 3(5): 407-408.


Frost, P. (2009). Black-White differences in cancer risk and the vitamin-D hypothesis. Journal of the National Medical Association 101: 1310-1313.


Frost, P. (2012). Vitamin D deficiency among northern Native Peoples: a real or apparent problem? International Journal of Circumpolar Health 71(S2): 18001


Frost, P. (2018). To supplement or not to supplement: are Inuit getting enough vitamin D? Études Inuit Studies 40(2): 271-291.


Frost, P. (2020). Ethnic differences in vitamin-D metabolism. E Scholarly Community Encyclopedia.


Fumagalli, M., I. Moltke, N. Grarup, F. Racimo, P. Bjerregaard, M.E. Jørgensen et al. (2015). Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science 349(6254): 1343-1347.


Helzlsouer, K.J. and Steering Committee of Vitamin D Pooling Project of Rarer Cancers (2010).  Abstract PL04-05: Vitamin D: panacea or a Pandora’s box for prevention? Cancer Prevention Research 3(1 Suppl 1): PL04-05.


Khrunin, A.V., G.V. Khvorykh, A.N. Fedorov, and S.A. Limborska (2020). Genomic landscape of the signals of positive natural selection in populations of Northern Eurasia: A view from Northern Russia. PLoS ONE 15(2): e0228778.


Malyarchuk, B.A. (2020). Polymorphism of GC gene, encoding vitamin D binding protein, in aboriginal populations of Siberia. Ecological Genetics 18(2): 243-250.


Michaëlsson, K., J.A. Baron, G. Snellman, R. Gedeborg, L. Byberg, J. Sundström et al. (2010). Plasma vitamin D and mortality in older men: a community-based prospective cohort study. American Journal of Clinical Nutrition 92(4): 841-848. 


Nabhan, G.P. (2004). Why Some Like It Hot. Food, Genes, and Cultural Diversity. Washington: Island Press/Shearwater Books.


Ridley, M. (2000).Genome: The Autobiography of a Species in 23 Chapters. New York: HarperCollins.


Snellman, G., H. Melhus, R. Gedeborg, et al. (2009). Seasonal genetic influence on serum 25-hydroxyvitamin D levels: a twin study. PLoS ONE 4(11): e7747.


Stolzenberg-Solomon, R.Z., E.J. Jacobs, A.A. Arslan, D. Qi, A.V. Patel, K.J. Helzlsouer et al.

(2010). Circulating 25-hydroxyvitamin D and risk of pancreatic cancer, Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. American Journal of Epidemiology 172(1): 81-93.


Tuohimaa, P. (2009). Vitamin D and aging. The Journal of Steroid Biochemistry and Molecular Biology 114(1-2): 78-84. 


Tuohimaa, P., T. Keisala, A. Minasyan, J. Cachat, and A Kalueff (2009). Vitamin D, nervous system and aging. Psychoneuroendocrinology 34S: S278-286.


van der Wielen R.P., M.R. Lowik, H. van den Berg, L.C. de Groot, J. Haller J, et al. (1995). Serum vitamin D concentrations among elderly people in Europe. Lancet 346: 207–210.

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