Evolutionary Biology

, Volume 41, Issue 3, pp 388–396 | Cite as

Evidence That Loss-of-Function Filaggrin Gene Mutations Evolved in Northern Europeans to Favor Intracutaneous Vitamin D3 Production

  • Jacob P. Thyssen
  • Daniel D. Bikle
  • Peter M. Elias
Synthesis Paper

Abstract

Skin pigmentation lightened progressively to a variable extent, as modern humans emigrated out of Africa, but extreme lightening occurred only in northern Europeans. Yet, loss of pigmentation alone cannot suffice to sustain cutaneous vitamin D3 (VD3) formation at the high latitudes of northern Europe. 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 differences in circulating 25-OH-VD3 levels in these same populations. By allowing additional UV-B penetration and intracutaneous VD3 formation, the latitude-dependent gradient in FLG mutations, likely together with other concurrent mutations in VD3 metabolic pathways, provide a non-pigment-based mechanism that sustains higher levels of circulating VD3 in northern Europeans. At the time that FLG mutations evolved, xerosis due to FLG deficiency was a lesser price to pay for enhanced VD3 production. Yet, the increase in FLG mutations has inadvertently contributed to an epidemic of atopic diseases that has emerged in recent decades.

Keywords

Filaggrin Human evolution Pigmentation Skin color Vitamin D3 

Abbreviations

7DHC

7-Dehydrocholesterol

FLG

Filaggrin

KYA

Thousand years ago

t-UCA

Trans-urocanic acid

UV

Ultraviolet

VD3

Vitamin D3

Supplementary material

11692_2014_9282_MOESM1_ESM.doc (298 kb)
Supplementary material 1 (DOC 298 kb)

References

  1. Aloia, J. F. (2008). African Americans, 25-hydroxyvitamin D, and osteoporosis: A paradox. American Journal of Clinical Nutrition, 88(2), 545S–550S.PubMedCentralPubMedGoogle Scholar
  2. Anno, S., Abe, T., & Yamamoto, T. (2008). Interactions between SNP alleles at multiple loci contribute to skin color differences between caucasoid and mongoloid subjects. International Journal of Biological Sciences, 4(2), 81–86.PubMedCentralPubMedCrossRefGoogle Scholar
  3. Basu Mallick, C., Iliescu, F. M., Mols, M., Hill, S., Tamang, R., Chaubey, G., et al. (2013). The light skin allele of SLC24A5 in South Asians and Europeans shares identity by descent. PLoS Genetics, 9(11), e1003912.PubMedCentralPubMedCrossRefGoogle Scholar
  4. Bikle, D. D. (2010). Vitamin D and the skin. Journal of Bone and Mineral Metabolism, 28(2), 117–130.PubMedCrossRefGoogle Scholar
  5. Bjorn, L. O., & Wang, T. (2000). Vitamin D in an ecological context. Int J Circumpolar Health, 59(1), 26–32.PubMedGoogle Scholar
  6. Bogh, M. K., Schmedes, A. V., Philipsen, P. A., Thieden, E., & Wulf, H. C. (2010). Vitamin D production after UVB exposure depends on baseline vitamin D and total cholesterol but not on skin pigmentation. The Journal of Investigative Dermatology, 130(2), 546–553.PubMedCrossRefGoogle Scholar
  7. Brookman, J., Chacon, J. N., & Sinclair, R. S. (2002). Some photophysical studies of cis- and trans-urocanic acid. Photochemical and Photobiological Sciences, 1(5), 327–332.PubMedCrossRefGoogle Scholar
  8. Brown, S. J., & McLean, W. H. (2012). One remarkable molecule: Filaggrin. The Journal of Investigative Dermatology, 132(3 Pt 2), 751–762.PubMedCentralPubMedCrossRefGoogle Scholar
  9. Cascella, R., Foti Cuzzola, V., Lepre, T., Galli, E., Moschese, V., Chini, L., et al. (2011). Full sequencing of the FLG gene in Italian patients with atopic eczema: Evidence of new mutations, but lack of an association. The Journal of Investigative Dermatology, 131(4), 982–984.PubMedCrossRefGoogle Scholar
  10. Chaplin, G., & Jablonski, N. G. (2009). Vitamin D and the evolution of human depigmentation. American Journal of Physical Anthropology, 139(4), 451–461.PubMedCrossRefGoogle Scholar
  11. Devos, M., Prawitt, J., Staumont-Salle, D., Hoste, E., Fleury, S., Bouchaert, E., et al. (2012). Filaggrin degradation by caspase-14 is required for UVB photoprotection but does not influence allergic sensitization in a mouse model of atopic dermatitis. The Journal of Investigative Dermatology, 132(12), 2857–2860.PubMedCrossRefGoogle Scholar
  12. Eckert, R. L., Broome, A. M., Ruse, M., Robinson, N., Ryan, D., & Lee, K. (2004). S100 proteins in the epidermis. The Journal of Investigative Dermatology, 123(1), 23–33.PubMedCrossRefGoogle Scholar
  13. Elias, P. M., & Williams, M. L. (2013). Re-appraisal of current theories for the development and loss of epidermal pigmentation in hominins and modern humans. Journal of Human Evolution, 64(6), 687–692.PubMedCentralPubMedCrossRefGoogle Scholar
  14. Gillie, O. (2012). The Scots’ Paradox: Can sun exposure, or lack of it, explain major paradoxes in epidemiology? Anticancer Research, 32(1), 237–248.PubMedGoogle Scholar
  15. Halldorsson, T. I., Meltzer, H. M., Thorsdottir, I., Knudsen, V., & Olsen, S. F. (2007). Is high consumption of fatty fish during pregnancy a risk factor for fetal growth retardation? A study of 44,824 Danish pregnant women. American Journal of Epidemiology, 166(6), 687–696.PubMedCrossRefGoogle Scholar
  16. Harding, C. R., Aho, S., & Bosko, C. A. (2013). Filaggrin—revisited. International Journal of Cosmetic Science, 35(5), 412–423.PubMedCrossRefGoogle Scholar
  17. Heimbeck, I., Wjst, M., & Apfelbacher, C. J. (2013). Low vitamin D serum level is inversely associated with eczema in children and adolescents in Germany. Allergy, 68(7), 906–910.PubMedCrossRefGoogle Scholar
  18. Holick, M. F. (2011). Vitamin D: Evolutionary, physiological and health perspectives. Current Drug Targets, 12(1), 4–18.PubMedCrossRefGoogle Scholar
  19. Irvine, A. D., McLean, W. H., & Leung, D. Y. (2011). Filaggrin mutations associated with skin and allergic diseases. New England Journal of Medicine, 365(14), 1315–1327.PubMedCrossRefGoogle Scholar
  20. Jones, G. (2008). Pharmacokinetics of vitamin D toxicity. American Journal of Clinical Nutrition, 88(2), 582S–586S.PubMedGoogle Scholar
  21. Kuan, V., Martineau, A. R., Griffiths, C. J., Hypponen, E., & Walton, R. (2013). DHCR7 mutations linked to higher vitamin D status allowed early human migration to northern latitudes. BMC Evolutionary Biology, 13, 144.PubMedCentralPubMedCrossRefGoogle Scholar
  22. Loomis, W. F. (1967). Skin-pigment regulation of vitamin-D biosynthesis in man. Science, 157(788), 501–506.PubMedCrossRefGoogle Scholar
  23. Mackintosh, J. A. (2001). The antimicrobial properties of melanocytes, melanosomes and melanin and the evolution of black skin. Journal of Theoretical Biology, 211(2), 101–113.PubMedCrossRefGoogle Scholar
  24. McPhee, J. (1992). The Crofter and the Laird (p. 168). Farrar, Straus & Giroux.Google Scholar
  25. Mildner, M., Jin, J., Eckhart, L., Kezic, S., Gruber, F., Barresi, C., et al. (2010). Knockdown of filaggrin impairs diffusion barrier function and increases UV sensitivity in a human skin model. The Journal of Investigative Dermatology, 130(9), 2286–2294.PubMedCrossRefGoogle Scholar
  26. Norton, H. L., & Hammer, M. (Eds.). (2008). Sequence variation in the pigmentation candidate gene SLC24A5 and evidence for independent evolution of light skin in European and East Asian populations. 77th Annual Mtg of the Amer Assn of Phys Anthropologists, Columbus, OH.Google Scholar
  27. Norton, H. L., Kittles, R. A., Parra, E., McKeigue, P., Mao, X., Cheng, K., et al. (2007). Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Molecular Biology and Evolution, 24(3), 710–722.PubMedCrossRefGoogle Scholar
  28. Olalde, I., Allentoft, M. E., Sanchez-Quinto, F., Santpere, G., Chiang, C. W., Degiorgio, M., et al. (2014). Derived immune and ancestral pigmentation alleles in a 7,000-year-old Mesolithic European. Nature, 507(7491), 225–228.Google Scholar
  29. Powe, C. E., Evans, M. K., Wenger, J., Zonderman, A. B., Berg, A. H., Nalls, M., et al. (2013). Vitamin D-binding protein and vitamin D status of black Americans and white Americans. New England Journal of Medicine, 369(21), 1991–2000.PubMedCentralPubMedCrossRefGoogle Scholar
  30. Presland, R. B. (2009). Function of filaggrin and caspase-14 in formation and maintenance of the epithelial barrier function. Dermatology Sinica, 27, 1–14.Google Scholar
  31. Rana, B. K., Hewett-Emmett, D., Jin, L., Chang, B. H., Sambuughin, N., Lin, M., et al. (1999). High polymorphism at the human melanocortin 1 receptor locus. Genetics, 151(4), 1547–1557.PubMedCentralPubMedGoogle Scholar
  32. Rhodes, L. E., Webb, A. R., Fraser, H. I., Kift, R., Durkin, M. T., Allan, D., et al. (2010). Recommended summer sunlight exposure levels can produce sufficient (> or=20 ng ml(-1)) but not the proposed optimal (> or=32 ng ml(-1)) 25(OH)D levels at UK latitudes. The Journal of Investigative Dermatology, 130(5), 1411–1418.PubMedCrossRefGoogle Scholar
  33. Robins, A. (2009). The evolution of light skin color: Role of vitamin D disputed. American Journal of Physical Anthropology, 139(4), 447–450.PubMedCrossRefGoogle Scholar
  34. Scott, I. R., Harding, C. R., & Barrett, J. G. (1982). Histidine-rich protein of the keratohyalin granules. Source of the free amino acids, urocanic acid and pyrrolidone carboxylic acid in the stratum corneum. Biochimica et Biophysica Acta, 719(1), 110–117.PubMedCrossRefGoogle Scholar
  35. Sinclair, C., O’Toole, E. A., Paige, D., El Bashir, H., Robinson, J., Dobson, R., et al. (2009). Filaggrin mutations are associated with ichthyosis vulgaris in the Bangladeshi population. British Journal of Dermatology, 160(5), 1113–1115.PubMedCrossRefGoogle Scholar
  36. Snellman, G., Melhus, H., Gedeborg, R., Olofsson, S., Wolk, A., Pedersen, N. L., et al. (2009). Seasonal genetic influence on serum 25-hydroxyvitamin D levels: A twin study. PLoS ONE, 4(11), e7747.PubMedCentralPubMedCrossRefGoogle Scholar
  37. Sturm, R. A. (2009). Molecular genetics of human pigmentation diversity. Human Molecular Genetics, 18(R1), R9–R17.PubMedCrossRefGoogle Scholar
  38. Thawer-Esmail, F., Jakasa, I., Todd, G., Wen, Y., Brown, S. J., Kroboth, K., et al. (2014). South African amaXhosa patients with atopic dermatitis have decreased levels of filaggrin breakdown products but no loss-of-function mutations in filaggrin. The Journal of Allergy and Clinical Immunology, 133(1), 280–282.PubMedCentralPubMedCrossRefGoogle Scholar
  39. Thomson, M. L. (1955). Relative efficiency of pigment and horny layer thickness in protecting the skin of Europeans and Africans against solar ultraviolet radiation. Journal of Physiology, 127(2), 236–246.PubMedCentralPubMedGoogle Scholar
  40. Thyssen, J. P., Thuesen, B., Huth, C., Standl, M., Carson, C. G., Heinrich, J., et al. (2012). Skin barrier abnormality caused by filaggrin (FLG) mutations is associated with increased serum 25-hydroxyvitamin D concentrations. The journal of Allergy and Clinical Immunology, 130(5), 1204–1207.PubMedCrossRefGoogle Scholar
  41. Thyssen, J. P., Godoy-Gijon, E., & Elias, P. M. (2013). Ichthyosis vulgaris: The filaggrin mutation disease. British Journal of Dermatology, 168(6), 1155–1166.PubMedCrossRefGoogle Scholar
  42. van Schoor, N. M., & Lips, P. (2011). Worldwide vitamin D status. Best practice and research. Clinical Endocrinology and Metabolism, 25(4), 671–680.PubMedGoogle Scholar
  43. Wang, T., Bengtsson, G., Karnefelt, I., & Bjorn, L. O. (2001). Provitamins and vitamins D(2)and D(3)in Cladina spp. over a latitudinal gradient: Possible correlation with UV levels. Journal of Photochemistry and Photobiology B: Biology, 62(1–2), 118–122.CrossRefGoogle Scholar
  44. Wang, T. J., Zhang, F., Richards, J. B., Kestenbaum, B., van Meurs, J. B., Berry, D., et al. (2010). Common genetic determinants of vitamin D insufficiency: A genome-wide association study. Lancet, 376(9736), 180–188.PubMedCentralPubMedCrossRefGoogle Scholar
  45. Winge, M. C., Bilcha, K. D., Lieden, A., Shibeshi, D., Sandilands, A., Wahlgren, C. F., et al. (2011). Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis. British Journal of Dermatology, 165(5), 1074–1080.PubMedCrossRefGoogle Scholar
  46. Witsch-Baumgartner, M., Schwentner, I., Gruber, M., Benlian, P., Bertranpetit, J., Bieth, E., et al. (2008). Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. Journal of Medical Genetics, 45(4), 200–209.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jacob P. Thyssen
    • 1
  • Daniel D. Bikle
    • 2
  • Peter M. Elias
    • 3
  1. 1.Department of Dermato-Allergology, National Allergy Research Centre, Gentofte University HospitalUniversity of CopenhagenHellerupDenmark
  2. 2.Endocrinology Service, Veterans Affairs Medical Center, and Department of MedicineUC San FranciscoSan FranciscoUSA
  3. 3.Dermatology Service, Veterans Affairs Medical Center, and Department of DermatologyUC San FranciscoSan FranciscoUSA

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